Professor Matthew Walker and his fellow researchers, at University College London (UCL), have some promising early evidence in epilepsy and NRF2 research. Their research targets two approaches, 1) By targeting anti-oxidant treatments to inhibit the enzymes that produce ROS (Approach A: An attacking approach) and 2) by increasing the ability of neurons to break ROS down into less damaging molecules (Approach B: A defensive approach).
The Epilepsy Research UK organization has provided £133,755, over 30 months, to explore a more in-depth study involving these two approaches a project entitled Preventing seizure induced cell death by NADPH oxidase inhibition and Nrf2 induction.
The research team will be using techniques to compare which of the two approaches is the most effective at preventing seizure-induced neuronal death and study longer-term consequences. Approach A will inhibit a well know ROS producing enzyme known as NADPH oxidase, and approach B enhance the activity of Nuclear factor eythroid 2-related factor 2 (Nrf2 – a key regulator of antioxidant defenses). Their research will study whether the therapies (alone and in combination) can prevent seizures following a brain trauma, and are effective in preserving memory. This study hopes to identify new treatments to prevent seizures and reduce damage to the brain.
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The Center for Disease Control (CDC) states that obesity is a significant public health problem. The “Healthy People” initiative shows that not one state in the United States meets the Healthy People goal of 15% body mass index (BMI).
Thirty states missed the goal by a percentage by 10% or more. Data was collected from the Behavioral Risk Factor Surveillance System (BRFSS).
Obesity and its associated metabolic disorders have been classified as a growing health epidemic and is causing a major strain on health systems. Overall, the health picture shows that overall 25.6% of respondents were considered obese, 26.4% of men were obese and 24.8% of women. The most at risk age group for both men and women was those aged 50–59 years.
Obesity vs Being Overweight
There is a difference between being obese and being overweight. Obesity is characterized by having too much body fat. Being overweight may be described as weighing too much. Weight may result from muscle, bone, fat, and/or body water.
Obesity occurs over a period of time as a person consumes more calories than they use. Factors impacting weight include genetics, diet, and lack of physical activity. Obesity has been associated with diseases such as diabetes, certain cancers, heart disease, stroke and arthritis.
Medical experts promote that 10% to 15% weight loss will make a big difference in lowering heath risks associated with obesity. Weight-loss can be achieved through healthy dietary changes as well as increased physical activity. Prescription medications or weight-loss surgery are also options to discuss with a medical professional. In considering a healthy diet, this article will investigate the impact that NRF2 synergy can have on obesity.
NRF2 Obesity Studies:
Obviously NRF2 activation alone would be insufficient to tackle obesity. However, there are some very interesting studies that show a healthy NRF2 pathway in the body does help manage obesity. The purpose of sharing some extracts from various health related NRF2 obesity studies is to encourage you to do further in-depth research for yourself, to whet the appetite for learning more about the topic. We share this information for educational purposes only. Consult with a medical professional for professional advice regarding any questions you have regarding obesity and weight-loss. Adipose Deficiency of Nrf2 in ob/ob Mice Results in Severe Metabolic Syndrome http://www.ncbi.nlm.nih.gov/pubmed/23238296
Two quotes from this study are fascinating to those interested in NRF2 Science.
1. “Our findings support a novel role for Nrf2 in regulating adipose development and function, by which Nrf2 controls the capacity of WAT expansion and insulin sensitivity and maintains glucose and lipid homeostasis.”
2. “In light of the new function of Nrf2 in adipogenesis and its canonical role in adaptive antioxidant response, our results suggest a novel mechanistic linkage between metabolic syndrome and oxidative stress, opening the possibility that manipulation of Nrf2 may prevent or treat obesity and associated metabolic syndrome.”
The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism. The Journal Of Nutritional Biochemistry [J Nutr Biochem] 2012 Oct; Vol. 23 (10), pp. 1201-6. Date of Electronic Publication: 2012 Jul 21.
This study also has some interesting findings related to NRF2, metabolism, fatty diets, obesity s such as diabetes.
