Nrf2: A Master Regulator of Detoxification and also Antioxidant, Anti-inflammatory, and other Cytoprotective mechanisms is raised by health promoting factors
Nrf2 is a transcription factor that activates over 500 genes involved in cytoprotection, including antioxidant, detoxification, anti-inflammatory, and mitochondrial functions. Raising Nrf2 activity through various health-promoting nutrients and factors has been shown to prevent and/or treat a wide range of chronic diseases in animal and human studies, including cardiovascular, neurodegenerative, cancer, kidney, metabolic, liver, lung, autoimmune, and inflammatory diseases. These diseases often involve oxidative stress, inflammation, and mitochondrial dysfunction, which Nrf2 is able to regulate through its effects on multiple cytoprotective genes.
The document summarizes recent research on the transcription factor Nrf2, which regulates antioxidant and cytoprotective mechanisms in the cell. It finds that Nrf2 activation by health-promoting nutrients and other factors can prevent or treat many chronic inflammatory diseases. Specifically, it discusses how factors like antioxidants, omega-3 fatty acids, carotenoids, isothiocyanates, and caloric restriction increase Nrf2 activity. This reduces oxidative stress, inflammation, and improves mitochondrial function, thereby protecting against diseases like cancer, diabetes, and neurodegenerative disorders. Traditionally healthy diets are rich in Nrf2-activating nutrients, while modern diets are often deficient in these.
1) Oxidative stress activates the transcription factor sterol regulatory element-binding protein 2 (SREBP2) in vascular endothelial cells. 2) SREBP2 increases expression of microRNA-92a (miR-92a), which targets genes involved in endothelial homeostasis like sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4. 3) This leads to activation of the NLRP3 inflammasome and reduced nitric oxide bioavailability, exacerbating endothelial dysfunction during oxidative stress.
This document discusses insulin signaling and diabetes. It describes how insulin is released by the pancreas in response to nutrients to regulate blood glucose levels. Insulin triggers the uptake and storage of glucose, fatty acids, and amino acids in tissues. At the cellular level, insulin binds to receptors on cells and activates downstream signaling pathways involving proteins like IRS and kinases that control processes like metabolism, gene expression, and cell growth. Type 2 diabetes occurs when there is insulin resistance and impaired insulin secretion, leading to hyperglycemia and health complications over time. Chronic inflammation is thought to contribute to the pathogenesis of type 2 diabetes.
The Role of Nrf2 in the Attenuation of Cardiovascular DiseaseLifeVantage
This document discusses the role of the transcription factor Nrf2 in attenuating cardiovascular disease through regulating antioxidant defenses. It begins by explaining how oxidative stress contributes to cardiovascular diseases and how early trials of antioxidant supplements were disappointing. It then describes how Nrf2 is the master regulator of cellular antioxidant defenses, regulating over 200 genes. Nrf2 is normally bound by Keap1 in the cytoplasm and targeted for degradation, but oxidative stress or phytochemicals can activate Nrf2 by modifying Keap1 or through kinase signaling. Activated Nrf2 upregulates antioxidant enzymes and other genes to maintain redox homeostasis and protect against disease. Exercise and certain phytochemicals are highlighted as potential ways to activate Nrf2 and attenu
This document discusses how plant polyphenols may help treat Alzheimer's disease by inhibiting NF-κB induced cytokine production. It first provides background on Alzheimer's disease and chronic neuroinflammation. It then describes the role of NF-κB in inflammation and how plant polyphenols could prevent the expression of pro-inflammatory genes regulated by NF-κB. The document proposes that plant polyphenols, due to their anti-inflammatory properties, have the potential to slow Alzheimer's disease progression by inhibiting NF-κB signaling in the brain.
This document summarizes research on eicosanoids, lipid mediators derived from arachidonic acid that play important roles in inflammation and immunity. It focuses on the roles of prostanoids and leukotrienes in organ transplantation. Prostanoids like prostaglandin E2 and prostacyclin generally have immunosuppressive effects, while thromboxane A2 enhances immune responses. Studies in animals and some human trials suggest these eicosanoids can influence transplant rejection and outcomes. Future research on specific receptors for these lipids may lead to new pharmacological approaches for controlling inflammation and promoting graft acceptance.
