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Nutrition

Back Clinic Nutrition Team. Food provides people with the necessary energy and nutrients to be healthy. By eating various foods, including good quality vegetables, fruits, whole-grain products, and lean meats, the body can replenish itself with the essential proteins, carbohydrates, fats, vitamins, and minerals to function effectively. Nutrients include proteins, carbohydrates, fats, vitamins, minerals, and water. Healthy eating does not have to be hard.

The key is to eat various foods, including vegetables, fruits, and whole grains. In addition, eat lean meats, poultry, fish, beans, and low-fat dairy products and drink lots of water. Limit salt, sugar, alcohol, saturated fat, and trans fat. Saturated fats usually come from animals. Look for trans fat on the labels of processed foods, margarine, and shortenings.

Dr. Alex Jimenez offers nutritional examples and describes the importance of balanced nutrition, emphasizing how a proper diet combined with physical activity can help individuals reach and maintain a healthy weight, reduce their risk of developing chronic diseases, and promote overall health and wellness.

Lifestyle Change Vs. Diets In El Paso, TX.

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Diets, Nutrition

Diets: The statistics are sobering. The typical American diet far exceeds the daily recommended intake levels in calories from sugars and solid fats, sodium, refined grains, and saturated fat. It is also lacking in the recommended amounts of fruits, vegetables, dairy, whole grains, and oils. The result is obesity and experts project that by 2030, in the United States alone, half of all adults will be obese.

That�s when people start dieting � and that is what gets them into trouble.

Diet vs. Lifestyle Change

Bottom line, diets are temporary. There are some serious consequences that can come from dieting, especially fad or crash diets. The effects of these types of diets can also seriously impact your chiropractic care, hindering your progress.

Also, because diets are temporary, once you return to your regular eating habits the weight usually comes back.

A lifestyle change is a far better choice. It involves making smart, healthy eating choices � choices that you maintain for the rest of your life. This also impacts your chiropractic care by strengthening your body and keeping it healthy so that it is in an optimal state for healing and responds well to treatment.

Types Of Diets

There are all sorts of diets out there. Some are blatantly unhealthy but others are sneaky. They come with claims of being healthy, of being created or endorsed by doctors, or include tons of vitamin supplements but very limited food intake. It is important to be able to spot these destructive fad diets so you don�t get suckered into their hype.

Some of the most common types of fad diets include high protein, low or no carb, liquid, cabbage, grapefruit, broth or juice, and food combining. Some of these can cause serious health problems including vital organ damage. Others can cause vitamin deficiencies and dehydration. None of them can (or should) be maintained over a long period of time, much less the rest of your life.

The Dangers Of Diets

Unhealthy dieting can come with some pretty scary dangers. Because they typically omit key foods or food groups your body can become imbalanced. Some of the dangers of dieting include dehydration, fatigue, weakness, vitamin and mineral deficiency, headaches, nausea, diarrhea, constipation, mental fogginess, loss of muscle mass, organ damage, and even heart attack and stroke.

One popular diet restricts carbs, often cutting them out completely. This includes all whole grains (which have vital minerals and fiber) as well as many fruits and vegetables. The result is a diet that is mostly protein and fat.

While the dieter may lose some weight on this plan, it is at a great cost. The extremely high intake of protein which exceeds the levels that the body should have can cause liver and kidney failure. The omission of vital grains, fruits, and vegetables can lead to serious vitamin deficiencies while the increased fat intake can lead to heart attack and stroke.

If a diet eliminates any of the key foods (lean meats, whole grains, fruits, and vegetables), it advocates losing more than 2 or 3 pounds a week, or it restricts caloric intake to less than 1,200 calories a day it is potentially unhealthy and should only be done 1) under a doctor�s close supervision, and 2) on a very temporary basis.

Healthy Eating Is A Lifestyle

When you make the life changing commitment to adopt a healthy eating lifestyle you open yourself up to a world of better health, more energy, and better focus. Your body will heal faster and you will feel better.

A diet of fresh fruits and vegetables, lean meats, fresh fish, and whole grains, along with lots of water should become a way of life. It is far healthier than the temporary diets that are out there and more effective too.

If you or a loved one need additional dietary guidance, give us a call. Our Doctor of Chiropractic is here to help!

Dr. Jimenez Takes A Look At Motivational Fitness

Organic Diet: 5 Reasons Why

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Diets, Nutrition

Organic Diet: It seems our moms were right; we are what we eat. Unfortunately in today’s marketplace, there are many valid worries about the foods we consume. Antibiotics, pesticides, and foods tainted with dangerous diseases are a top concern for many Americans. In addition, processed and genetically modified foods and artificial ingredients contribute to a number of health issues from obesity to cancer.

Our diet is one of the most important facets of maintaining overall good health for the long term. Farmer’s markets, small grocery stores, and the movement toward organic labeling shows the trend toward making healthier food choices.

If you are thinking about adding a few organic foods to your meal plan, or chucking all processed foods altogether, you are moving toward a healthier, higher performing body with fewer health issues.

Organic Diet: Five Reasons Why

#1: Fewer Chemicals

The practice of using a variety of pesticides in non-organic farming is widespread in the United States. No matter how fastidiously you wash them, foods with these toxins are harmful to your body. A recent article in The Huffington Post stated that toxic pesticides are present in 70% of the food found in grocery stores!

Many large, traditional farms aim to produce as much food as possible, as cheaply as they can. They turn to pesticides and herbicides to make the crops grow faster and last longer. It’s a sad fact, but the American public ends up paying a price anyway. An organic diet offers a respite from these chemically laden foods.

#2: Tastes Better

You may not even realize the taste you DON’T get when eating processed foods. Toxins that make them grow and keep them fresh deplete the taste dramatically.

Growing from properly maintained soil without the presence of pesticides, organic foods deliver a richer, more engaging flavor. Individuals who eat organic often eat less and are better satisfied with their meals because of the increased taste.

#3: More Nutrient Density

According to The Ideal Bite, organic foods contain up to 50% more nutrients than their non-organic counterparts. Depleted soil quality from over farming is a key reason for this situation. This means a person needs to eat less organic food to maintain the necessary dietary vitamins and minerals that ensures good health, offsetting the initial higher cost of choosing organic.

#4: Less Antibiotic Exposure

Large food manufacturing farms often choose to pump their animals full of antibiotics to reduce illness and promote rapid growth. Obviously, these make their way into the end product that we end up eating.

Too much exposure to antibiotics causes everything from early puberty in children to antibiotic resistance. If you become ill and require antibiotic medical treatment, long-term consumption of non-organic meat could literally hinder you from responding.

#5: Supports The Local Economy

In addition to building a strong body and mind, choosing organic contributes to the local community by supporting the small farmer. The small farmer is able to adopt to organic standards with less effort, and is more likely to embrace healthy soil practices and other ethical farming traits in the first place. Seek out local establishments for the widest variety of the freshest, locally grown food.

There are an assortment of reasons to choose an organic diet. In a nutshell, it is proven to offer great benefits to your long-term overall health. If you can’t commit to an entirely organic diet, substitute a few organic choices from your present food selections. Even changing small areas of your diet will provide better taste, greater nutrition, and stronger well-being.

Have more questions? We�re here for you! Simply ask our Doctor of Chiropractic during your next visit how eating organic foods can benefit you.

Good Nutrition & Chiropractic Care Contribute To Overall Well-Being

Respiratory Health And Nutrition

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Health, Nutrition, Physical Rehabilitation

Respiratory Health Abstract: Diet and nutrition may be important modifiable risk factors for the development,
progression and management of obstructive lung diseases such as asthma and chronic
obstructive pulmonary disease (COPD). This review examines the relationship between
dietary patterns, nutrient intake and weight status in obstructive lung diseases, at different
life stages, from in-utero influences through childhood and into adulthood. In vitro and
animal studies suggest important roles for various nutrients, some of which are supported by
epidemiological studies. However, few well-designed human intervention trials are available
to definitively assess the efficacy of different approaches to nutritional management of
respiratory diseases. Evidence for the impact of higher intakes of fruit and vegetables is
amongst the strongest, yet other dietary nutrients and dietary patterns require evidence from
human clinical studies before conclusions can be made about their effectiveness.

Keywords: respiratory disease; asthma; COPD; dietary patterns; antioxidants; vitamin C;
vitamin E; flavonoids; vitamin D; obesity; adipokines; undernutrition

1. Introduction:�Respiratory Health

Diet and nutrition are increasingly becoming recognized as modifiable contributors to chronic disease development and progression. Considerable evidence has emerged indicating the importance of dietary intake in obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) in both early life and disease development [1,2] and management of disease progression [3,4]. These�respiratory diseases are characterized by airway and systemic inflammation, airflow obstruction, deficits in lung function and significant morbidity and mortality, as well as being costly economic burdens [5,6]. Pharmacological management remains the mainstay for treatment of respiratory diseases, and while treatment options are advancing, dietary intake modification could be an important adjuvant to disease management and an important consideration for disease prevention. Dietary patterns as well as intake of individual nutrients have been evaluated in observational and experimental studies throughout life stages and disease stages to elucidate their role in respiratory diseases. This review concentrates on evidence regarding the role of dietary patterns, individual nutrients, weight status and adipokines in asthma and COPD.