“Recently, the Nrf2 pathway was identified as having regulatory functions in mitochondrial biogenesis, adipocyte differentiation and liver energy metabolism. Activation of Nrf2 increases energy metabolism and conversely suppresses lipid synthesis. Lard-based, but not soybean oil-based, high-fat diets reduce mRNA expression of Nrf2 and its downstream targets, suggesting a macronutrient influence on the activation of the Nrf2 pathway and susceptibility to oxidative stress. This review examines data revealing the Nrf2 pathway’s regulatory role in energy metabolism at the molecular, cellular and whole animal levels. Understanding the relationship of Nrf2 and energy metabolism in cells, tissues and physiologic systems will provide novel insights for nutritional interventions for obesity and its comorbidities such as diabetes.“
Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. European Journal Of Pharmacology [Eur J Pharmacol] 2009 Oct 12; Vol. 620 (1-3), pp. 138-44. Date of Electronic Publication: 2009 Aug 19.
“CDDO-Imidazolide or CDDO-Im is an extremely potent activator of Nrf2 signaling. In cells undergoing adipogenesis, CDDO-Im prevents lipid accumulation in an Nrf2-dependent manner. However, in vivo evidence for effects of CDDO-Im on obesity is lacking. The goals of these studies were to determine if CDDO-Im can prevent high-fat diet-induced obesogenesis in the mouse, and to elucidate the molecular target of drug action. Wild-type and Nrf2-disrupted C57BL/6J female mice were dosed 3 times per week with 30 micromol/kg CDDO-Im or vehicle by oral gavage, during 95 days of access to a control diet or a high-fat diet. Body weights, organ weights, hepatic fat accumulation and gene expression were measured. Treatment with CDDO-Im effectively prevented high-fat diet-induced increases in body weight, adipose mass, and hepatic lipid accumulation in wild-type mice but not in Nrf2-disrupted mice. Wild-type mice on a high-fat diet and treated with CDDO-Im exhibited higher oxygen consumption and energy expenditure than vehicle-treated mice, while food intake was lower in CDDO-Im-treated than vehicle-treated mice. Levels of gene transcripts for fatty acid synthesis enzymes were downregulated after CDDO-Im treatment in the liver of wild-type mice. This inhibitory effect of CDDO-Im on lipogenic gene expression was significantly reduced in Nrf2-disrupted mice. The results indicate that CDDO-Im is an exceedingly potent agent for preventing obesity, and identify the Nrf2 pathway as a novel target for management of obesogenesis.
Those familiar with NRF2 activation are aware that curcumin is a potent NRF2 activator. This next study investigates whether there are any health benefits from curcumin on weight-loss.
“New mechanisms and the anti-inflammatory role of curcumin in obesity and obesity-related metabolic diseases.” European Journal of Nutrition, Apr 2011
“The interactions of curcumin with several signal transduction pathways reverse insulin resistance, hyperglycemia, hyperlipidemia, and other inflammatory symptoms associated with obesity and metabolic diseases.“
“The modulation of several cellular transduction pathways by curcumin has recently been extended to elucidate the molecular basis for obesity and obesity-related metabolic diseases. These findings might enable novel phytochemical treatment strategies as well as curcumin translation to the clinical practice for the treatment and prevention of obesity-related chronic diseases.”
Emerging role of Nrf2 in adipocytes and adipose biology. Advances In Nutrition (Bethesda, Md.) [Adv Nutr] 2013 Jan 01; Vol. 4 (1), pp. 62-6
“Maintenance of a balanced redox state within the cell is of critical importance to a wide variety of biological systems. Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a critical regulator of key aspects of the antioxidant defense pathway and has long been a subject of interest regarding conditions of chronic stress such as inflammation and cancer. Recent data have emerged demonstrating that oxidative stress and Nrf2 also play critical roles in the biology of adipose tissue. This review examines data identifying the roles of Nrf2 and oxidative stress in the biological process of adipose cell differentiation as well as the implications of Nrf2 modulation on obesity. Working to understand the complex interplay among Nrf2, oxidative stress, and adipose biology could lead to a variety of possible treatments for obesity and other related disorders.”