This research article examines how activation of natural killer (NK) cells impacts susceptibility to Listeria monocytogenes (Lm) infection. The study finds that depletion of NK cells significantly reduces bacterial burdens and increases survival in infected mice, indicating NK cells increase host susceptibility to Lm infection. This effect is independent of early interferon-gamma (IFNγ) production by NK cells, as depletion of NK cells still protected IFNγ receptor-deficient mice. The article further investigates how a bacterial virulence protein, p60, drives NK cells to switch from producing IFNγ to producing the regulatory cytokine IL-10, which suppresses myeloid cell responses and increases bacterial burdens.
The document discusses a study investigating the effects of food restriction on gene expression. It was previously found that 15 genes were upregulated in the brain during food restriction, suggesting they are part of an ancient stress response pathway. The current study aims to test if these genes are also induced in other tissue types under food restriction. Mice were either food restricted or not for 5 days, then gene expression was analyzed using qPCR in various tissues including the kidney. It was found that Angptl4, Mertk, Arrdc2 and Cdkn1a were significantly upregulated in the kidney of food restricted mice compared to controls, providing further evidence they are part of a general stress response pathway activated by food restriction across multiple
The document summarizes recent research on the transcription factor Nrf2, which regulates antioxidant and cytoprotective mechanisms in the cell. It finds that Nrf2 activation by health-promoting nutrients and other factors can prevent or treat many chronic inflammatory diseases. Specifically, it discusses how factors like antioxidants, omega-3 fatty acids, carotenoids, isothiocyanates, and caloric restriction increase Nrf2 activity. This reduces oxidative stress, inflammation, and improves mitochondrial function, thereby protecting against diseases like cancer, diabetes, and neurodegenerative disorders. Traditionally healthy diets are rich in Nrf2-activating nutrients, while modern diets are often deficient in these.
1) Oxidative stress activates the transcription factor sterol regulatory element-binding protein 2 (SREBP2) in vascular endothelial cells. 2) SREBP2 increases expression of microRNA-92a (miR-92a), which targets genes involved in endothelial homeostasis like sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4. 3) This leads to activation of the NLRP3 inflammasome and reduced nitric oxide bioavailability, exacerbating endothelial dysfunction during oxidative stress.
This document discusses insulin signaling and diabetes. It describes how insulin is released by the pancreas in response to nutrients to regulate blood glucose levels. Insulin triggers the uptake and storage of glucose, fatty acids, and amino acids in tissues. At the cellular level, insulin binds to receptors on cells and activates downstream signaling pathways involving proteins like IRS and kinases that control processes like metabolism, gene expression, and cell growth. Type 2 diabetes occurs when there is insulin resistance and impaired insulin secretion, leading to hyperglycemia and health complications over time. Chronic inflammation is thought to contribute to the pathogenesis of type 2 diabetes.
The Role of Nrf2 in the Attenuation of Cardiovascular DiseaseLifeVantage
This document discusses the role of the transcription factor Nrf2 in attenuating cardiovascular disease through regulating antioxidant defenses. It begins by explaining how oxidative stress contributes to cardiovascular diseases and how early trials of antioxidant supplements were disappointing. It then describes how Nrf2 is the master regulator of cellular antioxidant defenses, regulating over 200 genes. Nrf2 is normally bound by Keap1 in the cytoplasm and targeted for degradation, but oxidative stress or phytochemicals can activate Nrf2 by modifying Keap1 or through kinase signaling. Activated Nrf2 upregulates antioxidant enzymes and other genes to maintain redox homeostasis and protect against disease. Exercise and certain phytochemicals are highlighted as potential ways to activate Nrf2 and attenu
This document discusses how plant polyphenols may help treat Alzheimer's disease by inhibiting NF-κB induced cytokine production. It first provides background on Alzheimer's disease and chronic neuroinflammation. It then describes the role of NF-κB in inflammation and how plant polyphenols could prevent the expression of pro-inflammatory genes regulated by NF-κB. The document proposes that plant polyphenols, due to their anti-inflammatory properties, have the potential to slow Alzheimer's disease progression by inhibiting NF-κB signaling in the brain.