2. Dietary Intake And Respiratory Diseases

2.1. Dietary Patterns:�Respiratory Health

Various dietary patterns have been linked to the risk of respiratory disease [7]. The Mediterranean diet has been found to have protective effects for allergic respiratory diseases in epidemiological studies [8]. This dietary pattern consists of a high intake of minimally processed plant foods, namely; fruit, vegetables, breads, cereals, beans, nuts and seeds, low to moderate intake of dairy foods, fish, poultry and wine and low intake of red meat. High intakes of olive oil result in a dietary composition that is low in saturated fat though still moderate in total fat. In children, several studies showed that adherence to the Mediterranean diet is inversely associated with atopy and has a protective effect on atopy, wheezing and asthma symptoms [9�11]. The Mediterranean diet may also be important for maternal diet, as a study in Spain found that a high Mediterranean diet score during pregnancy was protective for persistent wheeze and atopic wheeze in children at 6.5 years of age [12]. Though one cross-sectional study in Japan reported a strong association between the adherence to the Mediterranean diet and asthma control [13], there is less evidence available to support this dietary pattern in adults. The �western� dietary pattern, prevalent in developed countries, is characterised by high consumption of refined grains, cured and red meats, desserts and sweets, french fries, and high-fat dairy products [2,14]. This pattern of intake has been associated with increased risk of asthma in children [15,16]. Furthermore, in children, increased intake of fast food such as hamburgers and related eating behaviours, for example salty snack eating and frequent take away consumption, are correlated with the presence of asthma, wheezing and airway hyperresponsiveness (AHR) [17,18]. In adults, a western diet has been shown to be positively associated with increased frequency of asthma exacerbation [19], but not related to asthma risk. In addition, an acute challenge with a high fat fast food meal has been shown to worsen airway inflammation [20]. While this dietary pattern appears to be deleterious in children and adults with asthma, studies examining the effect of this dietary pattern in maternal diets have found no relationship with a consumption of a �western� style diet in pregnancy and risk of asthma in offspring [21]. Cross-sectional studies have also found that the �western� diet is associated with an increased risk of COPD [2]. In summary the Mediterranean diet appears to be protective in children, though there is less evidence for benefits in the maternal diet and in adults. There is evidence to suggest that a �western� style dietary pattern increases risk of asthma in children, has worse outcomes for adults with asthma and is related to COPD risk.

2.2. Fruit And Vegetables:�Respiratory Health

Fruit and vegetable intake has been investigated for potential benefits in association with respiratory conditions due to their nutrient profile consisting of antioxidants, vitamins, minerals, fibre and phytochemicals. The mechanisms by which the nutrients in fruit and vegetables exert beneficial effects in respiratory conditions are discussed in the sections below. Epidemiological evidence reviewed by Saadeh et al. [7] showed that fruit intake was associated with a low prevalence of wheezing and that cooked green vegetable intake was associated with a low prevalence of wheezing and asthma in school children aged 8�12 years old. Furthermore low vegetable intake in children was related to current asthma [7]. In adults, Grieger et al. [22] discusses the heterogeneous nature of the data describing fruit and vegetable intake and lung function, with one study showing no effect on lung function of higher fruit and vegetable intake over 10 years [23], yet in another study, increased fruit intake over 2 years was associated with increased FEV1 [23], while another study showed that a large decrease in fruit intake over 7 years was associated with decreased FEV1 [24]. We recently conducted an intervention in adults with asthma and found that subjects who consumed a high fruit and vegetable diet for 3 months, had a decreased risk of asthma exacerbation, compared to subjects who consumed a low fruit and vegetable diet [25]. A recent meta-analysis of adults and children, which analysed 12 cohorts, 4 population-based case-control studies, and 26 cross-sectional studies provides important new evidence showing that a high intake of fruit and vegetables reduces the risk of childhood wheezing, and that fruit and vegetable intake is negatively associated with asthma risk in adults and children [26]. While some studies of maternal diet have found no relationship with fruit and vegetable intake and asthma in children [27], other studies have found that increased fruit and vegetable intake were related to a decreased risk of asthma in children [21,28]. Increased fruit and vegetable intake may be protective against COPD development, with consumption of a �prudent� diet including increased fruit and vegetables being protective against lung function decline [3]. Two randomized controlled trials (RCT�s) manipulating fruit and vegetable intake have been conducted in COPD. A 12 week study showed no effect of a high fruit and vegetable intake on FEV1, systemic inflammation or airway oxidative stress [29]. However, a 3-year study in 120 COPD patients revealed an improvement in lung function in the high fruit and vegetable group compared to the control group [30], suggesting that longer term intervention is needed to provide a therapeutic effect. There is considerable evidence to suggest that a high intake of fruit and vegetables is favourable for all life stages of asthma and evidence is emerging which suggests the same in COPD.

2.3. Omega-3 Fatty Acids And Fish:�Respiratory Health

Omega-3 polyunsaturated fatty acids (PUFA) from marine sources and supplements have been shown to be anti-inflammatory through several cellular mechanisms including their incorporation into cellular membranes and resulting altered synthesis of eicosanoids [31]. Experimental studies have shown that long chain omega-3 PUFA�s decrease inflammatory cell production of pro-inflammatory prostaglandin (PG) E2, leukotriene (LT) B4 [32] and activity of nuclear factor-kappaB (NF-?B), a potent inflammatory transcription factor [33]. Long chain omega-3 PUFA�s also down regulate pro-inflammatory cell cytokine production (interleukin-1? (IL-1?), tumor necrosis factor-? (TNF-?)) by monocytes and macrophages, decrease expression of cellular adhesion molecules on monocytes and endothelial cells and reduce�production of ROS in neutrophils [34]. Saddeh et al. [7] reported that the evidence describing the relationship between omega-3 PUFA�s or fish consumption and respiratory conditions in childhood is contradictory. Some observational studies show that intake of oily fish is negatively associated with AHR and asthma [35,36]. However, evidence from Japan suggests that frequency of fish consumption is positively related to asthma risk [37] and in Saudi Arabia fish intake was not related to the presence of asthma or wheezing at all [18]. Similarly in adults, the data is heterogeneous, with omega-3 PUFAs or fish being associated with improved lung function [38] and decreased risk of asthma [39], AHR [35] and wheeze [36] in some, but not all studies [40]. Maternal dietary intake of oily fish was found to be protective of asthma in children 5 years of age if born to mothers with asthma [41] and a recent systematic review of omega-3 fatty acid supplementation studies in women during pregnancy found that the risk of asthma development in children was reduced [42]. The data examining the possible benefits of dietary omega-3 fatty acid supplementation in asthma are heterogeneous and as summarized by a 2002 Cochrane review [43], to date there is insufficient evidence to recommend omega-3 PUFA supplementation in asthma. Omega-3 PUFA may have positive effects in COPD, as higher levels of DHA in serum were found to decrease the risk of developing COPD [44]. Experimental studies in humans with COPD including supplementation with omega-3 found lower levels of TNF-? [45] and improved rehabilitation outcomes [46], though no improvements were seen in FEV1. Several studies using omega-3 PUFA supplementation in COPD are currently underway and will provide important new information to inform the field [47�49]. Consumption of oily fish or supplementation with omega-3 PUFA�s may have positive effects in asthma and COPD, though strong evidence to support the experimental and epidemiological data is not yet available.

3. Nutrients And Respiratory Disease

3.1. Antioxidants And Oxidative Stress

Dietary antioxidants are an important dietary factor in protecting against the damaging effects of oxidative stress in the airways, a characteristic of respiratory diseases [50]. Oxidative stress caused by reactive oxygen species (ROS), is generated in the lungs due to various exposures, such as air pollution, airborne irritants and typical airway inflammatory cell responses [51]. Also, increased levels of ROS generate further inflammation in the airways via activation of NF-?B and gene expression of pro-inflammatory mediators [52]. Antioxidants including vitamin C, vitamin E, flavonoids and carotenoids are abundantly present in fruits and vegetables, as well as nuts, vegetable oils, cocoa, red wine and green tea. Dietary antioxidants may have beneficial effects on respiratory health, from influences of the maternal diet on the fetus, and intake in children through to adults and pregnant women with asthma and adults with COPD. ?-tocopherol is a form of vitamin E, which helps maintain integrity of membrane fatty acids, by inhibiting lipid peroxidation [22]. Carotenoids are plant pigments and include; ?- and ?-carotene, lycopene, lutein and ?-cryptoxanthin. This group of fat soluble antioxidants have been shown to benefit respiratory health due to their ability to scavenge ROS and reduce oxidative stress [22]. The antioxidant lycopene, present predominantly in tomatoes, may be beneficial in respiratory conditions, indeed lycopene intake has been positively correlated with FEV1 in both asthma and COPD [53] and an�intervention study in asthma showed that lycopene supplementation could suppress neutrophilic airway inflammation [54]. Antioxidants may also be important in asthma during pregnancy, as while oxidative stress commonly increases during normal pregnancies, in women with asthma oxidative stress is heightened [55]. During pregnancy there is a compensatory increase in circulating and placental antioxidants in asthma versus women without asthma, to protect the foetus against damaging effects of oxidative stress [55,56]. Improving antioxidant intake in pregnant women with asthma may be beneficial as poor fetal growth outcomes are associated with low levels of circulating antioxidants and dietary antioxidants are the first defense mechanism against ROS [22]. Maternal intake of vitamin E, vitamin D, milk, cheese and calcium during pregnancy are negatively associated, while vitamin C is positively associated, with wheezing in early childhood [57,58]. Antioxidants including lycopene appear to have positive influences in respiratory conditions, further detail is provided below on evidence for vitamin C, vitamin E and flavonoids and their role in the maternal diet, diets of children and adults with asthma and adults with COPD.

