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Detoxification

Back Clinic Detoxification Support Team. Practiced worldwide, detoxification is about resting, cleansing, and nourishing the body from the inside out. By removing and eliminating toxins, feeding your body healthy nutrients, detoxifying can help protect you from disease and renew your ability to maintain optimum health through a range of methods, including chiropractic, meditation, and more. In addition, detoxification means cleansing the blood.

This is done by removing impurities from the blood in the liver, where toxins are processed for elimination. The body also eliminates toxins through the kidneys, intestines, lungs, lymphatic system, and skin. However, when these systems are compromised, and the impurities aren’t properly filtered, the body’s health becomes compromised. Therefore, everyone should detox at least once a year.

However, detoxing for nursing mothers, children, and patients with chronic degenerative diseases, cancer or tuberculosis should consult their doctor before starting a detoxing program. Also, consult your healthcare provider if you have questions about detoxing. But in today’s world, there are more toxins in the environment than ever.


The Body’s Natural Detox Machine: The Liver

The Body’s Natural Detox Machine: The Liver

Introduction

Everyone has different tips and tricks for being healthy and losing weight. Many individuals incorporate other diets, eating habits, and exercise regimes to lose excess weight, have energy throughout the day and feel good. One of the other diets many people seem to lean toward when it comes to losing weight and helping the body is detox. Surprisingly, many people seem misinformed about detox and dieting being the same; however, they are not, as detoxing is a natural process of body purification while dieting incorporates healthy eating habits, exercising, and healthy life choices. For the body, the best detoxing machine is the liver. Today’s article looks at how the liver detoxes the body, how factors can cause detox imbalances in the body, and how different food helps liver detoxification. We refer patients to certified providers specializing in liver or gastrointestinal treatments to help many individuals with liver issues. We also guide our patients by referring to our associated medical providers based on their examination when it’s appropriate. We find that education is the solution to asking our providers insightful questions. Dr. Alex Jimenez DC provides this information as an educational service only. Disclaimer

14 LaValle Triad 4 Liver Lymph Kidney

The Body’s Own Detox Machine: The Liver

Have you been experiencing gut sensitivities from the foods you eat? How about experiencing chronic fatigue throughout the entire day? What about experiencing pain and swelling in your abdominals or legs? Some of these issues may indicate that something is wrong with your liver. The liver is the most crucial organ with a massive responsibility for the vast array of functions of the body. The liver helps support many visceral functions like maintaining the body’s metabolism, immunity, digestion, and detoxification. Detoxification is a biochemical process where non-water-soluble compounds are transformed into water-soluble compounds flushed out of the body. The benefit of detox is that it helps protect the body from adverse effects of external and internal toxins. 

Since the liver is a massive organ, its essential role in the body is detoxification. Studies reveal that the detoxification process for the liver is in two phases. Phase 1 activated the enzymes in the body to prepare the substance to be removed. Phase 2 excretes the enzymes out of the body as urine, stool, and bile. These two phases help keep the body healthy and stop excessive toxins from harming the rest of the body.

 

The Lymphatic System

The lymphatic system is one of the central detoxification systems responsible for allowing waste products to leave and be carried away to the bloodstream, becoming one of the defense mechanisms for the body and purifying the body fluids for proper functioning. The lymphatic vasculatures also play an active role in immune regulation by impacting inflammatory and immune responses. This means that the lymphatic will produce white blood cells to attack foreign invaders entering the body. 

 

The Gut-Liver Axis

 

Since the liver is the master organ for detoxification, what is its relationship with the gut? Well, studies reveal that the gut microbiota forms a complex microbial community that significantly impacts human health. The gut microbiota can indirectly modulate the functionality of the extra-intestinal organs, which involves the liver. The gut connects to the liver with the intestines through bile acid metabolism. When there is a decrease in bile acid in the gut, it could trigger hepatic inflammation via inflammasomes. Inflammasomes are an essential component of innate immune response while being critical for the clearance of pathogens or damaged cells. When the inflammasomes start becoming mediators for hepatic inflammation, they could potentially be involved with detoxification imbalances in the body. 

 

Detoxification Imbalances

When there are decreased bile acids in the gut, the body could be at risk of developing intestinal dysbiosis. This causes impaired intestinal barrier function, which overlaps to leaky gut and aggravates hepatic inflammation in the liver. When this happens, toxins in the body become excessive and may cause immune and nervous system abnormalities while triggering imbalanced detoxification symptoms that correspond to issues similar to chronic conditions. Some of these detoxification imbalances include:

  • Fatigue
  • Allergies/intolerances
  • Sluggish metabolism
  • Weight gain easily
  • Intolerance to fats
  • Puffy – excess fluid
  • Body odor, bad breath, metallic taste
  • Profuse sweating even in cool weather

 


Naturally Detoxing Your Body-Video

Have you been dealing with allergies or food intolerances affecting your abdominals? Have you been feeling sluggish? What about feeling chronic fatigue throughout the entire day? Some of these symptoms are signs that your liver could suffer from some issues. The liver’s primary function in the body is to detoxify the body. The video above explains how the liver detoxifies the body and how drinks to cleanse the body don’t add additional benefits. The best way for a healthy liver to be functional and detox the body naturally is by eating the right foods that help support the liver, exercising regularly, drinking plenty of water to flush out the system, and getting adequate sleep.


Foods That Support Liver Detoxification

 

When it comes to supporting the liver, eating the right foods can provide energy and reduce inflammatory effects on the body. Studies reveal that eating various wild and semidomestic food plants can provide various components to liver function. Plants like dandelions contain taxasterols, which have antioxidant and anti-inflammatory properties that allow the liver to increase bile secretion. Other foods that help with liver functionality associated with other body functions include:

  • Berries (blueberries & cranberries)
  • Grapefruit
  • Prickly pear
  • Cruciferous vegetables
  • Garlic
  • Carrots
  • Beets
  • Olive oil
  • Nuts

Incorporating these healthy foods can not only be beneficial to the liver but can help the major organs and body to receive the nutrients that the body deserves.

 

Conclusion

The liver is a massive organ that helps the body to function correctly by harmful detoxifying pathogens through excretion. As a natural detoxifying machine, the liver has a casual relationship with the gut system by filtering the nutrients and transporting them out to different body areas. Harmful pathogens enter the body and disrupt the liver can lead to dysbiosis and liver dysfunction. Fortunately, there are nutritious foods that can help support the liver and even help flush out the toxins over time so the body can begin its healing process naturally.

 

References

Grant, D M. “Detoxification Pathways in the Liver.” Journal of Inherited Metabolic Disease, U.S. National Library of Medicine, 1991, pubmed.ncbi.nlm.nih.gov/1749210/.

Guan, Yong-Song, and Qing He. “Plants Consumption and Liver Health.” Evidence-Based Complementary and Alternative Medicine : ECAM, Hindawi Publishing Corporation, 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4499388/.

Karla, Arjun, et al. “Physiology, Liver – Statpearls – NCBI Bookshelf.” In: StatPearls [Internet]. Treasure Island (FL), StatPearls Publishing, 8 May 2022, www.ncbi.nlm.nih.gov/books/NBK535438/.

Konturek, Peter Christopher, et al. “Gut⁻Liver Axis: How Do Gut Bacteria Influence the Liver?” Medical Sciences (Basel, Switzerland), MDPI, 17 Sept. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6165386/.

Sharma, Deepika, and Thirumala-Devi Kanneganti. “The Cell Biology of Inflammasomes: Mechanisms of Inflammasome Activation and Regulation.” The Journal of Cell Biology, The Rockefeller University Press, 20 June 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4915194/.

Disclaimer

Exercising To Detoxify and Cleanse The Body

Exercising To Detoxify and Cleanse The Body

Detoxifying does not necessarily mean juicing and going on a diet. Detoxing is about cleansing the whole body of environmental pollutants, food waste, bacteria, and toxins. Things like medications and alcohol also need to be flushed from the body. When the body becomes unhealthy and overweight, it can put its systems in a chronically stressed state, leading to nerve energy production failure, fatigue, a weakened immune system, and disease. The body constantly works to cleanse itself. Exercise helps expedite the process.

Exercising To Detoxify and Cleanse The Body

Exercise To Detoxify

Exercise removes harmful toxins by getting the lungs and the blood pumping and increasing sweat production, which encourages detoxification. More blood circulating throughout the body allows the liver and the lymph nodes to flush out toxins properly. With exercise, fluid intake increases, allowing more sweat production to release toxins. Drinking more water during workouts also helps the kidneys function at optimal levels to flush out toxins, fats, and waste.

Aerobics

Any low-intensity aerobic exercise that increases heart rate and increases heavier breathing is recommended as long as the breathing is within the fat-burning heart rate. Exercises can be anything from:

Bouncing/Rebounding

Bouncing on a mini-trampoline, also known as rebounding, is another form of exercise that promotes toxin release. The low-impact motion stimulates the lymphatic system. Lymph nodes filter substances and fight off infections by attacking bacteria/germs that travel into the lymph fluid. Twenty minutes on the trampoline two or three times a week to detoxify.

Yoga

There are yoga poses that help to detoxify specific organs. Yoga can help the body cleanse inside and generate more energy.

Revolved Chair Pose

This pose stimulates the liver, spleen, digestive system, improves spinal alignment, and tones the abdominals.

  • Start with the feet together or hip-width apart, depending on what is most comfortable.
  • Bend the knees as if sitting in a chair.
  • The knees should be aligned with the center of the feet.
  • Place the palms of the hands together in a prayer position at the center of the heart.
  • Bring the elbow to the opposite knee.
  • Squeeze the shoulder blades together.
  • Allow the chest to open up.

Wide-Legged Forward Bend

This pose improves circulation, stretches, and strengthens the low back, hips, hamstrings, and calves.

  • Step with the feet 3 to 4 feet apart.
  • Hands-on hips.
  • Lift tall through the whole torso.
  • Fold slowly over the legs.
  • Bend from the hip joints without rounding the lower back.
  • If the back starts to round, stop folding forward.

Sweating and Detoxing

Sweat is one of the body’s primary ways of eliminating toxins. However, more sweat does not mean more toxins are being flushed. Excess sweat could be caused by the body overheating and can lead to dehydration. This is why it’s vital to maintain the body’s hydration levels while working out. Fluids like juice and sports drinks can help maintain hydration, but they contain sugar and other ingredients that could interfere with thorough detoxifying.


Body Composition


Before Starting A Detox Diet

Individuals are recommended to talk with their doctor, nutritionist, health coach about detox diet methods to lose and maintain weight.

Talk with a doctor

  • Seek consultation with a physician before starting any body detox cleanse, especially if there are underlying medical conditions like diabetes or kidney disease.
  • For individuals struggling with obesity, a physician can recommend alternative diet approaches and exercise programs.

Realistic expectations

  • Detox diets work primarily through caloric restriction like a conventional diet.
  • Individuals could feel better from a body cleanse because they will likely be avoiding processed foods and empty calories.

Adopt a long-term frame of mind

  • Diet and exercise to achieve and maintain a healthy weight is a lifelong journey.
  • Detox diets can be a helpful tool to get going in the right direction.
References

Ernst, E. “Alternative detox.” British medical bulletin vol. 101 (2012): 33-8. doi:10.1093/bmb/lds002

Klein, A V, and H Kiat. “Detox diets for toxin elimination and weight management: a critical review of the evidence.” Journal of human nutrition and dietetics: the official journal of the British Dietetic Association vol. 28,6 (2015): 675-86. doi:10.1111/jhn.12286

Obert, Jonathan et al. “Popular Weight Loss Strategies: a Review of Four Weight Loss Techniques.” Current gastroenterology reports vol. 19,12 61. 9 Nov. 2017, doi:10.1007/s11894-017-0603-8

Support Full Body Detox With Chiropractic

Support Full Body Detox With Chiropractic

If dealing with chronic disease, condition, or just poor overall health, detox support combined with chiropractic/health coaching is definitely an option that will help. Toxicity in the body can initiate or worsen existing health conditions. A detox is not about a massive diet overhaul or spending a lot of time at some clinic. Detox support involves making small changes/adjustments that will help support the body�s natural detoxing process without radical changes. One way that a detox is supported is with chiropractic.  
11860 Vista Del Sol, Ste. 128. Support Full Body Detox With Chiropractic
 

Detoxing the Body

The body is exposed to chemicals/toxins every day from food, air, and other particles that the body comes in contact with. However, the body has a natural ability for managing exposure to toxins to maintain overall health. If the toxins become too much to handle it can lead to a range of symptoms. Symptoms can range from:

Methods

Reducing the toxic load can be accomplished by supporting the body�s natural detox pathways. The body has organs/systems that detoxify and keep the body in balance. These support detoxification and include:
 
Reducing toxin exposure is a long term strategy for improved health. Detox options include:
  • Increased water intake
  • Nutritional adjustments that focus on increased nutrient whole foods and reduced processed chemical foods
  • Regular exercise
  • More sleep
  • Improved stress management skills/techniques
  • Reducing environmental exposure with hygiene and cleaning product awareness
  • Cleansing supplements
  • Lifestyle changes
  • Fasting, intermittent or longer with nutritionist/health coach supervision

Chiropractic Can Help

When the body struggles with toxin overload, the body can begin storing some of these toxins. Common areas include visceral fat and joints, like the spine. If toxins buildup in the spine, spinal misalignment can be exacerbated as it affects blood and nerve circulation. Spinal alignment restoration will help open and support the body’s natural detox abilities and prevent unnecessary storage of toxins.  
11860 Vista Del Sol, Ste. 128. Support Full Body Detox With Chiropractic
 
A chiropractic practitioner specializes in naturally restoring spinal alignment and the body’s balance. This supplies the body with the energy it needs to process and rid itself of toxins. When the body is optimally supported and its detox pathways cleared overall optimal health can be achieved. Contact Injury Medical Chiropractic Clinic and experience what chiropractic support can do.

Body Composition Support


 

Food

Neutralizing oxidative stress, lowering inflammation, and boosting metallothionein expression, food can support the body when detoxifying and countering the effects like brain fog, and neurodegenerative disorders. However, foods and nutrients that detoxify can be a part of a healthy diet and lifestyle that includes a regular fitness routine.
References
Klein, A V, and H Kiat. �Detox diets for toxin elimination and weight management: a critical review of the evidence.��Journal of human nutrition and dietetics: the official journal of the British Dietetic Association�vol. 28,6 (2015): 675-86. doi:10.1111/jhn.12286
What is the Role of Glutathione in Detox?

What is the Role of Glutathione in Detox?

Antioxidants like resveratrol, lycopene, vitamin C, and vitamin E can be found in many foods. However, one of the most powerful antioxidants is naturally produced by the body.�Glutathione is known as the �master antioxidant�. Many foods have some glutathione but it is ultimately broken down by digestion before it can be properly used. Research studies have found that dietary glutathione isn�t associated with glutathione in the blood. As previously mentioned, glutathione is naturally produced by the body. But, if your capacity to do so is affected, it can cause a variety of health issues.

 

Glutathione is essential for liver detox or detoxification. Unlike other ways in which we can detox the body, scientists have demonstrated the benefits of glutathione for detoxification. It�s also necessary for healthy immune function and antioxidant defenses against free radicals. Glutathione deficiency is associated with health problems from overtraining to HIV/AIDS. In the following article, we will look at the role of this well-known amino acid in detox or detoxification. Glutathione is made up of three essential amino acids, including L-cysteine, L-glutamic acid, and glycine. It is responsible for:

 

  • Promoting liver detox or detoxification before bile is released
  • Reducing harmful components and toxins, such as peroxides
  • Neutralizing free radicals and other chemicals or substances
  • Cleaning out the body and supporting the immune and nervous system

 

What is Glutathione Responsible for in Detox?

 

Glutathione is essential for liver detox or detoxification. Glutathione binds to harmful components and toxins before they�re eliminated which is an important step in getting them out of your body.�Glutathione may also be very essential for helping your body eliminate harmful components and toxins found in the food you eat and the environment. By way of instance, one research study found that in people who eat a lot of fish, the total amount of mercury in their bodies was associated with genes that regulate glutathione levels in the blood. The more glutathione people made, the less amount of mercury they had.

 

Glutathione is found in every cell and tissue of the body. However, concentrations are seven to 10 times higher in the liver than anywhere else in the body. That�s because the well-known tripeptide plays a fundamental role in the Phase II liver detoxification pathway. The Phase II liver detoxification pathway is the process of metabolizing molecules that need to be eliminated from the body. Glutathione commonly binds to these molecules to eliminate them from the body. Glutathione ultimately has the capacity to bind to harmful compounds and toxins, flagging them as hazardous.

 

This helps eliminate chemicals and substances, scientifically known as xenobiotics, which weren�t produced in the body. And it can identify drugs, environmental pollutants, or any number of chemicals and substances. It�s important that glutathione binds to these harmful compounds and toxins before they can bind to important cells and tissues.�But the detox process isn�t complete. The next step is to turn the harmful compounds and toxins into a form that can be further metabolized and/or eliminated. Glutathione plays a role in turning fat-soluble toxins into water-soluble toxins so you can eliminate them from your body. The Phase II liver detoxification pathway involving glutathione plays physiologically essential roles in detox or detoxification. Without it, you�d probably be filled with hazardous material.

 

In conclusion, glutathione is essential for liver detox or detoxification. Glutathione is made up of three essential amino acids, including L-cysteine, L-glutamic acid, and glycine. Unlike other ways in which we can detox the body, scientists have demonstrated the benefits of glutathione for detoxification. As previously mentioned, it�s also necessary for healthy immune function and antioxidant defenses against free radicals. Glutathione deficiency is associated with a variety of health problems. In the article above, we looked at the role of this well-known amino acid in detox or detoxification.

 

 

Glutathione is an essential antioxidant for liver detox or detoxification, regulating inflammation, and supporting healthy immune function. But it�s not like other nutrients where you can eat more of it to take advantage of its health benefits. Instead, the important part about glutathione is supporting your body�s natural ability to produce it on its own. Think less �glutathione supplement� and more �eating your broccoli and moderate exercise� to help your body cleanse and protect itself against harmful components and toxins as well as bacteria and viruses. – Dr. Alex Jimenez D.C., C.C.S.T. Insight

 


 

Protein Power Smoothie | El Paso, TX Chiropractor

 

Protein Power Smoothie

 

Serving: 1
Cook time: 5 minutes

 

� 1 scoop protein powder
� 1 tablespoon ground flaxseed
� 1/2 banana
� 1 kiwi, peeled
� 1/2 teaspoon cinnamon
� Pinch of cardamom
� Non-dairy milk or water, enough to achieve desired consistency

 

Blend all ingredients in a high-powered blender until completely smooth. Best served immediately.

 


 

Cucumbers | El Paso, TX Chiropractor

 

Cucumber is 96.5% Water

 

Because they’re so naturally high in water, cucumber is also very low in calories. It only has 14 calories per 100g (3.5oz). That means you can nibble on it all day without worrying about your waistline.

 


 

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas*& New Mexico*�

 

Curated by Dr. Alex Jimenez D.C., C.C.S.T.

 

References:

 

  • Paleo Leap Staff. �Glutathione: the Detox Antioxidant: Paleo Leap.� Paleo Leap | Paleo Diet Recipes & Tips, 1 Feb. 2017, paleoleap.com/glutathione-the-detox-antioxidant/.
  • Ask The Scientists Staff. �Glutathione – The Amazing Detoxification Molecule You Might Not Know.� Ask The Scientists, 19 Dec. 2019, askthescientists.com/qa/glutathione/.
  • Dr. Judy. �Glutathione: The Detox Boss.� Vitality Natural Health Care, 14 Apr. 2018, vitalitywellnessclinic.com/detox-immune-system/glutathione-the-detox-boss/.
  • Dowden, Angela. �Coffee Is a Fruit and Other Unbelievably True Food Facts.� MSN Lifestyle, 4 June 2020, www.msn.com/en-us/foodanddrink/did-you-know/coffee-is-a-fruit-and-other-unbelievably-true-food-facts/ss-BB152Q5q?li=BBnb7Kz&ocid=mailsignout#image=24.
What are the Phases of Liver Detoxification?

What are the Phases of Liver Detoxification?

People are exposed to toxins, such as pesticides and air pollutants in food and the environment, on a regular basis. Meanwhile, other toxins are produced in the body through normal functions and microbes. That’s why it’s fundamental to support the liver, one of the major detoxification systems in the body. If the liver isn’t working properly, harmful compounds can start to pile up in the cells and tissues, leading to a variety of health issues. Liver detoxification is a two-step process that converts fat-soluble toxins into water-soluble toxins that the body can eliminate accordingly.

 

In the following article, we will discuss the importance of liver detox, what happens in the two phases of liver detoxification, and how you can support liver detox to promote overall health.

 

The Importance of Liver Detox

 

The liver is responsible for the detoxification of all of the harmful compounds and toxins that the body is exposed to on a regular basis. Moreover, it’s fundamental to eliminate these from the liver and the rest of the body regularly to tremendously reduce their negative effects. If toxins start to pile up in the cells and tissues of the liver, it can potentially lead to liver damage as well as a variety of other health issues. By way of instance, toxins are associated with obesity, dementia, and even cancer. And they are also believed to be a factor in chronic health issues, such as fibromyalgia.

 

There are two main ways that the body eliminates toxins. First, fat-soluble toxins are metabolized in the liver to make them water-soluble. Then, water-soluble toxins are sent directly to the kidneys where these are eliminated in the urine. Another of the body�s safeguards against harmful compounds is that the blood collected from the gut goes to the liver first. The blood from the gut may be especially high in toxins if a person has a leaky gut. Through the detoxification of toxins first, the liver can considerably reduce the number of toxins that reach other organs, such as the brain and heart.

 

Phases of Liver Detoxification

 

The liver is one of the main detoxification systems in the body. Detoxification or detox in the liver is separated into two categories. They are known as Phase I and Phase II liver detoxification pathways.