This document summarizes research on eicosanoids, lipid mediators derived from arachidonic acid that play important roles in inflammation and immunity. It focuses on the roles of prostanoids and leukotrienes in organ transplantation. Prostanoids like prostaglandin E2 and prostacyclin generally have immunosuppressive effects, while thromboxane A2 enhances immune responses. Studies in animals and some human trials suggest these eicosanoids can influence transplant rejection and outcomes. Future research on specific receptors for these lipids may lead to new pharmacological approaches for controlling inflammation and promoting graft acceptance.
This research article examines how activation of natural killer (NK) cells impacts susceptibility to Listeria monocytogenes (Lm) infection. The study finds that depletion of NK cells significantly reduces bacterial burdens and increases survival in infected mice, indicating NK cells increase host susceptibility to Lm infection. This effect is independent of early interferon-gamma (IFNγ) production by NK cells, as depletion of NK cells still protected IFNγ receptor-deficient mice. The article further investigates how a bacterial virulence protein, p60, drives NK cells to switch from producing IFNγ to producing the regulatory cytokine IL-10, which suppresses myeloid cell responses and increases bacterial burdens.
The document discusses a study investigating the effects of food restriction on gene expression. It was previously found that 15 genes were upregulated in the brain during food restriction, suggesting they are part of an ancient stress response pathway. The current study aims to test if these genes are also induced in other tissue types under food restriction. Mice were either food restricted or not for 5 days, then gene expression was analyzed using qPCR in various tissues including the kidney. It was found that Angptl4, Mertk, Arrdc2 and Cdkn1a were significantly upregulated in the kidney of food restricted mice compared to controls, providing further evidence they are part of a general stress response pathway activated by food restriction across multiple
Intermittent fasting had a strong anti inflammatory effect beside the many other benefits. Intermittent fasting is an eating pattern and Interventional strategy where in individuals are subjected to varying periods of fasting. It doesn’t specify which foods you should eat but rather when you should eat them. Intermittent fasting (IF) is an eating pattern that cycles between periods of fasting and eating. It’s currently very popular in the health and fitness community. Recently attracted attention because:
1- Its Evidence-Based Health Benefits
2- Its potential for correcting metabolic Abnormalities
3- Better adherence than other methods
Nutritional immunology is a fascinating but highly complex and conflicted subject area. With almost every nutrient we consume having the ability to affect our immune response in one way or another and the activation of the immune system dramatically increasing nutrient requirements, understanding the genetic, cellular and metabolic mechanisms that interact, control and conflict with the immune system and how to manipulate them to our advantage, is fundamental to optimal health.
We are thrilled to announce that we have linked up with Professor Phillip Calder, a world renowned and highly cited expert in nutritional immunology, with over 500 publications to his name. Professor Calder will be joining us as our guest speaker for our January Webinar to help us kick off what promises to be our most exciting year of clinical nutrition education yet.
In this detailed Q&A session Professor Calder will shed light on a whole host of fascinating topics from the latest research into nutrition immunology, his projects involving nutrigenomics, probiotics and omega-3s, the real science behind effective clinical omega-3 interventions, his thoughts on the best forms of lipid supplementation, and doing some serious nutrition science myth busting.
1. General anaesthesia can have both direct and indirect effects on the immune system by impacting the innate immune response, adaptive immune response, cytokine production, neutrophil activity, and immunoglobulin levels.
2. Surgery alone increases pro-inflammatory cytokine levels, but anaesthetic agents may increase or decrease specific cytokine production depending on the agent.
3. Perioperative interventions like mechanical ventilation, blood transfusions, chronic pain, and immunosuppressive drugs for transplant patients can further impact the immune response. Precautions are needed for patients with these factors.