3.2. Vitamin C:�Respiratory Health

Vitamin C has been enthusiastically investigated for benefits in asthma and links to asthma prevention. In vitro data from endothelial cell lines showed that vitamin C could inhibit NF-?B activation by IL-1, TNF-? and block production of IL-8 via mechanisms not dependent on the antioxidant activity of vitamin C [59]. Anti-inflammatory and anti-asthmatic effects of vitamin C supplementation in vivo, have been shown through allergic mouse models of asthma. Jeong et al. [60] reported decreased AHR to methacholine and inflammatory cell infiltration of perivascular and peribronchiolar spaces when vitamin C was supplemented during allergen challenge. While Chang et al. [61] found that high dose Vitamin C supplementation in allergen challenged mice decreased eosinophils in BALF and increased the ratio of Th1/Th2 cytokine production shifting the inflammatory pattern to Th1 dominant. Observational studies in children showed consumption of fruit, a rich source of vitamin C, was related to reduced wheezing [62] and vitamin C intake was negatively associated with wheezing [63], while another study reported no relationship between vitamin C intake and lung function [64]. Grieger et al. [22] also reported conflicting evidence for effects of vitamin C intake in adults, with epidemiological studies showing a positive association between vitamin C intake and lung function in some [65], but not all studies [23,66]. Despite the observational data linking vitamin C to lung health, supplementation with vitamin C has not been shown to reduce the risk of asthma [66] which may be related to the interdependence of nutrients found in foods, resulting in lack of efficacy when supplementing with isolated nutrients. Evidence from experimental and observational studies suggests that Vitamin C might be important in COPD pathogenesis and management. Koike et al. [67] reported that in knock out mice unable to synthesize vitamin C, vitamin C supplementation was able to prevent smoke induced emphysema and also to restore damaged lung tissue and decrease oxidative stress caused by smoke induced emphysema. A case control study in Taiwan reported that subjects with COPD had lower dietary intake and lower serum levels of vitamin C than healthy controls [68]. Indeed an epidemiological study in the United Kingdom of over 7000 adults aged 45�74 years found that increased plasma vitamin C concentration was associated with a decreased risk of obstructive airways disease, suggestive of a protective effect [69]. Thus, in summary, while observational data has suggested that vitamin C is important for lung health, intervention trials�showing efficacy are lacking and it appears that supplementation with vitamin C-rich whole foods, such
as fruit and vegetables may be more effective.

3.3. Vitamin E:�Respiratory Health

The vitamin E family comprises of 4 tocopherols and 4 tocotrienols, with the most plentiful in the diet or in tissues being ?-tocopherol and ?-tocopherol [70]. Vitamin E works synergistically with vitamin C, as following neutralisation of ROS, oxidised vitamin E isoforms can be processed back into their reduced form by vitamin C [71]. Abdala-Valencia et al. [72] discuss the evidence for the roles of ?-tocopherol and ?-tocopherol in allergic lung inflammation in mechanistic animal studies and clinical trials. Supplementation of mice with ?-tocopherol reduced allergic airway inflammation and AHR [73], while ?-tocopherol was pro-inflammatory and augmented AHR, negating the positive effects of ?-tocopherol [74]. Other animal studies report that ?-tocopherol may assist in resolving inflammation caused by ozone exposure and endotoxin induced neutrophilic airway inflammation, owing to its ability to oxidize reactive nitrogen species [75,76]. A study in humans showed that both ? and ?-tocopherol may be effective in decreasing LPS induced neutrophilic inflammation [77]. The conflicting results from these supplementation studies are likely to be influenced by baseline tissue levels of vitamin E [72], with ?-tocopherol supplementation leading to improved lung function and wheeze in Europe, where ?-tocopherol levels are low [78�80], but not in the US, where ?-tocopherol intake is high due to soybean oil consumption [81�83]. As a result, meta-analysis of vitamin E effects on asthma outcomes is equivocal; it is likely that supplementation with physiological concentrations of ?-tocopherol in the context of a background diet low in ?-tocopherol, may be most beneficial in asthma and further research testing this hypothesis is required. In COPD, serum levels of vitamin E have been shown to be decreased during exacerbation, which suggests increased intake may be helpful to improve vitamin E concentrations [84]. Vitamin E has been shown to reduce biomarkers of oxidative stress in adults with COPD in one RCT [85], but not another [86]. In the Women�s Health Study (n = 38,597), the risk of developing chronic lung disease over a 10 year supplementation period was reduced by 10% in women using vitamin E supplements (600 IU on alternate days) [87]. Dietary intake of vitamin E lower than recommended dietary intakes has been reported in pregnant women with a family history of allergic disease [88] and recent work in animal models has highlighted ?-tocopherol may be important for allergic mothers in pregnancy. Allergic female mice were supplemented with ?-tocopherol prior to mating and following allergen challenge the offspring showed reduced response to allergen challenge with decreased eosinophils in BALF [89]. The offspring also showed reduced development of lung dendritic cells, necessary for producing allergic responses. Evidence from observational studies also suggests that reduced maternal dietary intake of vitamin E is related to an increased risk of childhood asthma and wheeze [90�92] and increased in vitro proliferative responses in cord blood mononuclear cells (CBMC) [93]. A mechanistic study by Wassall et al. [94] examined the effect of ?-tocopherol and vitamin C on CBMC and maternal peripheral blood mononuclear cells (PBMC). ?-tocopherol was mostly anti-inflammatory, although increased proliferation and increased TGF-? were seen with some allergens. However, the addition of vitamin C to the system had inflammatory actions, with increased production of pro-inflammatory cytokines, combined with reduced production of IL-10 and TGF-?. This study by Wassall et al. [94] demonstrates that supplementation�with these antioxidants does modulate immune responses in pregnancy, however several of the results are unexpected, highlighting the complex nature of the relationships between dietary nutrients and disease. In asthma the experimental data for vitamin E are compelling, yet supplementation benefits are not well described. In COPD there is currently not enough evidence to make conclusions about vitamin E supplementation.

3.4. Flavonoids:�Respiratory Health

Flavonoids are potent antioxidants and have anti-inflammatory as well as anti-allergic actions due in part, to their ability to neutralise ROS [95]. There are 6 classes of flavonoids including flavones, flavonols, flavanones, isoflavones and flavanols [96], which are widely distributed throughout the diet and found in fruit, vegetables, nuts, seeds, stems, flowers, roots, bark, dark chocolate, tea, wine and coffee [96]. Tanaka et al. [95] present the evidence for the benefits of dietary flavonoids in asthma development and progression. In addition to reducing oxidative stress, in vitro experiments have found that many individual flavonoids have inhibitory effects on IgE mediated immune responses such as histamine secretion by mast cells, shift in cytokine production from Th-2 to Th-1 production and decreased NF-?B activation and inhibition of TNF-? [97�100]. Experimental studies of flavonoids in animal models of allergic asthma have shown reduced airway and peripheral blood inflammation, decreased bronchoconstriction and AHR and lower eosinophils in BALF, blood and lung tissue [101�104]. In humans, evidence from a case control study in adults showed that apple and red wine consumption, rich sources of flavonoids, was associated with reduced asthma prevalence and severity [66]. However a follow-up study investigating intake of 3 subclasses of flavonoids did not find any associations with asthma prevalence or severity [105]. There are a limited number of experimental studies using flavonoid supplements in humans with asthma. Three RCT�s in adults with asthma using a product called pycnogenol, which contains a mixture of bioflavonoids, reported benefits including increased lung function, decreased symptoms and reduced need for rescue inhalers [106]. There is a paucity of evidence for the effects of flavonoids in the maternal diet and respiratory outcomes in children. One study which found a positive association of maternal apple intake and asthma in children at 5 years, suggests that the flavonoid content of apples may be responsible for the beneficial relationship [107]. Evidence for the effects of flavonoids in respiratory conditions is emerging and promising. Though like vitamin C, it may be difficult to disentangle the effects of flavonoids from other nutrients in flavonoid-rich foods. Supplementation of individual flavonoids in experimental animal studies has provided evidence to suggest that intervention trials in humans may be warranted.

3.5. Vitamin D:�Respiratory Health

Epidemiological studies show promising associations between vitamin D and lung health; however the mechanisms responsible for these effects are poorly understood. Vitamin D can be obtained from dietary sources or supplementation; however sun exposure is the main contributor to vitamin D levels [108]. While vitamin D has beneficial effects independent of UV exposure [109], it can be difficult to separate this potential confounder from direct effects of vitamin D on lung health [110]. The review by Foong and Zosky [111] presents the current evidence for the role of vitamin D deficiency in disease onset, progression and exacerbation in respiratory infections, asthma and COPD. Respiratory infections contribute to disease progression and exacerbation in both COPD and asthma. Vitamin D appears to have a protective role against the susceptibility to and severity of these infections [111], as active vitamin D (1,25 (OH)2D) modifies production of antimicrobial cathelicidins and defensins that kill bacteria and induce wound repair [112]. Activated vitamin D also decreases the expression of rhinovirus receptors in endothelial cell cultures and PBMC�s [113]. In vitro studies also support the link between vitamin D and airway remodelling as active vitamin D inhibits airway smooth muscle (ASM) cell proliferation [114] and deficiency impairs normal lung development [115]. Furthermore, animal models suggest that vitamin D can inhibit Th1 and Th2 cell cytokine production [116]. Epidemiological evidence links low levels of vitamin D with wheeze and respiratory infections, though evidence for the link with asthma onset is weak and inconsistent [111]. In children, low circulating vitamin D was related to lower lung function, increased corticosteroid use and exacerbation frequency [117]. Also in children with steroid resistant asthma, low vitamin D was related to increased ASM thickness [117]. Other observational studies report that in children, low levels of vitamin D are associated with asthma exacerbation [118]. Several observational studies support the role of vitamin D for protection against respiratory conditions in children. Zosky et al. [119] found that vitamin D deficiency at 18 weeks gestation was associated with lower lung function and current wheeze in children 6 years of age and an increased risk of asthma in boys. The role for vitamin D in enhancing steroid responsiveness suggested by observational studies [120] is supported by mechanistic studies [121], and in concert with the actions of vitamin D in infection, may explain the effect of vitamin D in reducing asthma exacerbations [111]. Only one intervention trial has been conducted using vitamin D in adults with asthma, which found that rate of first exacerbation was reduced in subjects who demonstrated an increase in circulating vitamin D3 following supplementation [122]. Data for the role of vitamin D in COPD onset is limited, though several cross-sectional studies have reported an association between low vitamin D levels, or deficiency, with COPD incidence [123]. Blood vitamin D levels have also been correlated with lung function in COPD patients [124,125]. Experimental data suggest that vitamin D may be important in COPD for its effect on normal lung growth and development, though human data to support this is not available. It is possible that COPD onset may also be impacted by cellular responses to cigarette smoke exposure which inhibits the protective immunomodulatory effects of vitamin D [126]. There is research suggesting a genetic link between vitamin D and COPD pathogenesis. In an observational study single nucleotide polymorphisms in the vitamin D binding protein (VDBP) predicted vitamin D levels in COPD patients and were found to be a risk factor for COPD [123]. The VDBP is also involved in macrophage activation as high levels of airway VDBP are related to increased macrophage activation, also high levels of serum VDBP were found to be related to lower lung function [127]. COPD progression may also be affected by vitamin D status through absence of the vitamin D receptor and parenchyma degradation [128]. COPD exacerbations are generally caused by viral or bacterial lung infections, and though vitamin D has a positive role in reducing infection, there is no evidence to support that vitamin D is associated with ameliorating exacerbations in COPD patients [129]. The extra-skeletal effects of vitamin D are well documented in both asthma and COPD, and deficiency is associated with negative respiratory and immune outcomes. At this stage however, more evidence from supplementation interventions is needed before widespread adoption of supplementation can be recommended.