 

Phase I Liver Detoxification Pathway

 

The Phase I liver detoxification pathway is the first line of defense against harmful components and toxins. It’s made up of a collection of enzymes known as the cytochrome P450 family. The enzymes help neutralize substances, such as caffeine and alcohol. They offer protection by converting these toxins into less harmful components. However, if the byproducts of the Phase I liver detoxification pathway are allowed to pile up in the liver, they can damage DNA and proteins. It is ultimately the role of the Phase II liver detoxification pathway to make sure that those toxins do not pile up in the liver.

 

Phase II Liver Detoxification Pathway

 

The Phase II liver detoxification pathway neutralizes the byproducts of the Phase I liver detoxification pathway as well as that of other remaining toxins. This is done by metabolizing fat-soluble toxins in the liver to make them water-soluble so that they can be eliminated from the body. This process is known as conjugation. Glutathione, sulfate, and glycine are the primary molecules responsible for this process. Under normal conditions, Phase II liver detoxification pathway enzymes produce low levels of glutathione. Under times of high toxic stress, the body increases glutathione production.

 

 

We are exposed to toxins like pesticides and air pollutants in the food we eat as well as in the environment every day while other harmful compounds are produced by microbes through normal functions in the body. It’s essential to support liver function because it is our main detoxification system. If the liver isn’t working properly, toxins and harmful compounds can start to pile up in the liver which can eventually cause a variety of health issues. The phases of liver detoxification are a two-step pathway that converts fat-soluble toxins into water-soluble toxins that the body can eliminate accordingly. In the article above, we discussed the importance of liver detox, the phases of liver detoxification, and how you can support liver detox to promote overall health.�- Dr. Alex Jimenez D.C., C.C.S.T. Insight

 


 

Image of zesty beet juice.

 

Zesty Beet Juice

Servings: 1
Cook time: 5-10 minutes

� 1 grapefruit, peeled and sliced
� 1 apple, washed and sliced
� 1 whole beet, and leaves if you have them, washed and sliced
� 1-inch knob of ginger, rinsed, peeled and chopped

Juice all ingredients in a high-quality juicer. Best served immediately.

 


 

Image of carrots.

 

Just one carrot gives you all of your daily vitamin A intake

 

Yes, eating just one boiled 80g (2�oz) carrot gives you enough beta carotene for your body to produce 1,480 micrograms (mcg) of vitamin A (necessary for skin cell renewal). That’s more than the recommended daily intake of vitamin A in the United States, which is about 900mcg. It’s best to eat carrots cooked, as this softens the cell walls allowing more beta carotene to be absorbed. Adding healthier foods into your diet is a great way to improve your overall health.

 


 

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas*& New Mexico*�

 

Curated by Dr. Alex Jimenez D.C., C.C.S.T.

 

References:

 

  • Ask The Scientists Staff. �Liver Detoxification Pathways.� Ask The Scientists, 30 Jan. 2019, askthescientists.com/qa/liver-detoxification-pathways/#:~:text=liver%20detoxification%20pathways.-,Phase%20I%20Liver%20Detoxification%20Pathway,toxins%20into%20less%20harmful%20ones.
  • Watts, Todd, and Jay Davidson. �Phases of Liver Detox: What They Do & How to Support Them.� Phases of Liver Detox: What They Do & How to Support Them – Microbe Formulas�, 24 Jan. 2020, microbeformulas.com/blogs/microbe-formulas/phases-of-liver-detox-what-they-do-how-to-support-them.
  • DM; Grant. �Detoxification Pathways in the Liver.� Journal of Inherited Metabolic Disease, U.S. National Library of Medicine, 1 July 1991, pubmed.ncbi.nlm.nih.gov/1749210/.
  • Dowden, Angela. �Coffee Is a Fruit and Other Unbelievably True Food Facts.� MSN Lifestyle, 4 June 2020, www.msn.com/en-us/foodanddrink/did-you-know/coffee-is-a-fruit-and-other-unbelievably-true-food-facts/ss-BB152Q5q?li=BBnb7Kz&ocid=mailsignout#image=24.
What are the Main Detoxification Systems?

What are the Main Detoxification Systems?

The body is capable of eliminating harmful components generated by the production of toxic metabolites and the ingestion of toxic substances. When these overwhelm the organs of detoxification and excretion, the body can store these chemicals in the connective tissues. Detoxification is essential for the restoration of the body�s regulatory mechanisms in order to improve function. In the following article, we will discuss what is detox and how each of the organs of detoxification is responsible for the proper functioning of the organism in general, among other fundamental tasks.

 

Liver

 

The liver performs a variety of fundamental tasks, including digestion and hormonal balance. It’s considered to be the body’s main detoxification system. Several functions of the liver include:

 

  • removing harmful compounds like food additives, toxic medications, and excess hormones, etc.
  • extracting waste material from the bloodstream and transforming them so that they can be excreted by the kidneys or intestines
  • eliminating toxic metabolites and other waste products from intestinal fermentation and putrefaction
  • a source of Kupffer�s cells which filter and eliminate foreign invaders, such as bacteria, fungi, viruses and cancerous cells

 

Kidneys

 

The kidneys help to purify the blood from harmful compounds, including food additives, toxic medications, excess hormones, and other chemicals, by extracting them from the bloodstream and eliminating them through the urine. For proper filtration of the blood, an individual’s blood pressure and volume should be stable. Furthermore, proper hydration is essential for proper kidney function.

 

Intestines

 

The gastrointestinal tract is also responsible for the detoxification and excretion of harmful compounds.�Throughout the different phases of digestion, harmful compounds are extracted and excreted by the liver into the bile and finally into the small intestine in order to continue through the intestinal tract to be eliminated in the stool. In the final phase of digestion, anything that can still be utilized in the colon, such as fiber, is ultimately broken down further with the help of the gut microbiome and it is transported to the liver for detoxification. The intestines are another essential detoxification system.

 

Respiratory Tract

 

The respiratory tract, including the lungs and the bronchi, eliminates harmful compounds in the form of carbonic gas. It may also excrete phlegm. Constant irritation by foreign invaders, such as bacteria, fungi, viruses, and cancerous cells, can cause the alveoli to act as an emergency exit for toxins that the liver, kidneys, and the gastrointestinal tract did not succeed in eliminating. These harmful compounds are transported by the bloodstream towards the lungs and bronchi where they are coughed up as phlegm. This phlegm consists of waste resulting from insufficient digestion and excretion.

 

Skin

 

The skin is the largest organ of protection and defense. It plays a fundamental role in the elimination of harmful compounds and it can help with kidney function. It evacuates waste products in the form of “crystals” that are soluble in liquids and are then eliminated in the form of sweat through the sweat glands. Crystals are the residues of the metabolism of foods that are high in protein, such as legumes, eggs, dairy products, fish, meats, and cereals. These may also result from an excess of refined sugar. Other types of waste products and harmful compounds are excreted in the form of rashes.

 

Lymph System

 

Finally, the lymph system is another main detoxification system. Lymph fluid allows waste products to leave the cells and be carried away to the bloodstream. Lymphatic capillaries are responsible for the defense of the body and purification of the body fluids to maintain its proper functioning.�Other sites of lymphocyte production are the spleen, the thymus, etc. If foreign invaders enter into the body, the production of white blood cells increases rapidly and proportionally to the intensity of the aggression. The lymph nodes that are closest to the site react first to defend and protect the body.

 

 

The body is capable of eliminating harmful components generated by the production of toxic metabolites and the ingestion of toxic substances. When these overwhelm the organs of detoxification and excretion, the body can store these chemicals in the connective tissues. Detoxification is essential for the restoration of the body�s regulatory mechanisms in order to improve function. In the following article, we will discuss what is detox and how each of the organs of detoxification, including the liver, kidneys, intestines, respiratory tract, skin, and lymph system, is responsible for the proper functioning of the organism in general, among other fundamental tasks. – Dr. Alex Jimenez D.C., C.C.S.T. Insight

 


 

Image of zesty beet juice.

 

Zesty Beet Juice

Servings: 1
Cook time: 5-10 minutes

� 1 grapefruit, peeled and sliced
� 1 apple, washed and sliced
� 1 whole beet, and leaves if you have them, washed and sliced
� 1-inch knob of ginger, rinsed, peeled and chopped

Juice all ingredients in a high-quality juicer. Best served immediately.

 


 

Image of carrots.

 

Just one carrot gives you all of your daily vitamin A intake

 

Yes, eating just one boiled 80g (2�oz) carrot gives you enough beta carotene for your body to produce 1,480 micrograms (mcg) of vitamin A (necessary for skin cell renewal). That’s more than the recommended daily intake of vitamin A in the United States, which is about 900mcg. It’s best to eat carrots cooked, as this softens the cell walls allowing more beta carotene to be absorbed. Adding healthier foods into your diet is a great way to improve your overall health.

 


 

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas*& New Mexico*�

 

Curated by Dr. Alex Jimenez D.C., C.C.S.T.

 

References:

 

  • Issels, Ilse Marie. �Information on Detoxification and the Organs That Remove Toxins.� Issels Integrative Immuno-Oncology, 22 May 2015, issels.com/publication-library/information-on-detoxification/.
  • Dowden, Angela. �Coffee Is a Fruit and Other Unbelievably True Food Facts.� MSN Lifestyle, 4 June 2020, www.msn.com/en-us/foodanddrink/did-you-know/coffee-is-a-fruit-and-other-unbelievably-true-food-facts/ss-BB152Q5q?li=BBnb7Kz&ocid=mailsignout#image=24.
What is the Role of a Detox Diet?

What is the Role of a Detox Diet?

Most detox diets are normally short-term diet and lifestyle modifications made to help eliminate toxins from your body. A common detox diet may include a period of fasting and a diet of fruits, vegetables, juices, and water. A detox diet may also include teas, supplements, and enemas or colon cleanses. According to healthcare professionals, the role of a detox diet is to rest your organs, stimulate your liver function, promote toxin elimination, improve circulation, and provide healthy nutrients. Detox diets are recommended due to possible exposure to harmful compounds like heavy metals and pollutants.

 

Detox diets are also believed to help improve a variety of health issues, including digestive problems, bloating, inflammation, allergies, autoimmune diseases, obesity, and chronic fatigue.�However, there currently aren’t enough research studies on detox diets in humans and those that exist are considered flawed. In the following article, we will discuss the role of a detox diet on health and wellness.

 

Potential Benefits of a Detox Diet

 

Healthcare professionals have attempted to demonstrate the exact mechanisms in which detox diets can help eliminate toxins from your body. As a matter of fact, because of the current lack of research studies on detox diets in humans, there is currently little to no evidence which even demonstrates if detox diets can remove any toxins from your body as most of these rarely specify the type of harmful components they aim to remove. Moreover, your body is capable of cleansing itself through sweat, urine, and feces. Your liver also makes toxins harmless and then releases them from your body.

 

However, there are several harmful components that aren’t easily removed by these processes, including persistent heavy metals, phthalates, bisphenol A (BPA), and organic pollutants (POPs). These generally accumulate in fat tissue or blood and can take an extended period for your body to flush them. These harmful compounds are generally limited or removed in commercial products today.

 

Detox diets may also have other possible health benefits and these can also help encourage the following, including:

 

  • Avoiding processed foods
  • Eating nutritious, healthy whole foods
  • Exercising regularly and sweating accordingly
  • Drinking juices, teas, and water
  • Losing excessive fat; weight loss
  • Limiting stress, relaxing, and getting good sleep
  • Avoiding dietary sources of heavy metals and POPs

 

Following these guidelines is generally associated with improved health and wellness, regardless of whether you�re following a detox diet.

 

Bottom Line

 

Many detox diets are typically short-term diet and lifestyle changes made to help eliminate toxins from your body. A well-known detox diet may include a period of fasting and a diet of fruits, vegetables, juices, and water. A detox diet may also include teas, supplements, and enemas or colon cleanses. According to healthcare professionals, the role of a detox diet is to rest your organs, stimulate your liver function, promote toxin elimination, improve circulation, and provide healthy nutrients. Detox diets are recommended due to possible exposure to harmful compounds like heavy metals and pollutants.

 

Detox diets are also believed to help improve a variety of health issues, including digestive problems, bloating, inflammation, allergies, autoimmune diseases, obesity, and chronic fatigue. However, there currently aren’t enough research studies on detox diets in humans and those that exist are considered flawed. In the article above, we discussed the role of a detox diet on health and wellness.

 

 

Detox diets are made to help eliminate toxins from your body. A detox diet may include fasting, followed by a diet made up of fruits, vegetables, juices, and water. A detox diet may also include teas, supplements, and enemas. The role of a detox diet is to help your organs rest, promote liver function, support toxin elimination, improve circulation, and to offer various healthy nutrients. Detox diets are recommended when a person has been exposed to harmful compounds like heavy metals and pollutants. Detox diets are also believed to help improve digestive problems, bloating, inflammation, allergies, autoimmune diseases, obesity, and chronic fatigue, among a variety of other health issues. However, further research studies are still required. – Dr. Alex Jimenez D.C., C.C.S.T. Insight

 


 

Image of zesty beet juice.

 

Zesty Beet Juice

Servings: 1
Cook time: 5-10 minutes

� 1 grapefruit, peeled and sliced
� 1 apple, washed and sliced
� 1 whole beet, and leaves if you have them, washed and sliced
� 1-inch knob of ginger, rinsed, peeled and chopped

Juice all ingredients in a high-quality juicer. Best served immediately.

 


 

Image of carrots.

 

Just one carrot gives you all of your daily vitamin A intake

 

Yes, eating just one boiled 80g (2�oz) carrot gives you enough beta carotene for your body to produce 1,480 micrograms (mcg) of vitamin A (necessary for skin cell renewal). That’s more than the recommended daily intake of vitamin A in the United States, which is about 900mcg. It’s best to eat carrots cooked, as this softens the cell walls allowing more beta carotene to be absorbed. Adding healthier foods into your diet is a great way to improve your overall health.

 


 

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas*& New Mexico*�

 

Curated by Dr. Alex Jimenez D.C., C.C.S.T.

 

References:

 

  • Bjarnadottir, Adda. �Do Detox Diets and Cleanses Really Work?� Healthline, Healthline Media, 10 Jan. 2019, www.healthline.com/nutrition/detox-diets-101.
  • Dowden, Angela. �Coffee Is a Fruit and Other Unbelievably True Food Facts.� MSN Lifestyle, 4 June 2020, www.msn.com/en-us/foodanddrink/did-you-know/coffee-is-a-fruit-and-other-unbelievably-true-food-facts/ss-BB152Q5q?li=BBnb7Kz&ocid=mailsignout#image=24.
Is Fructose Bad for Your Health?

Is Fructose Bad for Your Health?

Fructose is one of the main components of added sugar. It is a simple type of sugar that makes up about 50 percent of table sugar or sucrose. Table sugar is also made up of glucose or the main energy source of the human body. However, fructose needs to be turned into glucose by the liver before it can be used as fuel for energy by our cells. Fructose, sucrose, and glucose are all naturally found in fruits, vegetables, dairy products, and whole grains as well as in many processed foods. The effects of this simple sugar on our health have been a controversial topic for many years. Research studies are starting to demonstrate the connection between fructose and obesity, diabetes, and even cancer.

 

What is Fructose?

 

Fructose, also referred to as fruit sugar, is a monosaccharide or simple sugar like glucose. It’s naturally found in fruits, most root vegetables, agave, and honey. Moreover, it’s commonly added to processed foods as high-fructose corn syrup. The fructose used in high-fructose corn syrup mainly comes from corn, sugar beets, and sugar cane. High-fructose corn syrup is made from cornstarch and it has more of this simple sugar than glucose, compared to regular corn syrup. Fructose has the sweetest taste of the three sugars. It is digested and absorbed differently by the human body. Because monosaccharides are simple sugars, they don’t need to be broken down to be used as fuel for energy by our cells.

 

Natural foods that are high in fructose can include:

 

  • apples
  • apple juice
  • pears
  • prunes
  • dry figs
  • sorghum
  • asparagus
  • Jerusalem artichokes
  • chicory roots
  • leeks
  • onions
  • caramel
  • licorice
  • molasses
  • agave syrup
  • honey

 

Similar to glucose, fructose is absorbed directly into the bloodstream through the small intestine. Healthcare professionals have found that fructose has the least impact on blood sugar levels. It increases blood sugar levels much more gradually than glucose does and it doesn’t seem to immediately affect insulin levels. However, although this simple sugar has the least impact on blood sugar levels than any of the other simple types of sugars, it may ultimately cause more long-term negative effects on the human body. Fructose needs to be turned into glucose by the liver before it can be used as fuel for energy by our cells. Eating excess fructose can increase triglycerides and lead to metabolic syndrome.

 

Why is Fructose Bad for You?

 

When people eat a diet that is high in calories and processed foods with lots of high-fructose corn syrup, the liver can become overwhelmed and start turning fructose into fat. Research studies are starting to demonstrate the connection between this simple sugar and an increased risk of developing a variety of health issues, including obesity, type 2 diabetes, and even cancer. Many healthcare professionals also believe that eating excess fructose is one of the main causes of metabolic disorders. However, there currently isn’t enough evidence to demonstrate the full extent to which fructose can contribute to these health issues. Nevertheless, numerous research studies have justified these controversial concerns.

 

Research studies have demonstrated that eating excess fructose can increase LDL or bad cholesterol which may lead to fat accumulation around the organs and heart disease. As a result, evidence showed that the deposition of fat in the liver due to the negative effects of this simple sugar can also result in non-alcoholic fatty liver disease. Eating excess fructose may also affect body fat regulation. Other research studies have demonstrated that because fructose doesn’t suppress appetite as much as other types of sugars do, it can promote overeating which may lead to obesity, insulin resistance, and type 2 diabetes. Furthermore, evidence has demonstrated that fructose can increase uric acid levels and cause gout.

 

For information regarding if fructose is bad for your health, please review the following article:

Health implications of fructose consumption: A review of recent data

 


 

AS PREVIOUSLY MENTIONED IN THE FOLLOWING ARTICLE, FRUCTOSE IS ONE OF THE MAIN COMPONENTS OF ADDED SUGAR. IT IS A SIMPLE SUGAR THAT MAKES UP APPROXIMATELY 50 PERCENT OF TABLE SUGAR OR SUCROSE. TABLE SUGAR ALSO CONSISTS OF GLUCOSE OR THE MAIN ENERGY SOURCE OF THE HUMAN BODY. HOWEVER, FRUCTOSE NEEDS TO BE CONVERTED INTO GLUCOSE BY THE LIVER BEFORE IT CAN BE UTILIZED AS FUEL FOR ENERGY BY OUR CELLS. FRUCTOSE, SUCROSE, AND GLUCOSE ARE ALL NATURALLY FOUND IN SEVERAL FRUITS, VEGETABLES, DAIRY PRODUCTS, AND WHOLE GRAINS AS WELL AS IN MANY PROCESSED FOODS. THE EFFECTS OF THIS SIMPLE SUGAR ON OUR HEALTH HAVE BEEN A CONTROVERSIAL TOPIC FOR MANY YEARS. RESEARCH STUDIES ARE STARTING TO DEMONSTRATE THE CONNECTION BETWEEN FRUCTOSE AND OBESITY, DIABETES, AND EVEN CANCER. IN THE FOLLOWING ARTICLE, WE DISCUSS IF FRUCTOSE IS BAD FOR YOUR HEALTH. DRINKING SMOOTHIES ADD A HEALTHY NUTRITIONAL BOOST.� -�DR. ALEX JIMENEZ D.C., C.C.S.T. INSIGHTS

 


 

Image of sweet and spicy juice recipe.

 

 

Sweet and Spicy Juice

Servings: 1
Cook time: 5-10 minutes

� 1 cup honeydew melons
� 3 cups spinach, rinsed
� 3 cups Swiss chard, rinsed
� 1 bunch cilantro (leaves and stems), rinsed
� 1-inch knob of ginger, rinsed, peeled, and chopped
� 2-3 knobs whole turmeric root (optional), rinsed, peeled, and chopped

Juice all ingredients in a high-quality juicer. Best served immediately.

 


 

Image of red peppers.

 

 

Red peppers have almost 2.5 times more vitamin C than oranges

 

Citrus fruits like oranges are a great source of vitamin C, however, there are other fruits and vegetables that offer an even better boost of this essential nutrient. Just half a red pepper, eaten raw, offers more than your requirement of vitamin C for the day, according to healthcare professionals. Cut it into crudit�s for a healthy mid-morning or afternoon snack. Red peppers are also rich in a variety of other essential nutrients, including vitamin A, B6, folate, and antioxidants!

 


 

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas*& New Mexico*�

 

Curated by Dr. Alex Jimenez D.C., C.C.S.T.

 

References:

 

  • Gunnars, Kris. �Is Fructose Bad for You? The Surprising Truth.� Healthline, Healthline Media, 23 Apr. 2018, www.healthline.com/nutrition/why-is-fructose-bad-for-you#section1.
  • Nall, Rachel. �Is Fructose Bad for You? Benefits, Risks, and Other Sugars.� Medical News Today, MediLexicon International, 28 Nov. 2018, www.medicalnewstoday.com/articles/323818.
  • Groves, Melissa. �Sucrose vs Glucose vs Fructose: What’s the Difference?� Healthline, Healthline Media, 8 June 2018, www.healthline.com/nutrition/sucrose-glucose-fructose.
  • Rizkalla, Salwa W. �Health Implications of Fructose Consumption: A Review of Recent Data.� National Center for Biotechnology Information, BioMed Central, 4 Nov. 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC2991323/.
  • Daniluk, Julie. �5 Health Benefits of Red Peppers. Plus, Our World’s Healthiest Pizza Recipe.� Chatelaine, 26 Feb. 2016, www.chatelaine.com/health/healthy-recipes-health/five-health-benefits-of-red-peppers/.

 

How To Detox In The New Year

How To Detox In The New Year

Do you feel:

  • Weight gain over the holidays?
  • Stomach pain, burning, or aching 1-4 hours after eating?
  • Is waist girth equal to or larger than hip girth?
  • Tired/sluggish?
  • Mental sluggish?