This document summarizes research on the effects of exercise on gene expression of inflammatory markers in human peripheral blood cells. It reviews 37 studies that examined gene expression in white blood cells like lymphocytes and monocytes after acute and long-term exercise. The studies found that an acute bout of exercise can upregulate expression of some pro-inflammatory genes like IL-1β, IL-8 and CXCL16 in peripheral blood mononuclear cells. However, long-term regular exercise is associated with attenuated inflammatory response and upregulation of anti-inflammatory genes like IL-10 and IL-13. Gene expression changes depend on exercise duration and intensity. The immune system and inflammatory response play a role in diseases like cardiovascular disease and cancer, so understanding
Aging is the progressive accumulation of damage to an organism over time leading to disease and death. Aging research has been very intensive in the last years aiming at characterizing the Pathophysiology of aging and finding possibilities to fight age-related diseases. Various theories of aging have been proposed. In the last years advanced glycation end products (AGEs) have received particular attention in this context. AGEs are formed in high amounts in diabetes but also in the physiological organism during aging. Higher levels of diabetic complications are due to poor glycemic control. The incidence and prevalence of diabetes mellitus is rising. About 50% of people with diabetes mellitus are unaware of their condition. Pharmacotherapy and Therapeutic lifestyle change (Diet, Regular exercises, Sunshine, Vitamin D and Calcium normal levels) should be the cornerstone of diabetes management.
The Clinical Potential of Influencing Nrf2 Signaling in Degenerative and Immu...LifeVantage
This document discusses the potential for targeting the Nrf2 signaling pathway to treat degenerative and immunological disorders. It begins by describing the Nrf2 transcription factor and its role in regulating antioxidant and detoxification genes via the antioxidant response element. Under normal conditions Nrf2 is bound by Keap1 and targeted for degradation, but oxidative stress or electrophiles can activate Nrf2 signaling by disrupting this interaction. The document reviews studies investigating direct Nrf2 target genes and discusses evidence that imbalances in cellular redox status contribute to disease pathogenesis. It concludes that modulating Nrf2 signaling, either through activation or inhibition, offers promise as a therapeutic strategy for various disorders by restoring redox homeostasis.
A brief description of all topics to recent advances,SDD, host modulation and diabetes, host modulation in smokers, chemically modified tetracyclines, bisphosphonates
Vitamin D is a steroid hormone produced in the skin upon exposure to sunlight. It plays an important role in bone and mineral metabolism, and has wide-ranging functions throughout the body. Recent research suggests vitamin D may also play a role in brain development and function, immune regulation, and protection against diseases like multiple sclerosis, Parkinson's, epilepsy, and depression. Vitamin D deficiency is common and can result from factors like skin pigmentation, sunscreen use, obesity, aging, and limited sun exposure at higher latitudes.
Interferon-gamma (IFN-γ) is a cytokine that plays a key role in immunity and defense against infections. It is primarily produced by natural killer and T cells to activate macrophages and induce phagocytosis of pathogens. IFN-γ also enhances antigen presentation and stimulates the production of other proinflammatory cytokines. It promotes Th1 adaptive immunity and inhibits Th2 and Th17 responses. The main role of IFN-γ is in defense against intracellular pathogens by activating macrophages and stimulating immune effector mechanisms.
Dr. Lewis Teperman directs the Mary Lea Johnson Richards Organ Transplantation Center, where professionals analyze interferon and topics related to liver transplants. Interferons are proteins naturally produced by cells like white blood cells and epithelial cells that help the immune system combat harmful substances like viruses, bacteria, and cancer. There are three classes of interferons - alpha, beta, and gamma - that physicians can use to help treat diseases such as AIDS, leukemia, and hepatitis B.
Interferons (IFNs) are cytokines that were first recognized for their ability to interfere with viral infections. There are three main types of IFNs - alpha, beta, and gamma - which are classified based on their antigenicity and receptor binding. IFNs have diverse antiviral, immune enhancing, and antiproliferative properties. They work by binding to IFN receptors on cells and inducing the expression of interferon stimulated genes, which leads to an antiviral state. IFNs have many therapeutic applications for treating viral infections and cancers, though they can also cause side effects like fatigue, mood changes, and liver/blood abnormalities. Viruses have evolved various mechanisms to counteract the effects of IFNs.