3.6. Minerals:�Respiratory Health

Some minerals have also been found to be protective in respiratory conditions. In children, increased intake of magnesium, calcium and potassium is inversely related to asthma prevalence [7]. While several observational and experimental trials have been performed with conflicting results [130], a randomised controlled trial concluded that a low sodium diet had no therapeutic benefit for bronchial reactivity in adults with asthma [131]. Dietary magnesium may have beneficial bronchodilator effects in asthma [132]. Low dietary magnesium intake has been associated with negative effects on bronchial smooth muscle in severe asthma [133] and with lower lung function in children [134]. However further evidence of positive therapeutic effects are required before its importance in asthma and recommendations can be determined [135]. Dietary intake of selenium has been shown to be lower in asthmatics compared to non-asthmatics [136] and maternal plasma selenium levels were reported to be inversely associated with risk of asthma in children [137]. However case control studies in children have not found a relationship with selenium levels or intake with asthma related outcomes [18,138]. Furthermore, results from a large well designed RCT in adults with asthma showed no positive benefit of selenium supplementation [139]. Investigation of minerals in cord blood imply the importance of adequate intake during pregnancy, as levels of cord blood selenium were negatively associated with persistent wheeze, and levels of iron were negatively associated with later onset wheeze in children [140]. Studies on dietary intake of minerals and associations with COPD are sparse. A small study in Sweden found that in older subjects with severe COPD, intakes of folic acid and selenium were below recommended levels, and although intake of calcium was adequate, serum calcium levels were low, likely related to their vitamin D status as intake was lower than recommended [141]. Mineral intake may be important in respiratory diseases, yet evidence for supplementation is weak. It is likely that adequate intake of these nutrients in a whole diet approach is sufficient.

4. Obesity, Adipokines And Respiratory Disease

Overnutrition and resulting obesity are clearly linked with asthma, though the mechanisms involved are still under investigation. The review by Periyalil et al. [142] describes how immunometabolismadipose tissue derived immunological changes causing metabolic effects [143] contributes to the link between asthma and obesity. In the obese state dietary intake of lipids leads to increased circulating free fatty acids [144], which activate immune responses, such as activation of TLR4, leading to increased inflammation, both systemically and in the airways [20]. Adipose tissue also secretes adipokines and asthmatic subjects have higher concentrations of circulating leptin than healthy controls [14] which are further increased in females, though leptin is associated with BMI in both males and females [145]. Leptin receptors are present in the bronchial and alveolar epithelial cells and leptin has been shown to induce activation of alveolar macrophages [146] and have indirect effects on neutrophils [147]. Also leptin promotes Th1 proliferation inducing increased activation of neutrophils by TNF-? [148]. In vitro, leptin also activates alveolar macrophages taken from obese asthmatics, which induces airway inflammation through production of pro-inflammatory cytokines [149]. However, a causal role for leptin in the obese asthma relationship is yet to be established. Adiponectin, an anti-inflammatory adipokine, has beneficial effects in animal models of asthma [150], however, positive associations in human studies have only been seen in women [151]. In obesity, macrophage and mast cell infiltration into adipose tissue is upregulated [142]. Neutrophils also appear to dominate airway inflammation in the obese asthma phenotype [152], particularly in females [153], which may explain why inhaled corticosteroids are less effective in achieving control in obese asthma [154]. While the mechanisms are yet to be understood, a recent review reports that obesity in pregnancy is associated with higher odds of asthma in children, with increased risk as maternal BMI increases [155].

COPD is characterised not only by pulmonary deficits but also by chronic systemic inflammation and co-morbidities which may develop in response to the metabolic dysregulation that occurs with excess adipose tissue [156]. A recent meta-analysis of leptin levels in COPD reported a correlation with body mass index (BMI) and fat mass percent in stable COPD though absolute levels were not different to healthy controls [157]. During exacerbation, leptin levels increased and were positively associated with circulating TNF-? [157]. Bianco et al. [158] describes the role of adiponectin and its effect on inflammation in COPD. Adiponectin has anti-inflammatory effects and is present in high concentrations in serum of healthy subjects [159]. Adiponectin exists in several isoforms, which have varied biological effects [160] and interact with two receptors present in the lungs (AdipoR1 and AdipoR2) that have opposing effects on inflammation [161]. Single nucleotide polymorphisms in the gene encoding adiponectin are associated with cardiovascular disease, obesity and the metabolic syndrome [162]. The role of adiponectin in COPD however is not well understood. In COPD, serum adiponectin is increased and directly relates to disease severity and lung function decline [163]. There is an alteration in the oligomerisation of adiponectin in COPD resulting in increased concentrations of the anti-inflammatory higher-molecular weight isoform [164], and the expression of adiponectin receptors in the lung is also altered in comparison to healthy subjects [165]. Animal models have shown anti-inflammatory effects of adiponectin in the lung through the increased expression of TNF-? in alveolar macrophages in adiponectin deficient mice [166]. Further mechanistic studies have also shown the anti-inflammatory potential of adiponectin by reducing the effects of TNF-?, IL-1? and NF-?B and increasing expression of IL-10 through interaction with AdipoR1 [161]. However under certain conditions in cell lines and animal models adiponectin has been shown to have pro-inflammatory effects [167,168]. As both detrimental and protective effects have been seen, the complex modulation of adiponectin isoforms and receptors in COPD requires further exploration. Obesity, the resulting systemic inflammation and alterations in adipokines have significant negative effects in both asthma and COPD. While work examining the mechanisms of effect is extensive, evidence for interventions to improve the course of disease are limited to weight loss interventions in asthma at this stage.

5. Undernutrition And Respiratory Disease

Though underweight has not been well studied in asthma, an observational study in Japan reported that subjects with asthma who were underweight had poorer asthma control than their normal weight counterparts [169]. While there is widespread acknowledgement that malnutrition in pregnant women adversely effects of the lung development of the fetus [170], a recent review reported that the offspring of mothers who were underweight did not have an increased risk of asthma. Amongst the obstructive lung diseases, undernutrition is most commonly recognized as a feature of COPD. Itoh et al. [171] present a review on undernutrition in COPD and the evidence for nutritional therapy in management�of the disease. Weight loss, low body weight and muscle wasting are common in COPD patients with advanced disease and are associated with reduced survival time and an increased risk of exacerbation [172]. The causes of undernutrition in COPD are multifactorial and include reduced energy intake due to decreased appetite, depression, lower physical activity and dyspnoea while eating [173]. In addition, resting energy expenditure is increased in COPD, likely due to higher energy demands from increased work of breathing [174]. Also, systemic inflammation which is a hallmark of COPD, may influence energy intake and expenditure [175]. Cigarette smoke may also have deleterious effects on body composition in addition to the systemic effects of COPD. Smoking causes muscle fibre atrophy and decreased muscle oxidative capacity shown in cohorts of non-COPD smokers [176,177] and in animal models of chronic smoke exposure [178,179]. The mechanisms underlying muscle wasting in COPD are complex and multifaceted [180]. Increased protein degradation occurs in the whole body, though it is enhanced in the diaphragm [181]. Protein synthesis pathways are altered, indeed insulin like growth factor-1 (IGF-1) which is essential for muscle synthesis is decreased in cachectic COPD patients [182] and is lower in COPD patients during acute exacerbation, compared to healthy controls [183]. Increased oxidative stress, due to increased mitochondrial ROS production, occurs both systemically and in muscle tissue in cachectic COPD patients and is negatively associated with fat free mass (FFM) and muscle strength in COPD patients [184]. Furthermore myostatin induces muscle atrophy by inhibiting proliferation of myoblasts and mRNA expression of myostain is increased in cachectic COPD patients and is related to muscle mass [185]. Systemic inflammatory mediators such as TNF-? and NF-?B are also implicated in COPD muscle atrophy [186,187]. Nutritional supplementation therapy in undernourished COPD patients has been shown to induce weight gain, increase fat free mass, increase grip strength and exercise tolerance as well as improve quality of life [188]. Further studies point out the importance of not only high energy content, but also macronutrient composition of the nutritional supplement and inclusion of low intensity respiratory rehabilitation exercise [189,190]. Other dietary nutrients have been investigated for the benefits in COPD. Creatinine, found in meat and fish, did not have additive effects to rehabilitation, while sulforaphane, found in broccoli and wasabi, and curcumin, the pigment in turmeric, may have beneficial antioxidant properties [191�193]. Branched chain amino acid supplementation in COPD is associated with positive results including increases in whole body protein synthesis, body weight, fat free mass and arterial blood oxygen levels [194,195]. Undernutrition is not a significant problem in asthma, though is a major debilitating feature of COPD. There is promising evidence that nutritional supplementation in COPD is important and can help to alleviate some of the adverse effects of the disease, particularly muscle wasting and weight loss.

6. Conclusions: Respiratory Health

Dietary intake appears to be important in both the development and management of respiratory diseases, shown through epidemiological and cross-sectional studies and supported by mechanistic studies in animal models. Although more evidence is needed from intervention studies in humans, there is a clear link for some nutrients and dietary patterns. The dietary patterns associated with benefits in respiratory diseases include high fruit and vegetable intake, Mediterranean style diet, fish and omega-3 intake, while fast food intake and westernized dietary�patterns have adverse associations. Figure 1 shows a diagrammatic representation of the relationships of nutrition and obstructive lung diseases.

