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Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, affect millions of individuals worldwide. A variety of treatment options are available to treat the symptoms of several neurodegenerative diseases although the results are often limited. Research studies have found that oxidative stress caused by both internal and external factors can be a cause for the development of neurodegenerative diseases. The transcription factor, Nrf2, has been determined to function as a major defense mechanism against oxidative stress. The purpose of the article below is to show the effects of Nrf2 on neurodegenerative diseases.
Modulation of Proteostasis by Transcription Factor NRF2
Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.
Keywords:Neurodegenerative diseases, Unfolded protein response, Proteasome, Ubiquitin, Autophagy, Oxidative stress
Nuclear Factor (erythroid-derived 2)-like 2 (NRF2) is a basic-leucine-zipper protein considered nowadays as a master regulator of cellular homeostasis. It controls the basal and stress-inducible expression of over 250 genes that share in common a cis-acting enhancer termed the antioxidant response element (ARE) [1], [2], [3], [4], [5]. These genes participate in phase I, II and III detoxification reactions, glutathione and peroxiredoxin/thioredoxin metabolism, NADPH production through the pentose phosphate pathway and malic enzyme, fatty acid oxidation, iron metabolism, and proteostasis [6]. Given these wide cytoprotective functions, it is possible that a single pharmacological hit in NRF2 might mitigate the effect of the main culprits of chronic diseases, including oxidative, inflammatory and proteotoxic stress. The role of NRF2 in the modulation of the antioxidant defense and resolution of inflammation have been addressed in numerous studies (reviewed in [7]). Here, we will focus on its role in proteostasis, i.e., the homeostatic control of protein synthesis, folding, trafficking and degradation. Examples will be provided in the context of neurodegenerative diseases.
Loss of Proteostasis Influences NRF2 Activity in Neurodegenerative Diseases
A general hallmark of neurodegenerative diseases is the occurrence of aberrant aggregation of some proteins. Thus, misfolded protein aggregates of ?-synuclein (?-SYN) are found in Parkinson’s disease (PD), ?-amyloid (A?) plaques and hyper-phosphorylated TAU neurofibrillary tangles in Alzheimer’s disease (AD), huntingtin (Htt) in Huntington’s disease (HD), superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS), prion protein (PrP) in spongiform encephalopathies, etc. Protein aggregates can have an impact on several cellular pathways, which in turn may affect NRF2 levels and activity.
Different Layers of Regulation Tightly Control NRF2 Activity
Under physiological conditions, cells exhibit low NRF2 protein levels because of its rapid turnover. In response to different stimuli, NRF2 protein is accumulated, enters the nucleus and increases the transcription of ARE-containing genes. Therefore, management of NRF2 protein levels is a key point that should integrate positive and negative input signals. As we will discuss further, NRF2 is activated by diverse overlapping mechanisms to orchestrate a rapid and efficient response but on the other hand NRF2 could be inhibited, probably in a second phase, in order to switch off its response.
From the classic point of view, activation of NRF2 has been considered as a consequence of the cellular response to oxidant or electrophilic compounds. In this regard, the ubiquitin E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1) plays a crucial role. Molecular details will be further addressed in Section 4.1. In brief, KEAP1 acts as a redox sensor due to critical cysteine residues leading to NRF2 ubiquitination and proteasomal degradation. In addition to this classic modulation, NRF2 is profoundly regulated by signaling events. Indeed, different kinases have been shown to phosphorylate and regulate NRF2. For instance, NRF2 can be phosphorylated by mitogen activated protein kinases (MAPKs), although its contribution to NRF2 activity remains unclear [8], [9], [10], [11]. PKA kinase as well as some PKC isozymes [12], CK2 [13] or Fyn [14] phosphorylate NRF2 modifying its stability. Previous work from our group reported that glycogen synthase kinse-3? (GSK-3?) inhibits NRF2 by nuclear exclusion and proteasomal degradation [15], [25], [26], [27], [28], [29], [30]. The molecular details will be discussed in the Section 4.1. Furthermore, NRF2 is submitted to other types of regulation. For instance, NRF2 acetylation by CBP/p300 increases its activity [17], while it is inhibited by miR153, miR27a, miR142-5p, and miR144 [16], or by methylation of cytosine-guanine (CG) islands within the NRF2 promoter [18].
Impact of Protein Aggregates on NRF2 Regulatory Mechanisms
In this section we will focus in how accumulation of misfolded protein could impact NRF2 activity providing some of the pathways mentioned above as illustrative examples. Firstly, we need to consider that protein accumulation has been tightly linked with oxidative damage. Indeed, misfolded protein accumulation and aggregation induce abnormal production of reactive oxygen species (ROS) from mitochondria and other sources [19]. As mentioned above, ROS will modify redox-sensitive cysteines of KEAP1 leading to the release, stabilization and nuclear localization of NRF2.
Regarding proteinopathies, an example of dysregulated signaling events that may affect NRF2 is provided by the hyperactivation of GSK-3? in AD. GSK-3?, also known as TAU kinase, participates in the phosphorylation of this microtubule-associated protein, resulting in its aggregation, formation of neurofibrillary tangles and interruption of axonal transport (reviewed in [20]). On the other hand, GSK-3? dramatically reduces NRF2 levels and activity as mentioned above. Although not widely accepted, the amyloid cascade proposes that toxic A? oligomers increase GSK-3? activity together with TAU hyper-phosphorylation and neuron death [21], [22]. There are different models to explain how A? favors GSK3-? activity. For instance, A? binds to the insulin receptor and inhibits PI3K and AKT signaling pathways, which are crucial to maintain GSK-3? inactivated by phosphorylation at its N-terminal Ser9 residue [23]. On the other hand, extracellular A? interacts with Frizzled receptors, blocking WNT signaling [24] and again resulting in release of active GSK-3?. In summary, A? accumulation leads to abnormal hyperactivation of GSK-3?, thus impairing an appropriate NRF2 response.
As discussed in the following section, misfolded proteins lead to activation of PERK and MAPKs, which in turn up-regulate NRF2 [31], [8], [9], [10], [11]. Moreover, dysregulated CBP/p300 activity has been reported in several proteinopathies [32] and a global decrease in DNA methylation in AD brains was also shown [33], therefore providing grounds to explore the relevance of these findings in NRF2 regulation.
We and others have observed in necropsies of PD and AD patients an increase in NRF2 protein levels and some of its targets, such as heme oxygenase 1 (HMOX1), NADPH quinone oxidase 1 (NQO1), p62, etc., both by immunoblot and by immunohistochemistry [34], [35], [36], [37], [38], [39]. The up-regulation of NRF2 in these diseases is interpreted as an unsuccessful attempt of the diseased brain to recover homeostatic values. However, another study indicated that NRF2 is predominantly localized in the cytoplasm of AD hippocampal neurons, suggesting reduced NRF2 transcriptional activity in the brain [40]. It is conceivable that the disparity of these observations is related to changes in the factors that control NRF2 along the progressive stages of neurodegeneration.
Three major systems contribute to proteostasis, namely the unfolded protein response (UPR), the ubiquitin proteasome system (UPS) and autophagy. Next, we present evidence to envision NRF2 as a hub connecting emergency signals activated by protein aggregates with the protein derivative machinery.
NRF2 Participates in the Unfolded Protein Response (UPR)
NRF2 Activation in Response to the UPR
Oxidative protein folding in the ER is driven by a number of distinct pathways, the most conserved of which involves the protein disulfide-isomerase (PDI) and the sulfhydryl oxidase endoplasmic oxidoreductin 1 (ERO1? and ERO1? in mammals) as disulfide donor. Briefly, PDI catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins, as they fold, due to the reduction and oxidation of its own cysteine aminoacids. PDI is recycled by the action of the housekeeping enzyme ERO1, which reintroduces disulfide bonds into PDI [41]. Molecular oxygen is the terminal electron acceptor of ERO1, which generates stoichiometric amounts of hydrogen peroxide for every disulfide bond produced [42]. Peroxidases (PRX4) and glutathione peroxidases (GPX7 and GPX8) are key enzymes to reduce hydrogen peroxide in the ER. When this oxido-reductive system does not work properly, abnormal accumulation of misfolded proteins occurs in the ER and a set of signals named the unfolded protein response (UPR) is transmitted to the cytoplasm and nucleus to reestablish the ER homeostasis [43]. Three membrane-associated proteins have been identified for sensing ER stress in eukaryotes: activating transcription factor 6 (ATF6), pancreatic ER eIF2? kinase (PERK, also double-stranded RNA-activated protein kinase-like ER kinase), and inositol-requiring kinase1 (IRE1). The luminal domain of each sensor is bound to a 78 kDa chaperone termed glucose-regulated protein (GRP78/BIP). BIP dissociates upon ER stress to bind unfolded proteins, leading to the activation of the three sensors [44].
NRF2 and its homologue NRF1, also related to the antioxidant response, participate in the transduction of the UPR to the nucleus. In the case of NRF1, this protein is located at the ER membrane and undergoes nuclear translocation upon deglycosylation or cleavage. Then, UPR activation leads to the processing of NRF1 and nuclear accumulation of the resulting fragment in the nuclear compartment. However, the ability to transactivate ARE-containing genes of this NRF1 fragment is still under discussion [45].
Glover-Cutter and co-workers showed activation of the NRF2 orthologue of C. elegans, SKN-1, with different ER stressors. Increased SKN-1 expression was dependent on different UPR mediators, including IRE1 or PERK worm orthologues [46]. In PERK-deficient cells, impaired protein synthesis leads to accumulation of endogenous peroxides and subsequent apoptosis [47]. The effector used by PERK to protect the ER from these peroxides might be NRF2, since it has been reported that PERK phosphorylates NRF2 at Ser40, thus preventing its degradation by KEAP1 [31]. The induction of ASK1 is also likely to play a role in this route through the TRAF2-mediated kinase action of IRE1 [48]. Although the role of MAPKs in the regulation of NRF2 is still controversial, it was recently suggested that the IRE1-TRAF2-ASK1-JNK pathway might activate NRF2 [49] (Fig. 1). Interestingly, in C. elegans and human cells, new evidence suggests that cysteine sulfenylation of IRE1 kinase at its activation loop inhibits IRE1-mediated UPR and initiates a p38 antioxidant response driven by NRF2. The data suggest that IRE1 has an ancient function as a cytoplasmic sentinel that activates p38 and NRF2 [50].
Figure 1 Regulation of NRF2 by the UPR. Accumulation of unfolded or misfolded proteins inside the endoplasmic reticulum can initiate the unfolded protein response (UPR). First, the chaperone BIP is released from the intraluminal domain of the ER sensors IRE1 and PERK to bind unfolded/misfolded proteins. This enables dimerization and trans-auto-phosphorylation of their cytosolic domains. PERK activation results in direct NRF2 phosphorylation at Ser40, leading to NRF2 translocation to the nucleus and activation of target genes. IRE1 activation induces the recruitment of TRAF2 followed by ASK1 and JNK phosphorylation and activation. As JNK has been reported to phosphorylate and activate NRF2, it is reasonable to think that IRE1 activation would lead to increased NRF2 activity.
Many studies on the induction of the UPR have been conducted with the inhibitor of protein glycosylation tunicamycin. NRF2 appears to be essential for prevention of tunicamycin-induced apoptotic cell death [31] and its activation under these conditions is driven by the autophagic degradation of KEAP1 [51]. Accordingly, shRNA-mediated silencing of NRF2 expression in ?TC-6 cells, a murine insulinoma ?-cell line, significantly increased tunicamycin-induced cytotoxicity and led to an increase in the expression of the pro-apoptotic ER stress marker CHOP10. On the other hand, NRF2 activation by 1,2-dithiole-3-thione (D3T) reduced tunicamycin cytotoxicity and attenuated the expression of CHOP10 and PERK [52]. Interestingly, olfactory neurons submitted to systemic application of tunicamycin increased NRF2 in parallel with other UPR-members such as CHOP, BIP, XBP1 [53]. These results have been extended to in vivo studies, as lateral ventricular infusion of tunicamycin in rats induced expression of PERK and NRF2 in the hippocampus accompanied by significant cognitive deficits, increased TAU phosphorylation and A?42 deposits [54].