If you are experiencing any of these situations, then try to detox your body for the new year as part of your resolutions.

With the start of the new year comes the numerous ads on T.V. for detox programs and cleanses that will help people who are trying to get healthier as their new year�s resolution. The detox programs and cleanses that are shown as commercials and online ads will make anyone believe that lemon water, apple cider vinegar, and green juices can help detox the body and boost the metabolism. Even though these detox programs and cleanses are alluring and may reel in unsuspected individuals. The truth is that the endocrine system helps the body runs its detoxification process all day with natural, efficient, and effective essential nutrients that are critical for each of the endocrine functions.

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Naturally Detox Foods and Nutrients

If someone enjoys eating superfruits like goji or a�ai berries, there is nothing wrong with that because these berries have antioxidant properties for the body. Studies show that animal foods such as beef, pork, poultry, and many other animal products have contributed vital amino acids for liver detoxification and provide a rich source of sulfur that the body needs. With many commercial detox programs and �cleanses� that claims that it will temporarily eliminate the animal protein, however, this is not a requirement for a healthy detox. Any plant foods from the cruciferous and allium families are beneficial and crucial for the body due to sulfation via sulfotransferase enzymes for phase 2 detoxification.

There is also something else that plays a critical role in the biotransformation and detoxification of harmful compounds out of the body is none other than glutathione. Since glutathione is called the “master antioxidant,” it is a tripeptide, which is a molecule that is made up of three amino acids. Research shows that any foods can provide nutrients to help support glutathione production, especially a large proportion of animal foods like beef, pork, eggs, turkey, chicken, and lamb can provide nutrients for the body. With these nutrients contributing to the body, some of them are not found exclusively, even though they are strongly being represented but are being underscored. It is not necessary to eliminate animal foods; a person can still eat both plant foods and animal foods to help support healthy detoxification for the body.

Kidney Detoxification

Surprisingly, detoxing is not always about the liver. The kidneys need to detox as well since they are the liver�s assistants in the detoxification process of harmful toxins in the body. Since the liver can convert the fat-soluble toxins into water-soluble compounds, it makes it easier for the body to excrete the urine out of the body easily as the kidneys are regulating the detoxification.

The kidneys may be small, but they are very hardworking organs that are less than 0.5% of the body mass. In a healthy body, the filtration rate for the kidneys is about 150 quarts of blood daily. According to the information given by the National Kidney Foundation, it states that when there is frequent dehydration, it can lead to permanent kidney damage. By staying hydrated, this can prevent bad kidney function from happening and eliminating the harmful toxins out of the body.

Although this does not mean that a person should be guzzling water every day, even though it is recommended for a person to drink six to eight glasses of water, a day turns out to be a myth. In general, it is fine to use thirst as a reminder to drink water and to consume coffee and tea even counts even though there are diuretics. The research found in the Mayo Clinic found out that any foods like iceberg lettuce and cucumbers have high water content and can contribute to total water intake.

Sleep Is Very Important

Regarding detoxification, sleep is something that does not get too much attention. With the body trying to detoxify throughout the entire day, some factors can upregulate during the sleep period. Studies show that sleep or even a quick power nap is universal to all humans and animals. Not everyone exactly knows why sleep is essential, but there are many possibilities that when a person is sleeping, it is time for the brain to do a bit of cleaning for the body. This is because the brain has an easier time to process everything when the individual is not awake, and their attention is not on a hundred different things.

A recent discovery has found that the brain has a unique system called the glymphatic system, and that system is activated when a person is asleep. The glymphatic system can also clear beta-amyloid, which is the potential harmful protein that is associated with Alzheimer’s disease. Studies even show that the glymphatic system can clear beta-amyloid twice as effective when a person is sleeping than when they are awake. If a person wants to have a healthier year, then they should be aware of the importance of good quality sleep.

Conclusion

So for the new year, adding these detoxifying methods can help boost the body system and promote wellness. By adding nutritious foods that are filled with antioxidants and detoxifying properties that are beneficial to the body, getting enough sleep and staying hydrated is highly crucial for healthy body detoxification. Some products have advance detoxification properties that can help support the immune system and are designed for greater stability bioavailability, and digestive comfort for the body.

The scope of our information is limited to chiropractic, musculoskeletal, and nervous health issues or functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or disorders of the musculoskeletal system. Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.


References:

Publishing, Harvard Health. �The Dubious Practice of Detox.� Harvard Health, 2008, www.health.harvard.edu/staying-healthy/the-dubious-practice-of-detox.

Hodges, Romilly E, and Deanna M Minich. �Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application.� Journal of Nutrition and Metabolism, Hindawi Publishing Corporation, 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/.

Jessen, Nadia Aalling, et al. �The Glymphatic System: A Beginner’s Guide.� Neurochemical Research, U.S. National Library of Medicine, Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4636982/.

Labos, Christopher. �The Water Myth.� Office for Science and Society, 14 Aug. 2018, www.mcgill.ca/oss/article/health-nutrition/water-myth.

Masters, M, and R A McCance. �The Sulphur Content of Foods.� The Biochemical Journal, U.S. National Library of Medicine, Aug. 1939, www.ncbi.nlm.nih.gov/pmc/articles/PMC1264524/.

Mendelsohn, Andrew R, and James W Larrick. �Sleep Facilitates Clearance of Metabolites from the Brain: Glymphatic Function in Aging and Neurodegenerative Diseases.� Rejuvenation Research, U.S. National Library of Medicine, Dec. 2013, www.ncbi.nlm.nih.gov/pubmed/24199995.

Purves, Dale. �Why Do Humans and Many Other Animals Sleep?� Neuroscience. 2nd Edition., U.S. National Library of Medicine, 1 Jan. 1970, www.ncbi.nlm.nih.gov/books/NBK11108/.

Rasmussen, Martin Kaag, et al. �The Glymphatic Pathway in Neurological Disorders.� The Lancet. Neurology, U.S. National Library of Medicine, Nov. 2018, www.ncbi.nlm.nih.gov/pubmed/30353860.

Staff, Mayo Clinic. �Water: How Much Should You Drink Every Day?� Mayo Clinic, Mayo Foundation for Medical Education and Research, 6 Sept. 2017, www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/water/art-20044256.

Team, DFH. �A New Year Is Upon Us � It’s Detox Time!� Designs for Health, 31 Dec. 2019, blog.designsforhealth.com/node/923.

Team, NIDDKD. �Your Kidneys & How They Work.� National Institute of Diabetes and Digestive and Kidney Diseases, U.S. Department of Health and Human Services, 1 June 2018, www.niddk.nih.gov/health-information/kidney-disease/kidneys-how-they-work.

Team, NKF. �Can Dehydration Affect Your Kidneys?� National Kidney Foundation, 16 Apr. 2018, www.kidney.org/newsletter/can-dehydration-affect-your-kidneys.


Modern Integrative Wellness

By informing individuals about how the National University of Health Sciences provides the knowledge for future generations, the University offers a wide variety of medical professions for functional medicine.

Functional Endocrinology: Hepatic Biotransformation & Hormone Balance

Functional Endocrinology: Hepatic Biotransformation & Hormone Balance

Biotransformation is the process of a substance changes from one chemical to another being transformed by a chemical reaction within the body. In the human body though, biotransformation is the process of rendering nonpolar (fat-soluble) compounds to polar (water-soluble) substances so they can be excreted in urine, feces, and sweat. It also serves as an important defense mechanism in the body to eliminate toxic xenobiotics out of the body through the liver. The liver is the one that takes these toxins and transformed them into suitable compounds to excrete out of the body as biotransformation.

Screenshot 2019-10-14 09.38.39

Detoxification is also known as �detoxication� in literature. It is also a type of alternative medicine treatment that aims the body to get rid of unspecified �toxins.� It is highly important for a person to detox their body and with biotransformation, it can be classified into two categories, under normal sequences, which tends to react with a xenobiotic. They are called Phase 1 and Phase 2 reactions that help the body with detoxification.

Phase 1 Reactions

Phase 1 reaction is consisting of oxidation-reduction and hydrolysis. Research shows that Phase 1 is generally the first defense employed by the body to biotransform xenobiotics, steroid hormones, and pharmaceuticals. They create CYP450 (cytochrome P450) enzymes and are described as functionalization microsomal membrane-bound that are located in the liver but can also be in enterocytes, kidney, lungs and the brain in the body. The CYP450 enzymes can be beneficial or have consequences for an individual�s response to the effect of a toxin they are exposed to.

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Studies have been shown that phase 1 reactions have been affecting the elderly population. It states that hepatic phase 1 reaction involving oxidation, hydrolysis, and reduction appears to be more altered by age since the elderly population comprises the fastest-growing segment of the world�s population. It also states that there is a predictable, age-related decline in cytochrome P-540 function and combined with the polypharmacy that much of the elderly population experiences, this may lead to a toxic reaction of medication.

Phase 2 Reaction

Phase 2 reaction is part of the cellular biotransformation machinery and is a conjugation reaction in the body. They can involve the transfer of a number of hydrophilic compounds to enhanced the metabolites, and the excretion in the bile or urine in the body. The enzymes in Phase 2 reaction can also comprise multiple proteins and subfamilies to play an essential role in eliminating the biotransformed toxins and metabolizing steroid hormones and bilirubin in the body.

Screenshot 2019-10-14 09.40.07

Phase 2 enzymes can function not only in the liver but also in other tissues like the small intestines. When it combined with Phase 1, they can help the body naturally detox the toxins that the body may encounter. Hormones, toxins, and drugs undergo a hepatic transformation by Phase 1 and Phase 2 pathways in the liver, then are eliminated by phase 3 pathways.

Xenobiotics

Xenobiotics has been defined as chemicals that undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism and produce liver damage to a person. Xenobiotics like drugs, chemotherapy, food additives, and environmental pollutants can generate serval free radicals that lead to an increase of oxidative stress in the cells. Accumulation of oxidative stress in the body can lead to an increase in potential cellular reduction in the body.

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Research shows that the body has a major challenge when it is detoxifying xenobiotics out of the body system and the body must be able to remove the almost-limitless number of the xenobiotic compounds from the complex mixture of chemicals that are involved in normal metabolism.

Studies even show that if the body doesn�t have a normal metabolism, many xenobiotics would reach toxic concentrations. It can even reach the respiratory tract either through airborne toxins or the bloodstream. It is important to make sure that the body and especially the liver to be healthy. Since the liver is the largest internal organ, it is responsible for detoxifying the toxins out of the body as urine, bile, and sweat.

Conclusion

Biotransformation is the process of substance changes from one chemical to another. In the body, it is a process of rendering fat-soluble compounds to water-soluble compounds, so it can be excreted out of the body as either urine, feces, or sweat. The liver is the one that causes toxic xenobiotics to transform into biotransformation and going through phase 1 and 2 to excrete the toxins out of the body for a healthy function.

Phase 1 reactions in the body are the first line of defense of the body detoxifying itself. Phase 2 creates CYP450 (cytochrome P450) that helps the body take the xenobiotic toxins and oxidates to reduce and hydrolysis the toxins to metabolites. Those metabolites then transform into Phase 2 reactions, which conjugates the metabolites in the body to be excreted out of the body. There are many factors that can make the body have xenobiotics, but the liver is the main organ to detoxify the xenobiotics out of the system. If there is an abundance of xenobiotics in the body, it can cause toxicity reaction causing the body to develop chronic illnesses. These products are known to help support the intestines and liver detoxication as well as, to help support hepatic detoxication for optimal healthy body function.

October is Chiropractic Health Month. To learn more about it, check out Governor Abbott�s bill on our website to get full details.

The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .


References:

Chang, Jyh-Lurn, et al. �UGT1A1 Polymorphism Is Associated with Serum Bilirubin Concentrations in a Randomized, Controlled, Fruit and Vegetable Feeding Trial.� The Journal of Nutrition, U.S. National Library of Medicine, Apr. 2007, www.ncbi.nlm.nih.gov/pubmed/17374650/.

Croom, Edward. �Metabolism of Xenobiotics of Human Environments.� Progress in Molecular Biology and Translational Science, U.S. National Library of Medicine, 2012, www.ncbi.nlm.nih.gov/pubmed/22974737.

Hindawi, Unknown. �Xenobiotics, Oxidative Stress, and Antioxidants.� Xenobiotics, Oxidative Stress, and Antioxidants, 17 Nov. 2017, www.hindawi.com/journals/omcl/si/346976/cfp/.

Hodges, Romilly E, and Deanna M Minich. �Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application.� Journal of Nutrition and Metabolism, Hindawi Publishing Corporation, 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/.

Kaye, Alan D, et al. �Pain Management in the Elderly Population: a Review.� The Ochsner Journal, The Academic Division of Ochsner Clinic Foundation, 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC3096211/.

M.Haschek, Wanda, et al. �Respiratory System.� ScienceDirect, Academic Press, 17 Dec. 2009, www.sciencedirect.com/science/article/pii/B9780123704696000064.

panelEdwardCroom, Author links open overlay, et al. �Metabolism of Xenobiotics of Human Environments.� ScienceDirect, Academic Press, 11 Sept. 2012, www.sciencedirect.com/science/article/pii/B9780124158139000039.

Sodano, Wayne, and Ron Grisanti. �The Physiology and Biochemistry of Biotransformation/Detoxification.� Functional Medicine University, 2010.

Unknown, Unknown. �ToxTutor – Introduction to Biotransformation.� U.S. National Library of Medicine, National Institutes of Health, 2017, toxtutor.nlm.nih.gov/12-001.html.

Zhang, Yuesheng. �Phase II Enzymes.� SpringerLink, Springer, Berlin, Heidelberg, 1 Jan. 1970, link.springer.com/referenceworkentry/10.1007%2F978-3-642-16483-5_4510.

 

 

*Detox Your Body* | Detox Doctor | El Paso, TX (2019)

*Detox Your Body* | Detox Doctor | El Paso, TX (2019)

Mr. Fred Foreman is a club basketball coach in El Paso, TX. When he first started the 6 Day Detox Kit,�Mr. Foreman had to change his diet and lifestyle habits. Mr. Foreman discusses his experience with the 6 Day Detox Kit with Dr. Jimenez and expresses how much the nutritional program has helped improve his energy and performance, and overall health. Mr. Foreman recommends this kit to anyone that’s ready for a healthy change.

El Paso Back & Fitness Clinic

6 Day Detox Kit Injury Medical Chiropractic Fitness Clinic El Paso, TX. Our services are specialized and focused on injuries and the complete recovery process.�Our areas of practice includeWellness & Nutrition, Chronic Pain,�Personal Injury,�Auto Accident Care, Work Injuries, Back Injury, Low�Back Pain, Neck Pain, Migraine Treatment, Sports Injuries,�Severe Sciatica, Scoliosis, Complex Herniated Discs,�Fibromyalgia, Chronic Pain, Stress Management, and Complex Injuries. As El Paso�s Chiropractic Rehabilitation Clinic & Integrated Medicine Center,�we passionately are focused on treating patients after frustrating injuries and chronic pain syndromes. We focus on improving your ability through flexibility, mobility and agility programs tailored for all age groups and disabilities. We want you to live a life filled with more energy, positive attitude, better sleep, less pain, proper body weight and educated on how to maintain this way of life. I assure you, I will only accept the best for you� If you have enjoyed this video and we have helped you in any way, please feel free to subscribe and recommend�us. Recommend: Dr. Alex Jimenez – RN, DC, MSACP, CCST Health Grades: www.healthgrades.com/review/3SDJ4 Facebook Clinical Page: www.facebook.com/dralexjimene… Facebook Sports Page: www.facebook.com/pushasrx/ Facebook Injuries Page: www.facebook.com/elpasochirop… Facebook Neuropathy Page: www.facebook.com/ElPasoNeurop… Yelp: El Paso Rehabilitation Center: goo.gl/pwY2n2 Yelp: El Paso Clinical Center: Treatment: goo.gl/r2QPuZ Clinical Testimonies: www.dralexjimenez.com/categor… Information: Dr. Alex Jimenez � Chiropractor Clinical Site: www.dralexjimenez.com Injury Site: personalinjurydoctorgroup.com Sports Injury Site: chiropracticscientist.com Back Injury Site: elpasobackclinic.com Pinterest: www.pinterest.com/dralexjimenez/ Twitter: twitter.com/dralexjimenez Twitter: twitter.com/crossfitdoctor Recommend: PUSH-as-Rx �� Rehabilitation Center: www.pushasrx.com Facebook: www.facebook.com/PUSHftinessa… PUSH-as-Rx: www.push4fitness.com/team/
6 Day *DETOX DIET* Treatment | El Paso, TX (2019)

6 Day *DETOX DIET* Treatment | El Paso, TX (2019)

Fred Foreman is a basketball coach who depends on his overall health and wellness to be able to engage in his everyday responsibilities. As a result, coach Foreman started the 6 Day Detox Program from Xymogen, designed to help renew and enhance the human body’s cleansing and detoxification capabilities.

6-Day-Detox-Kit_US.png

Fred Foreman discusses his experience with the 6 Day Detox Program, describing the benefits he developed as well as the effort he had to implement, to support his overall health and wellness through the detox. Fred Foreman feels a great sense of fulfillment with the 6 Day Detox Program and he encourages other people, who also wish to improve their well-being, to detox their body. Coach Foreman highly recommends the 6 Day Detox Program as an alternative treatment choice for overall health and wellness.

Injury Medical & Chiropractic Clinic

six day detox el paso tx.

We are blessed to present to you El Paso�s Premier Wellness & Injury Care Clinic.

Our services are specialized and focused on injuries and the complete recovery process. Our areas of practice include Wellness & Nutrition, Chronic Pain, Personal InjuryAuto Accident Care, Work Injuries, Back Injury, Low Back Pain, Neck Pain, Migraine Treatment, Sports Injuries, Severe Sciatica, Scoliosis, Complex Herniated Discs, Fibromyalgia, Chronic Pain, Stress Management, and Complex Injuries.

As El Paso�s Chiropractic Rehabilitation Clinic & Integrated Medicine Center, we passionately are focused on treating patients after frustrating injuries and chronic pain syndromes. We focus on improving your ability through flexibility, mobility and agility programs tailored for all age groups and disabilities.

We want you to live a life filled with more energy, positive attitude, better sleep, less pain, proper body weight and educated on how to maintain this way of life.

I assure you, I will only accept the best for you�

If you have enjoyed this video and we have helped you in any way, please feel free to subscribe and recommend us.

Recommend: Dr. Alex Jimenez – RN, DC, MSACP, CCST

Health Grades: www.healthgrades.com/review/3SDJ4

Facebook Clinical Page: www.facebook.com/dralexjimene…

Facebook Sports Page: www.facebook.com/pushasrx/

Facebook Injuries Page: www.facebook.com/elpasochirop…

Facebook Neuropathy Page: www.facebook.com/ElPasoNeurop…

Yelp: goo.gl/pwY2n2

Clinical Testimonies: www.dralexjimenez.com/categor…

Information: Dr. Alex Jimenez � Chiropractor

Clinical Site: www.dralexjimenez.com

Injury Site: personalinjurydoctorgroup.com

Sports Injury Site: chiropracticscientist.com

Back Injury Site: elpasobackclinic.com

Pinterest: www.pinterest.com/dralexjimenez/

Twitter: twitter.com/dralexjimenez

Twitter: twitter.com/crossfitdoctor

Recommend: PUSH-as-Rx ��

Rehabilitation Center: www.pushasrx.com

Facebook: www.facebook.com/PUSHftinessa…

PUSH-as-Rx: www.push4fitness.com/team/

Multi-Dimensional Roles of Ketone Bodies

Multi-Dimensional Roles of Ketone Bodies

Ketone bodies are created by the liver and utilized as an energy source when glucose is not readily available in the human body. The two main ketone bodies are acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB), while acetone is the third and least abundant, ketone body. Ketones are always present in the blood and their levels increase during fasting and prolonged exercise.�Ketogenesis is the biochemical process by which organisms produce ketone bodies through the breakdown of fatty acids and ketogenic amino acids.

Ketone bodies are mainly generated in the mitochondria of liver cells. Ketogenesis occurs when there are low glucose levels in the blood, particularly after other cellular carbohydrate stores, such as glycogen, have been exhausted. This mechanism can also occur when there is insufficient amounts of insulin. The production of ketone bodies is ultimately initiated to make available energy which is stored in the human body as fatty acids. Ketogenesis occurs in the mitochondria where it is independently regulated.

Abstract

Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient remains and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

Introduction

Ketone bodies are a vital alternative metabolic fuel source for all the domains of life, eukarya, bacteria, and archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). Ketone body metabolism in humans has been leveraged to fuel the brain during episodic periods of nutrient deprivation. Ketone bodies are interwoven with crucial mammalian metabolic pathways such as ?-oxidation (FAO), the tricarboxylic acid cycle (TCA), gluconeogenesis, de novo lipogenesis (DNL), and biosynthesis of sterols. In mammals, ketone bodies are produced predominantly in the liver from FAO-derived acetyl-CoA, and they are transported to extrahepatic tissues for terminal oxidation. This physiology provides an alternative fuel that is augmented by relatively brief periods of fasting, which increases fatty acid availability and diminishes carbohydrate availability (Cahill GF Jr, 2006; McGarry and Foster, 1980; Robinson and Williamson, 1980). Ketone body oxidation becomes a significant contributor to overall energy mammalian metabolism within extrahepatic tissues in a myriad of physiological states, including fasting, starvation, the neonatal period, post-exercise, pregnancy, and adherence to low carbohydrate diets. Circulating total ketone body concentrations in healthy adult humans normally exhibit circadian oscillations between approximately 100�250 �M, rise to ~1 mM after prolonged exercise or 24h of fasting, and can accumulate to as high as 20 mM in pathological states like diabetic ketoacidosis (Cahill GF Jr, 2006; Johnson et al., 1969b; Koeslag et al., 1980; Robinson and Williamson, 1980; Wildenhoff et al., 1974). The human liver produces up to 300 g of ketone bodies per day (Balasse and Fery, 1989), which contribute between 5�20% of total energy expenditure in fed, fasted, and starved states (Balasse et al., 1978; Cox et al., 2016).