This document discusses interferons, which are proteins naturally produced in response to viral infections. There are three main types of interferons - alpha, beta, and gamma. Interferons work by binding to receptors on cells and activating signaling pathways that turn on genes to produce antiviral proteins. This inhibits viral replication and helps the immune system clear infections. Interferons are now produced recombinantly for use in treating certain viral infections and cancers. The document provides details on the structure, function, signaling, and clinical applications of the different interferon types.
1. HIF-1 is a transcription factor that is ubiquitously expressed and activated under hypoxic conditions to turn on genes needed for survival.
2. HIF-1 targets various genes including erythropoietin, nitric oxide synthase 2, transferrin, transferrin receptor, and vascular endothelial growth factor which are involved in oxygen delivery.
3. Under hypoxia, HIF-1 transcriptionally upregulates target genes containing hypoxia response elements like GLUT1 and VEGF through hypoxia response proteins.
This document discusses the effects of organophosphate (OP) insecticide exposure on human development. It begins by explaining the mechanism of OP poisoning, which is inhibition of the acetylcholinesterase enzyme, leading to acetylcholine accumulation and oxidative stress. Specific physiological outcomes of OP exposure are then outlined, including reduced fertility due to hormone imbalance and egg/sperm damage, altered glucose metabolism and insulin resistance contributing to diabetes, and cognitive decline resulting from neuronal damage. The document recommends increased antioxidant intake through foods to reduce oxidative stress in those with high OP exposure like farmworkers.
This document discusses the effects of organophosphate (OP) insecticide exposure on human development. It begins by explaining the mechanism of OP poisoning, which is inhibition of the acetylcholinesterase enzyme, leading to acetylcholine accumulation and oxidative stress. Specific physiological outcomes of OP exposure are then outlined, including reduced fertility due to hormone imbalance and egg/sperm damage, altered glucose metabolism and insulin resistance contributing to diabetes, and cognitive decline resulting from neuronal damage. The document recommends increased antioxidant intake through foods like vitamins A and E to reduce oxidative stress in highly exposed groups like farmworkers.
Interferons are glycoproteins that are produced in response to viral infections and other pathogens in order to activate the immune system. There are three main classes of interferons - alpha, beta, and gamma - which signal through different cell surface receptor complexes. Interferons have a variety of antiviral, antitumor, and immunomodulatory properties. They are currently used clinically to treat hepatitis C virus, hepatitis B virus, multiple sclerosis, and some cancers, though their mechanisms of action are still not fully understood. Research on interferons has contributed significantly to the development of molecular biology and our understanding of cytokines.
This document summarizes research on primary immunodeficiencies that cause increased susceptibility to fungal infections. It describes how innate and adaptive immunity normally defend against fungi through pattern recognition receptors, cytokines, and T cell responses. Deficiencies in the CARD9 protein, STAT1 and STAT3 genes, and the IL-17 and IL-22 pathways are highlighted as causing chronic mucocutaneous candidiasis by impairing Th17 responses. Autoantibodies against IL-17 and IL-22 in autoimmune polyendocrine syndrome type I can also phenocopy these genetic defects. Understanding these immunodeficiencies provides insight into antifungal immunity and opportunities for new therapies.
Interferons are proteins produced by host cells in response to viral infections that interfere with viral replication. They were first discovered in 1957 by Isaacs and Lindenmann who found that a substance from chicken cells could interfere with viral replication. There are three main types of interferon - alpha, beta, and gamma - which are distinguished by their producing cells. Interferons work by binding to receptors on target cells and inducing genes that create an antiviral state, inhibiting viral replication. They can be produced recombinantly by synthesizing their DNA, inserting it into E. coli, which are then fermented and purified to produce large amounts of the protein pharmaceutical.