NRF2 Up-Regulates Key Genes for the Maintenance of the ER Physiology
The ER lumen needs an abundant supply of GSH from the cytosol in order to maintain disulfide chemistry. NRF2 modulates crucial enzymes of the GSH metabolism in the brain, such as cystine/glutamate transport, ?-glutamate cysteine synthetase (?-GS), glutamate-cysteine ligase catalytic and modulator subunits (GCLC and GCLM), glutathione reductase (GR) and glutathione peroxidase (GPX) (reviewed in [55]). The relevance of NRF2 in the maintenance of GSH in the ER is supported by the finding that pharmacological or genetic activation of NRF2 results in increased GSH synthesis via GCLC/GCLM, while inhibiting the expression of these enzymes by NRF2-knockdown caused an accumulation of damaged proteins within the ER leading to the UPR activation [56].
In C. elegans several components of the UPR target genes regulated by SKN-1, including Ire1, Xbp1 and Atf6. Although NRF2 up-regulates the expression of several peroxidase (PRX) and glutathione peroxidase (GPX) genes in mammals (reviewed in [57]), only GPX8 is a bona fide ER-localized enzyme, harboring the KDEL retrieval signal [58]. Loss of GPX8 causes UPR activation, leakage of ERO1?-derived hydrogen peroxide to the cytosol and cell death. Hydrogen peroxide derived from ERO1? activity cannot diffuse from the ER to the cytosol owing to the concerted action of GPX8 and PRX4 [59]. In this regard, an analysis of the antioxidant defense pathway-gene expression array using RNA from wild type and NRF2-null mice tissue, revealed that the expression of GPX8 was down-regulated in the absence of NRF2 [60]. In line with this, transcriptome analysis from patient samples suffering from myeloproliferative neoplasms, polycythemia or myelofibrosis, diseases also associate with oxidative stress and low-grade chronic inflammation, show lower expression levels of both NRF2 and GPX8 compared with control subjects [61]. There are not yet studies that specifically involve GPX8 in human brain protection but a transcriptome analysis in mice indicates a compensatory GPX8 increase in response to the Parkinsonian toxin MPTP [62].
Impact of NRF2 on the UPR Dysregulation in Neurodegenerative Diseases
Malfunction of PDI enzymes and chronic activation of the UPR might subsequently initiate or accelerate neurodegeneration. Disease-affected neurons, animal models of neurodegenerative disease as well as post-mortem human tissues evidenced up-regulation of several UPR-markers in most of these disorders. The alteration of PDI/UPR pathway in neurodegenerative diseases has been nicely reviewed in [63] but the following highlights from brain post-mortem samples should be considered. PDI levels are increased in tangle-bearing neurons and in Lewy Bodies of AD and PD patients, respectively [64], [65]. PDI and ERP57 are up-regulated in CSF from ALS patients and in brains from CJD subjects [66], [67], [68]. BIP, PERK, IRE1 and ATF6 are elevated in samples from patients with AD, PD or ALS [69], [70], [71], [67]. BIP, CHOP and XBP1 are elevated in post-mortem brain samples from HD [72], [73]. Moreover, up-regulation of ERP57, GRP94 and BIP was found in cortex tissues from CJD patients [74]. Altogether, this evidence reveals that the accumulation of misfolded proteins in the brain parenchyma leads to a deleterious and chronic activation of the UPR. Interestingly, there is a recent study linking activation of NRF2 by PERK in early AD. In this study, the authors analyzed whether oxidative stress mediated changes in NRF2 and the UPR may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased pSer40-NRF2 were observed in human peripheral blood mononuclear cells isolated from individuals with mild cognitive impairment. Moreover, they reported impaired ER calcium homeostasis and up-regulated ER-stress markers in these cells from individuals with mild cognitive impairment and mild AD [75].
Mutual Regulation of NRF2 and the Ubiquitin Proteasome�System (UPS)
The UPS Modulates NRF2 Protein Levels
The UPS participates in the degradation of damaged or misfolded proteins and controls the levels of key regulatory molecules in the cytosol and the nucleus. The central core of this system is a large multisubunit enzyme that contains a proteolytic active complex named 20S. The 20S core proteasome degrades unfolded proteins, but binding to different regulatory protein complexes changes its substrate specificity and activity. For instance, the addition of one or two 19S regulatory subunits to the 20S core constitutes the 26S proteasome and changes its specificity towards native folded proteins [76], [77]. Proteasomal degradation needs covalent binding of ubiquitin. Conjugation of ubiquitin proceeds via a three-step cascade mechanism. First, the ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-requiring reaction. Then, one E2 enzyme (ubiquitin-carrier protein or ubiquitin-conjugating enzyme) transfers the activated ubiquitin from E1 to the substrate that is specifically bound to a member of the ubiquitin-protein ligase family, named E3. Although the exact fate of the ubiquitinated-protein will depend on the nature of the ubiquitin chain, this process generally results in the degradation by the 26S proteasome [78].
The E3-ligase KEAP1 is the best known inhibitor of NRF2. The mechanism of KEAP1 regulation elegantly explains how NRF2 levels adjust to oxidant fluctuations. Under basal conditions, newly synthesized NRF2 is grabbed by the homodimer KEAP1, which binds one NRF2 molecule at two amino acid sequences with low (aspartate, leucine, glycine; DLG) and high (glutamate, threonine, glycine, glutamate; ETGE) affinity. The interaction with KEAP1 aids to present NRF2 to the CULLIN3/RBX1 protein complex, resulting in its ubiquitination and subsequent proteasomal degradation. However, redox modification of KEAP1 impedes presentation of NRF2 to the UPS represented by CULLIN3/RBX1. As a result, newly synthetized NRF2 escapes KEAP1-dependent degradation, accumulates in the nucleus and activates ARE-containing genes [79], [80], [81], [82].
The E3-ligase adaptor ?-TrCP is also a homodimer that participates in the signaling events related to the phosphorylation of NRF2 by GSK-3?. This kinase phosphorylates specific serine residues of NRF2 (aspartate, serine, glycine, isoleucine serine; DSGIS) to create a degradation domain that is then recognized by ?-TrCP and tagged for proteasome degradation by a CULLIN1/RBX1 complex. The identification of the specific amino acids that are phosphorylated by GSK-3? in this degron was conducted by a combination of site-directed mutagenesis of the Neh6 domain, 2D-gel electrophoresis [15], [26] and mass spectroscopy [83]. Consequently, inhibition of GSK-3? by highly selective drugs or siRNAs against GSK-3 isoforms resulted in an increase in NRF2 protein levels. Similar results were found with siRNAs against ?-TrCP isoforms 1 and 2. Stabilization of NRF2 following GSK-3? inhibition occurred in KEAP1-deficient mouse embryo fibroblasts and in an ectopically expressed NRF2 deletion mutant lacking the critical ETGE residues for high-affinity binding to KEAP1, further demonstrating a KEAP1-independent regulation.
In the context of neurodegenerative diseases, we can envision the modulation of NRF2 by the UPS in two different ways. On the one hand, the KEAP1 system would sense redox imbalance derived from misfolded protein accumulation, while GSK-3/?-TrCP axis would act as an active participant in signaling transduction altered by loss of proteostasis (Fig. 2).
Figure 2 The UPS tightly controls NRF2 levels. Under homeostatic conditions, low NRF2 levels are maintained by the action of the E3 ligases adaptors KEAP1 and ?-TrCP. Left, NRF2 binds to the Kelch domains of a KEAP1 homodimer through a low (DLG) and a high (ETGE) affinity motifs. Through its BTB domain, KEAP1 simultaneously binds to a CULLIN3/RBX1 complex, enabling NRF2 ubiquitination and degradation by the 26 S proteasome. Moreover, GSK-3? phosphorylates Ser335 and Ser338 residues of NRF2 to create a degradation domain (DpSGIpSL) that is then recognized by the ubiquitin ligase adaptor ?-TrCP and tagged for proteasome degradation by a CULLIN3/RBX1 complex. Right, Upon exposure to reactive oxygen species or electrophiles critical Cys residues in KEAP1 are modified, rendering KEAP1 unable of interacting efficiently with NRF2 or CULLIN3/RBX1 and then this transcription factor increases its half-life and transcriptional activity towards ARE-genes. Signaling pathways that result in inhibition of GSK-3?, such AKT phosphorylation at Ser9, result in NRF2 impaired degradation by the proteasome, accumulation and induction of target genes.
NRF2 Increases UPS Activity Through the Transcriptional Control of Proteasome Subunits
NRF2 up-regulates the expression of several proteasome subunits, thus protecting the cell from the accumulation of toxic proteins. Twenty proteasome- and ubiquitination-related genes appear to be regulated by NRF2, according to a wide microarray analysis from liver RNA that was set up with the NRF2 inducer D3T [84]. In a posterior study, the same authors evidenced that the expression of most subunits of the 26S proteasome were enhanced up to three-fold in livers from mice treated with D3T. Subunit protein levels and proteasome activity were coordinately increased. However, no induction was seen in mice where the transcription factor NRF2 was disrupted. Promoter activity of the PSMB5 (20S) proteasome subunit increased with either NRF2 overexpression or treatment with activators in mouse embryonic fibroblasts, and AREs were identified in the proximal promoter of PSMB5 [85]. Pharmacological activation of NRF2 resulted in elevated expression levels of representative proteasome subunits (PSMA3, PSMA6, PSMB1 and PSMB5) only in non-senescent human fibroblasts containing functional NRF2 [86]. NRF2 activation during adaptation to oxidative stress results in high expression of the PSMB1 (20S) and PA28? subunits (or S11, proteasome regulator) [87]. Moreover, results from human embryonic stem cells revealed that NRF2 controls the expression of the proteasome maturation protein (POMP), a proteasome chaperone, which in turn modulates the proliferation of self-renewing human embryonic stem cells, three germ layer differentiation and cellular reprogramming [88]. All together, these studies indicate that NRF2 up-regulates the expression of key components of the UPS and therefore actively contributes to the clearance of proteins that otherwise would be toxic.
The NRF2-UPS Axis in Neurodegenerative Diseases
The role of the UPS in neurodegenerative diseases is a field of intensive debate. Initial studies reported decreased proteasome activity in human necropsies of patients affected from several neurodegenerative diseases. However, other studies employing in vitro and in vivo approaches found unchanged or even increased proteasome activity (reviewed in [89]). One possible explanation for this discrepancy is that the levels of the UPS components might change during disease progression and in different brain regions as is has been suggested for NRF2-targets.
Despite this controversy, it should be noted that up-regulation of ARE-containing proteasome genes will reinforce the UPS by increasing the clearance of toxic proteins in the brain. Indeed, ablation of NRF1, also modulator of the antioxidant response, in neuronal cells leads to impaired proteasome activity and neurodegeneration. Chromatin immunoprecipitation experiments and transcriptional analysis demonstrated that PSMB6 is regulated by NRF1. In addition, gene expression profiling led to the identification of NRF1 as a key transcriptional regulator of proteasome genes in neurons, suggesting that perturbations in NRF1 may contribute to the pathogenesis of neurodegenerative diseases [90]. Interestingly, NRF1 and its long isoform called TCF11 were shown to up-regulate ARE-containing proteasome genes upon proteasome inhibition in a feedback loop to compensate for reduced proteolytic activity [91], [92].