Recent studies now highlight imperative roles for ketone bodies in mammalian cell metabolism, homeostasis, and signaling under a wide variety of physiological and pathological states. Apart from serving as energy fuels for extrahepatic tissues like brain, heart, or skeletal muscle, ketone bodies play pivotal roles as signaling mediators, drivers of protein post-translational modification (PTM), and modulators of inflammation and oxidative stress. In this review, we provide both classical and modern views of the pleiotropic roles of ketone bodies and their metabolism.

Overview of Ketone Body Metabolism

The rate of hepatic ketogenesis is governed by an orchestrated series of physiological and biochemical transformations of fat. Primary regulators include lipolysis of fatty acids from triacylglycerols, transport to and across the hepatocyte plasma membrane, transport into mitochondria via carnitine palmitoyltransferase 1 (CPT1), the ?-oxidation spiral, TCA cycle activity and intermediate concentrations, redox potential, and the hormonal regulators of these processes, predominantly glucagon and insulin [reviewed in (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry and Foster, 1980; Williamson et al., 1969)]. Classically ketogenesis is viewed as a spillover pathway, in which ?-oxidation-derived acetyl-CoA exceeds citrate synthase activity and/or oxaloacetate availability for condensation to form citrate. Three-carbon intermediates exhibit anti-ketogenic activity, presumably due to their ability to expand the oxaloacetate pool for acetyl-CoA consumption, but hepatic acetyl-CoA concentration alone does not determine ketogenic rate (Foster, 1967; Rawat and Menahan, 1975; Williamson et al., 1969). The regulation of ketogenesis by hormonal, transcriptional, and post-translational events together support the notion that the molecular mechanisms that fine-tune ketogenic rate remain incompletely understood (see Regulation of HMGCS2 and SCOT/OXCT1).

Ketogenesis occurs primarily in hepatic mitochondrial matrix at rates proportional to total fat oxidation. After transport of acyl chains across the mitochondrial membranes and ?-oxidation, the mitochondrial isoform of 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) catalyzes the fate committing condensation of acetoacetyl-CoA (AcAc-CoA) and acetyl-CoA to generate HMG-CoA (Fig. 1A). HMG-CoA lyase (HMGCL) cleaves HMG-CoA to liberate acetyl-CoA and acetoacetate (AcAc), and the latter is reduced to d-?-hydroxybutyrate (d-?OHB) by phosphatidylcholine-dependent mitochondrial d-?OHB dehydrogenase (BDH1) in a NAD+/NADH-coupled near-equilibrium reaction (Bock and Fleischer, 1975; LEHNINGER et al., 1960). The BDH1 equilibrium constant favors d-?OHB production, but the ratio of AcAc/d-?OHB ketone bodies is directly proportional to mitochondrial NAD+/NADH ratio, and thus BDH1 oxidoreductase activity modulates mitochondrial redox potential (Krebs et al., 1969; Williamson et al., 1967). AcAc can also spontaneously decarboxylate to acetone (Pedersen, 1929), the source of sweet odor in humans suffering ketoacidosis (i.e., total serum ketone bodies > ~7 mM; AcAc pKa 3.6, ?OHB pKa 4.7). The mechanisms through which ketone bodies are transported across the mitochondrial inner membrane are not known, but AcAc/d-?OHB are released from cells via monocarboxylate transporters (in mammals, MCT 1 and 2, also known as solute carrier 16A family members 1 and 7) and transported in the circulation to extrahepatic tissues for terminal oxidation (Cotter et al., 2011; Halestrap and Wilson, 2012; Halestrap, 2012; Hugo et al., 2012). Concentrations of circulating ketone bodies are higher than those in the extrahepatic tissues (Harrison and Long, 1940) indicating ketone bodies are transported down a concentration gradient. Loss-of-function mutations in MCT1 are associated with spontaneous bouts of ketoacidosis, suggesting a critical role in ketone body import.

� With the exception of potential diversion of ketone bodies into non-oxidative fates (see Non-oxidative metabolic fates of ketone bodies), hepatocytes lack the ability to metabolize the ketone bodies they produce. Ketone bodies synthesized de novo by liver are (i) catabolized in mitochondria of extrahepatic tissues to acetyl-CoA, which is available to the TCA cycle for terminal oxidation (Fig. 1A), (ii) diverted to the lipogenesis or sterol synthesis pathways (Fig. 1B), or (iii) excreted in the urine. As an alternative energetic fuel, ketone bodies are avidly oxidized in heart, skeletal muscle, and brain (Balasse and Fery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988). Extrahepatic mitochondrial BDH1 catalyzes the first reaction of ?OHB oxidation, converting it to back AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). A cytoplasmic d-?OHB-dehydrogenase (BDH2) with only 20% sequence identity to BDH1 has a high Km for ketone bodies, and also plays a role in iron homeostasis (Davuluri et al., 2016; Guo et al., 2006). In extrahepatic mitochondrial matrix, AcAc is activated to AcAc-CoA through exchange of a CoA-moiety from succinyl-CoA in a reaction catalyzed by a unique mammalian CoA transferase, succinyl-CoA:3-oxoacid-CoA transferase (SCOT, CoA transferase; encoded by OXCT1), through a near equilibrium reaction. The free energy released by hydrolysis of AcAc-CoA is greater than that of succinyl-CoA, favoring AcAc formation. Thus ketone body oxidative flux occurs due to mass action: an abundant supply of AcAc and rapid consumption of acetyl-CoA through citrate synthase favors AcAc-CoA (+ succinate) formation by SCOT. Notably, in contrast to glucose (hexokinase) and fatty acids (acyl-CoA synthetases), the activation of ketone bodies (SCOT) into an oxidizable form does not require the investment of ATP. A reversible AcAc-CoA thiolase reaction [catalyzed by any of the four mitochondrial thiolases encoded by either ACAA2 (encoding an enzyme known as T1 or CT), ACAT1 (encoding T2), HADHA, or HADHB] yields two molecules of acetyl-CoA, which enter the TCA cycle (Hersh and Jencks, 1967; Stern et al., 1956; Williamson et al., 1971). During ketotic states (i.e., total serum ketones > 500 �M), ketone bodies become significant contributors to energy expenditure�and are utilized in tissues rapidly until uptake or saturation of oxidation occurs (Balasse et al., 1978; Balasse and Fery, 1989; Edmond et al., 1987). A very small fraction of liver-derived ketone bodies can be readily measured in the urine, and utilization and reabsorption rates by the kidney are proportionate to circulating concentration (Goldstein, 1987; Robinson and Williamson, 1980). During highly ketotic states (> 1 mM in plasma), ketonuria serves as a semi-quantitative reporter of ketosis, although most clinical assays of urine ketone bodies detect AcAc but not ?OHB (Klocker et al., 2013).

Ketogenic Substrates and their Impact on Hepatocyte Metabolism

Ketogenic substrates include fatty acids and amino acids (Fig. 1B). The catabolism of amino acids, especially leucine, generates about 4% of ketone bodies in post-absorptive state (Thomas et al., 1982). Thus the acetyl-CoA substrate pool to generate ketone bodies mainly derives from fatty acids, because during states of diminished carbohydrate supply, pyruvate enters the hepatic TCA cycle primarily via anaplerosis, i.e., ATP-dependent carboxylation to oxaloacetate (OAA), or to malate (MAL), and not oxidative decarboxylation to acetyl-CoA (Jeoung et al., 2012; Magnusson et al., 1991; Merritt et al., 2011). In liver, glucose and pyruvate contribute negligibly to ketogenesis, even when pyruvate decarboxylation to acetyl-CoA is maximal (Jeoung et al., 2012).

Acetyl-CoA subsumes several roles integral to hepatic intermediary metabolism beyond ATP generation via terminal oxidation (also see The integration of ketone body metabolism, post-translational modification, and cell physiology). Acetyl-CoA allosterically activates (i) pyruvate carboxylase (PC), thereby activating a metabolic control mechanism that augments anaplerotic entry of metabolites into the TCA cycle (Owen et al., 2002; Scrutton and Utter, 1967) and (ii) pyruvate dehydrogenase kinase, which phosphorylates and inhibits pyruvate dehydrogenase (PDH) (Cooper et al., 1975), thereby further enhancing flow of pyruvate into the TCA cycle via anaplerosis. Furthermore, cytoplasmic acetyl-CoA, whose pool is augmented by mechanisms that convert mitochondrial acetyl-CoA to transportable metabolites, inhibits fatty acid oxidation: acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA to malonyl-CoA, the lipogenic substrate and allosteric inhibitor of mitochondrial CPT1 [reviewed in (Kahn et al., 2005; McGarry and Foster, 1980)]. Thus, the mitochondrial acetyl-CoA pool both regulates and is regulated by the spillover pathway of ketogenesis, which orchestrates key aspects of hepatic intermediary metabolism.

Non-Oxidative Metabolic Fates of Ketone Bodies

The predominant fate of liver-derived ketones is SCOT-dependent extrahepatic oxidation. However, AcAc can be exported from mitochondria and utilized in anabolic pathways via conversion to AcAc-CoA by an ATP-dependent reaction catalyzed by cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). This pathway is active during brain development and in lactating mammary gland (Morris, 2005; Robinson and Williamson, 1978; Ohgami et al., 2003). AACS is also highly expressed in adipose tissue, and activated osteoclasts (Aguilo et al., 2010; Yamasaki et al., 2016). Cytoplasmic AcAc-CoA can be either directed by cytosolic HMGCS1 toward sterol biosynthesis, or cleaved by either of two cytoplasmic thiolases to acetyl-CoA (ACAA1 and ACAT2), carboxylated to malonyl-CoA, and contribute to the synthesis of fatty acids (Bergstrom et al., 1984; Edmond, 1974; Endemann et al., 1982; Geelen et al., 1983; Webber and Edmond, 1977).

While the physiological significance is yet to be established, ketones can serve as anabolic substrates even in the liver. In artificial experimental contexts, AcAc can contribute to as much as half of newly synthesized lipid, and up to 75% of new synthesized cholesterol (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Because AcAc is derived from incomplete hepatic fat oxidation, the ability of AcAc to contribute to lipogenesis in vivo would imply hepatic futile cycling, where fat-derived ketones can be utilized for lipid production, a notion whose physiological significance requires experimental validation, but could serve adaptive or maladaptive roles (Solinas et al., 2015). AcAc avidly supplies cholesterogenesis, with a low AACS Km-AcAc (~50 �M) favoring AcAc activation even in the fed state (Bergstrom et al., 1984). The dynamic role of cytoplasmic ketone metabolism has been suggested in primary mouse embryonic neurons and in 3T3-L1 derived-adipocytes, as AACS knockdown impaired differentiation of each cell type (Hasegawa et al., 2012a; Hasegawa et al., 2012b). Knockdown of AACS in mice in vivo decreased serum cholesterol (Hasegawa et al., 2012c). SREBP-2, a master transcriptional regulator of cholesterol biosynthesis, and peroxisome proliferator activated receptor (PPAR)-? are AACS transcriptional activators, and regulate its transcription during neurite development and in the liver (Aguilo et al., 2010; Hasegawa et al., 2012c). Taken together, cytoplasmic ketone body metabolism may be important in select conditions or disease natural histories, but are inadequate to dispose of liver-derived ketone bodies, as massive hyperketonemia occurs in the setting of selective impairment of the primary oxidative fate via loss of function mutations to SCOT (Berry et al., 2001; Cotter et al., 2011).

Regulation of HMGCS2 and SCOT/OXCT1

The divergence of a mitochondrial from the gene encoding cytosolic HMGCS occurred early in vertebrate evolution due to the need to support hepatic ketogenesis in species with higher brain to body weight ratios (Boukaftane et al., 1994; Cunnane and Crawford, 2003). Naturally occurring loss-of-function HMGCS2 mutations in humans cause bouts of hypoketotic hypoglycemia (Pitt et al., 2015; Thompson et al., 1997). Robust HMGCS2 expression is restricted to hepatocytes and colonic epithelium, and its expression and enzymatic activity are coordinated through diverse mechanisms (Mascaro et al., 1995; McGarry and Foster, 1980; Robinson and Williamson, 1980). While the full scope of physiological states that influence HMGCS2 requires further elucidation, its expression and/or activity is regulated during the early postnatal period, aging, diabetes, starvation or ingestion of ketogenic diet (Balasse and Fery, 1989; Cahill GF Jr, 2006; Girard et al., 1992; Hegardt, 1999; Satapati et al., 2012; Sengupta et al., 2010). In the fetus, methylation of 5� flanking region of Hmgcs2 gene inversely correlates with its transcription, and is partially reversed after birth (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983). Similarly, hepatic Bdh1 exhibits a developmental expression pattern, increasing from birth to weaning, and is also induced by ketogenic diet in a fibroblast growth factor (FGF)-21-dependent manner (Badman et al., 2007; Zhang et al., 1989). Ketogenesis in mammals is highly responsive to both insulin and glucagon, being suppressed and stimulated, respectively (McGarry and Foster, 1977). Insulin suppresses adipose tissue lipolysis, thus depriving ketogenesis of its substrate, while glucagon increases ketogenic flux through a direct effect on the liver (Hegardt, 1999). Hmgcs2 transcription is stimulated by forkhead transcriptional factor FOXA2, which is inhibited via insulin-phosphatidylinositol-3-kinase/Akt, and is induced by glucagon-cAMP-p300 signaling (Arias et al., 1995; Hegardt, 1999; Quant et al., 1990; Thumelin et al., 1993; von Meyenn et al., 2013; Wolfrum et al., 2004; Wolfrum et al., 2003). PPAR? (Rodriguez et al., 1994) together with its target, FGF21 (Badman et al., 2007) also induce Hmgcs2 transcription in the liver during starvation or administration of ketogenic diet (Badman et al., 2007; Inagaki et al., 2007). Induction of PPAR? may occur before the transition from fetal to neonatal physiology, while FGF21 activation may be favored in the early neonatal period via ?OHB-mediated inhibition of histone deacetylase (HDAC)-3 (Rando et al., 2016). mTORC1 (mammalian target of rapamycin complex 1) dependent inhibition of PPAR? transcriptional activity is also a key regulator of Hmgcs2 gene expression (Sengupta et al., 2010), and liver PER2, a master circadian oscillator, indirectly regulates Hmgcs2 expression (Chavan et al., 2016). Recent observations indicate that extrahepatic tumor-induced interleukin-6 impairs ketogenesis via PPAR? suppression (Flint et al., 2016). Despite these observations, it is important to note that physiological shifts in Hmgcs2 gene expression have not been mechanistically linked to HMGCS2 protein abundance or to variations of ketogenic rate.

HMGCS2 enzyme activity is regulated through multiple PTMs. HMGCS2 serine phosphorylation enhanced its activity in vitro (Grimsrud et al., 2012). HMGCS2 activity is allosterically inhibited by succinyl-CoA and lysine residue succinylation (Arias et al., 1995; Hegardt, 1999; Lowe and Tubbs, 1985; Quant et al., 1990; Rardin et al., 2013; Reed et al., 1975; Thumelin et al., 1993). Succinylation of HMGCS2, HMGCL, and BDH1 lysine residues in hepatic mitochondria are targets of the NAD+ dependent deacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). HMGCS2 activity is also enhanced by SIRT3 lysine deacetylation, and it is possible that crosstalk between acetylation and succinylation regulates HMGCS2 activity (Rardin et al., 2013; Shimazu et al., 2013). Despite the ability of these PTMs to regulate HMGCS2 Km and Vmax, fluctuations of these PTMs have not yet been carefully mapped and have not been confirmed as mechanistic drivers of ketogenesis in vivo.

SCOT is expressed in all mammalian cells that harbor mitochondria, except those of hepatocytes. The importance of SCOT activity and ketolysis was demonstrated in SCOT-KO mice, which exhibited uniform lethality due to hyperketonemic hypoglycemia within 48h after birth (Cotter et al., 2011). Tissue-specific loss of SCOT in neurons or skeletal myocytes induces metabolic abnormalities during starvation but is not lethal (Cotter et al., 2013b). In humans, SCOT deficiency presents early in life with severe ketoacidosis, causing lethargy, vomiting, and coma (Berry et al., 2001; Fukao et al., 2000; Kassovska-Bratinova et al., 1996; Niezen-Koning et al., 1997; Saudubray et al., 1987; Snyderman et al., 1998; Tildon and Cornblath, 1972). Relatively little is known at the cellular level about SCOT gene and protein expression regulators. Oxct1 mRNA expression and SCOT protein and activity are diminished in ketotic states, possibly through PPAR-dependent mechanisms (Fenselau and Wallis, 1974; Fenselau and Wallis, 1976; Grinblat et al., 1986; Okuda et al., 1991; Turko et al., 2001; Wentz et al., 2010). In diabetic ketoacidosis, the mismatch between hepatic ketogenesis and extrahepatic oxidation becomes exacerbated by impairment of SCOT activity. Overexpression of insulin-independent glucose transporter (GLUT1/SLC2A1) in cardiomyocytes also inhibits Oxct1 gene expression and downregulates ketones terminal oxidation in a non-ketotic state (Yan et al., 2009). In liver, Oxct1 mRNA abundance is suppressed by microRNA-122 and histone methylation H3K27me3 that are evident during the transition from fetal to the neonatal period (Thorrez et al., 2011). However, suppression of hepatic Oxct1 expression in the postnatal period is primarily attributable to the evacuation of Oxct1-expressing hematopoietic progenitors from the liver, rather than a loss of previously existing Oxct1 expression in terminally differentiated hepatocytes. In fact, expression of Oxct1 mRNA and SCOT protein in differentiated hepatocytes are extremely low (Orii et al., 2008).

SCOT is also regulated by PTMs. The enzyme is hyper-acetylated in brains of SIRT3 KO mice, which also exhibit diminished AcAc dependent acetyl-CoA production (Dittenhafer-Reed et al., 2015). Non-enzymatic nitration of tyrosine residues of SCOT also attenuates its activity, which has been reported in hearts of various diabetic mice models (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). In contrast, tryptophan residue nitration augments SCOT activity (Br�g�re et al., 2010; Rebrin et al., 2007). Molecular mechanisms of residue-specific nitration or de-nitration designed to modulate SCOT activity may exist and require elucidation.

Controversies in Extrahepatic Ketogenesis

In mammals the primary ketogenic organ is liver, and only hepatocytes and gut epithelial cells abundantly express the mitochondrial isoform of HMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry and Foster, 1980; Robinson and Williamson, 1980). Anaerobic bacterial fermentation of complex polysaccharides yields butyrate, which is absorbed by colonocytes in mammalians for terminal oxidation or ketogenesis (Cherbuy et al., 1995), which may play a role in colonocyte differentiation (Wang et al., 2016). Excluding gut epithelial cells and hepatocytes, HMGCS2 is nearly absent in almost all other mammalian cells, but the prospect of extrahepatic ketogenesis has been raised in tumor cells, astrocytes of the central nervous system, the kidney, pancreatic ? cells, retinal pigment epithelium (RPE), and even in skeletal muscle (Adijanto et al., 2014; Avogaro et al., 1992; El Azzouny et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Le Foll et al., 2014; Nonaka et al., 2016; Takagi et al., 2016a; Thevenet et al., 2016; Zhang et al., 2011). Ectopic HMGCS2 has been observed in tissues that lack net ketogenic capacity (Cook et al., 2016; Wentz et al., 2010), and HMGCS2 exhibits prospective ketogenesis-independent �moonlighting� activities, including within the cell nucleus (Chen et al., 2016; Kostiuk et al., 2010; Meertens et al., 1998).

Any extrahepatic tissue that oxidizes ketone bodies also has the potential to accumulate ketone bodies via HMGCS2 independent mechanisms (Fig. 2A). However, there is no extrahepatic tissue in which a steady state ketone body concentration exceeds that in the circulation (Cotter et al., 2011; Cotter et al., 2013b; Harrison and Long, 1940), underscoring that ketone bodies are transported down a concentration gradient via MCT1/2-dependent mechanisms. One mechanism of apparent extrahepatic ketogenesis may actually reflect relative impairment of ketone oxidation. Additional potential explanations fall within the realm of ketone body formation. First, de novo ketogenesis may occur via reversible enzymatic activity of thiolase and SCOT (Weidemann and Krebs, 1969). When the concentration of acetyl-CoA is relatively high, reactions normally responsible for AcAc oxidation operate in the reverse direction (GOLDMAN, 1954). A second mechanism occurs when ?-oxidation-derived intermediates accumulate due to a TCA cycle bottleneck, AcAc-CoA is converted to l-?OHB-CoA through a reaction catalyzed by mitochondrial 3-hydroxyacyl-CoA dehydrogenase, and further by 3-hydroxybutyryl CoA deacylase to l-?OHB, which is indistinguishable by mass spectrometry or resonance spectroscopy from the physiological enantiomer d-?OHB (Reed and Ozand, 1980). l-?OHB can be chromatographically or enzymatically distinguished from d-?OHB, and is present in extrahepatic tissues, but not in liver or blood (Hsu et al., 2011). Hepatic ketogenesis produces only d-?OHB, the only enantiomer that is a BDH substrate (Ito et al., 1984; Lincoln et al., 1987; Reed and Ozand, 1980; Scofield et al., 1982; Scofield et al., 1982). A third HMGCS2-independent mechanism generates d-?OHB through amino acid catabolism, particularly that of leucine and lysine. A fourth mechanism is only apparent because it is due to a labeling artifact and is thus termed pseudoketogenesis. This phenomenon is attributable to the reversibility of the SCOT and thiolase reactions, and can cause overestimation of ketone body turnover due to the isotopic dilution of ketone body tracer in extrahepatic tissue (Des Rosiers et al., 1990; Fink et al., 1988). Nonetheless, pseudoketogenesis may be negligible in most contexts (Bailey et al., 1990; Keller et al., 1978). A schematic (Fig. 2A) indicates a useful approach to apply while considering elevated tissue steady state concentration of ketones.