New player on an old field; the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome. Current Diabetes Reviews [Curr Diabetes Rev] 2013 Mar 1; Vol. 9 (2), pp. 137-45
“Nuclear erythroid factor 2 like 2 (Nrf2) has been described as a transcription factor that serves as a master regulator of the adaptive response to exogenous and endogenous oxidative and electrophilic stresses. Evidence of Nrf2 crosstalk with other molecular pathways is increasing; recent publications have proposed a role of Nrf2 in the development of obesity and in the highly regulated process of adipocyte differentiation through its interaction with other transcription factors and receptors implicated in metabolic regulation. In the present review, we discuss the available data on the possible role of Nrf2 in obesity and metabolic syndrome and the feasibility of using Nrf2 as a therapeutic target in the clinical setting.”
There has been an increased awareness and many resulting questions following Angelina Jolie’s announcement that she has had a preventative double mastectomy to prevent the further spread of cancer.
The gene within her body that led to her decision is called BRCA1. BRCA1 is a tumor suppressor protein in carcinoma and normal cell types and protects normal cell’s DNA from uncontrolable cell growth. However when BRCA genes become mutated, they fail to protect the body from tumors and can lead to the spread of different types of cancers, including breast and ovarian cancer. Mutation of the BRCA gene in men can cause pancreatic, skin or prostate cancer. The study of this condition is extremely complex and requires more in depth understanding than what this article can provide. This article is for educational purposes only, consult with a medical professional to discuss personal conditions.
Readers of this web site know that oxidative stress (a major contributor to the etiology of cancer) occurs as the reactive oxygen species (ROS) and the cell’s antioxidant enzymes become imbalanced. The studies below investigate the effects of this in relation to BRCA and various cancers.
A recent study shows that a connection exists between NRF2 expression and the protection that the BRCA1 gene can provide. The study entitled, “Nrf2 is associated with the regulation of basal transcription activity of the BRCA1 gene.” The abstract states, “BRCA1 is closely related to the pathogenesis of breast cancer. The activity of BRCA1 promoter is regulated by transcriptional factors. The transcription factor Nrf2 (Nuclear factor-erythroid-2p45-related factor 2) is a potent transcriptional activator and plays a central role in inducible expression of many cytoprotective genes. In this report, we found that over-expression of Nrf2 stimulated BRCA1 expression, knockdown of Nrf2 attenuated BRCA1 expression. Nrf2 also interacted with CBP and p300 to form an active transcription complex, which could bind to the ARE (antioxidant response element) site on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Our finding could lead to a better understanding of the development of breast cancer.” We look forward to further studies and results from the Department of Oncology, Department of Breast Surgery, Breast Cancer Institute, Shanghai Cancer Center, Shanghai Medical College and Fudan University who have conducted the research.
The finding of the study further showed that low concentrations DIM were able to protect cells from oxidative stress via the tumor suppressor BRCA1. The researchers found that the BRCA1 protein expression occurred in two breast cancer cell lines as well as prostate cancer, lung cancer and cervical cancer. Cells with low basal expression responded more positively than high basal expression suggesting the importance of NRF2 activation as a preventative measure rather than as a cure for disease.