Regarding NRF2, there is a correlation among reduction of NRF2, RPT6 (19 S) and PSMB5 (20 S) levels in the midbrain of DJ-1-deficient mice treated with the neurotoxin paraquat [93]. Moreover, the naturally-occurring compound sulforaphane (SFN) gives a more robust image of NRF2 as a crucial modulator of the UPS. In vitro experiments with murine neuroblastoma Neuro2A cells evidenced an enhanced expression of the catalytic subunits of the proteasome, as well as its peptidase activities in response to SFN. This drug protected cells from hydrogen peroxide-mediated cytotoxicity and protein oxidation in a manner dependent on proteasome function [94]. In addition, Liu and co-workers employed a reporter mouse to monitor the UPS activity in response to SFN in the brain. These mice ubiquitously express the green fluorescence protein (GFP) fused to a constitutive degradation signal that promotes its rapid degradation by the UPS (GFPu). In cerebral cortex, SFN reduced the level of GFPu with a parallel increase in chymotrypsin-like (PSMB5), caspase-like (PSMB2), and trypsin-like (PSMB1) activities of the 20 S proteasome. In addition, treatment of Huntington-derived cells with SFN revealed that NRF2 activation enhanced mHtt degradation and reduced mHtt cytotoxicity [95]. The major mechanism of SFN action is through induction of NRF2 [96]. The specific contribution of NRF2 should be addressed employing NRF2-null systems in further studies.
Functional Connection Between NRF2 and Macroautophagy
NRF2 Protein Levels are Modulated by the Adaptor Protein P62
Autophagy refers to the degradation of cytosolic components inside lysosomes. This process is used for the clearance of long-lived and misfolded proteins as well as damaged organelles. A direct link between NRF2 and autophagy was first observed in connection with the adaptor protein p62, also termed SQSTM1 [97], [98], [99], [100], [101]. This protein shuttles ubiquitinated proteins to the proteasomal and lysosomal degradation machineries and sequesters damaged proteins into aggregates prior to their degradation. P62 presents an ubiquitin-associated (UBA) domain, for binding to ubiquitinated proteins, and a LC3-interacting region (LIR) for integration with the autophagosomal membrane through the autophagy receptor LC3.
Although the p62-mediated induction of NRF2 and its target genes was first reported in 2007 [102], the molecular mechanism was not fully understood until the discovery of its interaction with KEAP1 [103], [98], [99], [100], [101]. Komatsu and coworkers identified a KEAP1 interacting region (KIR) in p62 that bound KEAP1 in the same basic surface pocket as NRF2 and with a binding affinity similar to the ETGE motif in NRF2, suggesting competition between p62 and NRF2. The phosphorylation of Ser351 in the KIR motif in p62 (349-DPSTGE-354) was shown to increase its affinity for KEAP1, competing with NRF2 binding and allowing its accumulation and transcriptional activation of its target genes [98], [99]. In fact, p62 overexpression led to reduced NRF2 ubiquitination and consequent stabilization as well as induction of its target genes [104]. Some kinases have been suggested to participate in p62 phosphorylation. The mammalian target of rapamycin complex 1 (mTORC1) may be implicated, as treatment with the mTOR inhibitor rapamycin suppressed the phosphorylation of p62 and the down-regulation of KEAP1 upon arsenite treatment. Recently, it was demonstrated that TGF-?-activated kinase 1 (TAK1) could also phosphorylate p62, enhancing KEAP1 degradation and NRF2-up-regulation. The authors of this study suggest this is a way to regulate cellular redoxtasis under steady-state conditions, as TAK1-deficiency up-regulates ROS in the absence of any exogenous oxidant in different mouse tissues in parallel with a reduction in NRF2 protein levels [105].
A p62 construct lacking the UBA domain was still capable of binding KEAP1, implying that the interaction did not depend on ubiquitinated KEAP1 [101]. However, the p62 homologue in Drosophila melanogaster, named Ref(2), does not contain a KIR motif and does not directly interact with DmKEAP1, although it can bind to ubiquitinated DmKEAP1 through the UBA domain. Moreover, DmKEAP1 can directly interact with Atg8 (homologue to mammalian LC3). KEAP1 deficiency results in Atg8 and autophagy induction dependent on the NRF2 orthologue CncC and independent on TFEB/MITF [106]. The relationship between NRF2 and autophagy seems to be conserved though, highlighting its functional relevance.
The induction of NRF2 by p62 is the result of both the competition to bind KEAP1 and degradation of KEAP1 in the lysosome. Silencing of p62 with siRNA doubled KEAP1 half-life in parallel with a decrease in NRF2 and its target genes [101]. In agreement, ablation of p62 expression evidenced increased levels of KEAP1 compared with wild type mice. Very relevant, the increment in KEAP1 levels was not affected by proteasome inhibitors but was reduced under starvation-inducing autophagy [107]. In fact, KEAP1 is present in mammalian cells in autophagic vesicles decorated with p62 and LC3 [99], [100], [103]. All these data suggest that KEAP1 is a substrate of the macroautophagy machinery, but this issue should be analyzed with more detail because of the existence of some controversial results. KEAP1 protein levels were increased in Atg7-null mice, a key effector of macroautophagy [107], but pharmacological inhibition of macroautophagy with torin1, E64/pepstatin or bafilomycin failed to accumulate KEAP1 [107], [100]. Overall, these results suggest that increased p62 levels sequester KEAP1 into autophagic vacuoles and probably these results in KEAP1 autophagic degradation allowing NRF2 activation (Fig. 3). Two different studies reported that the sulfinic acid reductases SESTRINS play an important role in this context. SESTRIN 2 interacts with p62, KEAP1 and RBX1 and facilitates p62-dependent degradation of KEAP1 and NRF2 activation of target genes [108]. Another study showed that SESTRIN 2 interacted with ULK1 and p62, promoting phosphorylation of p62 at Ser403 which facilitated degradation of cargo proteins including KEAP1 [109].
Figure 3 NRF2 levels are regulated by the adaptor protein p62. The phosphorylation of Ser 351 in the KIR motif of p62 (349-DPSTGE-354) by mTORC1, TAK1 or other kinases results in increased affinity for binding to KEAP1 due to resemblance to the ETGE motif in NRF2. As a consequence, phosphorylated p62 displaces NRF2 and binds KEAP1. The LIR motif in p62 enables interaction with LC3 in the autophagosomal membrane, so that p62-KEAP1 complex is eventually degraded in the lysosome. As a consequence NRF2 is able to accumulate, translocate to the nucleus and increase the transcription of ARE-containing genes, including p62. This regulatory mechanism provides a perdurable NRF2 response, as KEAP1 has to be newly synthesized in order to inhibit NRF2 activity.
Modulation of Macroautophagy Genes by NRF2
NRF2 regulates the expression of relevant genes for macroautophagy as well as it does for the UPR and the UPS. The first evidence came from studies in which p62 expression was shown to be induced upon exposure to electrophiles, ROS and nitric oxide [110], [111], [112]. The mechanism of induction was described some years later with the finding that p62 contains a functional ARE in its gene promoter [99]. In a recent study, several other functional AREs were found and validated following bioinformatics analysis and ChIP assays. Moreover, mouse embryonic fibroblasts and cortical neurons from Nrf2-knockout mice exhibited reduced p62 expression, which could be rescued with an NRF2-expressing lentivirus. Similarly, NRF2 deficiency reduced p62 levels in injured neurons from mice hippocampus [36]. Therefore, it has been suggested that NRF2 activation increases p62 levels, resulting in KEAP1 degradation and favoring further NRF2 stabilization in a positive feedback loop. This non-canonical mechanism of NRF2 induction requires changes in gene expression and might be a relevant response to prolonged cellular stress.
The cargo recognition protein NDP52 was shown to be transcriptionally regulated by NRF2. NDP52 works in a similar way to p62, recognizing ubiquitinated proteins and interacting with LC3 through a LIR domain, so that cargoes are degraded in lysosomes. Five putative AREs were found in Ndp52 promoter DNA sequence. Three of them were identified with different mutant constructs and ChIP assays as indispensable for NRF2-mediated Ndp52 transcription [113]. Of note, Ndp52 mRNA levels were reduced in the hippocampus of Nrf2-knockout mice. One of these sequences was also validated in an independent study as an NRF2-regulated ARE [36].
However, the role of NRF2 in the modulation of autophagy is not limited to the induction of these two cargo-recognition proteins. In order to gain deeper insight in the role of NRF2 in the modulation of additional autophagy-related genes, our group screened the chromatin immunoprecipitation database ENCODE for two proteins, MAFK and BACH1, which bind the NRF2-regulated AREs. Using a script generated from the JASPAR’s consensus ARE sequence, we identified several putative AREs in many autophagy genes. Twelve of these sequences were validated as NRF2 regulated AREs in nine autophagy genes, whose expression was diminished in mouse embryo fibroblasts of Nrf2-knockout mice but could be restored by an NRF2-expressing lentivirus. Our study demonstrated that NRF2 activates the expression of some genes involved in different steps of the autophagic process, including autophagy initiation (ULK1), cargo recognition (p62 and NDP52), autophagosome formation (ATG4D, ATG7 and GABARAPL1), elongation (ATG2B and ATG5), and autolysosome clearance (ATG4D). Consequently, autophagy flux in response to hydrogen peroxide was impaired when NRF2 was absent [36].
Relevance of NRF2-Mediated Macroautophagy Genes Expression in Neurodegenerative Disorders
Defective autophagy has been shown to play an important role in several neurodegenerative diseases [114] and ablation of autophagy leads to neurodegeneration in mice [115], [116]. Atg7-knockout mice revealed that autophagy deficiency results in p62 accumulation in ubiquitin-positive inclusion bodies. KEAP1 was sequestered in these inclusion bodies, leading to NRF2 stabilization and induction of target genes [103]. Importantly, excessive accumulation of p62 together with ubiquitinated proteins has been identified in neurodegenerative diseases, including AD, PD and ALS [117]. In fact, neurons expressing high levels of APP or TAU of AD patients also expressed p62 and nuclear NRF2, suggesting their attempt to degrade intraneuronal aggregates through autophagy [36].
NRF2 deficiency aggravates protein aggregation in the context of AD. In fact, increased levels of phosphorylated and sarkosyl-insoluble TAU are found in Nrf2-knockout mice, although no difference in kinase or phosphatase activities could be detected comparing with the wild-type background [113]. Importantly, NDP52 was demonstrated to co-localize with TAU in murine neurons and direct interaction between phospho-TAU and NDP52 was shown by co-immunoprecipitation experiments both in mice and AD samples, pointing to its role in TAU degradation. Interestingly, silencing of NDP52, p62 or NRF2 in neurons resulted in increased phospho-TAU [113], [118]. Moreover, increased intraneuronal APP aggregates were found in the hippocampus of APP/PS1?E9 mice when NRF2 was absent. This correlated with altered autophagy markers, including increased phospho-mTOR/mTOR and phospho-p70S6k/p70S6k ratios (indicative of autophagy inhibition), augmented levels of pre-cathepsin D and a larger number of multivesicular bodies [119]. In mice co-expressing human APP (V717I) and TAU (P301L), NRF2 deficiency led to increased levels of total and phospho-TAU in the insoluble fraction and increased intraneuronal APP aggregates, together with reduced neuronal levels of p62, NDP52, ULK1, ATG5 and GABARAPL1. Co-localization between the adaptor protein p62 and APP or TAU was reduced in the absence of NRF2 [36]. Overall, these results highlight the importance of NRF2 in neuronal autophagy.