Respiratory Health

Though antioxidants are associated with positive effects on inflammation, clinical outcomes and respiratory disease prevention, intervention studies of individual antioxidants do not indicate widespread adoption of supplementation [196]. Differences in results from individual studies including whole foods such as fruit and vegetables and fish could be influenced by the nutritional profile owing to the region it was grown or produced. In considering studies using single nutrients it is also important to acknowledge that nutrients in the diet are consumed as whole foods that contain other micronutrients, fibre and compounds with both known and unknown anti and pro-inflammatory potential. Furthermore investigations of single nutrients should ideally control for other antioxidants and dietary sources of pro-inflammatory nutrients. While this limitation is common, it is a significant challenge to control for dietary intake of other nutrients in clinical trials. A whole foods approach to nutrient supplementation�for example, increasing intake of fruit and vegetables, has the benefit of increasing intake of multiple nutrients, including vitamin C, vitamin E, carotenoids and flavonoids and shows more promise in respiratory diseases in terms of reducing risk of COPD [3] and incidence of asthma exacerbations [25].

The evidence for mechanisms of vitamin D in lung development and immune function are yet to be fully established. It appears that vitamin D is important in respiratory diseases and infections, however the temporal role of vitamin D deficiency in disease onset, pathogenesis and exacerbations and whether supplementation is indicated is yet to be clarified.

Overnutrition in respiratory disease is clearly associated with adverse effects, highlighted by detrimental effects induced by immunometabolism. Further understanding of the relationship between mediators of immunometabolism and respiratory diseases and their mechanisms may provide therapeutic options. Undernutrition still poses risk in some respiratory conditions. Appropriate nutritional supplementation in advanced COPD is indicated, and several nutrients appear to be beneficial in COPD development and exacerbation.

The field of nutrition and respiratory disease continues to develop and expand, though further work is required in the form of randomized controlled dietary manipulation studies using whole foods to enable provision of evidence based recommendations for managing respiratory conditions.

Bronwyn S. Berthon and Lisa G. Wood *

Centre for Asthma and Respiratory Diseases, Level 2, Hunter Medical Research Institute,
University of Newcastle, Lot 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia;
E-Mail: bronwyn.berthon@newcastle.edu.au

* Author to whom correspondence should be addressed; E-Mail: lisa.wood@newcastle.edu.au;
Tel.: +61-2-4042-0147; Fax: +61-2-4042-0046.

Author Contributions

Bronwyn Berthon and Lisa Wood contributed to the study concept and design and were both involved in the preparation and completion of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

� 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).

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A Healthy Diet Benefits Your Life: 8 Wonderful Ways

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Diets

Healthy Diet: It’s hard to turn on the television or cruise the internet without being bombarded with headlines about “Americans don’t sleep enough” or “one third of adults are obese.”

While stress, heredity, and smoking are all factors that play into a person’s well being, one of the biggest is a healthy diet. Choosing to eat healthy benefits the body in a number of key areas. Still gobbling up the pizza and slurping down the diet soda, unconvinced? See if these eight points about a healthy diet change your mind.

1. Healthy Diet Strengthens & Improves Muscle Function

Healthy muscles carry us where we want to go. The right foods, along with proper exercise, build and maintain muscle mass, maintaining strength and mobility.

2. Promotes A Longer Life

Feeding your body what it needs can add years to your life. Reducing stress is one way to promote health, and a healthy diet is another. Foods rich in minerals and vitamins build up every cell in your body, preparing it to fight illness and stay alive longer.

3. Enables Richer Years

An individual who is healthy maintains a higher level of physical activity and brain function than their less healthy peers. A stronger body provides a richer life with more unique experiences.

4. Makes You Prettier

If you won’t eat healthy for your insides, maybe a better outside will motivate some dietary changes. We all want to be physically attractive. Healthy foods contribute to clear skin and shiny hair that no amount of high priced beauty products provides. Fueling the body with rich omega fatty and other healthy foods nourishes skin, hair, and nails.

5. Makes You Smarter

Research shows certain dietary choices power up your brain to function at a higher level, and help everyday brain function. Introducing “brain foods” into your diet aid with memory retention and problem solving skills.

This is one of the best reasons to commit to a healthy diet of vitamin-rich foods, as a healthy brain allows a much more active and independent lifestyle, from working longer to being able to drive.

6. Decreases Your Injury Risk

A high-functioning body with strong bones and muscles maintains balance, handles heavy loads, and holds up under stress better than its weaker counterparts. Muscles and bones lacking calcium and protein over time grow weaker.

This, unfortunately, causes the body to be less stable and more prone to injury. Falls, slips, and twists end up with more serious injuries if a person’s body isn’t strong and healthy.

7. Fights Bad Genes

If you are already worried about the cancer that runs on mom’s side or the heart attack risk that runs on dad’s side, take heart. While you can’t change your DNA, you can use a healthy diet to combat some of your genetic disposition to disease.

Ingraining a healthy diet into your life, as well as exercise and regular doctor checkups, helps minimize the risk of falling victim to your family’s predisposed illnesses.

If you end up with an illness, whether or not from heredity, a healthy diet….

8. Prepares You To Fight Illness

A nutrient-rich diet boosts a person’s immune system to be able to fight off infection and illness. When a person falls victim to a disease or other medical condition, their diet helps them fight it off so it hopefully doesn’t get worse and is cured quickly.

A healthy diet is integral to a long, happy life. Deciding to eat healthy and maintain that commitment consistently may seem like a big change in lifestyle at first, but it will benefit you and your loved ones in ways that are practically immeasurable.

Tips For Preventing Dehydration

This article is copyrighted by Blogging Chiros LLC for its Doctor of Chiropractic members and may not be copied or duplicated in any manner including printed or electronic media, regardless of whether for a fee or gratis without the prior written permission of Blogging Chiros, LLC.

Nutritional Tips Every Chiropractic Patient Should Follow

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Nutrition

Nutritional Tips: Chiropractic care effectively and naturally treats a multitude of conditions and diseases. The overall premise is to return the body to its natural alignment by removing subluxations, which takes care of the root cause of many problems.

Spinal adjustments, however, aren�t necessarily the Holy Grail for total health. It’s essential for chiropractic patients to also make adjustments in their everyday lives. By doing so, they�ll maximize the effects of their chiropractic treatments, and experience better overall health in general.

Nutrition is one of the biggest factors and plays a large role in a patient’s recovery. The old adage “you are what you eat” is true. Feeding the body with vital vitamins and minerals promotes growth and healing. Filling up on fried, fatty foods does the opposite.

Let’s Look At Four Nutritional Tips Every Chiropractic Patient Should Follow:

Watch Your Calories

Individuals recovering from spinal or other injuries heal quicker when they avoid carrying excess weight. This is especially true if the injury has sidelined them from normal physical exercise.

Choose lean cuts of meat and fresh fruits and vegetables, and practice portion control. A diet with few excess calories offers the dual benefit of helping you avoid packing on the pounds, and helping you heal faster.

Pay Attention To Calcium Intake

Bones need calcium for strength, so it should be a priority to consume foods that are rich with it. According to healthconsciousness.com, the four most calcium-rich foods are dark leafy greens, low-fat cheese, milk, and yogurt.

If you are visiting a chiropractor for issues or conditions concerning your bones or nerves, he or she may recommend that you introduce these foods into your diet as soon as possible.

Make Protein A Priority

Muscle injuries are one of the most popular reasons for chiropractic visits. Protein helps build and heal muscle tissue, helping it to renew itself back to a pre-injury state.

If your daily intake of protein is low, it can hinder the healing process and stand in the way of chiropractic visits giving you the maximum results. Fish and lean meats are the foods that offer the highest protein.

Other vegetarian options are tofu, soy beans, eggs, milk, and nuts. Help your muscles rebuild and heal by adding high protein foods into every meal menu.

Stay Hydrated

Why do most of us view water drinking with dread? Its not that bad! If you wish to promote healing, it’s imperative to drink enough water every day.

Water provides an entire slew of benefits, from transporting those important nutrients to where they need to be, to flushing harmful toxins out of the body. Aim for eight glasses of water a day, and try to drink it throughout the day.

Getting into this habit will boost overall health, and promote healing of injuries and other medical conditions.

While it’s a smart goal to try to ingest all the nutrients you need through food and drink, supplements are available to bridge the gap. Before beginning a supplement regimen, talk to you chiropractor for recommendations on the type and dosage that will aid and improve your unique situation.

You may also want to download a smartphone app to track your daily intake of calories, calcium, protein and liquid. There are many available, one being My Fitness Pal.

Easy and free to use, this is a powerful tool to keep you on the right nutritional track.

Making the commitment to chiropractic treatment is a big step in the right direction for your overall health and well-being. Incorporate these nutritional tips to your daily routine in order to get the most out of your chiropractic care.

Good Nutrition & Chiropractic Care Contribute To Overall Well-Being

Prostate Cancer, Nutrition And Dietary Interventions

by Dr Alex Jimenez DC, APRN, FNP-BC, CFMP, IFMCP | Cancer Health, Nutrition

Prostate Cancer: Abstract

Prostate cancer (PCa) remains a leading cause of mortality in US men and the prevalence continues to rise world-wide especially in countries where men consume a �Western-style� diet. Epidemiologic, preclinical and clinical studies suggest a potential role for dietary intake on the incidence and progression of PCa. ‘This minireview provides an overview of recent published literature with regard to nutrients, dietary factors, dietary patterns and PCa incidence and progression. Low carbohydrates intake, soy protein, omega-3 (w-3) fat, green teas, tomatoes and tomato products and zyflamend showed promise in reducing PCa risk or progression. A higher saturated fat intake and a higher ?-carotene status may increase risk. A �U� shape relationship may exist between folate, vitamin C, vitamin D and calcium with PCa risk. Despite the inconsistent and inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa is promising. The combination of all the beneficial factors for PCa risk reduction in a healthy dietary pattern may be the best dietary advice. This pattern includes rich fruits and vegetables, reduced refined carbohydrates, total and saturated fats, and reduced cooked meats. Further carefully designed prospective trials are warranted.