The timing of the protection appears to make a big difference, i.e whether it occurs prior to the tumors developing. To quote from the study, “Our findings have implications for understanding chemoprevention and its limitations. Since DIM’s protective effects occurred at physiologic concentrations, it is reasonable to speculate that DIM blocks carcinogenesis, in part, by enabling normal cells to mount a more effective antioxidant response. This antioxidant response may include an increased ability of cells to repair oxidative DNA damage, since BRCA1 contributes to various DNA repair processes. Tumor cells often exhibit oxidative stress due to impaired antioxidant defenses. Thus, the presence of pre-existing cancer cells that are protected by antioxidants is a possible explanation for the mixed results obtained in clinical studies using antioxidants to prevent cancer. Here, the ability of DIM to promote survival of oxidatively stressed tumor cells could limit its activity as a chemoprevention agent”
The study above was followed up by a further paper published in 2009 entitled, “Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner.” The abstract states, “The indole-3-carbinol (I3C) metabolite 3,3′-diindolylmethane (DIM) is a proposed cancer prevention agent for various tumor types, including breast cancer. Here, we show that DIM up-regulates expression of the tumor suppressor protein BRCA1 in carcinoma and normal cell types. Up-regulation of BRCA1 was dose and time dependent, and it was observed at physiologically relevant micromolar and submicromolar DIM concentrations when cells were exposed for 72 hours. Treatment with the parent compound (I3C) or DIM (1 micromol/L) protected against cell killing due to H(2)O(2) and other oxidants, and the protection was abrogated by knockdown of BRCA1. DIM stimulated signaling by the antioxidant transcription factor NFE2L2 (NRF2) through the antioxidant response element in a BRCA1-dependent manner. We further showed that DIM rapidly stimulated phosphorylation of BRCA1 on Ser (1387) and Ser (1524) and that these phosphorylations are required for protection against oxidative stress. DIM-induced phosphorylation of BRCA1 on Ser (1387) was dependent on ataxia-telangiectasia mutated. Finally, in our assay systems, H(2)O(2)-induced cell death was not due to apoptosis. However, a significant component of cell death was attributable to autophagy, and both DIM and BRCA1 inhibited H(2)O(2)-induced autophagy. Our findings suggest that low concentrations of DIM protect cells against oxidative stress via the tumor suppressor BRCA1 by several distinct mechanisms.”
The 2010 study “Redox regulation in cancer: a double-edged sword with therapeutic potential.” The message from this study validates the previous two. Namely that prevention is better than cure. The study states that, “Nrf2 plays an essential role in maintaining cellular homeostasis and hence represents a critical target for prevention of oxidative stress- or inflammation-associated carcinogenesis.”
Thanks to Angelina Jolie for being willing to share the news of her health condition publicly and raising awareness of breast cancer and spur interest in finding a cure for this disease.
A classic NRF2 study entitled, “Nrf2, a multi-organ protector?” predates many of the latest studies regarding NRF2. It was however one of those landmark studies that paved the way for later studies.
The study states, “Nrf2 may serve as a master regulator of the ARE-driven cellular defense system against oxidative stress.” and then goes on to investigate whether multiple organs in the body are protected from the activation of NRF2.
The researchers conclude their abstract with the following statement, “The widespread nature of Nrf2 may have an important therapeutic potential, allowing prevention of carcinogenesis and neurodegenerative diseases.”
The paper claims that humans are bombarded by wide variety of toxic insults each and every day. Toxins such as carcinogens, electrophiles, reactive oxygen species, diesel exhaust, inflammation, calcium disturbance, UV light, and cigarette smoke. They also state that “many studies have shown that NRF2 is crucial in protecting a variety of tissues such as lung, liver, kidney, stomach, small intestine, central nervous system, splenocytes, macrophages, erythrocytes, and retinal epithelia.”
Why is it important to protect these multiple organs from the toxins? Well, the research goes on to state that “Reactive oxygen species (ROS) and electrophiles cause cellular damage leading to many diseases including cancer, autoimmune disease, and neurodegenerative disease; such toxic insults are normally detoxified by phase II detoxification enzymes and antioxidant proteins”.
Studies have shown that the following organs have benefited from NRF2 activation. (read the full study to obtain references for studies relating to these findings below).
Lung and liver
Nrf2 has been shown to protect the lungs from butylated hydroxytoluene-induced acute respiratory distress syndrome, hyperoxic injury, and bleomycin-mediated pulmonary fibrosis. It does so by detoxifying pathways and antioxidant potentials. Smokers and those impacted by second hand smoke will be interested to know that studies demonstrate Nrf2 protection against cigarette smoke-induced emphysema and COPD.
Nrf2 also assists in protecting the liver, through increased sensitivity to acetaminophen-induced centrilobular hepatocellular necrosis and hepatotoxicity.
The article further states that additional studies have demonstrated that “Nrf2 protects GI tract from carcinogenesis, implying a role for Nrf2 in cell cycle regulation and cancer prevention…. Thus, constitutive and inducible expression of phase II enzymes through the Nrf2-ARE pathway can modify the susceptibility of GI tract to carcinogenesis.”