� Kidney has recently received attention as a potentially ketogenic organ. In the vast majority of states, the kidney is a net consumer of liver-derived ketone bodies, excreting or reabsorbing ketone bodies from the bloodstream, and kidney is generally not a net ketone body generator or concentrator (Robinson and Williamson, 1980). The authors of a classical study concluded that minimal renal ketogenesis quantified in an artificial experimental system was not physiologically relevant (Weidemann and Krebs, 1969). Recently, renal ketogenesis has been inferred in diabetic and autophagy deficient mouse models, but it is more likely that multi-organ shifts in metabolic homeostasis alter integrative ketone metabolism through inputs on multiple organs (Takagi et al., 2016a; Takagi et al., 2016b; Zhang et al., 2011). One recent publication suggested renal ketogenesis as a protective mechanism against ischemia-reperfusion injury in the kidney (Tran et al., 2016). Absolute steady state concentrations of ?OHB from extracts of mice renal tissue were reported at ~4�12 mM. To test whether this was tenable, we quantified ?OHB concentrations in renal extracts from fed and 24h fasted mice. Serum ?OHB concentrations increased from ~100 �M to 2 mM with 24h fasting (Fig. 2B), while renal steady state ?OHB concentrations approximate 100 �M in the fed state, and only 1 mM in the 24h fasted state (Fig. 2C�E), observations that are consistent with concentrations quantified over 45 years ago (Hems and Brosnan, 1970). It remains possible that in ketotic states, liver-derived ketone bodies could be renoprotective, but evidence for renal ketogenesis requires further substantiation. Compelling evidence that supports true extrahepatic ketogenesis was presented in RPE (Adijanto et al., 2014). This intriguing metabolic transformation was suggested to potentially allow RPE-derived ketones to flow to photoreceptor or M�ller glia cells, which could aid in the regeneration of photoreceptor outer segment.

?OHB as a Signaling Mediator

Although they are energetically rich, ketone bodies exert provocative �non-canonical� signaling roles in cellular homeostasis (Fig. 3) (Newman and Verdin, 2014; Rojas-Morales et al., 2016). For example, ?OHB inhibits Class I HDACs, which increases histone acetylation and thereby induces the expression of genes that curtail oxidative stress (Shimazu et al., 2013). ?OHB itself is a histone covalent modifier at lysine residues in livers of fasted or streptozotocin induced diabetic mice (Xie et al., 2016) (also see below, The integration of ketone body metabolism, post-translational modification, and cell physiology, and Ketone bodies, oxidative stress, and neuroprotection).

?OHB is also an effector via G-protein coupled receptors. Through unclear molecular mechanisms, it suppresses sympathetic nervous system activity and reduces total energy expenditure and heart rate by inhibiting short chain fatty acid signaling through G protein coupled receptor 41 (GPR41) (Kimura et al., 2011). One of the most studied signaling effects of ?OHB proceeds through GPR109A (also known as HCAR2), a member of the hydrocarboxylic acid GPCR sub-family expressed in adipose tissues (white and brown) (Tunaru et al., 2003), and in immune cells (Ahmed et al., 2009). ?OHB is the only known endogenous ligand of GPR109A receptor (EC50 ~770 �M) activated by d-?OHB, l-?OHB, and butyrate, but not AcAc (Taggart et al., 2005). The high concentration threshold for GPR109A activation is achieved through adherence to a ketogenic diet, starvation, or during ketoacidosis, leading to inhibition of adipose tissue lipolysis. The anti-lipolytic effect of GPR109A proceeds through inhibition of adenylyl cyclase and decreased cAMP, inhibiting hormone sensitive triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). This creates a negative feedback loop in which ketosis places a modulatory brake on ketogenesis by diminishing the release of non-esterified fatty acids from adipocytes (Ahmed et al., 2009; Taggart et al., 2005), an effect that can be counterbalanced by the sympathetic drive that stimulates lipolysis. Niacin (vitamin B3, nicotinic acid) is a potent (EC50 ~ 0.1 �M) ligand for GRP109A, effectively employed for decades for dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010a; Lukasova et al., 2011; Tunaru et al., 2003). While niacin enhances reverse cholesterol transport in macrophages and reduces atherosclerotic lesions (Lukasova et al., 2011), the effects of ?OHB on atherosclerotic lesions remain unknown. Although GPR109A receptor exerts protective roles, and intriguing connections exist between ketogenic diet use in stroke and neurodegenerative diseases (Fu et al., 2015; Rahman et al., 2014), a protective role of ?OHB via GPR109A has not been demonstrated in vivo.

Finally, ?OHB may influence appetite and satiety. A meta-analysis of studies that measured the effects of ketogenic and very low energy diets concluded that participants consuming these diets exhibit higher satiety, compared to control diets (Gibson et al., 2015). However, a plausible explanation for this effect is the additional metabolic or hormonal elements that might modulate appetite. For example, mice maintained on a rodent ketogenic diet exhibited increased energy expenditure compared to chow control-fed mice, despite similar caloric intake, and circulating leptin or genes of peptides regulating feeding behavior were not changed (Kennedy et al., 2007). Among proposed mechanisms that suggest appetite suppression by ?OHB includes both signaling and oxidation (Laeger et al., 2010). Hepatocyte specific deletion of circadian rhythm gene (Per2)�and chromatin immunoprecipitation studies revealed that PER2 directly activates the Cpt1a gene, and indirectly regulates Hmgcs2, leading to impaired ketosis in Per2 knockout mice (Chavan et al., 2016). These mice exhibited impaired food anticipation, which was partially restored by systemic ?OHB administration. Future studies will be needed to confirm the central nervous system as a direct ?OHB target, and whether ketone oxidation is required for the observed effects, or whether another signaling mechanism is involved. Other investigators have invoked the possibility of local astrocyte-derived ketogenesis within the ventromedial hypothalamus as a regulator of food intake, but these preliminary observations also will benefit from genetic and flux-based assessments (Le Foll et al., 2014). The relationship between ketosis and nutrient deprivation remains of interest because hunger and satiety are important elements in failed weight loss attempts.

Integration of Ketone Body Metabolism, Post-Translational Modification, and Cell Physiology

Ketone bodies contribute to compartmentalized pools of acetyl-CoA, a key intermediate that exhibits prominent roles in cellular metabolism (Pietrocola et al., 2015). One role of acetyl-CoA is to serve as a substrate for acetylation, an enzymatically-catalyzed histone covalent modification (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016). A large number of dynamically acetylated mitochondrial proteins, many of which may occur through non-enzymatic mechanisms, have also emerged from computational proteomics studies (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Lysine deacetylases use a zinc cofactor (e.g., nucleocytosolic HDACs) or NAD+ as co-substrate (sirtuins, SIRTs) (Choudhary et al., 2014; Menzies et al., 2016). The acetylproteome serves as both sensor and effector of the total cellular acetyl-CoA pool, as physiological and genetic manipulations each result in non-enzymatic global variations of acetylation (Weinert et al., 2014). As intracellular metabolites serve as modulators of lysine residue acetylation, it is important to consider the role of ketone bodies, whose abundance is highly dynamic.

?OHB is an epigenetic modifier through at least two mechanisms. Increased ?OHB levels induced by fasting, caloric restriction, direct administration or prolonged exercise provoke HDAC inhibition or histone acetyltransferase activation (Marosi et al., 2016; Sleiman et al., 2016) or to oxidative stress (Shimazu et al., 2013). ?OHB inhibition of HDAC3 could regulate newborn metabolic physiology (Rando et al., 2016). Independently, ?OHB itself directly modifies histone lysine residues (Xie et al., 2016). Prolonged fasting, or steptozotocin-induced diabetic ketoacidosis increased histone ?-hydroxybutyrylation. Although the number of lysine ?-hydroxybutyrylation and acetylation sites was comparable, stoichiometrically greater histone ?-hydroxybutyrylation than acetylation was observed. Distinct genes were impacted by histone lysine ?-hydroxybutyrylation, versus acetylation or methylation, suggesting distinct cellular functions. Whether ?-hydroxybutyrylation is spontaneous or enzymatic is not known, but expands the range of mechanisms through ketone bodies dynamically influence transcription.

Essential cell reprogramming events during caloric restriction and nutrient deprivation may be mediated in SIRT3- and SIRT5-dependent mitochondrial deacetylation and desuccinylation, respectively, regulating ketogenic and ketolytic proteins at post-translational level in liver and extrahepatic tissues (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Even though stoichiometric comparison of occupied sites does not necessarily link directly to shifts in metabolic flux, mitochondrial acetylation is dynamic and may be driven by acetyl-CoA concentration or mitochondrial pH, rather than enzymatic acetyltransferases (Wagner and Payne, 2013). That SIRT3 and SIRT5 modulate activities of ketone body metabolizing enzymes provokes the question of the reciprocal role of ketones in sculpting the acetylproteome, succinylproteome, and other dynamic cellular targets. Indeed, as variations of ketogenesis reflect NAD+ concentrations, ketone production and abundance could regulate sirtuin activity, thereby influencing total acetyl-CoA/succinyl-CoA pools, the acylproteome, and thus mitochondrial and cell physiology. ?-hydroxybutyrylation of enzyme lysine residues could add another layer to cellular reprogramming. In extrahepatic tissues, ketone body oxidation may stimulate analogous changes in cell homeostasis. While compartmentation of acetyl-CoA pools is highly regulated and coordinates a broad spectrum of cellular changes, the ability of ketone bodies to directly shape both mitochondrial and cytoplasmic acetyl-CoA concentrations requires elucidation (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen and Thompson, 2012). Because acetyl-CoA concentrations are tightly regulated, and acetyl-CoA is membrane impermeant, it is crucial to consider the driver mechanisms coordinating acetyl-CoA homeostasis, including the rates of production and terminal oxidation in the TCA cycle, conversion into ketone bodies, mitochondrial efflux via carnitine acetyltransferase (CrAT), or acetyl-CoA export to cytosol after conversion to citrate and release by ATP citrate lyase (ACLY). The key roles of these latter mechanisms in cell acetylproteome and homeostasis require matched understanding of the roles of ketogenesis and ketone oxidation (Das et al., 2015; McDonnell et al., 2016; Moussaieff et al., 2015; Overmyer et al., 2015; Seiler et al., 2014; Seiler et al., 2015; Wellen et al., 2009; Wellen and Thompson, 2012). Convergent technologies in metabolomics and acylproteomics in the setting of genetically manipulated models will be required to specify targets and outcomes.

Anti- and Pro-Inflammatory Responses to Ketone Bodies

Ketosis and ketone bodies modulate inflammation and immune cell function, but varied and even discrepant mechanisms have been proposed. Prolonged nutrient deprivation reduces inflammation (Youm et al., 2015), but the chronic ketosis of type 1 diabetes is a pro-inflammatory state (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kurepa et al., 2012). Mechanism-based signaling roles for ?OHB in inflammation emerge because many immune system cells, including macrophages or monocytes, abundantly express GPR109A. While ?OHB exerts a predominantly anti-inflammatory response (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), high concentrations of ketone bodies, particularly AcAc, may trigger a pro-inflammatory response (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kurepa et al., 2012).

Anti-inflammatory roles of GPR109A ligands in atherosclerosis, obesity, inflammatory bowel disease, neurological disease, and cancer have been reviewed (Graff et al., 2016). GPR109A expression is augmented in RPE cells of diabetic models, human diabetic patients (Gambhir et al., 2012), and in microglia during neurodegeneration (Fu et al., 2014). Anti-inflammatory effects of ?OHB are enhanced by GPR109A overexpression in RPE cells, and abrogated by pharmacological inhibition or genetic knockout of GPR109A (Gambhir et al., 2012). ?OHB and exogenous nicotinic acid (Taggart et al., 2005), both confer anti-inflammatory effects in TNF? or LPS-induced inflammation by decreasing the levels of pro-inflammatory proteins (iNOS, COX-2), or secreted cytokines (TNF?, IL-1?, IL-6, CCL2/MCP-1), in part through inhibiting NF-?B translocation (Fu et al., 2014; Gambhir et al., 2012). ?OHB decreases ER stress and the NLRP3 inflammasome, activating the antioxidative stress response (Bae et al., 2016; Youm et al., 2015). However, in neurodegenerative inflammation, GPR109A-dependent ?OHB-mediated protection does not involve inflammatory mediators like MAPK pathway signaling (e.g., ERK, JNK, p38) (Fu et al., 2014), but may require COX-1-dependent PGD2 production (Rahman et al., 2014). It is intriguing that macrophage GPR109A is required to exert a neuroprotective effect in an ischemic stroke model (Rahman et al., 2014), but the ability of ?OHB to inhibit the NLRP3 inflammasome in bone marrow derived macrophages is GPR109A independent (Youm et al., 2015). Although most studies link ?OHB to anti-inflammatory effects, ?OHB may be pro-inflammatory and increase markers of lipid peroxidation in calf hepatocytes (Shi et al., 2014). Anti- versus pro-inflammatory effects of ?OHB may thus depend on cell type, ?OHB concentration, exposure duration, and the presence or absence of co-modulators.

Unlike ?OHB, AcAc may activate pro-inflammatory signaling. Elevated AcAc, especially with a high glucose concentration, intensifies endothelial cell injury through an NADPH oxidase/oxidative stress dependent mechanism (Kanikarla-Marie and Jain, 2015). High AcAc concentrations in umbilical cord of diabetic mothers were correlated with higher protein oxidation rate and MCP-1 concentration (Kurepa et al., 2012). High AcAc in diabetic patients was correlated with TNF? expression (Jain et al., 2002), and AcAc, but not ?OHB, induced TNF?, MCP-1 expression, ROS accumulation, and diminished cAMP level in U937 human monocyte cells (Jain et al., 2002; Kurepa et al., 2012).

Ketone body dependent signaling phenomena are frequently triggered only with high ketone body concentrations (> 5 mM), and in the case of many studies linking ketones to pro- or anti-inflammatory effects, through unclear mechanisms. In addition, due to the contradictory effects of ?OHB versus AcAc on inflammation, and the ability of AcAc/?OHB ratio to influence mitochondrial redox potential, the best experiments assessing the roles of ketone bodies on cellular phenotypes compare the effects of AcAc and ?OHB in varying ratios, and at varying cumulative concentrations [e.g., (Saito et al., 2016)]. Finally, AcAc can be purchased commercially only as a lithium salt or as an ethyl ester that requires base hydrolysis before use. Lithium cation independently induces signal transduction cascades (Manji et al., 1995), and AcAc anion is labile. Finally, studies using racemic d/l-?OHB can be confounded, as only the d-?OHB stereoisomer can be oxidized to AcAc, but d-?OHB and l-?OHB can each signal through GPR109A, inhibit the NLRP3 inflammasome, and serve as lipogenic substrates.

Ketone Bodies, Oxidative Stress, and Neuroprotection

Oxidative stress is typically defined as a state in which ROS are presented in excess, due to excessive production and/or impaired elimination. Antioxidant and oxidative stress mitigating roles of ketone bodies have been widely described both in vitro and in vivo, particularly in the context of neuroprotection. As most neurons do not effectively generate high-energy phosphates from fatty acids�but do oxidize ketone bodies when carbohydrates are in short supply, neuroprotective effects of ketone bodies are especially important (Cahill GF Jr, 2006; Edmond et al., 1987; Yang et al., 1987). In oxidative stress models, BDH1 induction and SCOT suppression suggest that ketone body metabolism can be reprogrammed to sustain diverse cell signaling, redox potential, or metabolic requirements (Nagao et al., 2016; Tieu et al., 2003).

Ketone bodies decrease the grades of cellular damage, injury, death and lower apoptosis in neurons and cardiomyocytes (Haces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Invoked mechanisms are varied and not always linearly related to concentration. Low millimolar concentrations of (d or l)-?OHB scavenge ROS (hydroxyl anion), while AcAc scavenges numerous ROS species, but only at concentrations that exceed the physiological range (IC50 20�67 mM) (Haces et al., 2008). Conversely, a beneficial influence over the electron transport chain�s redox potential is a mechanism commonly linked to d-?OHB. While all three ketone bodies (d/l-?OHB and AcAc) reduced neuronal cell death and ROS accumulation triggered by chemical inhibition of glycolysis, only d-?OHB and AcAc prevented neuronal ATP decline. Conversely, in a hypoglycemic in vivo model, (d or l)-?OHB, but not AcAc prevented hippocampal lipid peroxidation (Haces et al., 2008; Maalouf et al., 2007; Marosi et al., 2016; Murphy, 2009; Tieu et al., 2003). In vivo studies of mice fed a ketogenic diet (87% kcal fat and 13% protein) exhibited neuroanatomical variation of antioxidant capacity (Ziegler et al., 2003), where the most profound changes were observed in hippocampus, with increase glutathione peroxidase and total antioxidant capacities.

Ketogenic diet, ketone esters (also see Therapeutic use of ketogenic diet and exogenous ketone bodies), or ?OHB administration exert neuroprotection in models of ischemic stroke (Rahman et al., 2014); Parkinson�s disease (Tieu et al., 2003); central nervous system oxygen toxicity seizure (D’Agostino et al., 2013); epileptic spasms (Yum et al., 2015); mitochondrial encephalomyopathy, lactic acidosis and stroke-like (MELAS) episodes syndrome (Frey et al., 2016) and Alzheimer�s disease (Cunnane and Crawford, 2003; Yin et al., 2016). Conversely, a recent report demonstrated histopathological evidence of neurodegenerative progression by a ketogenic diet in a transgenic mouse model of abnormal mitochondrial DNA repair, despite increases in mitochondrial biogenesis and antioxidant signatures (Lauritzen et al., 2016). Other conflicting reports suggest that exposure to high ketone body concentrations elicits oxidative stress. High ?OHB or AcAc doses induced nitric oxide secretion, lipid peroxidation, reduced expression of SOD, glutathione peroxidase and catalase in calf hepatocytes, while in rat hepatocytes the MAPK pathway induction was attributed to AcAc but not ?OHB (Abdelmegeed et al., 2004; Shi et al., 2014; Shi et al., 2016).

Taken together, most reports link ?OHB to attenuation of oxidative stress, as its administration inhibits ROS/superoxide production, prevents lipid peroxidation and protein oxidation, increases antioxidant protein levels, and improves mitochondrial respiration and ATP production (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Maalouf et al., 2007; Maalouf and Rho, 2008; Marosi et al., 2016; Tieu et al., 2003; Yin et al., 2016; Ziegler et al., 2003). While AcAc has been more directly correlated than ?OHB with the induction of oxidative stress, these effects are not always easily dissected from prospective pro-inflammatory responses (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kanikarla-Marie and Jain, 2016). Moreover, it is critical to consider that the apparent antioxidative benefit conferred by pleiotropic ketogenic diets may not be transduced by ketone bodies themselves, and neuroprotection conferred by ketone bodies may not entirely be attributable to oxidative stress. For example during glucose deprivation, in a model of glucose deprivation in cortical neurons, ?OHB stimulated autophagic flux and prevented autophagosome accumulation, which was associated with decreased neuronal death (Camberos-Luna et al., 2016). d-?OHB induces also the canonical antioxidant proteins FOXO3a, SOD, MnSOD, and catalase, prospectively through HDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).

Non-Alcoholic Fatty Liver Disease (NAFLD) and Ketone Body Metabolism

Obesity-associated NAFLD and nonalcoholic steatohepatitis (NASH) are the most common causes of liver disease in Western countries (Rinella and Sanyal, 2016), and NASH-induced liver failure is one of the most common reasons for liver transplantation. While excess storage of triacylglycerols in hepatocytes >5% of liver weight (NAFL) alone does not cause degenerative liver function, the progression to NAFLD in humans correlates with systemic insulin resistance and increased risk of type 2 diabetes, and may contribute to the pathogenesis of cardiovascular disease and chronic kidney disease (Fabbrini et al., 2009; Targher et al., 2010; Targher and Byrne, 2013). The pathogenic mechanisms of NAFLD and NASH are incompletely understood but include abnormalities of hepatocyte metabolism, hepatocyte autophagy and endoplasmic reticulum stress, hepatic immune cell function, adipose tissue inflammation, and systemic inflammatory mediators (Fabbrini et al., 2009; Masuoka and Chalasani, 2013; Targher et al., 2010; Yang et al., 2010). Perturbations of carbohydrate, lipid, and amino acid metabolism occur in and contribute to obesity, diabetes, and NAFLD in humans and in model organisms [reviewed in (Farese et al., 2012; Lin and Accili, 2011; Newgard, 2012; Samuel and Shulman, 2012; Sun and Lazar, 2013)]. While hepatocyte abnormalities in cytoplasmic lipid metabolism are commonly observed in NAFLD (Fabbrini et al., 2010b), the role of mitochondrial metabolism, which governs oxidative disposal of fats is less clear in NAFLD pathogenesis. Abnormalities of mitochondrial metabolism occur in and contribute to NAFLD/NASH pathogenesis (Hyotylainen et al., 2016; Serviddio et al., 2011; Serviddio et al., 2008; Wei et al., 2008). There is general (Felig et al., 1974; Iozzo et al., 2010; Koliaki et al., 2015; Satapati et al., 2015; Satapati et al., 2012; Sunny et al., 2011) but not uniform (Koliaki and Roden, 2013; Perry et al., 2016; Rector et al., 2010) consensus that, prior to the development of bona fide NASH, hepatic mitochondrial oxidation, and in particular fat oxidation, is augmented in obesity, systemic insulin resistance, and NAFLD. It is likely that as NAFLD progresses, oxidative capacity heterogenity, even among individual mitochondria, emerges, and ultimately oxidative function becomes impaired (Koliaki et al., 2015; Rector et al., 2010; Satapati et al., 2008; Satapati et al., 2012).