Keywords: Diet, Prostate cancer, Nutrients, Dietary pattern, Lifestyle, Prevention, Treatment, Nutrition, Dietary intervention, Review

Introduction: Prostate Cancer

Prostate cancer (PCa) is the second most common cancer in men, with nearly a million new cases diagnosed worldwide per year [1], with approximately a six-fold higher incidence in Western than in non-Western countries. Diet, lifestyle, environmental and genetic factors are hypothesized to play a role in these differences. This review focuses on the latest evidence of the potential role of dietary factors on PCa and includes epidemiologic and clinical trial evidence for the impact of protein, fat, carbohydrate, fiber, phytochemicals, other food components, whole foods and dietary patterns on PCa incidence, development and/or progression. Data from meta-analyses or well-designed randomized trials and prospective studies are emphasized in this review. It should be noted that studies of dietary intake or nutrition and cancer are often subject to various limitations and thus complicate interpretation of results. For example, when a study is designed to examine the effect of the amount of fat intake, alteration in fat intake inevitably will change intake of protein and/or carbohydrate, and may change the intake of other nutrients as well. As a result, it is difficult to attribute the effect to change in fat intake alone. In addition, the impact of macronutrients potentially involves aspects of both absolute quantity and the type of macronutrients consumed. Both aspects may potentially affect cancer initiation and/or development independently, but they are not always distinguishable in research designs. Though this topic was recently reviewed [2], given the extensive new literature on the topic, an updated review is presented herein and a summary table is provided for a quick reference (Table 1).

Nutrients Carbohydrates Given the hypothesis that insulin is a growth factor for PCa, it has been hypothesized that reducing carbohydrates and thus lowering serum insulin may slow PCa growth [3]. Indeed, in animal models, either a no-carbohydrate ketogenic diet (NCKD) [4,5] or a low-carbohydrate diet (20% kcal as carbohydrate) has favorable effects on slowing prostate tumor growth [6,7]. In human studies, one�study found that high intake of refined carbohydrates was associated with increased risk of PCa [7]. In addition to the amount of carbohydrates, type of carbohydrates may impact on PCa but research has been inconclusive. The potential to reduce PCa risk and progression via impacting carbohydrate metabolism is actively being investigated with Metformin. Metformin reduced PCa cell proliferation and delayed progression in vitro and in vivo, respectively [8-10] and reduced incident risk and mortality in humans [11-13]. Two single arm clinical trials also showed a positive effect of metformin in affecting markers of PCa proliferation and progression [14,15]. However, other retrospective cohort studies have not supported an effect of metformin on recurrence or incident risk of PCa [16-22]. Despite the potential for reducing either total or simple carbohydrates in benefiting PCa control, evidence is lacking from randomized controlled trials (RCT). Two randomized trials are on-going examining the impact of a low-carbohydrate diet (approximately 5% kcal) on the PSA doubling time among PCa patients post radical prostatectomy (NCT01763944) and on glycemic response among patients initiating androgen deprivation therapy (ADT) (NCT00932672 ). Findings from these trials will shed light on the effect of carbohydrate intake on markers of PCa progression and the role of reduced carbohydrate intake on offsetting the side effects of ADT.

Protein

The ideal level of protein intake for optimal overall health or prostate health is unclear. Despite the popularity of low carbohydrate diets that are high in protein, recent human studies reported that low protein intake was associated with lower risk for cancer and overall mortality among men 65 and younger. Among men older than 65, low protein intake was associated with a higher risk for cancer and overall mortality [23]. In animal models the ratio between protein and carbohydrate impacted on cardiometabolic health, aging and longevity [24]. The role of dietary protein and the protein to carbohydrate ratio on PCa development and progression requires further study.

Animal-Based Proteins

Studying protein intake, like all aspects of nutritional science, can be challenging. For example, animal meat, which is a source of protein in Western diets, is composed not only of protein, but also of fat, cholesterol, minerals and other nutrients. The amount of these nutrients including fatty acids may vary from one animal meat to the other. Previous studies in human have shown that consumption of skinless poultry, which is lower in cholesterol and saturated fat than many red meats, was not associated with the recurrence or progression of PCa [25]. However, consumption of baked poultry was inversely associated with advanced PCa [26,27], while cooked red meat was associated with increased advanced PCa risk [26,27]. Thus, how the food is prepared may modify its impact on PCa risk and progression. Overall, fish consumption may be associated with reduced PCa mortality, but high temperature cooked fish may contribute to PCa carcinogenesis [28]. Thus, it may be advisable to consume fish regularly but cooking temperature should be kept moderate.

Dairy-Based Protein

Another common protein source is dairy products, such as milk, cheese and yogurt. Previous studies have shown that dairy increased overall PCa risk but not with aggressive or lethal PCa [29,30]. In addition, both whole milk and low-fat milk consumption were reported to either promote or delay PCa progression [29,31]. In the Physicians Health follow up cohort with 21,660 men, total dairy consumption was found to be associated with increased PCa incidence [32]. In particular, low fat or skim milk increased low grade PCa, whereas whole milk increased fatal PCa risk. Though the exact component(s) of dairy products driving these associations is unknown, the high concentrations of saturated fat and calcium may be involved. A cross-sectional study of 1798 men showed that dairy protein was positively associated with serum IGF-1 [33] levels which may stimulate initiation or progression of PCa. Thus, further research is needed to clarify the relationship between dairy intake and PCa. There is insufficient data to provide recommendations specifically related to dairy or dairy protein and PCa risk or progression.

Plant-Based Proteins

Soy and soy-based products are rich in protein and phytoestrogens that may facilitate PCa prevention, but its role on PCa is unclear. In a study in mice, intake of soy products was associated with decreased hepatic aromatase, 5?-reductase, expression of androgen receptor and its regulated genes, FOXA1, urogenital tract weight and PCa tumor progression [34]. A recent randomized trial of 177 men with high-risk disease after radical prostatectomy found that soy protein supplementation for two years had no effect on risk of PCa recurrence [35]. Although epidemiological and pre-clinical studies [36,37] support a potential role for soy/soy isoflavones in PCa risk reduction or progression, a meta-analysis did not find significant impact of soy intake in PSA levels, sex hormone-binding globulin, testosterone, free testosterone, estradiol or dihydrotestosterone [38]. Another RCT in patients before prostatectomy also did not find any effect of soy isoflavone supplement up to six weeks on PSA, serum total testosterone, free testosterone, total estrogen, estradiol or total cholesterol [39]. Since most RCTs�conducted have been small and of short duration, further examination is needed.

Many studies have continued to examine the primary isoflavone in soy, genistein, and its effect on PCa. The potential for genistein to inihibit PCa cell detachment, invasion and metastasis is reported [40]. Genistein may modify glucose update and glucose transporter (GLUT) expression in PCa cells [41], or exert its anti-tumor effect by down regulating several microRNAs [42]. Studies using tumor cells and animal models suggest genistein may compete with and block endogenous estrogens from binding to the estrogen receptor, thereby inhibiting cellular proliferation, growth, and inducing differentiation and, specifically, genistein may inhibit cell detachment, protease production, cell invasion and thus prevent metastasis [36,40,43]. However, neither plasma nor urinary genistein levels were associated with PCa risk in case control studies [44,45]. In a phase 2 placebo-controlled RCT with 47 men, supplementation of 30 mg genistein for three to six weeks significantly reduced androgen-related markers of PCa progression [46]. In addition, genistein may be beneficial in improving cabazitaxel chemotherapy in metastatic castration-resistant PCa [37]. Clinical studies are warranted to further examine the role of soy and soy isoflavones for PCa prevention or treatment. A definitive recommendation regarding protein intake for PCa prevention or treatment is not available yet.

Fat

Research findings examining fat consumption with PCa risk or progression are conflicting. Both the total absolute intake [47] of dietary fat and the relative fatty acid composition may independently relate to PCa initiation and/or progression. While animal studies repeatedly show that reducing dietary fat intake slows tumor growth [48-50] and high fat diets, especially animal fat and corn oil increase PCa progression [51], human data are less consistent. Case�control studies and cohort studies have shown either no association between total fat consumption and PCa risk [52-55] or an inverse association between fat intake and PCa survival, particularly among men with localized PCa [47]. In addition, a cross-sectional study showed that fat intake expressed as percent of total calorie intake was positively associated with PSA levels in 13,594 men without PCa [56]. Given these conflicting data, it is possible that the type of fatty acid [56] rather than total amount may play an important role in PCa development and progression. A study found plasma saturated fatty acids to be positively associated with PCa risk in a prospective cohort of 14,514 men of the Melbourne Collaborative Cohort Study [57]. In addition, another study found that eating more plant-based fat was associated with reduced PCa risk [58]. These studies support the current dietary guideline of eating less animal-based fat and more plant-based fat.