The Nrf2-ARE pathway also assists in neuroprotection. Neuroblastoma cells received protection from oxidative glutamate toxicity and H2O2-induced apoptosis (cell death).
The protective effects of Nrf2 are not limited to the organs previously mentioned but have provedkey to protecting other cell types as well. Sulforaphane was shown to protect retinal pigment epithelial cells from photooxidative damage. Macrophages and epithelial cells were protected from from diesel exhaust chemicals. Nrf2 protects gallstone genes and is very beneficial in wound healing. Lastly, NRF2 has been shown to benefit against the progression of autoimmune diseases like lupus, MS and Parkinson’s disease.
The researchers state “Our hypothesis for Nrf2-conferred multi-organ protection phenomenon is that Nrf2 protects multiple tissues by coordinately up-regulating classic ARE-driven detoxification and antioxidant genes as well as cell type-specific targets that are required for basic defense in each unique environment.”
A wide variety of cells are impacted positively by NRF2 activation such as lung, liver, kidney, stomach, small intestine, central nervous system, splenocytes, macrophages, erythrocytes, and retinal epithelia. Common to all these organs is the fact that each cell utilizes the Nrf2-ARE pathway as a protector.
In conclusion, the paper presents evidence supporting the hypothesis that Nrf2 is central to multi-organ protection within the bod. To quote the authors further, “As numerous studies have demonstrated the great potential for the Nrf2-ARE pathway as a therapeutic target in preventing cancer, autoimmune disease, and neurodegenerative disease, it is important to identify ways to modulate cell-specific Nrf2 activity so as to facilitate the development of novel therapeutic strategies for treatment of these diseases.”
The article is for educational purposes only. Please consult with a medical professional to discuss your personal medical details.
Our original article highlighting the Michael J. Fox Foundation’s interest in NRF2 activation solutions for Parkinson’s disease met with a lot of interest, so we decided to do a follow up piece highlighting an additional study that is currently underway.
This time, the Michael J. Fox Foundation has provided a grant in its search for a Parkinson’s Disease (PD) cure to Dr. Martin Martinov, PhD. His research project is entitled “Identification of Nrf2 Activators Using an In Silico Modeling Platform, Followed by Evaluation of These Compounds in an Alpha-Synuclein Model of PD”.
End-in-Mind: As demonstrated in numerous medical studies, Oxidative stress plays a crucial role in the advancement of many disease conditions. This includes Parkinson’s disease (PD). The aim of this study is to determine whether the transcription factor NF-E2-related factor (Nrf2) induces antioxidant protection and phase II detoxification enzymes. Numerous studies have been published on Pubmed which suggests protection to vulnerable neurons through the NRF2/ARE pathway. This neuronal Nrf2 up-regulation study is considered an attractive therapeutic strategy for PD by the Michael J. Fox Foundation.
Project Description: Gradient Biomodeling, LLC claims to have identified two new potent non-toxic Nrf2 pathway activators. Their approach claims to have higher modulators than two other NRF2 activators, BHQ and Sulforaphane. Their preliminary experiments show evidence of blood brain barrier penetration.. The main objective is to determine whether these Nrf2 activators will result in neuroprotection in pre-clinical Parkinson’s disease conditions.
Progress Report: Thus far the experiments prove that blood brain barrier penetration takes place. Furthermore, the compounds offer protection of dopaminergic neurons in vitro. The researchers are continuing to explore methods to improve solubility of GB822 in the gut, or to bypass the gut via alternative delivery of the compound.
Nrf2 Research Moving Forward: Nrf2 research studies will continue to be the topic of study not just for treatment of Parkinson’s Disease, but also for the other hundreds of diseases associated with Oxidative Stress as well. The recent FDA’s approval of the NRF2 activator, Tecfidera for the treatment of MS symptoms will further the interest in using NRF2 activators to treat disease conditions. It is estimated that more than 4 million people have Parkinson’s Disease. Those impacted by the disease including patients, families, care providers and medical practitioners are interested in finding a solution to slow down or eradicate the disease.
This article is educational purposes only, consult with a medical professional to discuss your own medical conditions.