This document discusses several studies related to omega-3 fatty acids and their effects on cardiovascular health markers. One study showed that a 1 g/day dose of Omacor (an omega-3 supplement) increased the omega-3 index in subjects' blood from 3.6% to 5.4% on average, but about 16% of subjects did not achieve an EPA+DHA level over 4.8%. The same study reduced the arachidonic acid to EPA ratio from 20 to 7.2. Another section discusses the role of transcription factors like NF-kB in inflammatory conditions and diseases.
Mavis Computel Limited is a private limited liability company that provides ICT solutions across various industries in Nigeria. It offers products and services such as digital pen/paper computing solutions, power solutions, lighting solutions, signage systems, security systems, and software development. Notable clients include Nigerian Communications Commission, Trustfund Pensions, Transmission Company of Nigeria, and MTN Nigeria. The company has a staff of six with over 60 years of combined experience in ICT. It partners with companies like Boundless Security Systems to deliver solutions to its clients. Contact details are provided.
Agape is defined as “the love of God for mankind.” We are dedicated to selling high quality well designed Christian lifestyle apparel. Our message is simple: let your love in the inside shine onto the outside.
Intermittent fasting had a strong anti inflammatory effect beside the many other benefits. Intermittent fasting is an eating pattern and Interventional strategy where in individuals are subjected to varying periods of fasting. It doesn’t specify which foods you should eat but rather when you should eat them. Intermittent fasting (IF) is an eating pattern that cycles between periods of fasting and eating. It’s currently very popular in the health and fitness community. Recently attracted attention because:
1- Its Evidence-Based Health Benefits
2- Its potential for correcting metabolic Abnormalities
3- Better adherence than other methods
Nutritional immunology is a fascinating but highly complex and conflicted subject area. With almost every nutrient we consume having the ability to affect our immune response in one way or another and the activation of the immune system dramatically increasing nutrient requirements, understanding the genetic, cellular and metabolic mechanisms that interact, control and conflict with the immune system and how to manipulate them to our advantage, is fundamental to optimal health.
We are thrilled to announce that we have linked up with Professor Phillip Calder, a world renowned and highly cited expert in nutritional immunology, with over 500 publications to his name. Professor Calder will be joining us as our guest speaker for our January Webinar to help us kick off what promises to be our most exciting year of clinical nutrition education yet.
In this detailed Q&A session Professor Calder will shed light on a whole host of fascinating topics from the latest research into nutrition immunology, his projects involving nutrigenomics, probiotics and omega-3s, the real science behind effective clinical omega-3 interventions, his thoughts on the best forms of lipid supplementation, and doing some serious nutrition science myth busting.
1. General anaesthesia can have both direct and indirect effects on the immune system by impacting the innate immune response, adaptive immune response, cytokine production, neutrophil activity, and immunoglobulin levels.
2. Surgery alone increases pro-inflammatory cytokine levels, but anaesthetic agents may increase or decrease specific cytokine production depending on the agent.
3. Perioperative interventions like mechanical ventilation, blood transfusions, chronic pain, and immunosuppressive drugs for transplant patients can further impact the immune response. Precautions are needed for patients with these factors.
This document summarizes research on the effects of exercise on gene expression of inflammatory markers in human peripheral blood cells. It reviews 37 studies that examined gene expression in white blood cells like lymphocytes and monocytes after acute and long-term exercise. The studies found that an acute bout of exercise can upregulate expression of some pro-inflammatory genes like IL-1β, IL-8 and CXCL16 in peripheral blood mononuclear cells. However, long-term regular exercise is associated with attenuated inflammatory response and upregulation of anti-inflammatory genes like IL-10 and IL-13. Gene expression changes depend on exercise duration and intensity. The immune system and inflammatory response play a role in diseases like cardiovascular disease and cancer, so understanding
Aging is the progressive accumulation of damage to an organism over time leading to disease and death. Aging research has been very intensive in the last years aiming at characterizing the Pathophysiology of aging and finding possibilities to fight age-related diseases. Various theories of aging have been proposed. In the last years advanced glycation end products (AGEs) have received particular attention in this context. AGEs are formed in high amounts in diabetes but also in the physiological organism during aging. Higher levels of diabetic complications are due to poor glycemic control. The incidence and prevalence of diabetes mellitus is rising. About 50% of people with diabetes mellitus are unaware of their condition. Pharmacotherapy and Therapeutic lifestyle change (Diet, Regular exercises, Sunshine, Vitamin D and Calcium normal levels) should be the cornerstone of diabetes management.