Different Transcription Factors Act Coordinately to Modulate Proteostasis
Under steady state conditions, proteostasis is controlled via protein-protein interactions and post-translational modifications obtaining a rapid response. However, cellular adaptation requires the transcriptional regulation of the UPR, UPS and autophagy genes. Considering that nerve cells are continuously submitted to low-grade toxic insults, including oxidative and proteotoxic stress, a reinforcement of proteostasis induced by transcriptional modulation might help preventing brain degeneration.
In the case of the UPR, the activation of each of the three arms will finally result in the transcriptional induction of certain genes (reviewed in [43]). For instance, an ATF6-derived fragment (ATF6f) binds to ER-stress response elements (ERSE) and induces the expression of several genes, including XBPI, BIP and CHOP. In addition, PERK signaling leads to the activation of the transcription factor ATF4, which controls the expression of multiple UPR-related genes and some others including the NRF2 target genes Hmox1 and p62. Finally, IRE1 activation results in the generation of an active transcription factor, spliced XBP1 (XBP1s), which controls the transcription of genes encoding proteins involved in protein folding.
On the other hand, NRF1 was shown to be necessary for proteasomal gene expression in the brain, as Nrf1-knockout mice exhibited reduced expression of genes encoding various subunits of the 20S core, as well the 19S regulatory complex together with impaired proteasomal function [90]. Both NRF1 and NRF2 bind to ARE sequences in the promoter regions of its target genes, which suggests they have overlapping transcriptional activities, although they differ in their regulatory mechanisms and cellular localization [120].
Transcription factors of the Forkhead box O (FOXO) family control the expression of multiple autophagy-related genes. Similar to what occurs with NRF2, there are multiple layers of regulation of the activity of FOXO members, which can be induced upon nutritional or oxidative stress [121]. Finally, the transcription factor TFEB, considered the master regulator of lysosomal biogenesis, plays a crucial role in regulation of autophagy under nutritional stress conditions. Thus, inhibition of mTORC1 leads to nuclear translocation of TFEB and induction of the expression of autophagy genes [122].
Overall, the existence of different transcriptional regulators of these machineries also suggests crosstalk and partially redundant mechanisms that may assure proteostasis under different circumstances. Accordingly, NRF2 may have a relevant role in tissues that support high levels of oxidative stress. For instance, oxidative stress-induced NRF2 may function under nutrient-rich conditions to transcriptionally up-regulate autophagy, similar to what has been found for TFEB under starvation conditions. Moreover, the brain functions largely under nutrient-rich conditions, posing NRF2 as a relevant mechanism to activate autophagy in neurons.
Promising�Therapeutic Potential for NRF2 in Proteinopathies
In the past few years, a great progress has been made in the knowledge of the regulatory roles of the UPR, UPS and autophagy on NRF2 activity, as well as the reciprocal NRF2-mediated transcription of components of these three systems. Therefore, new therapeutic possibilities may arise based on the exploitation of NRF2 as a crucial regulator of protein clearance in neurodegenerative diseases.
However, a key remaining question is whether it will be useful or deleterious to increase NRF2 levels in brain. Analysis of epidemiological data may provide a partial answer, as it indicates that the NFE2L2 gene is highly polymorphic and some single nucleotide polymorphisms found in its promoter regulatory region may provide a range of �physiological� variability in gene expression at the population level and some haplotypes were associated with decreased risk and/or delayed onset of AD, PD or ALS [123]. Moreover, as discussed by Hayes and colleagues [124], NRF2 effect might have an U-shaped response, meaning that too low NRF2 levels may result in a loss of cytoprotection and increased susceptibility to stressors, while too much NRF2 might disturb homeostatic balance towards a reductive scenario (reductive stress), which would favor protein misfolding and aggregation. Low NRF2 levels in the brain support the idea that a slight up-regulation may be sufficient to achieve a benefit under pathological conditions. In fact, the protective role of pharmacological NRF2-mediated activation of protein clearance has been shown in different neurodegeneration cell culture and in vivo models.
SFN is a pharmacological NRF2 activator that was demonstrated to induce proteasomal and autophagy gene expression [95], [36]. Interestingly, Jo and colleagues demonstrated that SFN reduced the levels of phosphorylated TAU and increased Beclin-1 and LC3-II, suggesting NRF2 activation may facilitate degradation of this toxic protein through autophagy [113]. Moreover, degradation of mHtt was enhanced with SFN, and this was reverted with the use of MG132, indicating proteasomal degradation of this toxic protein [95]. Autophagy-mediated degradation of phospho- and insoluble-TAU was reported with the organic flavonoid fisetin. This compound was able to induce autophagy by simultaneously promoting the activation and nuclear translocation of both TFEB and NRF2, along with some of its target genes. This response was prevented by TFEB or NRF2 silencing [125]. Bott and colleagues reported beneficial effects of a simultaneous NRF2, NRF1 and HSF1 activator on protein toxicity in spinal and bulbar muscular atrophy, a neurodegenerative disorder caused by expansion of polyglutamine-encoding CAG repeats in which protein aggregates are present [126]. The potential of NRF2 activation for the treatment of neurodegenerative disorders has been demonstrated with the approval of BG-12, the oral formulation of the NRF2 inducer dimethyl fumarate (DMF), for the treatment of multiple sclerosis [127], [128]. The success of DMF with autoimmune diseases with a strong inflammatory component suggests that neurodegenerative diseases might benefit from repositioning this drug. In a recent preclinical study of an ?-synucleinopathy model of PD, DMF was shown to be neuroprotective due, in part, to its induction of autophagy [129]. Studies reporting beneficial effects of NRF2 on neurodegeneration but not focusing on its effect on protein clearance are even more abundant (for a comprehensive review, see [7]). This is quite relevant, as it highlights the multiple damaging processes that can be simultaneously targeted by a single hit in NRF2, also including oxidative stress, neuroinflammation or mitochondrial dysfunction. However, future work will be needed to definitely determine if pharmacological activation of NRF2 may be a valid strategy to facilitate degradation of toxic proteins in the brain.
As explained before, exacerbated GSK-3? activity was reported in neurodegenerative diseases and it has been speculated that consequent NRF2 reduction can be partially responsible for the deleterious outcome. Under these pathological conditions, GSK-3 inhibitors could also cooperate to increase NRF2 levels and proteostasis. The beneficial effects of GSK-3 inhibitors have been reported in different models of neurodegeneration and, more interesting, GSK-3 repression was shown to reduce the levels of toxic proteins [130], [131], [132], [133]. Although no direct links between GSK-3 inhibition and NRF2-transcriptional regulation of genes promoting proteostasis have been observed yet, it is reasonable to speculate that down-regulation of GSK-3 activity would result in increased NRF2 levels, which eventually will result in reinforced proteostasis.
The transcriptional activity of NRF2 as well as the cellular capacity to maintain proteostasis decrease with age, the main risk factor for the development of neurodegenerative diseases. It is reasonable to think that the reinforcement of NRF2 and, consequently, proteostasis would, at least, delay the accumulation of protein aggregates and neurodegeneration. Indeed, treatment of human senescent fibroblasts with 18?-glycyrrhetinic acid (18?-GA) triterpenoid promoted NRF2 activation, leading to proteasome induction and enhanced life span. This study suggests that pharmacological activation of NRF2 is possible even in late life [86]. Moreover, a later study showed that this compound mediated SKN-1 and proteasome activation in C.elegans with beneficial effects on AD progression in relevant nematode models [134].
All things considered, NRF2-mediated induction of proteostasis-related genes seems to be beneficial in different proteinopathies.
Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More
Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below.
Key sections:
00:01:14 – Cancer and mortality
00:19:04 – Aging
00:26:30 – Brain and behavior
00:38:06 – Final recap
00:40:27 – Dose
Full timeline:
00:00:34 – Introduction of sulforaphane, a major focus of the video.
00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
00:02:12 – Prostate cancer risk.
00:02:23 – Bladder cancer risk.
00:02:34 – Lung cancer in smokers risk.
00:02:48 – Breast cancer risk.
00:03:13 – Hypothetical: what if you already have cancer? (interventional)
00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
00:04:38 – Sulforaphane and cancer.
00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
00:08:32 – Inhibition of breast cancer stem cells.
00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
00:19:04 – Beginning of aging section.
00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
00:20:34 – Importance of low inflammation for longevity.
00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
00:37:19 – Sulforaphane and duchenne muscular dystrophy.
00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
00:41:01 – Anecdotes on sprouting at home.
00:43:14 – On cooking temperatures and sulforaphane activity.
00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
00:44:56 – Cooking techniques and cruciferous vegetables.
00:46:06 – Isothiocyanates as goitrogens.
The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2, otherwise known as Nrf2, is a transcription factor which regulates the expression of a variety of antioxidant and detoxifying enzymes. Research studies have also demonstrated its role in controlling oxidative stress. Most neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are characterized by oxidative stress and chronic inflammation, the common targets of Nrf2 treatment approaches. Dr. Alex Jimenez D.C., C.C.S.T. Insight
Concluding Remarks
Transcription factor NRF2 orchestrates a proteostatic response by sensing to and modulating changes in the UPR, UPS and autophagy (Fig. 4). Consequently, the lack of NRF2 has been shown to aggravate proteinopathy, suggesting that NRF2 is necessary for optimal protein clearance. All together, we can speculate that NRF2 might be an interesting therapeutic target for proteinopathies.
Figure 4 NRF2 as a hub connecting proteotoxic-derived emergency signals to a protective transcriptional response. The accumulation of unfolded/misfolded proteins will lead to the activation of the unfolded protein response (UPR) in the ER. Activation of PERK or MAPK may result in the transcriptional induction of the ER-resident Gpx8 and several enzymes regulating GSH levels, critical to ensure correct protein folding. Protein aggregates inhibit proteasome activity (UPS), probably avoiding NRF2 degradation. NRF2 has been shown to specifically modulate the transcription of Psma3, Psma6, Psmb1, Psmb5 and Pomp genes. Several other subunits were up-regulated in an NRF2-dependent manner in response to D3T, probably enlarging the list of proteasome subunits regulated by NRF2. Autophagy is the main pathway for the degradation of protein aggregates. Autophagy also regulates NRF2, connecting this degradation pathway with NRF2 transcriptional induction of p62, Ndp52, Ulk1, Atg2b, Atg4c, Atg5, Atg7 and Gabarapl1.
According to the article above, while the symptoms of neurodegenerative diseases can be treated through a variety of treatment options, research studies have demonstrated that Nrf2 activation can be a helpful treatment approach. Because Nrf2 activators target broad mechanisms of disease, all neurodegenerative diseases can benefit from the use of the Nrf2 transcription factor. The findings of Nrf2 have revolutionized the treatment of neurodegenerative diseases. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Additional Topic Discussion: Relieving Knee Pain without Surgery
Knee pain is a well-known symptom which can occur due to a variety of knee injuries and/or conditions, including�sports injuries. The knee is one of the most complex joints in the human body as it is made-up of the intersection of four bones, four ligaments, various tendons, two menisci, and cartilage. According to the American Academy of Family Physicians, the most common causes of knee pain include patellar subluxation, patellar tendinitis or jumper’s knee, and Osgood-Schlatter disease. Although knee pain is most likely to occur in people over 60 years old, knee pain can also occur in children and adolescents. Knee pain can be treated at home following the RICE methods, however, severe knee injuries may require immediate medical attention, including chiropractic care. �
Oxidative stress is described as cell damage caused by free radicals, or unstable molecules, which can ultimately affect healthy function. The human body creates free radicals to neutralize bacteria and viruses, however, external factors, such as oxygen, pollution, and radiation, can often also produce free radicals. Oxidative stress has been associated with numerous health issues.