The data regarding omega-6 (w-6) and omega-3 (w-3) polyunsaturated fatty acid (PUFA) consumption and PCa risk are also conflicting. While there are data to support a link between increased w-6 PUFA intake (mainly derived from corn oil) and risk of overall and high-grade PCa [57,59], not all data support such a link [60]. In fact, a greater polyunsaturated fat intake was associated with a lower all cause mortality among men with nonmetastatic PCa in the Health Professionals Follow-up study [58]. The postulated mechanism linking w-6 PUFAs and PCa risk is the conversion of arachidonic acid (w-6 PUFA) to eicosanoids (prostaglandin E-2, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids) leading to inflammation and cellular growth [61]. Conversely, w-3 PUFAs, which are found primarily in cold water oily fish, may slow growth of PCa through a number of mechanisms [61-63]. In a study of 48 men with low risk PCa under active surveillance, repeat biopsy in six months showed that prostate tissue w-3 fatty acids, especially eicosapentaenoic acid (EPA), may protect against PCa progression [64]. In vitro and animal studies suggest that w-3 PUFAs induce anti-inflammatory, pro-apoptotic, antiproliferative and anti-angiogenic pathways [65,66]. Moreover, a mouse study comparing various types of fat found that only the fish oil diet (that is, omega-3 based diet) slowed PCa growth relative to other dietary fats [67]. In regards to human data, a phase II randomized trial showed that a low-fat diet with w-3 supplementation four to six weeks prior to radical prostatectomy decreased PCa proliferation and cell cycle progression (CCP) score [62,68]. A low-fat fish oil diet resulted in decreased 15(S)- hydroxyeicosatetraenoic acid levels and lowered CCP score relative to a Western diet [69]. The potential benefits of omega-3 fatty acids from fish are supported by epidemiological literature showing that w-3 fatty acid intake was inversely associated with fatal PCa risk [70,71]. Despite the promise of omega-3 fatty acids, not all studies agree. Supplementing 2 g alpha-linolenic acid (ALA) per day for 40 months in 1,622 men with PSA <4 ng/ml did not change their PSA [72]. However, another study found that a high blood serum n-3 PUFA and docosapentaenoic acid (DPA) was associated with reduced total PCa risk while high serum EPA and docosahexaenoic acid (DHA) was possibly associated with increased high-grade PCa risk [73]. Further research is required to understand better the role of omega-3 PUFAs in PCa prevention or treatment.

Cholesterol

Many pre-clinical studies have shown that the accumulation of cholesterol contributes to the progression of PCa [74-76]. It was suggested that a high cholesterol in Lin et al. BMC Medicine (2015) 13:3 Page 5 of 15 circulation may be a risk factor for solid tumors, primarily through the upregulation of cholesterol synthesis, inflammatory pathways [77] and intratumoral steroidogenesis [78]. According to a recent study with 2,408 men scheduled for biopsy, serum cholesterol was independently associated with prediction of PCa risk [79]. Consistent with the cholesterol findings, usage of the cholesterol lowering drug statin post radical prostatectomy (RP) was significantly associated with reduced risk of biochemical recurrence in 1,146 radical prostatectomy patients [80]. Another study also showed that statins may reduce PCa risk by lowering progression [81]. Although the mechanism has not been established, more recent studies also showed that a low high-density lipoprotein (HDL) cholesterol level was associated with a higher risk for PCa and, thus, a higher HDL was protective [81-84]. These findings support the notion that a heart-healthy dietary intervention that lowers cholesterol may benefit prostate health also.

Vitamins & Minerals

Herein we will review the recent data on vitamins A, B complex, C, D, E, and K and selenium. In the two large clinical trials: the Carotene and Retinol Efficacy Trial (CARET; PCa was a secondary outcome) and the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health prospective cohort study, excessive multivitamin supplementation was associated with a higher risk of developing aggressive PCa, particularly among those taking individual ?-carotene supplements [85,86]. Similarly, high serum ?-carotene levels were associated with a higher risk for PCa among 997 Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor cohort [87]. However, ?-carotene supplement was not found to affect risk for lethal PCa during therapy [88], or in the Danish prospective cohort study of 26,856 men [89]. Circulating retinol also was not associated with PCa risk in a large case�control study [90]. Thus, the association between vitamin A and PCa is still unclear.

Preclinical evidence suggests folate depletion may slow tumor growth, while supplementation has no effect on growth or progression, but may directly lead to epigenetic changes via increases in DNA methylation [91]. Two meta-analyses also showed that circulating folate levels were positively associated with an increased risk of PCa [92,93], while dietary or supplemental folate had no effect on PCa risk [94] in a cohort study with 58,279 men in the Netherlands [95] and a case�control study in Italy and Switzerland [96]. In fact, one study of a cohort of men undergoing radical prostatectomy at several Veterans Administration facilities across the US even showed that higher serum folate levels were associated with lower PSA and, thus, lower risk for biochemical failure [97]. Another study using data from the 2007 to 2010 National Health and Nutrition Examination Survey showed that a higher folate status may be protective against elevated PSA levels among 3,293 men, 40-years old and older, without diagnosed PCa [98]. It was suggested that folate may play a dual role in prostate carcinogenesis and, thus, the complex relationship between folate and PCa awaits further investigation [99].

Despite the potential role of vitamin C (ascorbic acid) as an antioxidant in anticancer therapy, trials examining dietary intake or supplementation of vitamin C are few. A RCT showed no effect of vitamin C intake on PCa risk [89]. Furthermore, vitamin C at high doses may act more as a pro-oxidant than antioxidant, complicating the research design and interpretation.

The primary active form of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol) aids in proper bone formation, induces differentiation of some immune cells, and inhibits pro-tumor pathways, such as proliferation and angiogenesis, and has been suggested to benefit PCa risk [100]; however, findings continue to be inconclusive. More recent studies found that increased serum vitamin D levels were associated with decreased PCa risk [101,102]. Further, supplementing vitamin D may slow PCa progression or induce apoptosis in PCa cells [103-105]. Other studies, however, reported either no impact of vitamin D supplement on PSA [106] or no effect of vitamin D status on PCa risk [107,108]. Some studies contrarily reported that a lower vitamin D status was associated with a lower PCa risk in older men [109], or a higher serum vitamin D was associated with a higher PCa risk [110,111]. A study even suggested that a �U� shaped relationship may exist between vitamin D status and PCa and the optimal range of circulating vitamin D for PCa prevention may be narrow [112]. This is consistent with the findings for other nutrients that a greater intake of a favorable nutrient may not always be better.

A recent study showed that the association between vitamin D and PCa was modulated by vitamin D-binding protein [113] which may have partially explained the previous inconsistent findings. Further, a meta-analysis investigating the association between Vitamin D receptor (VDR) polymorphisms (BsmI and FokI) and PCa risk reported no relationship with PCa risk [114]. Thus, the role of vitamin D in PCa remains unclear.

In a large randomized trial with a total of 14,641 US male physicians ?50-years old, participants randomly received 400 IU of vitamin E every other day for an overall mean of 10.3 (13.8) years. Vitamin E supplementation had no immediate or long-term effects on the risk of total cancers or PCa [115]. However, a moderate dose of vitamin E supplement (50 mg or about 75 IU) resulted in lower PCa risk among 29,133 Finnish male smokers [116]. Multiple preclinical studies suggest vitamin E slows tumor growth, partly due to inhibiting DNA synthesis and inducing�apoptotic pathways [117]. Unfortunately, human studies have been less than supportive. Two observational studies (the Cancer Prevention Study II Nutrition Cohort and the NIH-AARP Diet and Health Study) both showed no association between vitamin E supplementation and PCa risk [118,119]. However, a higher serum ?-tocopherol but not the ?-tocopherol level was associated with decreased risk of PCa [120,121] and the association may be modified by genetic variations in vitamin E related genes [122]. On the contrary, a prospective randomized trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), showed vitamin E supplementation significantly increased PCa risk [123] and that a higher plasma ?-tocopherol level may interact with selenium supplements to increase high grade PCa risk [124]. This finding is consistent with a case-cohort study of 1,739 cases and 3,117 controls that showed vitamin E increased PCa risk among those with low selenium status but not those with high selenium status [125]. Thus, more research is needed to examine the association between vitamin E and PCa and the dose effect and interaction with other nutrients should be considered.

Vitamin K has been hypothesized to help prevent PCa by reducing bioavailable calcium. Preclinical studies show the combination of vitamins C and K have potent antitumor activity in vitro and act as chemo- and radiosensitizers in vivo [126]. To date, few studies have investigated this, although one study using the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort found an inverse relationship between vitamin K (as menaquinones) intake and PCa incidence [127]. Little to no preclinical studies have been conducted to examine the role of calcium with PCa. Retrospective and meta-analyses suggest increased or reduced PCa risk with increased calcium intake, while others suggest no association [128,129]. Another study suggests a �U�-shaped association, where very low calcium levels or supplementation are both associated with PCa [130].

Selenium, on the other hand, has been hypothesized to prevent PCa. While in vitro studies suggested that selenium inhibited angiogenesis and proliferation while inducing apoptosis [131], results from SELECT showed no benefit of selenium alone or in combination with vitamin E for PCa chemoprevention [123]. Further, selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status in a randomly selected cohort of 1,739 cases with high-grade (Gleason 7�10) PCa and 3,117 controls [125]. A prospective Netherlands Cohort Study, which included 58,279 men, 55- to 69-years old, also showed that toenail selenium was associated with a reduced risk of advanced PCa [132]. Further research is needed to clarify the role of selenium with PCa.

Phytochemicals

Along with vitamins and minerals [2], plants contain phytochemicals with potential anti-cancer effects. Typically not considered essential compounds, phytochemicals have antioxidant and anti-inflammatory properties.

Silibinin is a polyphenolic flavonoid found in the seeds of milk thistle. It has been shown in vitro and in vivo to inhihit PCa growth by targeting epidermal growth factor receptor (EGFR), IGF-1 receptor (IGF-1R), and nuclear factor-kappa B (NF-kB) pathways [133,134]. A recent study showed that silibinin may be useful in PCa prevention by inhibiting TGF?2 expression and cancerassociated fibroblast (CAF)-like biomarkers in the human prostate stromal cells [135]. Thus, silibinin is a promising candidate as a PCa chemopreventive agent that awaits further research.

Curcumin is used as food additive in Asia and as an herbal medicine for inflammation [136]. In vitro, curcumin inhibits the pro-inflammatory protein NF-?B while inducing apoptosis through increased expression of proapoptotic genes [137]. In vivo, curcumin slows PCa growth in mice while sensitizing tumors to chemo- and radiotherapies [136]; however, no human trial has examined its impact on PCa.