Ketogenesis is often used as a proxy for hepatic fat oxidation. Impairments of ketogenesis emerge as NAFLD progresses in animal models, and likely in humans. Through incompletely defined mechanisms, hyperinsulinemia suppresses ketogenesis, possibly contributing to hypoketonemia compared to lean controls (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; Sunny et al., 2011; Vice et al., 2005). Nonetheless, the ability of circulating ketone body concentrations to predict NAFLD is controversial (M�nnist� et al., 2015; Sanyal et al., 2001). Robust quantitative magnetic resonance spectroscopic methods in animal models revealed increased ketone turnover rate with moderate insulin resistance, but decreased rates were evident with more severe insulin resistance (Satapati et al., 2012; Sunny et al., 2010). In obese humans with fatty liver, ketogenic rate is normal (Bickerton et al., 2008; Sunny et al., 2011), and hence, the rates of ketogenesis are diminished relative to the increased fatty acid load within hepatocytes. Consequently, ?-oxidation-derived acetyl-CoA may be directed to terminal oxidation in the TCA cycle, increasing terminal oxidation, phosphoenolpyruvate-driven gluconeogenesis via anaplerosis/cataplerosis, and oxidative stress. Acetyl-CoA also possibly undergoes export from mitochondria as citrate, a precursor substrate for lipogenesis (Fig. 4) (Satapati et al., 2015; Satapati et al., 2012; Solinas et al., 2015). While ketogenesis becomes less responsive to insulin or fasting with prolonged obesity (Satapati et al., 2012), the underlying mechanisms and downstream consequences of this remain incompletely understood. Recent evidence indicates that mTORC1 suppresses ketogenesis in a manner that may be downstream of insulin signaling (Kucejova et al., 2016), which is concordant with the observations that mTORC1 inhibits PPAR?-mediated Hmgcs2 induction (Sengupta et al., 2010) (also see Regulation of HMGCS2 and SCOT/OXCT1).

Preliminary observations from our group suggest adverse hepatic consequences of ketogenic insufficiency (Cotter et al., 2014). To test the hypothesis that impaired ketogenesis, even in carbohydrate-replete and thus �non-ketogenic� states, contributes to abnormal glucose metabolism and provokes steatohepatitis, we generated a mouse model of marked ketogenic insufficiency by administration of antisense oligonucleotides (ASO) targeted to Hmgcs2. Loss of HMGCS2 in standard low-fat chow-fed adult mice caused mild hyperglycemia and markedly increased production of hundreds of hepatic metabolites, a suite of which strongly suggested lipogenesis activation. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation. These findings support the central hypotheses that (i) ketogenesis is not a passive overflow pathway but rather a dynamic node in hepatic and integrated physiological homeostasis, and (ii) prudent ketogenic augmentation to mitigate NAFLD/NASH and disordered hepatic glucose metabolism is worthy of exploration.

How might impaired ketogenesis contribute to hepatic injury and altered glucose homeostasis? The first consideration is whether the culprit is deficiency of ketogenic flux, or ketones themselves. A recent report suggests that ketone bodies may mitigate oxidative stress-induced hepatic injury in response to n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Recall that due to lack of SCOT expression in hepatocytes, ketone bodies are not oxidized, but they can contribute to lipogenesis, and serve a variety of signaling roles independent of their oxidation (also see Non-oxidative metabolic fates of ketone bodies and ?OHB as a signaling mediator). It is also possible that hepatocyte-derived ketone bodies may serve as a signal and/or metabolite for neighboring cell types within the hepatic acinus, including stellate cells and Kupffer cell macrophages. While the limited literature available suggests that macrophages are unable to oxidize ketone bodies, this has only been measured using classical methodologies, and only in peritoneal macrophages (Newsholme et al., 1986; Newsholme et al., 1987), indicating that a re-assessment is appropriate given abundant SCOT expression in bone marrow-derived macrophages (Youm et al., 2015).

Hepatocyte ketogenic flux may also be cytoprotective. While salutary mechanisms may not depend on ketogenesis per se, low carbohydrate ketogenic diets have been associated with amelioration of NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar and Crawford, 2012). Our observations indicate that hepatocyte ketogenesis may feedback and regulate TCA cycle flux, anaplerotic flux, phosphoenolpyruvate-derived gluconeogenesis (Cotter et al., 2014), and even glycogen turnover. Ketogenic impairment directs acetyl-CoA to increase TCA flux, which in liver has been linked to increased ROS-mediated injury (Satapati et al., 2015; Satapati et al., 2012); forces diversion of carbon into de novo synthesized lipid species that could prove cytotoxic; and prevents NADH re-oxidation to NAD+ (Cotter et al., 2014) (Fig. 4). Taken together, future experiments are required to address mechanisms through which relative ketogenic insufficiency may become maladaptive, contribute to hyperglycemia, provoke steatohepatitis, and whether these mechanisms are operant in human NAFLD/NASH. As epidemiological evidence suggests impaired ketogenesis during the progression of steatohepatitis (Embade et al., 2016; Marinou et al., 2011; M�nnist� et al., 2015; Pramfalk et al., 2015; Safaei et al., 2016) therapies that increase hepatic ketogenesis could prove salutary (Degirolamo et al., 2016; Honda et al., 2016).

Ketone Bodies and Heart Failure (HF)

With a metabolic rate exceeding 400 kcal/kg/day, and a turnover of 6�35 kg ATP/day, the heart is the organ with the highest energy expenditure and oxidative demand (Ashrafian et al., 2007; Wang et al., 2010b). The vast majority of myocardial energy turnover resides within mitochondria, and 70% of this supply originates from FAO. The heart is omnivorous and flexible under normal conditions, but the pathologically remodeling heart (e.g., due to hypertension or myocardial infarction) and the diabetic heart each become metabolically inflexible (Balasse and Fery, 1989; BING, 1954; Fukao et al., 2004; Lopaschuk et al., 2010; Taegtmeyer et al., 1980; Taegtmeyer et al., 2002; Young et al., 2002). Indeed, genetically programmed abnormalities of cardiac fuel metabolism in mouse models provoke cardiomyopathy (Carley et al., 2014; Neubauer, 2007). Under physiological conditions normal hearts oxidize ketone bodies in proportion to their delivery, at the expense of fatty acid and glucose oxidation, and myocardium is the highest ketone body consumer per unit mass (BING, 1954; Crawford et al., 2009; GARLAND et al., 1962; Hasselbaink et al., 2003; Jeffrey et al., 1995; Pelletier et al., 2007; Tardif et al., 2001; Yan et al., 2009). Compared to fatty acid oxidation, ketone bodies are more energetically efficient, yielding more energy available for ATP synthesis per molecule of oxygen invested (P/O ratio) (Kashiwaya et al., 2010; Sato et al., 1995; Veech, 2004). Ketone body oxidation also yields potentially higher energy than FAO, keeping ubiquinone oxidized, which raises redox span in the electron transport chain and makes more energy available to synthetize ATP (Sato et al., 1995; Veech, 2004). Oxidation of ketone bodies may also curtail ROS production, and thus oxidative stress (Veech, 2004).

Preliminary interventional and observational studies indicate a potential salutary role of ketone bodies in the heart. In the experimental ischemia/reperfusion injury context, ketone bodies conferred potential cardioprotective effects (Al-Zaid et al., 2007; Wang et al., 2008), possibly due to the increase mitochondrial abundance in heart or up-regulation of crucial oxidative phosphorylation mediators (Snorek et al., 2012; Zou et al., 2002). Recent studies indicate that ketone body utilization is increased in failing hearts of mice (Aubert et al., 2016) and humans (Bedi et al., 2016), supporting prior observations in humans (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph and Schinz, 1973; Tildon and Cornblath, 1972). Circulating ketone body concentrations are increased in heart failure patients, in direct proportion to filling pressures, observations whose mechanism and significance remains unknown (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al., 1972), but mice with selective SCOT deficiency in cardiomyocytes exhibit accelerated pathological ventricular remodeling and ROS signatures in response to surgically induced pressure overload injury (Schugar et al., 2014).

Recent intriguing observations in diabetes therapy have revealed a potential link between myocardial ketone metabolism and pathological ventricular remodeling (Fig. 5). Inhibition of the renal proximal tubular sodium/glucose co-transporter 2 (SGLT2i) increases circulating ketone body concentrations in humans (Ferrannini et al., 2016a; Inagaki et al., 2015) and mice (Suzuki et al., 2014) via increased hepatic ketogenesis (Ferrannini et al., 2014; Ferrannini et al., 2016a; Katz and Leiter, 2015; Mudaliar et al., 2015). Strikingly, at least one of these agents decreased HF hospitalization (e.g., as revealed by the EMPA-REG OUTCOME trial), and improved cardiovascular mortality (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a; Zinman et al., 2015). While the driver mechanisms behind beneficial HF outcomes to linked SGLT2i remain actively debated, the survival benefit is likely multifactorial, prospectively including ketosis but also salutary effects on weight, blood pressure, glucose and uric acid levels, arterial stiffness, the sympathetic nervous system, osmotic diuresis/reduced plasma volume, and increased hematocrit (Raz and Cahn, 2016; Vallon and Thomson, 2016). Taken together, the notion that therapeutically increasing ketonemia either in HF patients, or those at high risk to develop HF, remains controversial but is under active investigation in pre-clinical and clinical studies (Ferrannini et al., 2016b; Kolwicz et al., 2016; Lopaschuk and Verma, 2016; Mudaliar et al., 2016; Taegtmeyer, 2016).

Ketone Bodies in Cancer Biology

Connections between ketone bodies and cancer are rapidly emerging, but studies in both animal models and humans have yielded diverse conclusions. Because ketone metabolism is dynamic and nutrient state responsive, it is enticing to pursue biological connections to cancer because of the potential for precision-guided nutritional therapies. Cancer cells undergo metabolic reprogramming in order to maintain rapid cell proliferation and growth (DeNicola and Cantley, 2015; Pavlova and Thompson, 2016). The classical Warburg effect in cancer cell metabolism arises from the dominant role of glycolysis and lactic acid fermentation to transfer energy and compensate for lower dependence on oxidative phosphorylation and limited mitochondrial respiration (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). Glucose carbon is primarily directed through glycolysis, the pentose phosphate pathway, and lipogenesis, which together provide intermediates necessary for tumor biomass expansion (Grabacka et al., 2016; Shukla et al., 2014; Yoshii et al., 2015). Adaptation of cancer cells to glucose deprivation occurs through the ability to exploit alternative fuel sources, including acetate, glutamine, and aspartate (Jaworski et al., 2016; Sullivan et al., 2015). For example, restricted access to pyruvate reveals the ability of cancer cells to convert glutamine into acetyl-CoA by carboxylation, maintaining both energetic and anabolic needs (Yang et al., 2014). An interesting adaptation of cancer cells is the utilization of acetate as a fuel (Comerford et al., 2014; Jaworski et al., 2016; Mashimo et al., 2014; Wright and Simone, 2016; Yoshii et al., 2015). Acetate is also a substrate for lipogenesis, which is critical for tumor cell proliferation, and gain of this lipogenic conduit is associated with shorter patient survival and greater tumor burden (Comerford et al., 2014; Mashimo et al., 2014; Yoshii et al., 2015).

Non-cancer cells easily shift their energy source from glucose to ketone bodies during glucose deprivation. This plasticity may be more variable among cancer cell types, but in vivo implanted brain tumors oxidized [2,4-13C2]-?OHB to a similar degree as surrounding brain tissue (De Feyter et al., 2016). �Reverse Warburg effect� or �two compartment tumor metabolism� models hypothesize that cancer cells induce ?OHB production in adjacent fibroblasts, furnishing the tumor cell�s energy needs (Bonuccelli et al., 2010; Martinez-Outschoorn et al., 2012). In liver, a shift in hepatocytes from ketogenesis to ketone oxidation in hepatocellular carcinoma (hepatoma) cells is consistent with activation of BDH1 and SCOT activities observed in two hepatoma cell lines (Zhang et al., 1989). Indeed, hepatoma cells express OXCT1 and BDH1 and oxidize ketones, but only when serum starved (Huang et al., 2016). Alternatively, tumor cell ketogenesis has also been proposed. Dynamic shifts in ketogenic gene expression are exhibited during cancerous transformation of colonic epithelium, a cell type that normally expresses HMGCS2, and a recent report suggested that HMGCS2 may be a prognostic marker of poor prognosis in colorectal and squamous cell carcinomas (Camarero et al., 2006; Chen et al., 2016). Whether this association requires or involves ketogenesis, or a moonlighting function of HMGCS2, remains to be determined. Conversely, apparent ?OHB production by melanoma and glioblastoma cells, stimulated by the PPAR? agonist fenofibrate, was associated with growth arrest (Grabacka et al., 2016). Further studies are required to characterize roles of HMGCS2/SCOT expression, ketogenesis, and ketone oxidation in cancer cells.

Beyond the realm of fuel metabolism, ketones have recently been implicated in cancer cell biology via a signaling mechanism. Analysis of BRAF-V600E+ melanoma indicated OCT1-dependent induction of HMGCL in an oncogenic BRAF-dependent manner (Kang et al., 2015). HMGCL augmentation was correlated with higher cellular AcAc concentration, which in turn enhanced BRAFV600E-MEK1 interaction, amplifying MEK-ERK signaling in a feed-forward loop that drives tumor cell proliferation and growth. These observations raise the intriguing question of prospective extrahepatic ketogenesis that then supports a signaling mechanism (also see ?OHB as a signaling mediator and Controversies in extrahepatic ketogenesis). It is also important to consider independent effects of AcAc, d-?OHB, and l-?OHB on cancer metabolism, and when considering HMGCL, leucine catabolism may also be deranged.

The effects of ketogenic diets (also see Therapeutic use of ketogenic diet and exogenous ketone bodies) in cancer animal models are varied (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al., 2014; Seyfried et al., 2011; Shukla et al., 2014). While epidemiological associations among obesity, cancer, and ketogenic diets are debated (Liskiewicz et al., 2016; Wright and Simone, 2016), a meta-analysis using ketogenic diets in animal models and in human studies suggested a salutary impact on survival, with benefits prospectively linked to the magnitude of ketosis, time of diet initiation, and tumor location (Klement et al., 2016; Woolf et al., 2016). Treatment of pancreatic cancer cells with ketone bodies (d-?OHB or AcAc) inhibited growth, proliferation and glycolysis, and a ketogenic diet (81% kcal fat, 18% protein, 1% carbohydrate) reduced in vivo tumor weight, glycemia, and increased muscle and body weight in animals with implanted cancer (Shukla et al., 2014). Similar results were observed using a metastatic glioblastoma cell model in mice that received ketone supplementation in the diet (Poff et al., 2014). Conversely, a ketogenic diet (91% kcal fat, 9% protein) increased circulating ?OHB concentration and diminished glycemia�but had no impact on either tumor volume or survival duration in glioma-bearing rats (De Feyter et al., 2016). A glucose ketone index has been proposed as a clinical indicator that improves metabolic management of ketogenic diet-induced brain cancer therapy in humans and mice (Meidenbauer et al., 2015). Taken together, roles of ketone body metabolism and ketone bodies in cancer biology are tantalizing because they each pose tractable therapeutic options, but fundamental aspects remain to be elucidated, with clear influences emerging from a matrix of variables, including (i) differences between exogenous ketone bodies versus ketogenic diet, (ii) cancer cell type, genomic polymorphisms, grade, and stage; and (iii) timing and duration of exposure to the ketotic state.

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Ketogenesis is created by ketone bodies through the breakdown of fatty acids and ketogenic amino acids. This biochemical process provides energy to various organs, specifically the brain, under circumstances of fasting as a response to an unavailability of blood glucose. Ketone bodies are mainly produced in the mitochondria of liver cells. While other cells are capable of carrying out ketogenesis, they are not as effective at doing so as liver cells. Because ketogenesis occurs in the mitochondria, its processes are regulated independently. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Therapeutic Application of Ketogenic Diet and Exogenous Ketone Bodies

The applications of ketogenic diets and ketone bodies as therapeutic tools have also arisen in non-cancerous contexts including obesity and NAFLD/NASH (Browning et al., 2011; Foster et al., 2010; Schugar and Crawford, 2012); heart failure (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); neurological and neurodegenerative disease (Martin et al., 2016; McNally and Hartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang and Cheng, 2010; Yao et al., 2011); inborn errors of metabolism (Scholl-B�rgi et al, 2015); and exercise performance (Cox et al., 2016). The efficacy of ketogenic diets has been especially appreciated in therapy of epileptic seizure, particularly in drug-resistant patients. Most studies have evaluated ketogenic diets in pediatric patients, and reveal up to a ~50% reduction in seizure frequency after 3 months, with improved effectiveness in select syndromes (Wu et al., 2016b). The experience is more limited in adult epilepsy, but a similar reduction is evident, with better response in symptomatic generalized epilepsy patients (Nei et al., 2014). Underlying anti-convulsant mechanisms remain unclear, although postulated hypotheses include reduced glucose utilization/glycolysis, reprogrammed glutamate transport, indirect impact on ATP-sensitive potassium channel or adenosine A1 receptor, alteration of sodium channel isoform expression, or effects on circulating hormones including leptin (Lambrechts et al., 2016; Lin et al., 2017; Lutas and Yellen, 2013). It remains unclear whether the anti-convulsant effect is primarily attributable to ketone bodies, or due to the cascade metabolic consequences of low carbohydrate diets. Nonetheless, ketone esters (see below) appear to elevate the seizure threshold in animal models of provoked seizures (Ciarlone et al., 2016; D’Agostino et al., 2013; Viggiano et al., 2015).

Atkins-style and ketogenic, low carbohydrate diets are often deemed unpleasant, and can cause constipation, hyperuricemia, hypocalcemia, hypomagnesemia, lead to nephrolithiasis, ketoacidosis, cause hyperglycemia, and raise circulating cholesterol and free fatty acid concentrations (Bisschop et al., 2001; Kossoff and Hartman, 2012; Kwiterovich et al., 2003; Suzuki et al., 2002). For these reasons, long-term adherence poses challenges. Rodent studies commonly use a distinctive macronutrient distribution (94% kcal fat, 1% kcal carbohydrate, 5% kcal protein, Bio-Serv F3666), which provokes a robust ketosis. However, increasing the protein content, even to 10% kcal substantially diminishes the ketosis, and 5% kcal protein restriction confers confounding metabolic and physiological effects. This diet formulation is also choline depleted, another variable that influences susceptibility to liver injury, and even ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; Kennedy et al., 2007; Pissios et al., 2013; Schugar et al., 2013). Effects of long-term consumption of ketogenic diets in mice remain incompletely defined, but recent studies in mice revealed normal survival and the absence of liver injury markers in mice on ketogenic diets over their lifespan, although amino acid metabolism, energy expenditure, and insulin signaling were markedly reprogrammed (Douris et al., 2015).

Mechanisms increasing ketosis through mechanisms alternative to ketogenic diets include the use of ingestible ketone body precursors. Administration of exogenous ketone bodies could create a unique physiological state not encountered in normal physiology, because circulating glucose and insulin concentrations are relatively normal, while cells might spare glucose uptake and utilization. Ketone bodies themselves have short half-lives, and ingestion or infusion of sodium ?OHB salt to achieve therapeutic ketosis provokes an untoward sodium load. R/S-1,3-butanediol is a non-toxic dialcohol that is readily oxidized in the liver to yield d/l-?OHB (Desrochers et al., 1992). In distinct experimental contexts, this dose has been administered daily to mice or rats for as long as seven weeks, yielding circulating ?OHB concentrations of up to 5 mM within 2 h of administration, which is stable for at least an additional 3h (D’Agostino et al., 2013). Partial suppression of food intake has been observed in rodents given R/S-1,3-butanediol (Carpenter and Grossman, 1983). In addition, three chemically distinct ketone esters (KEs), (i) monoester of R-1,3-butanediol and d-?OHB (R-3-hydroxybutyl R-?OHB); (ii) glyceryl-tris-?OHB; and (iii) R,S-1,3-butanediol acetoacetate diester, have also been extensively studied (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al., 1995b; Kashiwaya et al., 2010). An inherent advantage of the former is that 2 moles of physiological d-?OHB are produced per mole of KE, following esterase hydrolysis in the intestine or liver. Safety, pharmacokinetics, and tolerance have been most extensively studied in humans ingesting R-3-hydroxybutyl R-?OHB, at doses up to 714 mg/kg, yielding circulating d-?OHB concentrations up to 6 mM (Clarke et al., 2012a; Cox et al., 2016; Kemper et al., 2015; Shivva et al., 2016). In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al., 2010; Kemper et al., 2015; Veech, 2013). Recent findings indicate that during exercise in trained athletes, R-3-hydroxybutyl R-?OHB ingestion decreased skeletal muscle glycolysis and plasma lactate concentrations, increased intramuscular triacylglycerol oxidation, and preserved muscle glycogen content, even when co-ingested carbohydrate stimulated insulin secretion (Cox et al., 2016). Further development of these intriguing results is required, because the improvement in endurance exercise performance was predominantly driven by a robust response to the KE in 2/8 subjects. Nonetheless, these results do support classical studies that indicate a preference for ketone oxidation over other substrates (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), including during exercise, and that trained athletes may be more primed to utilize ketones (Johnson et al., 1969a; Johnson and Walton, 1972; Winder et al., 1974; Winder et al., 1975). Finally, the mechanisms that might support improved exercise performance following equal caloric intake (differentially distributed among macronutrients) and equal oxygen consumption rates remain to be determined. Clues may emerge from animal studies, as temporary exposure to R-3-hydroxybutyl R-?OHB in rats was associated with increased treadmill time, improved cognitive function, and an apparent energetic benefit in ex vivo perfused hearts (Murray et al., 2016).

Future Perspective

Once largely stigmatized as an overflow pathway capable of accumulating toxic emissions from fat combustion in carbohydrate restricted states (the �ketotoxic� paradigm), recent observations support the notion that ketone body metabolism serves salutary roles even in carbohydrate-laden states, opening a �ketohormetic� hypothesis. While the facile nutritional and pharmacological approaches to manipulate ketone metabolism make it an attractive therapeutic target, aggressively posed but prudent experiments remain in both the basic and translational research laboratories. Unmet needs have emerged in the domains of defining the role of leveraging ketone metabolism in heart failure, obesity, NAFLD/NASH, type 2 diabetes, and cancer. The scope and impact of ‘non-canonical� signaling roles of ketone bodies, including regulation of PTMs that likely feed back and forward into metabolic and signaling pathways, require deeper exploration. Finally, extrahepatic ketogenesis could open intriguing paracrine and autocrine signaling mechanisms and opportunities to influence co-metabolism within the nervous system and tumors to achieve therapeutic ends.