Oxidative stress and other stressors turn on internal protective mechanisms which can help regulate the human body’s antioxidant response. Nrf2 is a protein which senses levels of oxidative stress and enables the cells to protect themselves from internal and external factors. Nrf2 has also been demonstrated to help regulate genes involved in the production of antioxidant enzymes and stress-response genes. The purpose of the article below is to explain the effects of Nrf2 in cancer.
Abstract
The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.
The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to endogenous and exogenous stresses caused by reactive oxygen species (ROS) and electrophiles [1]. The key signaling proteins within the pathway are the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) that binds together with small Maf proteins to the antioxidant response element (ARE) in the regulatory regions of target genes, and Keap1 (Kelch ECH associating protein 1), a repressor protein that binds to Nrf2 and promotes its degradation by the ubiquitin proteasome pathway (Fig. 1). Keap1 is a very cysteine-rich protein, mouse Keap1 having a total of 25 and human 27 cysteine residues, most of which can be modified in vitro by different oxidants and electrophiles [2]. Three of these residues, C151, C273 and C288, have been shown to play a functional role by altering the conformation of Keap1 leading to nuclear translocation of Nrf2 and subsequent target gene expression [3] (Fig. 1). The exact mechanism whereby cysteine modifications in Keap1 lead to Nrf2 activation is not known, but the two prevailing but not mutually exclusive models are (1) the �hinge and latch� model, in which Keap1 modifications in thiol residues residing in the IVR of Keap1 disrupt the interaction with Nrf2 causing a misalignment of the lysine residues within Nrf2 that can no longer be polyubiquitinylated and (2) the model in which thiol modification causes dissociation of Cul3 from Keap1 [3]. In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs) (Fig. 2). In addition to modifications of Keap1 thiols resulting in Nrf2 target gene induction, proteins such as p21 and p62 can bind to Nrf2 or Keap1 thereby disrupting the interaction between Nrf2 and Keap1 [1], [3] (Fig. 3).
Fig. 1. Structures of Nrf2 and Keap1 and the cysteine code. (A) Nrf2 consists of 589 amino acids and has six evolutionarily highly conserved domains, Neh1-6. Neh1 contains a bZip motif, a basic region � leucine zipper (L-Zip) structure, where the basic region is responsible for DNA recognition and the L-Zip mediates dimerization with small Maf proteins. Neh6 functions as a degron to mediate degradation of Nrf2 in the nucleus. Neh4 and 5 are transactivation domains. Neh2 contains ETGE and DLG motifs, which are required for the interaction with Keap1, and a hydrophilic region of lysine residues (7 K), which are indispensable for the Keap1-dependent polyubiquitination and degradation of Nrf2. (B) Keap1 consists of 624 amino acid residues and has five domains. The two protein�protein interaction motifs, the BTB domain and the Kelch domain, are separated by the intervening region (IVR). The BTB domain together with the N-terminal portion of the IVR mediates homodimerization of Keap1 and binding with Cullin3 (Cul3). The Kelch domain and the C-terminal region mediate the interaction with Neh2. (C) Nrf2 interacts with two molecules of Keap1 through its Neh2 ETGE and DLG motifs. Both ETGE and DLG bind to similar sites on the bottom surface of the Keap1 Kelch motif. (D) Keap1 is rich in cysteine residues, with 27 cysteines in human protein. Some of these cysteines are located near basic residues and are therefore excellent targets of electrophiles and oxidants. The modification pattern of the cysteine residues by electrophiles is known as the cysteine code. The cysteine code hypothesis proposes that structurally different Nrf2 activating agents affect different Keap1 cysteines. The cysteine modifications lead to conformational changes in the Keap1 disrupting the interaction between the Nrf2 DLG and Keap1 Kelch domains, thus inhibiting the polyubiquitination of Nrf2. The functional importance of Cys151, Cys273 and Cys288 has been shown, as Cys273 and Cys288 are required for suppression of Nrf2 and Cys151 for activation of Nrf2 by inducers [1], [3].
Fig. 2. The Nrf2-Keap1 signaling pathway. (A and B) in basal conditions, two Keap1 molecules bind to Nrf2 and Nrf2 is polyubiquitylated by the Cul3-based E3 ligase complex. This polyubiquitilation results in rapid Nrf2 degradation by the proteasome. A small proportion of Nrf2 escapes the inhibitory complex and accumulates in the nucleus to mediate basal ARE-dependent gene expression, thereby maintaining the cellular homeostasis. (C) Under stress conditions, inducers modify the Keap1 cysteines leading to the inhibition of Nrf2 ubiquitylation via dissociation of the inhibitory complex. (D) According to the hinge and latch model, modification of specific Keap1 cysteine residues leads to conformational changes in Keap1 resulting in the detachment of the Nrf2 DLG motif from Keap1. Ubiquitination of Nrf2 is disrupted but the binding with the ETGE motif remains. (E) In the Keap1-Cul3 dissociation model, the binding of Keap1 and Cul3 is disrupted in response to electrophiles, leading to the escape of Nrf2 from the ubiquitination system. In both of the suggested models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the Antioxidant Response Element (ARE) and drive the expression of Nrf2 target genes such as NQO1, HMOX1, GCL and GSTs [1], [3].
Fig. 3. Mechanisms for constitutive nuclear accumulation of Nrf2 in cancer. (A) Somatic mutations in Nrf2 or Keap1 disrupt the interaction of these two proteins. In Nrf2, mutations affect ETGE and DLG motifs, but in Keap1 mutations are more evenly distributed. Furthermore, oncogene activation, such as KrasG12D[5], or disruption of tumor suppressors, such as PTEN [11] can lead to transcriptional induction of Nrf2 and an increase in nuclear Nrf2. (B) Hypermethylation of the Keap1 promoter in lung and prostate cancer leads to reduction of Keap1 mRNA expression, which increases the nuclear accumulation of Nrf2 [6], [7]. (C) In familial papillary renal carcinoma, the loss of fumarate hydratase enzyme activity leads to the accumulation of fumarate and further to succination of Keap1 cysteine residues (2SC). This post-translational modification leads to the disruption of Keap1-Nrf2 interaction and nuclear accumulation of Nrf2 [8], [9]. (D) Accumulation of disruptor proteins such as p62 and p21 can disturb Nrf2-Keap1 binding and results in an increase in nuclear Nrf2. p62 binds to Keap1 overlapping the binding pocket for Nrf2 and p21 directly interacts with the DLG and ETGE motifs of Nrf2, thereby competing with Keap1 [10].
Mechanisms of Activation and Dysregulation of Nrf2 in Cancer
Although cytoprotection provided by Nrf2 activation is important for cancer chemoprevention in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth [4]. Several mechanisms by which Nrf2 signaling pathway is constitutively activated in various cancers have been described: (1) somatic mutations in Keap1 or the Keap1 binding domain of Nrf2 disrupting their interaction; (2) epigenetic silencing of Keap1 expression leading to defective repression of Nrf2; (3) accumulation of disruptor proteins such as p62 leading to dissociation of the Keap1-Nrf2 complex; (4) transcriptional induction of Nrf2 by oncogenic K-Ras, B-Raf and c-Myc; and (5) post-translational modification of Keap1 cysteines by succinylation that occurs in familial papillary renal carcinoma due to the loss of fumarate hydratase enzyme activity [3], [4], [5], [6], [7], [8], [9], [10] (Fig. 3). Constitutively abundant Nrf2 protein causes increased expression of genes involved in drug metabolism thereby increasing the resistance to chemotherapeutic drugs and radiotherapy. In addition, high Nrf2 protein level is associated with poor prognosis in cancer [4]. Overactive Nrf2 also affects cell proliferation by directing glucose and glutamine towards anabolic pathways augmenting purine synthesis and influencing the pentose phosphate pathway to promote cell proliferation [11] (Fig. 4).
Fig. 4. The dual role of Nrf2 in tumorigenesis. Under physiological conditions, low levels of nuclear Nrf2 are sufficient for the maintenance of cellular homeostasis. Nrf2 inhibits tumor initiation and cancer metastasis by eliminating carcinogens, ROS and other DNA-damaging agents. During tumorigenesis, accumulating DNA damage leads to constitutive hyperactivity of Nrf2 which helps the autonomous malignant cells to endure high levels of endogenous ROS and to avoid apoptosis. Persistently elevated nuclear Nrf2 levels activate metabolic genes in addition to the cytoprotective genes contributing to metabolic reprogramming and enhanced cell proliferation. Cancers with high Nrf2 levels are associated with poor prognosis because of radio and chemoresistance and aggressive cancer cell proliferation. Thus, Nrf2 pathway activity is protective in the early stages of tumorigenesis, but detrimental in the later stages. Therefore, for the prevention of cancer, enhancing Nrf2 activity remains an important approach whereas for the treatment of cancer, Nrf2 inhibition is desirable [4], [11].
Given that high Nrf2 activity commonly occurs in cancer cells with adverse outcomes, there is a need for therapies to inhibit Nrf2. Unfortunately, due to structural similarity with some other bZip family members, the development of specific Nrf2 inhibitors is a challenging task and only a few studies of Nrf2 inhibition have been published to date. By screening natural products, Ren et al. [12] identified an antineoplastic compound brusatol as an Nrf2 inhibitor that enhances the chemotherapeutic efficacy of cisplatin. In addition, PI3K inhibitors [11], [13] and Nrf2 siRNA [14] have been used to inhibit Nrf2 in cancer cells. Recently, we have utilized an alternative approach, known as cancer suicide gene therapy, to target cancer cells with high Nrf2 levels. Nrf2-driven lentiviral vectors [15] containing thymidine kinase (TK) are transferred into cancer cells with high ARE activity and the cells are treated with a pro-drug, ganciclovir (GCV). GCV is metabolized to GCV-monophosphate, which is further phosphorylated by cellular kinases into a toxic triphosphate form [16] (Fig. 5). This leads to effective killing of not only TK containing tumor cells, but also the neighboring cells due to the bystander effect [17]. ARE-regulated TK/GCV gene therapy can be further enhanced via combining a cancer chemotherapeutic agent doxorubicin to the treatment [16], supporting the notion that this approach could be useful in conjuction with traditional therapies.
Fig. 5. Suicide gene therapy. Constitutive Nrf2 nuclear accumulation in cancer cells can be exploited by using Nrf2-driven viral vector for cancer suicide gene therapy [16]. In this approach, lentiviral vector (LV) expressing thymidine kinase (TK) under minimal SV40 promoter with four AREs is transduced to lung adenocarcinoma cells. High nuclear Nrf2 levels lead to robust expression of TK through Nrf2 binding. Cells are then treated with a pro-drug, ganciclovir (GCV), which is phosphorylated by TK. Triphosphorylated GCV disrupts DNA synthesis and leads to effective killing of not only TK containing tumor cells, but also the neighboring cells due to the bystander effect.
Nrf2 is a master regulator which triggers the production of powerful antioxidants in the human body which help eliminate oxidative stress. Various antioxidant enzymes, such as superoxide dismutase, or SOD, glutathione, and catalase, are also activated through the Nrf2 pathway. Furthermore, certain phytochemicals like turmeric, ashwagandha, bacopa, green tea, and milk thistle, activate Nrf2. Research studies have found that Nrf2 activation can naturally enhance cellular protection and restore balance to the human body.
Dr. Alex Jimenez D.C., C.C.S.T. Insight
Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More
Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below.
Key sections:
00:01:14 – Cancer and mortality
00:19:04 – Aging
00:26:30 – Brain and behavior
00:38:06 – Final recap
00:40:27 – Dose
Full timeline:
00:00:34 – Introduction of sulforaphane, a major focus of the video.