The Clinical Potential of Influencing Nrf2 Signaling in Degenerative and Immu...LifeVantage
This document discusses the potential for targeting the Nrf2 signaling pathway to treat degenerative and immunological disorders. It begins by describing the Nrf2 transcription factor and its role in regulating antioxidant and detoxification genes via the antioxidant response element. Under normal conditions Nrf2 is bound by Keap1 and targeted for degradation, but oxidative stress or electrophiles can activate Nrf2 signaling by disrupting this interaction. The document reviews studies investigating direct Nrf2 target genes and discusses evidence that imbalances in cellular redox status contribute to disease pathogenesis. It concludes that modulating Nrf2 signaling, either through activation or inhibition, offers promise as a therapeutic strategy for various disorders by restoring redox homeostasis.
A brief description of all topics to recent advances,SDD, host modulation and diabetes, host modulation in smokers, chemically modified tetracyclines, bisphosphonates
Vitamin D is a steroid hormone produced in the skin upon exposure to sunlight. It plays an important role in bone and mineral metabolism, and has wide-ranging functions throughout the body. Recent research suggests vitamin D may also play a role in brain development and function, immune regulation, and protection against diseases like multiple sclerosis, Parkinson's, epilepsy, and depression. Vitamin D deficiency is common and can result from factors like skin pigmentation, sunscreen use, obesity, aging, and limited sun exposure at higher latitudes.
Interferon-gamma (IFN-γ) is a cytokine that plays a key role in immunity and defense against infections. It is primarily produced by natural killer and T cells to activate macrophages and induce phagocytosis of pathogens. IFN-γ also enhances antigen presentation and stimulates the production of other proinflammatory cytokines. It promotes Th1 adaptive immunity and inhibits Th2 and Th17 responses. The main role of IFN-γ is in defense against intracellular pathogens by activating macrophages and stimulating immune effector mechanisms.
Dr. Lewis Teperman directs the Mary Lea Johnson Richards Organ Transplantation Center, where professionals analyze interferon and topics related to liver transplants. Interferons are proteins naturally produced by cells like white blood cells and epithelial cells that help the immune system combat harmful substances like viruses, bacteria, and cancer. There are three classes of interferons - alpha, beta, and gamma - that physicians can use to help treat diseases such as AIDS, leukemia, and hepatitis B.
Interferons (IFNs) are cytokines that were first recognized for their ability to interfere with viral infections. There are three main types of IFNs - alpha, beta, and gamma - which are classified based on their antigenicity and receptor binding. IFNs have diverse antiviral, immune enhancing, and antiproliferative properties. They work by binding to IFN receptors on cells and inducing the expression of interferon stimulated genes, which leads to an antiviral state. IFNs have many therapeutic applications for treating viral infections and cancers, though they can also cause side effects like fatigue, mood changes, and liver/blood abnormalities. Viruses have evolved various mechanisms to counteract the effects of IFNs.
This document discusses interferons, which are proteins naturally produced in response to viral infections. There are three main types of interferons - alpha, beta, and gamma. Interferons work by binding to receptors on cells and activating signaling pathways that turn on genes to produce antiviral proteins. This inhibits viral replication and helps the immune system clear infections. Interferons are now produced recombinantly for use in treating certain viral infections and cancers. The document provides details on the structure, function, signaling, and clinical applications of the different interferon types.
1. HIF-1 is a transcription factor that is ubiquitously expressed and activated under hypoxic conditions to turn on genes needed for survival.
2. HIF-1 targets various genes including erythropoietin, nitric oxide synthase 2, transferrin, transferrin receptor, and vascular endothelial growth factor which are involved in oxygen delivery.