Pomegranate

The peel and fruit of pomegranates and walnuts are rich in ellagitannins (punicalagins). These phytochemicals are readily metabolized to the active form ellagic acid by gut flora [138]. Preclinical experiments show ellagitannins inhibit PCa proliferation and angiogenesis under hypoxic conditions and induce apoptosis [137,138]. In prospective trials in men with a rising PSA after primary treatment, pomegranate juice or POMx, a commercially available pomegranate extract, increased the PSA doubling time relative to baseline [139,140], although no trials included a placebo group. Results are pending from a prospective placebo RCT using pomegranate extract in men with a rising PSA. However, in a placebo controlled trial, two pills of POMx daily for up to four weeks prior to radical prostatectomy had no impact on tumor pathology or oxidative stress or any other tumor measures [141].

Green Tea

Green tea contains a number of antioxidant polyphenols including catechins, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), (?)-epicatechin-3-gallate (ECG) and (?)-epicatechin. Preclinical studies suggest EGCG inhibits PCa growth, induces intrinsic and extrinsic apoptotic pathways and decreases inflammation by inhibiting NFkB [137]. Furthermore, the antioxidant properties of EGCG are 25 to 100 times more potent than vitamins C and E [131]. In a prospective randomized preprostatectomy trial, men consuming brewed green tea Lin et al. BMC Medicine (2015) 13:3 Page 7 of 15 prior to surgery had increased levels of green tea polyphenols in their prostate tissue [142]. In a small proof-ofprinciple trial with 60 men, daily supplementation of 600 mg green tea catechin extract reduced PCa incidence by 90% (3% versus 30% in the placebo group) [143]. Another small trial also showed that EGCG supplement resulted in a significant reduction in PSA, hepatocyte growth factor and vascular endothelial growth factor in men with PCa [144]. These studies suggest green tea polyphenols may lower PCa incidence and reduce PCa progression but more research is needed to confirm and clarify its mechanism [137,143,145].

Resveratrol

While most in vitro studies suggest resveratrol inhibits PCa growth [146-148], resveratrol suppresses tumor growth in some [137] but not all animal models [149], possibly due to limited bioavailability [150,151]. To date, there are no clinical trials investigating the preventive or therapeutic effects of resveratrol on PCa.

Zyflamend

Zyflamend is an anti-inflammatory mixture of herbs that has been shown to reduce PCa progression by lowering the expression of markers including pAKT, PSA, histone deacetylases and androgen receptor in animal models and PCa cell line [152-154]. Despite its anti-cancer potential [155], very few studies have been conducted in humans [156,157]. In an open-label Phase I trial of 23 patients with high-grade prostatic intraepithelial neoplasia, Zyflamend alone or in conjunction with other dietary supplements for 18 months reduced the risk for developing PCa [156]. More RCTs in humans are needed to confirm the efficacy and clinical application of this herbal supplement.

Other Whole Foods Fruits & Vegetables

Fruits and vegetables are rich sources of vitamins, minerals and phytochemicals. Several epidemiologic studies found inverse relationships between total fruit and vegetable intake [158], and cruciferous vegetable intake and PCa risk [159,160]. Allium vegetables, such as garlic, leeks, chives, and shallots, contain multiple sulfurous phytochemicals that were suggested to enhance the immune system, inhibit cell growth, modulate expression of androgen-responsive genes and induce apoptosis [161]. Although the number of published studies is limited, both preclinical and epidemiologic data suggest allium vegetable intake may be protective against PCa, particularly localized disease [162]. A randomized trial with 199 men also found that a blend supplement of pomegranate, green tea, broccoli and turmeric significantly reduced the rate of rise in PSA in men with PCa [163].

Tomatoes & Tomato Products

A number of studies have examined the association between tomatoes and tomato products with PCa but the findings are inconclusive. The antioxidant lycopene, which is rich in tomatoes, has also been studied specifically for its impact on PCa. In vitro, lycopene halts the cell cycle in several PCa cell lines and decreases IGF-1 signaling by inducing IGF-1 binding proteins [131]. While some animal studies found lycopene specifically slows PCa growth [164] or reduces PCa epithelial cells at stages of initiation, promotion and progression [165], two studies found conflicting findings between tomato paste and lycopene [166,167]. Prospective human studies found higher lycopene consumption [168,169] or higher serum levels were associated with lower PCa risk [170], but others have not [171,172]. Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PCa at six-month follow-up biopsy (P = 0.003) [173]. Two short-term preprostatectomy trials using tomato sauce or lycopene supplementation demonstrated lycopene uptake in prostate tissue and antioxidant and potential anticancer effects [174,175]. While several clinical trials suggested an inverse relationship between lycopene supplementation, PSA levels and decreases in cancerrelated symptoms [171,176], no large-scale randomized trials have tested the role of lycopene or tomato products on PCa prevention or treatment.

Coffee

Coffee contains caffeine and several unidentified phenolic compounds that may serve as antioxidants. Epidemiological studies suggest an inverse relationship between coffee consumption and PCa risk, mainly for advanced or lethal stage disease, and the findings were independent of caffeine content [177,178]. Although several epidemiological studies [179-182] found no association between coffee consumption and PCa risk, a recent meta-analysis of prospective studies concluded that coffee consumption may reduce PCa risk [183]. The potential mechanism(s) and pathway(s) involved are unknown but may include antioxidant, anti-inflammatory effects, glucose and insulin metabolism, and potential impact on IGF-I and circulating sex hormones.

Dietary Patterns

Even though many single nutrients or food factors have been examined for their impact or association with PCa risk or progression, the results have largely been inconclusive. A potential reason for the inconsistency is the fact that the impact of single nutrient or food factor may be too small to be detected. In addition, nutrients naturally existing in foods often are highly correlated and may interact with each other and, thus, affect the impact on PCa. Thus, dietary pattern analysis has received an increasing Lin et al. BMC Medicine (2015) 13:3 Page 8 of 15 interest but research has been limited and the existing results have been inconclusive. In a cohort of 293,464 men, a high dietary quality, as indicated by the Healthy Eating Index (HEI) score, was associated with a lower risk of total PCa risk [70]. The Mediterranean diet, which is high in vegetables, olive oil, complex carbohydrates, lean meats and antioxidants, is consistently recommended to patients for prevention of cardiovascular disease and obesity [184], and may show promise in PCa prevention [185]. Fish and omega-3 fatty acid consumption in the Mediterranean pattern were significantly and inversely associated with fatal PCa risk. In addition, adherence to the Mediterranean diet after diagnosis of non-metastatic PCa was associated with lower overall mortality [186]. Whereas, a Western pattern with high intakes of red meats, processed meats, fried fish, chips, high-fat milk and white bread, was associated with a higher risk for PCa [187].

Furthermore, Asian countries with high consumption of omega-3 PUFAs, soy and green tea-based phytochemicals, have lower PCa incidences versus countries consuming a �Western-style� diet [188]. However, not all studies [189-191] supported an association between certain dietary pattern and risk of PCa. It is possible that the methodology used in identifying dietary patterns may not have captured all the dietary factors associated with PCa risk. Alternatively, each dietary pattern may contain both beneficial and harmful components resulting in an overall null association. More research is needed to continue searching for dietary patterns that combine most of the beneficial nutrients/food factors for PCa and limit most of the negative nutrients/ food factors.

Future Direction For Clinical Trials

Based on the multitude of epidemiologic, preclinical and clinical trials described in this review, dietary interventions for the prevention and treatment of PCa hold great promise. In addition, several dietary factors and vitamins/supplements may be associated with PCa risk and/ or progression of disease. Prospective randomized trials are clearly indicated to identify specific nutrients or combination therapies for the prevention and treatment of PCa.

Recently, active surveillance (AS) has emerged as a viable option for men with lower risk PCa. Men on AS are motivated to adhere to diet and lifestyle modifications [192], making this subset a good target for dietary intervention and quality of life trials [193]. PCa survivors who are more active and report �healthy� eating habits (that is, consuming low-fat, low-refined carbohydrate diets rich in fruits and vegetables) have better overall quality of life versus their inactive, unhealthy counterparts [194]. Thus, more randomized trials are warranted to determine the overall long-term effects of dietary intervention in this population. Specifically, key questions to address in future trials are: 1) Can dietary interventions delay the need for treatment in men on AS; 2) Can dietary interventions prevent recurrence for men after treatment; 3) Can dietary interventions delay progression among men with recurrent disease and, thus, delay the need for hormonal therapy; 4) Can dietary interventions reduce the side effects of PCa treatments including hormonal therapy and newer targeted therapies; and 5) Is there any role for dietary interventions alone or combined with targeted therapies in men on hormonal therapy to prevent castrate-resistance or after the emergence of castrate resistance disease? Because increasing evidence shows that metabolic abnormalities increase risk for PCa, lifestyle intervention that improves metabolic profile is a win-win option for PCa prevention and treatment [195,196].

Conclusions: Prostate Cancer

Future research is required to determine the ideal diet for PCa prevention or treatment. However, several dietary factors and some dietary patterns hold promise in reducing PCa risk or progression and are consistent with current dietary guidelines for Americans [197]. For counseling patients on diet for primary and secondary PCa prevention, many believe �heart healthy equals prostate healthy.� Thus, given the current inconclusive results, the best dietary advice for PCa prevention or management seems to include: increasing fruits and vegetables, replacing refined carbohydrates with whole grains, reducing total and saturated fat, reducing overcooked meats and consuming a moderate amount of calories or reducing carbohydrates with a primary goal of obtaining and maintaining a healthy body weight.

Competing interests The authors declare that they have no competing interests.

Authors� contributions P-HL and SF conducted the review, P-HL drafted the manuscript and SF and WA edited and provided critical input. All authors read and approved the final manuscript.

Acknowledgements Funding was provided by grants 1K24CA160653 (Freedland), NIH P50CA92131 (W. Aronson). This manuscript is the result of work supported with resources and the use of facilities at the Veterans Administration Medical Center, West Los Angeles (W. Aronson).

Author details 1 Department of Medicine, Division of Nephrology, Duke University Medical Center, Box 3487, Durham, NC 27710, USA. 2 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. 3 Department of Urology, UCLA School of Medicine, Los Angeles, CA, USA. 4 Urology Section, Department of Surgery, Durham Veterans Affairs Medical Center, Division of Urology, Durham, NC, USA. 5 Duke Prostate Center, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.