00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
00:02:12 – Prostate cancer risk.
00:02:23 – Bladder cancer risk.
00:02:34 – Lung cancer in smokers risk.
00:02:48 – Breast cancer risk.
00:03:13 – Hypothetical: what if you already have cancer? (interventional)
00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
00:04:38 – Sulforaphane and cancer.
00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
00:08:32 – Inhibition of breast cancer stem cells.
00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
00:19:04 – Beginning of aging section.
00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
00:20:34 – Importance of low inflammation for longevity.
00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
00:37:19 – Sulforaphane and duchenne muscular dystrophy.
00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
00:41:01 – Anecdotes on sprouting at home.
00:43:14 – On cooking temperatures and sulforaphane activity.
00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
00:44:56 – Cooking techniques and cruciferous vegetables.
00:46:06 – Isothiocyanates as goitrogens.
Acknowledgments
This work was supported by the Academy of Finland, the Sigrid Juselius Foundation and the Finnish Cancer Organisations.
In conclusion, nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a protein which increases the production of antioxidants which protect the human body against oxidative stress. As described above, the stimulation of the Nrf2 pathway are being studies for the treatment of diseases caused by oxidative stress, including cancer. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Additional Topic Discussion: Relieving Knee Pain without Surgery
Knee pain is a well-known symptom which can occur due to a variety of knee injuries and/or conditions, including�sports injuries. The knee is one of the most complex joints in the human body as it is made-up of the intersection of four bones, four ligaments, various tendons, two menisci, and cartilage. According to the American Academy of Family Physicians, the most common causes of knee pain include patellar subluxation, patellar tendinitis or jumper’s knee, and Osgood-Schlatter disease. Although knee pain is most likely to occur in people over 60 years old, knee pain can also occur in children and adolescents. Knee pain can be treated at home following the RICE methods, however, severe knee injuries may require immediate medical attention, including chiropractic care.
DNA supports approximately 20,000 genes, each holding a program for the creation of a protein or enzyme required for a healthy lifestyle. Every one of these patterns needs to be constantly regulated by a sort of “promoter” which manages exactly how much of each substance and/or chemical is generated and under which conditions these will also develop.
By connecting to a particular kind of the switch-like promoter areas, known as the Antioxidant Response Element, or ARE, the Nrf2 factor�supports the speed of creation for hundreds of distinct genes which enable the cells to survive under stressful circumstances. These genes then generate a selection of antioxidant enzymes which develop a defense network by neutralizing oxidants and by cleaning up the toxic by-products left behind in their�production, in addition to helping restore the�damage they caused.
What is Oxidative Stress?
Several oxidants like the superoxide radical, or O2-., and hydrogen peroxide, or H2O2, have been created through the practice of burning off the substances and/or chemicals which sustain the human body. The human body�possesses antioxidant enzymes which�neutralize and detoxify reactive foods and drinks we consume. The Nrf2 modulates their production to keep equilibrium and underscores the demand for all these enzymes. This balance can be interrupted by a�couple of factors, including age.
As we age,�the human body creates less Nrf2 and this delicate equilibrium can gradually begin to�turn towards the oxidative side, a state referred to as oxidative stress. Disease may also cause the overproduction of oxidants. Infections, allergies, and autoimmune disorders can additionally trigger our immune cells to create reactive oxidants, such as O2-. , H2O2, OH and HOCl, where healthy cells become damaged and respond with inflammation. Diseases associated with aging, including heart attacks, stroke, cancer, and neurodegenerative conditions like Alzheimer’s disease, also increase the development of oxidants, generating stress and an inflammation response.
What are Nrf2 Activators?
The Nrf2 protein, also called a transcription factor due to the way it can support and control enzymes and genes, is the secret element of a sequence of biochemical reactions within the cell which reacts to modifications in cognitive equilibrium as well as oxidative balance. The sensing elements of this pathway modify and discharge Nrf2, triggering it so it might spread into the nucleus of the cell towards the DNA. The Nrf2 may alternatively turn on or switch off the genes and enzymes it supports to protect the cell.
Fortunately, a variety of substances which are Nrf2 activators develop through the consumption of certain plants and extracts utilized centuries ago in Chinese and Native American traditional remedies. These phytochemicals seem to be equally as powerful with fewer side-effects, as the Nrf2-activating pharmaceutical products which are being used today.
Nuclear factor erythroid 2-related factor, more commonly known as Nrf2, is a transcription factor which protects the cell by regulating genes, enzymes and antioxidant responses. Transcription factors are a type of protein which attach to DNA to promote the creation of specific substances and chemicals, including glutathione S-transferases, or GSTs. Nrf2 activation induces the production of active proteins which exhibit a powerful antioxidant capacity to help decrease oxidative stress.
Dr. Alex Jimenez D.C., C.C.S.T. Insight
The Science Behind Nrf2 Activation
Once the initial Nrf2-activating dietary supplement was created in 2004, minimal information was known concerning the function of the Nrf2 pathway. Approximately 200 newspapers in the literature on Nrf2, also known as nuclear factor-like 2 or NFE2L2, existed and researchers were only just starting to discover the antioxidant response of Nrf2 in mammals. As of 2017, however, over 9,300 academic research studies on this “master regulator,” have been printed.
In reality, Nrf2 regulates many antioxidant enzymes which don’t correlate to the genes, instead, they offer protection against a variety of stress-related circumstances which are encountered by cells, organs and ultimately organisms, under healthy and pathological conditions. Based on this new quantity of information from published academic research studies, researchers can now develop better Nrf2 dietary supplements.
As of 2007,�research studies have demonstrated the complex function of the Nrf2 pathway. Nrf2 activators have been found to mimic factors of different structures within the human body. Through these pathways, Nrf2 activators have been equipped to feel changing conditions throughout the cell in order to keep balance and respond to the evolving requirements of the genes.
Why Use Nrf2-Activating Supplements?
As Nrf2-activation abilities diminish with age in organisms, changes may begin to occur. Research studies have demonstrated that the focus of Nrf2 in cells declines with age, showing increased markers of oxidative stress. A variety of age-related diseases like atherosclerosis and cardiovascular disease, arthritis, cancer, obesity, type 2 diabetes, hypertension, cataracts, and Alzheimer’s disease as well as Parkinson’s diseases can develop due to these changes. Oxidative stress has been found with these health issues.
By stimulating the cell’s capacity to increase the production of Nrf2 activators, Nrf2 dietary supplements can help revive the human body’s own ability to counteract the effects of oxidative stress. Polyunsaturated fatty acids, or PUFAs, are one of the most readily oxidized molecules and they’re particularly vulnerable to suffer damage from free radicals. Thiobarbituric acid, or TBARS, production can increase with age, indicating heightened oxidative stress along with a drop in Nrf2-regulated pathways.
Biologically, gene induction is a really slow mechanism, generally requiring hours to transfer through a pathway. As a result,�many enzymes possess their very own on/off switches which could be triggered in minutes by different regulatory enzymes. Researchers have developed proprietary compositions of Nrf2 activators which utilize this knowledge base of activation. Nrf2 activation is composed not just of the Nrf2 transcription factor being discharged from its inhibitor and migrating to the cell nucleus, but also binding to specific DNA sequences to encourage cytoprotective gene expression, regulating the pace at that Nrf2 is taken out of the nucleus.
Understanding the elimination procedure and the activation of Nrf2 in the human body has allowed researchers to build combinations of different Nrf2 activators to accomplish the reflection of genes through its modulation. The combination of the knowledge base, together with the wide variety of other research studies has�helped produce Nrf2 activators for use as dietary supplements. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topic Discussion: Relieving Knee Pain without Surgery
Knee pain is a well-known symptom which can occur due to a variety of knee injuries and/or conditions, including�sports injuries. The knee is one of the most complex joints in the human body as it is made-up of the intersection of four bones, four ligaments, various tendons, two menisci, and cartilage. According to the American Academy of Family Physicians, the most common causes of knee pain include patellar subluxation, patellar tendinitis or jumper’s knee, and Osgood-Schlatter disease. Although knee pain is most likely to occur in people over 60 years old, knee pain can also occur in children and adolescents. Knee pain can be treated at home following the RICE methods, however, severe knee injuries may require immediate medical attention, including chiropractic care.
How important is nutrition for our brain health? In the current work force, we are continuously stressed, often forced to finish tasks faster in order to meet ever so demanding deadlines. In addition, we are expected to maintain our optimal mental health, as this can be an essential�part towards delivering quality work. When our mental health is being affected by our hectic lifestyles, however, several practices which can help you start thinking more clearly can include sleeping properly, controlling stress, and even taking nutritional supplements for your brain health.
One nutritional supplement which has been widely recognized for its ability to boost brain health is curcumin, the active ingredient found in turmeric. Well-known for its antioxidant properties and its capacity to control inflammation in the human body, this powerful herb can also promote good mood and cognition. Another specific group which has reported significant benefits with the increased use of curcumin, is the elderly population. Below, we will discuss how curcumin can help boost brain health as well as demonstrate additional benefits this golden gem can have on our overall health and wellness.
Curcumin: a Golden Gem for Brain Health
In accordance with the Journal of Pharmacology, curcumin is made-up of a variety of substances which can encourage biological mechanisms that counteract age-related cognitive decline, dementia, or mood disorders. One randomized, double-blind, placebo-controlled trial analyzed the acute, of approximately 1 and 3 hours following a single dose, chronic, of approximately 4 weeks, and acute-on-chronic, of approximately 1 and 3 hours after one dose subsequently after chronic treatment, consequences of a curcumin formulation on cognitive function, mood, and blood biomarkers in 60 healthy adults ranging from the 60 to 85 years of age. After about one hour of application, the curcumin had considerably enhanced the participant’s functionality on attention and working memory tasks, in comparison with the placebo. Working memory and mood, which included general fatigue, change in calmness, contentedness and fatigue triggered by emotional strain were fundamentally improved following chronic therapy.
Curcumin boosts BDNF (brain-derived neurotrophic factor), the brain hormone which helps boost the development of new neurons that are in charge of improving memory and learning as well as supplying a substantial option for countering the aging brain. Additionally, this powerful ingredient increases blood circulation to the brain, also providing a much better attention span for greater work productivity.
Appreciating its anxiolytic effects can be one of the greatest benefits of carrying curcumin. According to the Journal of Clinical Psychopharmacology, a randomized double-blinded and double-blind trial with 60 subjects experiencing stress-related symptoms, including exhaustion, were to get routine curcumin nutritional supplements, and placebo for 30 days. The results indicated a greater quality of life, and diminished stress and fatigue for those receiving regular curcumin intakes. This progressive compound is believed to be able to help alleviate depression by altering the release of dopamine and serotonin, two powerful hormones which help keep the human mind and body at ease. Curcumin also promotes the optima health and wellness of inflammation pathways from the brain, which ultimately will help improve energy, mood, and production levels.
Curcumin may additionally promote cognition via its powerful antioxidant action which improves the bioavailability of DHA, the potent omega-3 fatty acid demonstrated to boost brain health. A research study in the American Journal of Geriatric Psychiatry revealed that curcumin really does protect the brain from neurodegeneration. The evaluation and analysis included 40 participants ranging from the ages of 51 to 84 years of age. Each individual subject consumed 90mg of curcumin twice per day or placebo for 18 weeks. The results indicated enhanced long-term healing, visual memory, and focus. With its tremendous medicinal properties, curcumin can also support neuroplasticity, which empowers the brain to change and fortify itself even through the natural degeneration with aging.