Acknowledgments

Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Footnotes

Ncbi.nlm.nih.gov

In conclusion, ketone bodies are created by the liver in order to be used as an energy source when there is not enough glucose readily available in the human body. Ketogenesis occurs when there are low glucose levels in the blood, particularly after other cellular carbohydrate stores have been exhausted. The purpose of the article above was to discuss the multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.

Curated by Dr. Alex Jimenez

Referenced from:�Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

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Additional Topic Discussion:�Acute Back Pain

Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �

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EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

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What Are The Risks Of Nrf2 Overexpression?

What Are The Risks Of Nrf2 Overexpression?

The nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2, is a protective mechanism which functions as a “master regulator” of the human body’s antioxidant response. Nrf2 senses the levels of oxidative stress within the cells and triggers protective antioxidant mechanisms. While Nrf2 activation can have many benefits, Nrf2 “overexpression” can have several risks. It appears that a balanced degree of NRF2 is essential towards preventing the overall development of a variety of diseases in addition to the general improvement of these health issues. However, NRF2 can also cause complications. The main cause behind NRF2 “overexpression” is due to a genetic mutation or a continuing chronic exposure to a chemical or oxidative stress, among others. Below, we will discuss the downsides of Nrf2 overexpression and demonstrate its mechanisms of action within the human body.

Cancer

Research studies found that mice that don’t express NRF2 are more inclined to develop cancer in response to physical and chemical stimulation. Similar research studies, however, showed that NRF2 over-activation, or even KEAP1 inactivation, can result in the exacerbation of certain cancers, particularly if those pathways have been interrupted. Overactive�NRF2 can occur through smoking, where continuous NRF2 activation is believed to be the cause of lung cancer in smokers. Nrf2 overexpression might cause cancerous cells not to self-destruct, while intermittent NRF2 activation can prevent cancerous cells from triggering toxin induction. Additionally, because NRF2 overexpression increases the human body’s antioxidant ability to function beyond redox homeostasis, this boosts cell division and generates an unnatural pattern of DNA and histone methylation. This can ultimately�make�chemotherapy and radiotherapy less effective against cancer. Therefore, limiting NRF2 activation with substances like DIM, Luteolin, Zi Cao, or salinomycin could be ideal for patients with cancer although Nrf2 overactivation should not be considered to be the only cause for cancer. Nutrient deficiencies can affect genes, including NRF2. This might be one way as to how deficiencies contribute to tumors.

Liver

The overactivation of Nrf2, can also affect the function of specific organs in the human body. NRF2 overexpression can ultimately block the production of the insulin-like growth factor 1, or IGF-1, from the liver, which is essential for the regeneration of the liver.

Heart

While the acute overexpression of Nrf2 may have its benefits, continuous overexpression of NRF2 may cause long-term harmful effects on the heart, such as cardiomyopathy. NRF2 expression can be increased through high levels of cholesterol, or the activation of HO-1. This is believed to be the reason why chronic elevated levels of cholesterol might cause cardiovascular health issues.

Vitiligo

NRF2 overexpression has also been demonstrated to inhibit the capability to repigment in vitiligo as it might obstruct Tyrosinase, or TYR, action which is essential for repigmentation through melaninogenesis. Research studies have demonstrated that this process may be one of the primary reasons as to why people with vitiligo don’t seem to activate Nrf2 as efficiently as people without vitiligo.

Why NRF2 May Not Function Properly

Hormesis

NRF2 has to be hormetically activated in order to be able to take advantage of its benefits. In other words, Nrf2 shouldn’t trigger every minute or every day,�therefore, it’s a great idea to take breaks from it, by way of instance, 5 days on 5 days off or every other day. NRF2 must also accomplish a specific threshold to trigger its hormetic response, where a small stressor may not be enough to trigger it.

DJ-1 Oxidation

Protein deglycase DJ-1, or just DJ-1, also called the Parkinson’s disease protein, or PARK7, is a master regulator and detector of the redox status in the human body. DJ-1 is essential towards regulating how long NRF2 can perform its function and produce an antioxidant response. In the case that DJ-1 becomes overoxidized, the cells will make the DJ-1 protein less accessible. This process induces NRF2 activation to expire too fast since DJ-1 is paramount for maintaining balanced levels of NRF2 and preventing them from being broken down in the cell. In case the DJ-1 protein is non-existent or overoxidized, NRF2 expression will probably be minimal, even using DIM or alternative NRF2 activators. DJ-1 expression is imperative to restore impaired NRF2 action.

Chronic Illness

If you have a chronic illness, including CIRS, chronic infections/dysbiosis/SIBO, or heavy metal build up, such as mercury and/or that from root canals, these can obstruct the systems of NRF2 and phase two detoxification. Rather than oxidative stress turning NRF2 into an antioxidant, NRF2 will not trigger and oxidative stress can remain in the cell and cause damage, meaning, there is no antioxidant response. This is a significant reason why many people with CIRS have several sensitivities and reach to numerous factors. Some people believe they may be�having a herx response, however, this reaction may only be damaging the cells farther. Treating chronic illness, however, will permit the liver to discharge toxins into the bile, gradually developing the hormetic response of NRF2 activation. If the bile remains toxic and it’s not excreted from the human body, it will reactivate NRF2’s oxidative stress and cause you to feel worse once it’s reabsorbed from the gastrointestinal, or GI, tract. For example, ochratoxin A may block NRF2. Aside from treating the problem, histone deacetylase inhibitors can block the oxidative reaction from a number of the factors which trigger NRF2 activation but it might also prevent NRF2 from triggerring�normally, which might ultimately fail to serve its purpose.

Fish Oil Dysregulation

Cholinergics are substances which boost acetylcholine, or ACh, and choline in the brain through the increase of ACh, particularly when inhibiting the breakdown of ACh. Patients with CIRS often have problems with the dysregulation of acetylcholine levels in the human body, especially in the brain. Fish oil triggers NRF2, activating its protective antioxidant mechanism within the cells. People with chronic illnesses might have problems with cognitive stress and acetylcholine excitotoxicity, from organophosphate accumulation, which might cause fish oil to create�inflammation within the human body. Choline deficiency additionally induces NRF2 activation. Including choline into your diet, (polyphenols, eggs, etc.) can help enhance the effects of cholinergic dysregulation.

What Decreases NRF2?

Decreasing NRF2 overexpression is best for people that have cancer, although it may be beneficial for a variety of other health issues.

Diet, Supplements, and Common Medicines:

  • Apigenin (higher doses)
  • Brucea javanica
  • Chestnuts
  • EGCG (high doses increase NRF2)
  • Fenugreek (Trigonelline)
  • Hiba (Hinokitiol / ?-thujaplicin)
  • High Salt Diet
  • Luteolin (Celery, green pepper, parsley, perilla leaf, and chamomile tea – higher doses may increase NRF2 – 40 mg/kg luteolin three times per week )
  • Metformin (chronic intake)
  • N-Acetyl-L-Cysteine (NAC, by blocking the oxidative response, esp at high doses)
  • Orange Peel (have polymethoxylated flavonoids)
  • Quercetin (higher doses may increase NRF2 – 50 mg/kg/d quercetin)
  • Salinomycin (drug)
  • Retinol (all-trans retinoic acid)
  • Vitamin C when combined with Quercetin
  • Zi Cao (Purple Gromwel has Shikonin/Alkannin)

Pathways and Other:

  • Bach1
  • BET
  • Biofilms
  • Brusatol
  • Camptothecin
  • DNMT
  • DPP-23
  • EZH2
  • Glucocorticoid Receptor signaling (Dexamethasone and Betamethasone as well)
  • GSK-3? (regulatory feedback)
  • HDAC activation?
  • Halofuginone
  • Homocysteine (ALCAR can reverse this homocysteine induce low levels of NRF2)
  • IL-24
  • Keap1
  • MDA-7
  • NF?B
  • Ochratoxin A(aspergillus and pencicllium species)
  • Promyelocytic leukemia protein
  • p38
  • p53
  • p97
  • Retinoic acid receptor alpha
  • Selenite
  • SYVN1 (Hrd1)
  • STAT3 inhibition (such as Cryptotanshinone)
  • Testosterone (and Testosterone propionate, although TP intranasally may increase NRF2)
  • Trecator (Ethionamide)
  • Trx1 (via reduction of Cys151 in Keap1 or of Cys506 in the NLS region of Nrf2)
  • Trolox
  • Vorinostat
  • Zinc Deficiency (makes it worse in the brain)

Nrf2 Mechanism Of Action

Oxidative stress triggers through CUL3 where NRF2 from KEAP1, a negative inhibitor, subsequently enters the nucleus of these cells, stimulating the transcription of the AREs, turning sulfides into disulfides, and turning them into more antioxidant genes, leading to the upregulation of antioxidants, such as GSH, GPX, GST, SOD, etc.. The rest of these can be seen in the list below:
  • Increases AKR
  • Increases ARE
  • Increases ATF4
  • Increases Bcl-xL
  • Increases Bcl-2
  • Increases BDNF
  • Increases BRCA1
  • Increases c-Jun
  • Increases CAT
  • Increases cGMP
  • Increases CKIP-1
  • Increases CYP450
  • Increases Cul3
  • Increases GCL
  • Increases GCLC
  • Increases GCLM
  • Increases GCS
  • Increases GPx
  • Increases GR
  • Increases GSH
  • Increases GST
  • Increases HIF1
  • Increases HO-1
  • Increases HQO1
  • Increases HSP70
  • Increases IL-4
  • Increases IL-5
  • Increases IL-10
  • Increases IL-13
  • Increases K6
  • Increases K16
  • Increases K17
  • Increases mEH
  • Increases Mrp2-5
  • Increases NADPH
  • Increases Notch 1
  • Increases NQO1
  • Increases PPAR-alpha
  • Increases Prx
  • Increases p62
  • Increases Sesn2
  • Increases Slco1b2
  • Increases sMafs
  • Increases SOD
  • Increases Trx
  • Increases Txn(d)
  • Increases UGT1(A1/6)
  • Increases VEGF
  • Reduces ADAMTS(4/5)
  • Reduces alpha-SMA
  • Reduces ALT
  • Reduces AP1
  • Reduces AST
  • Reduces Bach1
  • Reduces COX-2
  • Reduces DNMT
  • Reduces FASN
  • Reduces FGF
  • Reduces HDAC
  • Reduces IFN-?
  • Reduces IgE
  • Reduces IGF-1
  • Reduces IL-1b
  • Reduces IL-2
  • Reduces IL-6
  • Reduces IL-8
  • Reduces IL-25
  • Reduces IL-33
  • Reduces iNOS
  • Reduces LT
  • Reduces Keap1
  • Reduces MCP-1
  • Reduces MIP-2
  • Reduces MMP-1
  • Reduces MMP-2
  • Reduces MMP-3
  • Reduces MMP-9
  • Reduces MMP-13
  • Reduces NfkB
  • Reduces NO
  • Reduces SIRT1
  • Reduces TGF-b1
  • Reduces TNF-alpha
  • Reduces Tyr
  • Reduces VCAM-1
  • Encoded from the NFE2L2 gene, NRF2, or nuclear erythroid 2-related factor 2, is a transcription factor in the basic leucine zipper, or bZIP, superfamily which utilizes a Cap’n’Collar, or CNC structure.
  • It promotes nitric enzymes, biotransformation enzymes, and xenobiotic efflux transporters.
  • It is an essential regulator at the induction of the phase II antioxidant and detoxification enzyme genes, which protect cells from damage caused by oxidative�stress and electrophilic attacks.
  • During homeostatic conditions, Nrf2 is sequestered in the cytosol through bodily attachment of the N-terminal domain of Nrf2, or the Kelch-like ECH-associated protein or Keap1, also referred to as INrf2 or Inhibitor of Nrf2, inhibiting Nrf2 activation.
  • It may also be controlled by mammalian selenoprotein thioredoxin reductase 1, or TrxR1, which functions as a negative regulator.
  • Upon vulnerability to electrophilic stressors, Nrf2 dissociates from Keap1, translocating into the nucleus, where it then heterodimerizes with a range of transcriptional regulatory protein.
  • Frequent interactions comprise with those of transcription authorities Jun and Fos, which can be members of the activator protein family of transcription factors.
  • After dimerization, these complexes then bind to antioxidant/electrophile responsive components ARE/EpRE and activate transcription, as is true with the Jun-Nrf2 complex, or suppress transcription, much like the Fos-Nrf2 complex.
  • The positioning of the ARE, which is triggered or inhibited, will determine which genes are transcriptionally controlled by these variables.
  • When ARE is triggered:
  1. Activation of the�synthesis of antioxidants is capable of detoxifying ROS like catalase, superoxide-dismutase, or SOD, GSH-peroxidases, GSH-reductase, GSH-transferase, NADPH-quinone oxidoreductase, or NQO1, Cytochrome P450 monooxygenase system, thioredoxin, thioredoxin reductase, and HSP70.
  2. Activation of this GSH synthase permits a noticeable growth of the�GSH intracellular degree, which is quite protective.
  3. The augmentation of this synthesis and degrees of phase II enzymes like UDP-glucuronosyltransferase, N-acetyltransferases, and sulfotransferases.
  4. The upregulation of HO-1, which is a really protective receptor with a potential growth of CO that in conjunction with NO allows vasodilation of ischemic cells.
  5. Reduction of iron overload through elevated ferritin and bilirubin as a lipophilic antioxidant. Both the phase II proteins along with the antioxidants are able to fix the chronic oxidative stress and also to revive a normal redox system.
  • GSK3? under the management of AKT and PI3K, phosphorylates Fyn resulting in Fyn nuclear localization, which Fyn phosphorylates Nrf2Y568 leading to nuclear export and degradation of Nrf2.
  • NRF2 also dampens the TH1/TH17 response and enriches the TH2 response.
  • HDAC inhibitors triggered the Nrf2 signaling pathway and up-regulated that the Nrf2 downstream targets HO-1, NQO1, and glutamate-cysteine ligase catalytic subunit, or GCLC, by curbing Keap1 and encouraging dissociation of Keap1 from Nrf2, Nrf2 nuclear translocation, and Nrf2-ARE binding.
  • Nrf2 includes a half-life of about 20 minutes under basal conditions.
  • Diminishing the IKK? pool through Keap1 binding reduces I?B? degradation and might be the elusive mechanism by which Nrf2 activation is proven to inhibit NF?B activation.
  • Keap1 does not always have to be downregulated to get NRF2 to operate, such as chlorophyllin, blueberry, ellagic acid, astaxanthin, and tea polyphenols may boost NRF2 and KEAP1 at 400 percent.
  • Nrf2 regulates negatively through the term of stearoyl CoA desaturase, or SCD, and citrate lyase, or CL.

Genetics

KEAP1

rs1048290

  • C allele – showed a significant risk for and a protective effect against drug resistant epilepsy (DRE)

rs11085735 (I’m AC)

  • associated with rate of decline of lung function in the LHS

MAPT

rs242561

  • T allele – protective allele for Parkinsonian disorders – had stronger NRF2/sMAF binding and was associated with the higher MAPT mRNA levels in 3 different regions in brain, including cerebellar cortex (CRBL), temporal cortex (TCTX), intralobular white matter (WHMT)

NFE2L2 (NRF2)

rs10183914 (I’m CT)

  • T allele – increased levels of Nrf2 protein and delayed age of onset of Parkinson’s by four years

rs16865105 (I’m AC)

  • C allele – had higher risk of Parkinson’s Disease

rs1806649 (I’m CT)

  • C allele – has been identified and may be relevant for breast cancer etiology.
  • associated with increased risk of hospital admissions during periods of high PM10 levels

rs1962142 (I’m GG)

  • T allele – was associated with a low level of cytoplasmic NRF2 expression (P = 0.036) and negative sulfiredoxin expression (P = 0.042)
  • A allele – protected from forearm blood flow (FEV) decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)

rs2001350 (I’m TT)

  • T allele – protected from FEV decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)

rs2364722 (I’m AA)

  • A allele – protected from FEV decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)

rs2364723

  • C allele – associated with significantly reduced FEV in Japanese smokers with lung cancer

rs2706110

  • G allele – showed a significant risk for and a protective effect against drug resistant epilepsy (DRE)
  • AA alleles – showed significantly reduced KEAP1 expression
  • AA alleles – was associated with an increased risk of breast cancer (P = 0.011)

rs2886161 (I’m TT)

  • T allele – associated with Parkinson’s Disease

rs2886162

  • A allele – was associated with low NRF2 expression (P = 0.011; OR, 1.988; CI, 1.162�3.400) and the AA genotype was associated with a worse survival (P = 0.032; HR, 1.687; CI, 1.047�2.748)

rs35652124 (I’m TT)

  • A allele – associated with higher associated with age at onset for Parkinson’s Disease vs G allele
  • C allele – had increase NRF2 protein
  • T allele – had less NRF2 protein and greater risk of heart disease and blood pressure

rs6706649 (I’m CC)

  • C allele – had lower NRF2 protein and increase risk for Parkinson’s Disease

rs6721961 (I’m GG)

  • T allele – had lower NRF2 protein
  • TT alleles – association between cigarette smoking in heavy smokers and a decrease in semen quality
  • TT allele – was associated with increased risk of breast cancer [P = 0.008; OR, 4.656; confidence interval (CI), 1.350�16.063] and the T allele was associated with a low extent of NRF2 protein expression (P = 0.0003; OR, 2.420; CI, 1.491�3.926) and negative SRXN1 expression (P = 0.047; OR, 1.867; CI = 1.002�3.478)
  • T allele – allele was also nominally associated with ALI-related 28-day mortality following systemic inflammatory response syndrome
  • T allele – protected from FEV decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)
  • G allele – associated with increased risk of ALI following major trauma in European and African-Americans (odds ratio, OR 6.44; 95% confidence interval
  • AA alleles – associated with infection-induced asthma
  • AA alleles – exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked
  • AA alleles – had a significantly higher risk for developing T2DM (OR 1.77; 95% CI 1.26, 2.49; p = 0.011) relative to those with the CC genotype
  • AA alleles – strong association between wound repair and late toxicities of radiation (associated with a significantly higher risk for developing late effects in African-Americans with a trend in Caucasians)
  • associated with oral estrogen therapy and risk of venous thromboembolism in postmenopausal women

rs6726395 (I’m AG)

  • A allele – protected from FEV1 decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)
  • A allele – associated with significantly reduced FEV1 in Japanese smokers with lung cancer
  • GG alleles – had higher NRF2 levels and decreased risk of macular degeneration
  • GG alleles – had higher survival with Cholangiocarcinoma

rs7557529 (I’m CT)

  • C allele – associated with Parkinson’s Disease
Dr Jimenez White Coat
Oxidative stress and other stressors can cause cell damage which may eventually lead to a variety of health issues. Research studies have demonstrated that Nrf2 activation can promote the human body’s protective antioxidant mechanism, however, researchers have discussed that Nrf2 overexpression can have tremendous risks towards overall health and wellness. Various types of cancer can also occur with Nrf2 overactivation. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below. Key sections:
  • 00:01:14 – Cancer and mortality
  • 00:19:04 – Aging
  • 00:26:30 – Brain and behavior
  • 00:38:06 – Final recap
  • 00:40:27 – Dose
Full timeline:
  • 00:00:34 – Introduction of sulforaphane, a major focus of the video.
  • 00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
  • 00:02:12 – Prostate cancer risk.
  • 00:02:23 – Bladder cancer risk.
  • 00:02:34 – Lung cancer in smokers risk.
  • 00:02:48 – Breast cancer risk.
  • 00:03:13 – Hypothetical: what if you already have cancer? (interventional)
  • 00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
  • 00:04:38 – Sulforaphane and cancer.
  • 00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
  • 00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
  • 00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
  • 00:08:32 – Inhibition of breast cancer stem cells.
  • 00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
  • 00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
  • 00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
  • 00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
  • 00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
  • 00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
  • 00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
  • 00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
  • 00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
  • 00:19:04 – Beginning of aging section.
  • 00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
  • 00:20:34 – Importance of low inflammation for longevity.
  • 00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
  • 00:23:40 – Mid-video recap: cancer, aging sections
  • 00:24:14 – Mouse studies suggest sulforaphane might improve adaptive immune function in old age.
  • 00:25:18 – Sulforaphane improved hair growth in a mouse model of balding. Picture at 00:26:10.
  • 00:26:30 – Beginning of brain and behavior section.
  • 00:27:18 – Effect of broccoli sprout extract on autism.
  • 00:27:48 – Effect of glucoraphanin on schizophrenia.
  • 00:28:17 – Start of depression discussion (plausible mechanism and studies).
  • 00:31:21 – Mouse study using 10 different models of stress-induced depression show sulforaphane similarly effective as fluoxetine (prozac).
  • 00:32:00 – Study shows direct ingestion of glucoraphanin in mice is similarly effective at preventing depression from social defeat stress model.
  • 00:33:01 – Beginning of neurodegeneration section.
  • 00:33:30 – Sulforaphane and Alzheimer’s disease.
  • 00:33:44 – Sulforaphane and Parkinson’s disease.
  • 00:33:51 – Sulforaphane and Hungtington’s disease.
  • 00:34:13 – Sulforaphane increases heat shock proteins.
  • 00:34:43 – Beginning of traumatic brain injury section.
  • 00:35:01 – Sulforaphane injected immediately after TBI improves memory (mouse study).
  • 00:35:55 – Sulforaphane and neuronal plasticity.
  • 00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
  • 00:37:19 – Sulforaphane and duchenne muscular dystrophy.
  • 00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
  • 00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
  • 00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
  • 00:41:01 – Anecdotes on sprouting at home.
  • 00:43:14 – On cooking temperatures and sulforaphane activity.
  • 00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
  • 00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
  • 00:44:56 – Cooking techniques and cruciferous vegetables.
  • 00:46:06 – Isothiocyanates as goitrogens.
According to research studies, Nrf2, is a fundamental transcription factor which activates the cells’ protective antioxidant mechanisms to detoxify the human body. The overexpression of Nrf2, however, can cause health issues. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�. Curated by Dr. Alex Jimenez
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Additional Topic Discussion:�Acute Back Pain

Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.  
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EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

***
The Role Of Nrf2 Activation

The Role Of Nrf2 Activation

Many current research studies on cancer have allowed health professionals to understand the way the body detoxes. By analyzing upregulated genes in tumorous cells, researchers discovered the nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2. NRF2 is an important transcription factor which activates the human body’s protective antioxidant mechanisms in order to regulate oxidation from both external and internal factors to prevent increased levels of oxidative stress.