Curcumin can also promote anti-seizure action. With its antioxidant properties, this golden gem can help slow down reactive astrocyte expression, which helps cells survive within the mind. According to the Neuropharmacology Laboratory, Department of Pharmacology, the antioxidant properties of curcumin helped alleviate migraines, cognitive impairment, and cognitive stress in rats. A dental pre-treatment of curcumin was given to male rats which were additionally treated together with Pentylenetrazole, or PZT, every other day. The study demonstrated that curcumin enhanced the seizure score and indicated a diminished amount of myoclonic jerks. Furthermore, the outcome measures of the research study demonstrated that curcumin restructures seizures, oxidative stress, and brain function. Moreover, it helps protect memory function which may also be jeopardized by seizure activity.
Using its capability to strengthen fatty acids in the mind, curcumin helps athletes achieve better physical performance by boosting critical thinking, improving problem solving, and developing improved choices. The neuroprotective properties in curcumin also help regenerate tissues. In reality, based on Stem Cell Research and Therapy, a research study was conducted between the effects of curcumin on endogenous stem cells which were impartial. The study demonstrated that curcumin played an essential role in the healing of cells from combating the activation of microglia cells. Scientists in the Institute of Neuroscience and Medicine in Julich, Germany, observed the effects of impartial stem cell generation. During a 72-hour period, the evaluation and analysis demonstrated and indicated that the turmeric curcumin improved cellular generation by up to 80 percent. This shows how powerful curcumin could be for successful brain health function.
Dr. Alex Jimenez’s Insight
Nutrition is a fundamental factor in overall health and wellness. In today’s stressful world, however, it can often become difficult to eat a proper meal, let alone making sure we are taking in all the necessary nutrients we require on a regular basis. That, plus the added pressure of the workforce can have detrimental effects on our brain health. Dietary supplements, such as curcumin, have been demonstrated to have tremendous benefits on brain health. Although we may not always have the “free time” to sit down and have a properly balanced meal, taking nutritional supplements like curcumin, among others, can help improve the human body’s general well-being.
While many research studies have found that natural remedies and botanicals, such as dietary supplements apart from vitamins and minerals, continue to be the most common complementary health approach in the United States today, more and more alternative treatment options, such as chiropractic care, have started to incorporate these into their practices. As a matter of fact, a majority of chiropractors give nutritional advice, as well as recommendations for other lifestyle recommendations, as a general part of their treatment plan. Because chiropractic care is based on the notion of naturally treating the human body as a whole, enhancing it’s own healing properties without the use of drugs and/or medications as well as other invasive procedures, this healthcare profession relies on offering the necessary health maintenance components for optimal health and wellness. These components can include nutrition, water, rest, exercise, and clean air. Many chiropractors also offer curcumin supplements to help promote recovery.
This exceptional nutritional supplement, curcumin, helps improve mental clarity, improve cognition, improve endurance, and supplies anxiolytic benefits. Whether it’s more work fabricating, or a much better disposition, curcumin is a hidden golden gem for health.�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topics: Back Pain
Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.
Allergy Sufferers!�As winter gives way to spring, seasonal allergies can really get you down. Whether you get a few sniffles and some sneezing or you are down for the count with every terrible allergy symptom known to man, it can make spring pretty unbearable.
There is no shortage of allergy medications on the market, but they come with their own issues. The majority of them cause drowsiness and other unpleasant side effects, leaving you barely able to function. Those that are made from a �non drowsy� formula sound great, but if you have certain health conditions, like high blood pressure, you are out of luck � and stuck either taking the ones that make you sleep sucking it up and dealing with your allergies sans medication.
That�s no way to live.
What Are Allergies?
When your immune produces histamines in response to an allergen that you encounter the physiological reaction that you experience is broadly referred to as allergies or hay fever. The allergens may be simple substances that normally do not affect people, but when your body is out of balance, it can cause a variety of problems.
Symptoms of allergies include:
Runny nose
Stuffy nose
Headache
Sneezing
Itchy eyes
Coughing or scratchy throat
Skin Rash or Hives
Swelling
Diarrhea
Nausea
Fatigue
Anaphylaxis, severe, life threatening allergies can include swelling of the airways, tongue, and throat, inability to breathe due to blocked airway, and other dangerous symptoms.
The allergens can be something you come in contact with, like poison ivy, something you breathe in, like mold or dust, or it can be something you ingest, like strawberries or peanuts. Different people will have different allergies, but those who are allergic to the same things may not have the same reaction. Often a doctor or allergist will diagnose your allergies.
Chiropractic Care For Allergy Sufferers
Chiropractic treatments have been found to be very effective for relieving allergy symptoms and even stopping allergies at their source. It reduces the severity of allergy symptoms as well as the frequency of occurrence. It does not work like allergy medications which have an anti-histamine effect and only work as a short term fix for your allergy symptoms.
Chiropractic treatments help your body become more balanced so that it is better equipped for combating allergies at the source. When your spine is not aligned it can impact your nervous system leading to a variety of problems � including allergies. Your immune system can be affected, causing it to malfunction.
A chiropractor can help relieve the stress on your nervous system by aligning your spine. This takes the pressure off of nerves, allowing your immune system to function at a more optimal level. This makes it easier for your body to ward off infections while recognizing allergens as harmless.
When your immune system encounters allergens it doesn�t overreact to them. Instead, the reaction is much more subdued, or even nonexistent. Chiropractic has also been found to help asthma patients breathe easier. Asthma symptoms are diminished.
Chiropractic care is more than just spinal manipulation, though. It promotes whole body wellness. Patients are taught exercise, stress relief, and nutrition so that the entire system is treated. The whole body treatment plan for chiropractic patients will help you be allergy free in a short time.
It is important to follow your chiropractic plan thoroughly and consistently. Get plenty of rest and take time to destress. The more you can relax and take care of yourself, the healthier you will be overall. Chiropractic care can help so many health conditions; it can actually make you healthier. Allergy sufferers or if you are struggling with allergies for the first time, give chiropractic care a try you just might be surprised.
El Paso, Tx. Wellness chiropractor, Dr. Alexander Jimenez examines Functional Medicine.�What it�is and how it can help in having a healthy lifestyle.
The Challenge
Of total healthcare costs in the United States, more than 86% is due to chronic conditions.1 In 2015, health care spending reached $3.2 trillion, accounting for 17.8% of GDP.2 This exceeded the combined federal expenditures for national defense, homeland security, education, and welfare. By 2023, if we don�t change how we confront this challenge, annual healthcare costs in the U.S. will rise to over $4 trillion,3,4 the equivalent�in a single year�of four Iraq wars, making the cost of care using the current model economically unsustainable. If our health outcomes were commensurate with such costs, we might decide they were worth it. Unfortunately, the U.S. spends twice the median per-capita costs of other industrialized countries, as calculated by the Organization for Economic Cooperation and Development (OECD),5 despite having relatively poor outcomes for such a massive investment.6
Our current healthcare model fails to confront both the causes of and solutions for chronic disease and must be replaced with a model of comprehensive care geared to effectively treating and reversing this escalating crisis.This transformation requires something different than is usually available in our very expensive healthcare system.7
A Contributing Factor�Outdated Clinical Model
Despite notable advances in treating and preventing infectious disease and trauma, the acute-care model that dominated 20th century medicine has not been effective in treating and preventing chronic disease.
Adopting a new operating system for 21st century medicine requires that we:
Recognize and validate more appropriate and successful clinical models
Re-shape the education and clinical practices of health professionals to help them achieve proficiency in the assessment, treatment, and prevention of chronic disease
Reimburse equitably for lifestyle medicine and expanded preventive strategies, acknowledging that the greatest health threats now arise from how we live, work, eat, play, and move
This problem can�t be solved by drugs and surgery, however helpful those tools may be in managing acute signs and symptoms. It can�t be solved be adding new or unconventional tools, such as botanical medicine and acupuncture, to a failing model. It can�t be solved by pharmacogenomics (although advances in that discipline should help reduce deaths from inappropriately prescribed medication�estimated to be the fourth leading cause of hospital deaths12). The costly riddle of chronic disease can only be solved by shifting our focus from suppression and management of symptoms to addressing their underlying causes. Specifically, we must integrate what we know about how the human body works with individualized, patient-centered, science-based care that addresses the causes of complex, chronic disease, which are rooted in lifestyle choices, environmental exposures, and genetic influences.
This perspective is completely congruent with what we might call the �omics� revolution. Formerly, scientists believed that once we deciphered the human genome we would be able to answer almost all the questions about the origins of disease.What we actually learned, however, is that human biology is far more complex than that. In fact, humans are not genetically hardwired for most diseases; instead, gene expression is altered by myriad influences, including environment, lifestyle, diet, activity patterns, psycho-social-spiritual factors, and stress.These lifestyle choices and environmental exposures can push us toward (or away from) disease by turning on�or o � certain genes.That insight has helped to fuel the global interest in Functional Medicine, which has that principle at its very core.
A Strategic Response
Functional Medicine directly addresses the underlying causes of disease by using a systems-oriented approach with transformative clinical concepts, original tools, an advanced process of care (see box below), and by engaging both patient and practitioner in a therapeutic partnership.
Functional Medicine practitioners look closely at the myriad interactions among genetic, environmental, and lifestyle factors that can influence long-term health and complex, chronic disease (see Figure 1).A major premise of Functional Medicine is that, with science, clinical wisdom, and innovative tools, we can identify many of the underlying causes of chronic disease and intervene to remediate the clinical imbalances, even before overt disease is present.
Functional Medicine exemplifies just the kind of systems-oriented, personalized medicine that is needed to transform clinical practice.The Functional Medicine model of comprehensive care and primary prevention for complex, chronic illness is grounded in both science (evidence about common underlying mechanisms and pathways of disease as well as evidence about the contributions of environmental and lifestyle factors to disease) and art (the healing partnership and the search for insight in the therapeutic encounter).
What Is Functional Medicine?
Functional Medicine asks how and why illness occurs and restores health by addressing the root causes of disease for each individual. It is an approach to health care that conceptualizes health and illness as part of a continuum in which all components of the human biological system interact dynamically with the environment, producing patterns and effects that change over time. Functional Medicine helps clinicians identify and ameliorate dysfunctions in the physiology and biochemistry of the human body as a primary method of improving patient health. Chronic disease is almost always preceded by a period of declining function in one or more of the body�s systems. Functional Medicine is often described as the clinical application of systems biology. Restoring health requires reversing (or substantially improving) the specific dysfunctions that have contributed to the disease state. Each patient represents a unique, complex, and interwoven set of environmental and lifestyle influences on intrinsic functionality (their genetic vulnerabilities) that have set the stage for the development of disease or the maintenance of health.
To manage the complexity inherent in this approach, IFM has created practical models for obtaining and evaluating clinical information that lead to individualized, patient-centered, science-based therapies. Functional Medicine concepts, practices, and tools have evolved considerably over a 30-year period, reflecting the dramatic growth in the evidence base concerning the key common pathways to disease (e.g., inflammation, oxidative stress); the role of diet, stress, and physical activity; the emerging sciences of genomics, proteomics, and metabolomics; and the effects of environmental toxins (in the air, water, soil, etc.) on health.
Elements Of Functional Medicine
The knowledge base�or �footprint��of Functional Medicine is shaped by six core foundations:
Gene-Environment Interaction: Functional Medicine is based on understanding the metabolic processes of each individual at the cellular level. By knowing how each person�s genes and environment interact to create their unique biochemical phenotype, it is possible to design targeted interventions that correct the specific issues that lead to destructive processes such as inflammation and oxidation, which are at the root of many diseases.
Upstream Signal Modulation: Functional Medicine interventions seek to influence biochemical pathways �upstream� and prevent the overproduction of damaging end products, rather than blocking the effects of those end products. For example, instead of using drugs that block the last step in the production of inflammatory mediators (NSAIDs, etc.), Functional Medicine treatments seek to prevent the upregulation of those mediators in the first place.
Multimodal Treatment Plans: The Functional Medicine approach uses a broad range of interventions to achieve optimal health including diet, nutrition, exercise and movement; stress management; sleep and rest, phytonutrient, nutritional and pharmaceutical supplementation; and various other restorative and reparative therapies.These interventions are all tailored to address the antecedents, triggers, and mediators of disease or dysfunction in each individual patient.
Understanding the Patient in Context: Functional Medicine uses a structured process to uncover the significant life events of each patient�s history to gain a better understanding of who they are as an individual. IFM tools (the �Timeline� and the �Matrix� model) are integral to this process for the role they play in organizing clinical data and mediating clinical insights.This approach to the clinical encounter ensures that the patient is heard, engenders the therapeutic relationship, expands therapeutic options, and improves the collaboration between patient and clinician.
Systems Biology-Based Approach: Functional Medicine uses systems biology to understand and identify how core imbalances in specific biological systems can manifest in other parts of the body. Rather than an organ systems-based approach, Functional Medicine addresses core physiological processes that cross anatomical boundaries including: assimilation of nutrients, cellular defense and repair, structural integrity, cellular communication and transport mechanisms, energy production, and biotransformation.The �Functional Medicine Matrix� is the clinician�s key tool for understanding these network effects and provides the basis for the design of effective multimodal treatment strategies.
Patient-Centered and Directed: Functional Medicine practitioners work with the patient to find the most appropriate and acceptable treatment plan to correct, balance, and optimize the fundamental underlying issues in the realms of mind, body, and spirit. Beginning with a detailed and personalized history, the patient is welcomed into the process of exploring their story and the potential causes of their health issues. Patients and providers work together to determine the diagnostic process, set achievable health goals, and design an appropriate therapeutic approach.
To assist clinicians in understanding and applying Functional Medicine, IFM has created a highly innovative way of representing the patient�s signs, symptoms, and common pathways of disease. Adapting, organizing, and integrating into the Functional Medicine Matrix the seven biological systems in which core clinical imbalances are found actually creates an intellectual bridge between the rich basic science literature concerning physiological mechanisms of disease and the clinical studies, clinical diagnoses, and clinical experience acquired during medical training.These core clinical imbalances serve to marry the mechanisms of disease with the manifestations and diagnoses of disease.
Structural integrity: sub-cellular membranes to musculoskeletal integrity
Using this construct, it is possible to see that one disease/condition may have multiple causes (i.e., multiple clinical imbalances), just as one fundamental imbalance may be at the root of many seemingly disparate conditions (see Figure 2).
Constructing The Model & Putting It Into Practice
The scientific community has made incredible strides in helping practitioners understand how environment and lifestyle, interacting continuously through an individual�s genetic heritage, psychosocial experiences, and personal beliefs, can impair one or all of the seven core clinical imbalances. IFM has developed concepts and tools that help to collect, organize, and make sense of the data gathered from an expanded history, physical exam, and laboratory evaluation, including:
The GOTOIT system, which presents a logical method for eliciting the patient�s whole story and ensuring that assessment and treatment are in accord with that story:
G = Gather Information
O = Organization Information
T = Tell the Complete Story Back to the Patient
O = Order and Prioritize
I = InitiateTreatment
T = Track Outcomes
The Functional Medicine Timeline, which helps to connect key events in the patient�s life with the onset of symptoms of dysfunction.
The Functional Medicine Matrix, which provides a unique and succinct way to organize and analyze all of a patient�s health data (see Figure 3).
The patient�s lifestyle influences are entered across the bottom of the Matrix, and the Antecedents,Triggers, and Mediators (ATMs) of disease/dysfunction are entered in the upper left corner.The centrality of the patient�s mind, spirit, and emotions, with which all other elements interact, is clearly shown in the figure. Using this information architecture, the clinician can create a comprehensive snapshot of the patient�s story and visualize the most important clinical elements of Functional Medicine:
1. Identifying each patient�s ATMs of disease and dysfunction.
2. Discovering the factors in the patient�s lifestyle and environment that influence the expression of health or disease.
3. Applying all the data collected about a patient to a matrix of biological systems, within which disturbances in function originate and are expressed.
4. Integrating all this information to create a comprehensive picture of what is causing the patient�s problems, where they are originating, what has influenced their development, and�as a result of this critical analysis�where to intervene to begin reversing the disease process or substantially improving health.
A Functional Medicine treatment plan may involve one or more of a broad range of therapies, including many different dietary interventions (e.g., elimination diet, high phytonutrient diversity diet, low glycemic-load diet), nutraceuticals (e.g., vitamins, minerals, essential fatty acids, botanicals), and lifestyle changes (e.g., improving sleep quality/quantity, increasing physical activity, decreasing stress and learning stress management techniques, quitting smoking). Nutrition is so vital to the practice of Functional Medicine that IFM has established a core emphasis on Functional Nutrition and has funded the development of a set of unique, innovative tools for developing and applying dietary recommendations.
Scientific support for the Functional Medicine approach to treatment can be found in a large and rapidly expanding evidence base about the therapeutic effects of nutrition (including both dietary choices and the clinical use of vitamins, minerals, and other nutrients such as sh oils)13,15,15; botanicals16,17,18; exercise19 (aerobics, strength training, flexibility); stress management 20; detoxification 21,22,23; acupuncture�24,25,26; manual medicine (massage, manipulation)27,28,29; and mind/body techniques 30,31,32 such as meditation, guided imagery, and biofeedback.
All of this work is done within the context of an equal partnership between the practitioner and patient.The practitioner engages the patient in a collaborative relationship, respecting the patient�s role and knowledge of self, and ensuring that the patient learns to take responsibility for their own choices and for complying with the recommended interventions. Learning to assess a patient�s readiness to change and then providing the necessary guidance, training, and support are just as important as ordering the right lab tests and prescribing the right therapies.
Summary
The practice of Functional Medicine involves four essential components: (1) eliciting the patient�s complete story during the Functional Medicine intake; (2) identifying and addressing the challenges of the patient�s modifiable lifestyle factors and environmental exposures; (3) organizing the patient�s clinical imbalances by underlying causes of disease in a systems biology matrix framework; and (4) establishing a mutually empowering partnership between practitioner and patient.
A great strength of Functional Medicine is its relevance to all healthcare disciplines and medical specialties, any of which can�to the degree allowed by their training and licensure�apply a Functional Medicine approach, using the Matrix as a basic template for organizing and coupling knowledge and data. In addition to providing a more effective approach to preventing, treating, and reversing complex chronic disease, Functional Medicine can also provide a common language and a uni ed model that can be applied across a wide variety of health professions to facilitate integrated care.
Functional Medicine is playing a key role in the effort to solve the modern epidemic of chronic disease that is creating a health crisis both nationally and globally. Because chronic disease is a food- and lifestyle-driven, environment- and genetics-influenced phenomenon, we must have an approach to care that integrates all these elements in the context of the patient�s complete story. Functional Medicine does just that and provides an original and creative approach to the collection and analysis of this broad array of information. Using all the concepts and tools that IFM has developed, Functional Medicine practitioners contribute vital skills for treating and reversing complex, chronic disease.
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The benefits that come from a ketogenic diet are much like those of any strict low-carb diet. The effect may be greater since protein is significantly more restricted. This raises ketones more, and reduces insulin (the fat-storing hormone).
Weight Loss
Turning your body to some fat-burning machine has clear benefits for weight loss. Fat burning is significantly increased while insulin, the hormone that focuses on fat-storing, drops considerably. This produces the perfect circumstances.
About 20 scientific research of the maximum category (RCTs) reveal that, compared to other diets, low-fat and ketogenic diets result in more effective weight reduction.
Reverse Type 2 Diabetes
A ketogenic diet is excellent for reversing type 2 diabetes, because it lowers blood-sugar levels as well as also helping to reverse the negative effect of elevated insulin levels from this condition.
Improved Mental Focus
Ketosis ends in a steady stream of gas (ketones) to the brain. And on a ketogenic diet you stay away from swings in blood glucose. This contributes to the experience of concentration and attention.
A lot of people use keto diets specifically for improved mental performance. Interestingly, there is a frequent misperception that eating a great deal of carbs6 is necessary for proper brain functioning. When ketones aren’t available but this is only true.
Following a couple of times (up to a week) of keto adaptation, through that people can experience some difficulty concentrating, have headaches and be easily irritated, both the human body and mind can run smoothly on ketones.
Inside this state, lots of men and women experience more energy and enhanced mental focus.
Increased physical endurance
Ketogenic diets may vastly increase your physical endurance, by giving you constant access to all of the energy of your own fat stores.
The body’s source of stored carbohydrates (glycogen) only lasts for a few hours of intense exercise, or less. But your fat stores hold sufficient energy to easily last for weeks or perhaps months.
When you’re accommodated to burning primarily carbs — like most individuals are now — that your fat stores aren’t readily accessible, and they can not fuel your brain. This results in needing to fill up by eating before, during and after exercise sessions that are longer. Or even simply to fuel your everyday activities and prevent “hanger” (hungry and irritable). On a ketogenic diet this dilemma is solved. As the body and brain can be fueled 24/7 from the stores that are powerful, you can keep going.
Whether you are competing in a bodily endurance event, or just trying to remain focused on reaching some other target, your body gets the fuel it needs to keep you going and going.
Two Problems
So how is it possible that the majority of people feel that carbohydrates are essential to do exercise? There are just two reasons. Not, and to unlock the power of ketogenic diets for bodily endurance rather suffer reduced performance, you’ll need:
Enough fluid and salt
Fourteen days of adaptation into burning fat — it does not happen immediately
Metabolic Syndrome
There are many studies demonstrating that low-carb diets improve markers of metabolic syndrome, such as blood lipids, insulin levels, HDL-cholesterol, LDL particle size and fasting blood sugar levels. Improvements have been demonstrated to be greater when carbs and protein are limited to some the point of becoming.
Epilepsy
The ketogenic diet is a proven medical therapy for epilepsy that’s been utilized since the 1920s. Traditionally it has been used in children with uncontrolled epilepsy despite drugs.
More recently it has also been tested successfully by adults with epilepsy, with similar good results. There are randomized controlled trials that demonstrate the potency of the ketogenic diet in seizures in patients with epilepsy.
Employing a ketogenic diet in epilepsy is that usually enables people to take less anti-epileptic drugs, while staying seizure-free. It is not uncommon to even be in a position to completely stop taking these drugs.
As a number of medications have side effects, such as nausea, reduced concentration, personality changes or even reduced IQ — being able to shoot less or no medications can be enormously beneficial.
More Prevalent Advantages
The advantages will be the most frequent ones. However there are many others that are potentially even more unexpected and, at least for some people, lifechanging.
The scope of our information is limited to chiropractic and spinal injuries and conditions. To discuss options on the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .�
By Dr. Alex Jimenez
Additional Topics: Wellness
Overall health and wellness are essential towards maintaining the proper mental and physical balance in the body. From eating a balanced nutrition as well as exercising and participating in physical activities, to sleeping a healthy amount of time on a regular basis, following the best health and wellness tips can ultimately help maintain overall well-being. Eating plenty of fruits and vegetables can go a long way towards helping people become healthy.
IFM's Find A Practitioner tool is the largest referral network in Functional Medicine, created to help patients locate Functional Medicine practitioners anywhere in the world. IFM Certified Practitioners are listed first in the search results, given their extensive education in Functional Medicine
Chiropractic Care For Allergy Sufferers