Principles of Nrf2

NRF2 is essential towards maintaining overall health and wellness because it�serves the primary purpose of regulating how we manage everything we’re exposed to on a daily basis and not become sick. NRF2 activation plays a role in the phase II detoxification system.�Phase II detoxification takes lipophilic, or�fat soluble, free radicals and converts them into hydrophilic, or water soluble,�substances for excretion while inactivating exceptionally reactive metabolites and chemicals as a consequence of phase I.

NRF2 activation reduces overall oxidation and inflammation of the human body through a hormetic effect. To trigger NRF2, an inflammatory reaction due to oxidation must occur in order for the cells to produce an adaptive response and create antioxidants, such as glutathione. To break down the principle of Nrf2, essentially, oxidative stress activates NRF2 which then activates an antioxidant response in the human body. NRF2 functions to balance redox signaling, or the equilibrium of oxidant and antioxidant levels in the cell.

A great illustration of how this process functions can be demonstrated with exercise. Through every workout, the muscle adapts so that it can accommodate another workout session. If NRF2 becomes under- or over-expressed due to chronic infections or increased exposure to toxins, which may be observed in patients who have chronic inflammatory response syndrome, or CIRS, the health issues may worsen�following NRF2 activation. Above all, if DJ-1 becomes over-oxidized, NRF2 activation will end�too quickly.

Effects of NRF2 Activation

NRF2 activation is highly expressed in the lungs, liver, and kidneys. Nuclear erythroid 2-related factor 2, or NRF2, most commonly functions by counteracting increased levels of oxidation in the human body which can lead to oxidative stress. Nrf2 activation can help treat a variety of health issues, however, over-activation of Nrf2 may worsen various problems, which are demonstrated below.

Periodic activation of Nrf2 can help:

  • Aging (ie Longevity)
  • Autoimmunity and Overall Inflammation (ie Arthritis, Autism)
  • Cancer and Chemoprotection (ie EMF Exposure)
  • Depression and Anxiety (ie PTSD)
  • Drug Exposure (Alcohol, NSAIDs )
  • Exercise and Endurance Performance
  • Gut Disease (ie SIBO, Dysbiosis, Ulcerative Colitis)
  • Kidney Disease (ie Acute Kidney Injury, Chronic Kidney Disease, Lupus Nephritis)
  • Liver Disease (ie Alcoholic Liver Disease, Acute Hepatitis, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Cirrhosis)
  • Lung Disease (ie Asthma, Fibrosis)
  • Metabolic And Vascular Disease (ie Atherosclerosis, Hypertension, Stroke, Diabetes)
  • Neurodegeneration (ie Alzheimer’s, Parkinson’s, Huntington’s and ALS)
  • Pain (ie Neuropathy)
  • Skin Disorders (ie Psoriasis, UVB/Sun Protection)
  • Toxin Exposure (Arsenic, Asbestos, Cadmium, Fluoride, Glyphosate, Mercury, Sepsis, Smoke)
  • Vision (ie Bright Light, Sensitivity, Cataracts, Corneal Dystrophy)

Hyperactivation of Nrf2 can worsen:

  • Atherosclerosis
  • Cancer (ie Brain, Breast, Head, Neck Pancreatic, Prostate, Liver, Thyroid)
  • Chronic Inflammatory Response Syndrome (CIRS)
  • Heart Transplant (while open NRF2 may be bad, NRF2 can help with repair)
  • Hepatitis C
  • Nephritis (severe cases)
  • Vitiligo

Furthermore, NRF2 can help make specific nutritional supplements, drugs,�and medications work. Many natural�supplements can also help trigger NRF2. Through current research studies, researchers have demonstrated that a large number of compounds which were once believed to be antioxidants were really pro-oxidants. That’s because nearly all of them need NRF2 to function, even supplements like curcumin and fish oil. Cocoa, for example, was shown to generate antioxidant effects in mice which possess the NRF2 gene.

Ways To Activate NRF2

In the case of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, stroke or even autoimmune diseases, it’s probably best to have Nrf2 upregulated, but in a hormetic fashion. Mixing NRF2 activators may also have an additive or synergistic effect, as occasionally it can be dose-dependent. The top ways to increase Nrf2 expression are listed below:

  • HIST (Exercise) + CoQ10 + Sun (these synergize very well)
  • Broccoli Sprouts + LLLT on my head and gut
  • Butyrate + Super Coffee + Morning Sun
  • Acupuncture (this is an alternative method, laser acupuncture may also be used)
  • Fasting
  • Cannabidiol (CBD)
  • Lion’s Mane + Melatonin
  • Alpha-lipoic acid + DIM
  • Wormwood
  • PPAR-gamma Activation

The following comprehensive listing containing over 350 other ways to activate Nrf2 through diet, lifestyle and devices, probiotics, supplements, herbs and oils, hormones and neurotransmitters, drugs/medications and chemicals, pathways/transcription factors, as well as other ways, is only a brief guide as to what can trigger Nrf2. For the sake of brevity in this article, we have left out over 500 other foods, nutritional supplements and compounds which can help activate Nrf2. The following are listed below:

Diet:

  • Acai Berries
  • Alcohol (Red wine is better, especially if there is a cork in it, as protocatechuic aldehyde from corks can also activate NRF2. In general, alcohol is not recommended, although acute intake increases NRF2. Chronic intake may decrease NRF2.
  • Algae (kelp)
  • Apples
  • Black Tea
  • Brazil Nuts
  • Broccoli Sprouts (and other isothiocyanates, sulforaphane as well as cruciferous vegetables like bok choy that have D3T)
  • Blueberries (0.6-10 g/day)
  • Carrots (falcarinone)
  • Cayenne Pepper (Capsaicin)
  • Celery (Butylphthalide)
  • Chaga (Betulin)
  • Chamomile Tea
  • Chia
  • Chinese Potato
  • Chokeberries (Aronia)
  • Chocolate (Dark or Cocoa)
  • Cinnamon
  • Coffee (such as chlorogenic acid, Cafestol and Kahweol)
  • Cordyceps
  • Fish (and Shellfish)
  • Flaxseed
  • Garlic
  • Ghee (possibly)
  • Ginger (and Cardamonin)
  • Gojiberries
  • Grapefruit (Naringenin – 50 mg/kg/d naringenin)
  • Grapes
  • Green Tea
  • Guava
  • Heart Of Palm
  • Hijiki/Wakame
  • Honeycomb
  • Kiwi
  • Legumes
  • Lion’s Mane
  • Mahuwa
  • Mangos (Mangiferin)
  • Mangosteen
  • Milk (goat, cow – via regulation of microbiome)
  • Mulberries
  • Olive Oil (pomace – hydroxytyrosol and Oleanolic Acid)
  • Omega 6 Fatty Acids (Lipoxin A4)
  • Osange Oranges (Morin)
  • Oyster Mushrooms
  • Papaya
  • Peanuts
  • Pigeon Peas
  • Pomegranate (Punicalagin, Ellagic Acid)
  • Propolis (Pinocembrin)
  • Purple Sweet Potatoes
  • Rambutan (Geraniin)
  • Onions
  • Reishi
  • Rhodiola Rosea (Salidroside)
  • Rice Bran (cycloartenyl ferulate)
  • Riceberry
  • Rooibos Tea
  • Rosemary
  • Sage
  • Safflower
  • Sesame Oil
  • Soy (and isoflavones, Daidzein, Genistein)
  • Squash
  • Strawberries
  • Tartary Buckwheat
  • Thyme
  • Tomatoes
  • Tonka Beans
  • Turmeric
  • Wasabi
  • Watermelon

Lifestyle and Devices:

  • Acupuncture and Electroacupuncture (via collagen cascade on ECM)
  • Blue light
  • Brain Games (increases NRF2 in the hippocampus)
  • Caloric Restriction
  • Cold (showers, plunges, ice bath, gear, cryotheraphy)
  • EMFs (low frequency, such as PEMF)
  • Exercise (Acute exercise like HIST or HIIT seems to be more beneficial for inducing NRF2, while longer exercise doesn�t induce NRF2, but does increase glutathione levels)
  • High Fat Diet (diet)
  • High Heat (Sauna)
  • Hydrogen Inhalation and Hydrogen Water
  • Hyperbaric Oxygen Therapy
  • Infrared Therapy (such as Joovv)
  • Intravenous Vitamin C
  • Ketogenic Diet
  • Ozone
  • Smoking (not recommended – acutely smoking increase NRF2, chronically smoking decreases NRF2. If you choose to smoke, Holy Basil may help protect against downregulation of NRF2)
  • Sun (UVB and Infrared)

Probiotics:

  • Bacillus subtilis (fmbJ)
  • Clostridium butyricum (MIYAIRI 588)
  • Lactobacillus brevis
  • Lactobacillus casei (SC4 and 114001)
  • Lactobacillus collinoides
  • Lactobacillus gasseri (OLL2809, L13-Ia, and SBT2055)
  • Lactobacillus helveticus (NS8)
  • Lactobacillus paracasei (NTU 101)
  • Lactobacillus plantarum (C88, CAI6, FC225, SC4)
  • Lactobacillus rhamnosus (GG)

Supplements, Herbs, and Oils:

  • Acetyl-L-Carnitine (ALCAR) and Carnitine
  • Allicin
  • Alpha-lipoic acid
  • Amentoflavone
  • Andrographis paniculata
  • Agmatine
  • Apigenin
  • Arginine
  • Artichoke (Cyanropicrin)
  • Ashwaganda
  • Astragalus
  • Bacopa
  • Beefsteak (Isogemaketone)
  • Berberine
  • Beta-caryophyllene
  • Bidens Pilosa
  • Black Cumin Seed Oil (Thymoquinone)
  • Boswellia
  • Butein
  • Butyrate
  • Cannabidiol (CBD)
  • Carotenioids (like Beta-carotene [synergy with Lycopene – 2 � 15 mg/d lycopene], Fucoxanthin, Zeaxanthin, Astaxanthin, and Lutein)
  • Chitrak
  • Chlorella
  • Chlorophyll
  • Chrysanthemum zawadskii
  • Cinnamomea
  • Common Sundew
  • Copper
  • Coptis
  • CoQ10
  • Curcumin
  • Damiana
  • Dan Shen/Red Sage (Miltirone)
  • DIM
  • Dioscin
  • Dong Ling Cao
  • Dong Quai (female ginseng)
  • Ecklonia Cava
  • EGCG
  • Elecampane / Inula
  • Eucommia Bark
  • Ferulic Acid
  • Fisetin
  • Fish Oil (DHA/EPA – 3 � 1 g/d fish oil containing 1098 mg EPA and 549 mg DHA)
  • Galangal
  • Gastrodin (Tian Ma)
  • Gentiana
  • Geranium
  • Ginkgo Biloba (Ginkgolide B)
  • Glasswort
  • Gotu Kola
  • Grape Seed Extract
  • Hairy Agrimony
  • Haritaki (Triphala)
  • Hawthorn
  • Helichrysum
  • Henna (Juglone)
  • Hibiscus
  • Higenamine
  • Holy Basil/Tulsi (Ursolic Acid)
  • Hops
  • Horny Goat Weed (Icariin/Icariside)
  • Indigo Naturalis
  • Iron (not recommended unless essential)
  • I3C
  • Job’s Tears
  • Moringa Oleifera (such as Kaempferol)
  • Inchinkoto (combo of Zhi Zi and Wormwood)
  • Kudzu Root
  • Licorice Root
  • Lindera Root
  • Luteolin (high doses for activation, lower doses inhibit NRF2 in cancer though)
  • Magnolia
  • Manjistha
  • Maximowiczianum (Acerogenin A)
  • Mexican Arnica
  • Milk Thistle
  • MitoQ
  • Mu Xiang
  • Mucuna Pruriens
  • Nicotinamide and NAD+
  • Panax Ginseng
  • Passionflower (such as Chrysin, but chyrisin may also reduce NRF2 via dysregulation of PI3K/Akt signaling)
  • Pau d�arco (Lapacho)
  • Phloretin
  • Piceatannol
  • PQQ
  • Procyanidin
  • Pterostilbene
  • Pueraria
  • Quercetin (high doses only, lower doses inhibit NRF2)
  • Qiang Huo
  • Red Clover
  • Resveratrol (Piceid and other phytoestrogens essentially, Knotweed)
  • Rose Hips
  • Rosewood
  • Rutin
  • Sappanwood
  • Sarsaparilla
  • Saururus chinensis
  • SC-E1 (Gypsum, Jasmine, Licorice, Kudzu, and Balloon Flower)
  • Schisandra
  • Self Heal (prunella)
  • Skullcap (Baicalin and Wogonin)
  • Sheep Sorrel
  • Si Wu Tang
  • Sideritis
  • Spikenard (Aralia)
  • Spirulina
  • St. John’s Wort
  • Sulforaphane
  • Sutherlandia
  • Tao Hong Si Wu
  • Taurine
  • Thunder God Vine (Triptolide)
  • Tocopherols (such as Vitamin E or Linalool)
  • Tribulus R
  • Tu Si Zi
  • TUDCA
  • Vitamin A (although other retinoids inhibit NRF2)
  • Vitamin C (high dose only, low dose does inhibit�NRF2)
  • Vitex/Chaste Tree
  • White Peony (Paeoniflorin from Paeonia lactiflora)
  • Wormwood (Hispidulin and Artemisinin)
  • Xiao Yao Wan (Free and Easy Wanderer)
  • Yerba Santa (Eriodictyol)
  • Yuan Zhi (Tenuigenin)
  • Zi Cao (will reduce NRF2 in cancer)
  • Zinc
  • Ziziphus Jujube

Hormones and Neurotransmitters:

  • Adiponectin
  • Adropin
  • Estrogen (but may decrease NRF2 in breast tissue)
  • Melatonin
  • Progesterone
  • Quinolinic Acid (in protective response to prevent excitotoxicity)
  • Serotonin
  • Thyroid Hormones like T3 (can increase NRF2 in healthy cells, but decrease it in cancer)
  • Vitamin D

Drugs/Medications and Chemicals:

  • Acetaminophen
  • Acetazolamide
  • Amlodipine
  • Auranofin
  • Bardoxolone methyl (BARD)
  • Benznidazole
  • BHA
  • CDDO-imidazolide
  • Ceftriaxone (and beta-lactam antibiotics)
  • Cialis
  • Dexamethasone
  • Diprivan (Propofol)
  • Eriodictyol
  • Exendin-4
  • Ezetimibe
  • Fluoride
  • Fumarate
  • HNE (oxidized)
  • Idazoxan
  • Inorganic arsenic and sodium arsenite
  • JQ1 (may inhibit NRF2 as well, unknown)
  • Letairis
  • Melphalan
  • Methazolamide
  • Methylene Blue
  • Nifedipine
  • NSAIDs
  • Oltipraz
  • PPIs (such as Omeprazole and Lansoprazole)
  • Protandim – great results in vivo, but weak/non-existent at activating NRF2 in humans
  • Probucol
  • Rapamycin
  • Reserpine
  • Ruthenium
  • Sitaxentan
  • Statins (such as Lipitor and Simvastatin)
  • Tamoxifen
  • Tang Luo Ning
  • tBHQ
  • Tecfidera (Dimethyl fumarate)
  • THC (not as strong as CBD)
  • Theophylline
  • Umbelliferone
  • Ursodeoxycholic Acid (UDCA)
  • Verapamil
  • Viagra
  • 4-Acetoxyphenol

Pathways/Transcription Factors:

  • ?7 nAChR activation
  • AMPK
  • Bilirubin
  • CDK20
  • CKIP-1
  • CYP2E1
  • EAATs
  • Gankyrin
  • Gremlin
  • GJA1
  • H-ferritin ferroxidase
  • HDAC inhibitors (such as valproic acid and TSA, but can cause NRF2 instability)
  • Heat Shock Proteins
  • IL-17
  • IL-22
  • Klotho
  • let-7 (knocks down mBach1 RNA)
  • MAPK
  • Michael acceptors (most)
  • miR-141
  • miR-153
  • miR-155 (knocks down mBach1 RNA as well)
  • miR-7 (in brain, helps with cancer and schizophrenia)
  • Notch1
  • Oxidatives stress (such as ROS, RNS, H2O2) and Electrophiles
  • PGC-1?
  • PKC-delta
  • PPAR-gamma (synergistic effects)
  • Sigma-1 receptor inhibition
  • SIRT1 (increases NRF2 in the brain and lungs but may decrease it overall)
  • SIRT2
  • SIRT6 (in the liver and brain)
  • SRXN1
  • TrxR1 inhibition (attenuation or depletion as well)
  • Zinc protoporphyrin
  • 4-HHE

Other:

  • Ankaflavin
  • Asbestos
  • Avicins
  • Bacillus amyloliquefaciens (used in agriculture)
  • Carbon Monoxide
  • Daphnetin
  • Glutathione Depletion (depletion of 80%�90% possibly)
  • Gymnaster koraiensis
  • Hepatitis C
  • Herpes (HSV)
  • Indian ash tree
  • Indigowoad Root
  • Isosalipurposide
  • Isorhamentin
  • Monascin
  • Omaveloxolone (strong, aka RTA-408)
  • PDTC
  • Selenium Deficiency (selenium deficiency can increase NRF2)
  • Siberian Larch
  • Sophoraflavanone G
  • Tadehagi triquetrum
  • Toona sinensis (7-DGD)
  • Trumpet Flower
  • 63171 and 63179 (strong)
Dr Jimenez White Coat
The nuclear erythroid 2-related factor 2 signaling pathway, best known by the acronym Nrf2, is a transcription factor which plays the major role of regulating the protective antioxidant mechanisms of the human body, particularly in order to control oxidative stress. While increased levels of oxidative stress can activate Nrf2, its effects are tremendously enhanced through the presence of specific compounds. Certain foods and supplements help activate Nrf2 in the human body, including the isothiocyanate sulforaphane from broccoli sprouts. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below.

Key sections:

  • 00:01:14 – Cancer and mortality
  • 00:19:04 – Aging
  • 00:26:30 – Brain and behavior
  • 00:38:06 – Final recap
  • 00:40:27 – Dose

Full timeline:

  • 00:00:34 – Introduction of sulforaphane, a major focus of the video.
  • 00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
  • 00:02:12 – Prostate cancer risk.
  • 00:02:23 – Bladder cancer risk.
  • 00:02:34 – Lung cancer in smokers risk.
  • 00:02:48 – Breast cancer risk.
  • 00:03:13 – Hypothetical: what if you already have cancer? (interventional)
  • 00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
  • 00:04:38 – Sulforaphane and cancer.
  • 00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
  • 00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
  • 00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
  • 00:08:32 – Inhibition of breast cancer stem cells.
  • 00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
  • 00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
  • 00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
  • 00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
  • 00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
  • 00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
  • 00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
  • 00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
  • 00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
  • 00:19:04 – Beginning of aging section.
  • 00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
  • 00:20:34 – Importance of low inflammation for longevity.
  • 00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
  • 00:23:40 – Mid-video recap: cancer, aging sections
  • 00:24:14 – Mouse studies suggest sulforaphane might improve adaptive immune function in old age.
  • 00:25:18 – Sulforaphane improved hair growth in a mouse model of balding. Picture at 00:26:10.
  • 00:26:30 – Beginning of brain and behavior section.
  • 00:27:18 – Effect of broccoli sprout extract on autism.
  • 00:27:48 – Effect of glucoraphanin on schizophrenia.
  • 00:28:17 – Start of depression discussion (plausible mechanism and studies).
  • 00:31:21 – Mouse study using 10 different models of stress-induced depression show sulforaphane similarly effective as fluoxetine (prozac).
  • 00:32:00 – Study shows direct ingestion of glucoraphanin in mice is similarly effective at preventing depression from social defeat stress model.
  • 00:33:01 – Beginning of neurodegeneration section.
  • 00:33:30 – Sulforaphane and Alzheimer’s disease.
  • 00:33:44 – Sulforaphane and Parkinson’s disease.
  • 00:33:51 – Sulforaphane and Hungtington’s disease.
  • 00:34:13 – Sulforaphane increases heat shock proteins.
  • 00:34:43 – Beginning of traumatic brain injury section.
  • 00:35:01 – Sulforaphane injected immediately after TBI improves memory (mouse study).
  • 00:35:55 – Sulforaphane and neuronal plasticity.
  • 00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
  • 00:37:19 – Sulforaphane and duchenne muscular dystrophy.
  • 00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
  • 00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
  • 00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
  • 00:41:01 – Anecdotes on sprouting at home.
  • 00:43:14 – On cooking temperatures and sulforaphane activity.
  • 00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
  • 00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
  • 00:44:56 – Cooking techniques and cruciferous vegetables.
  • 00:46:06 – Isothiocyanates as goitrogens.

According to many current research studies, the nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2, is a fundamental transcription factor which activates the cells’ protective antioxidant mechanisms to detoxify the human body from both external and internal factors and prevent increased levels of oxidative stress. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.

Curated by Dr. Alex Jimenez

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Additional Topic Discussion:�Acute Back Pain

Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �

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EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

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