3. Under hypoxia, HIF-1 transcriptionally upregulates target genes containing hypoxia response elements like GLUT1 and VEGF through hypoxia response proteins.
This document discusses the effects of organophosphate (OP) insecticide exposure on human development. It begins by explaining the mechanism of OP poisoning, which is inhibition of the acetylcholinesterase enzyme, leading to acetylcholine accumulation and oxidative stress. Specific physiological outcomes of OP exposure are then outlined, including reduced fertility due to hormone imbalance and egg/sperm damage, altered glucose metabolism and insulin resistance contributing to diabetes, and cognitive decline resulting from neuronal damage. The document recommends increased antioxidant intake through foods to reduce oxidative stress in those with high OP exposure like farmworkers.
This document discusses the effects of organophosphate (OP) insecticide exposure on human development. It begins by explaining the mechanism of OP poisoning, which is inhibition of the acetylcholinesterase enzyme, leading to acetylcholine accumulation and oxidative stress. Specific physiological outcomes of OP exposure are then outlined, including reduced fertility due to hormone imbalance and egg/sperm damage, altered glucose metabolism and insulin resistance contributing to diabetes, and cognitive decline resulting from neuronal damage. The document recommends increased antioxidant intake through foods like vitamins A and E to reduce oxidative stress in highly exposed groups like farmworkers.
Interferons are glycoproteins that are produced in response to viral infections and other pathogens in order to activate the immune system. There are three main classes of interferons - alpha, beta, and gamma - which signal through different cell surface receptor complexes. Interferons have a variety of antiviral, antitumor, and immunomodulatory properties. They are currently used clinically to treat hepatitis C virus, hepatitis B virus, multiple sclerosis, and some cancers, though their mechanisms of action are still not fully understood. Research on interferons has contributed significantly to the development of molecular biology and our understanding of cytokines.
This document summarizes research on primary immunodeficiencies that cause increased susceptibility to fungal infections. It describes how innate and adaptive immunity normally defend against fungi through pattern recognition receptors, cytokines, and T cell responses. Deficiencies in the CARD9 protein, STAT1 and STAT3 genes, and the IL-17 and IL-22 pathways are highlighted as causing chronic mucocutaneous candidiasis by impairing Th17 responses. Autoantibodies against IL-17 and IL-22 in autoimmune polyendocrine syndrome type I can also phenocopy these genetic defects. Understanding these immunodeficiencies provides insight into antifungal immunity and opportunities for new therapies.
Interferons are proteins produced by host cells in response to viral infections that interfere with viral replication. They were first discovered in 1957 by Isaacs and Lindenmann who found that a substance from chicken cells could interfere with viral replication. There are three main types of interferon - alpha, beta, and gamma - which are distinguished by their producing cells. Interferons work by binding to receptors on target cells and inducing genes that create an antiviral state, inhibiting viral replication. They can be produced recombinantly by synthesizing their DNA, inserting it into E. coli, which are then fermented and purified to produce large amounts of the protein pharmaceutical.
This document discusses several studies related to omega-3 fatty acids and their effects on cardiovascular health markers. One study showed that a 1 g/day dose of Omacor (an omega-3 supplement) increased the omega-3 index in subjects' blood from 3.6% to 5.4% on average, but about 16% of subjects did not achieve an EPA+DHA level over 4.8%. The same study reduced the arachidonic acid to EPA ratio from 20 to 7.2. Another section discusses the role of transcription factors like NF-kB in inflammatory conditions and diseases.
Mavis Computel Limited is a private limited liability company that provides ICT solutions across various industries in Nigeria. It offers products and services such as digital pen/paper computing solutions, power solutions, lighting solutions, signage systems, security systems, and software development. Notable clients include Nigerian Communications Commission, Trustfund Pensions, Transmission Company of Nigeria, and MTN Nigeria. The company has a staff of six with over 60 years of combined experience in ICT. It partners with companies like Boundless Security Systems to deliver solutions to its clients. Contact details are provided.
Agape is defined as “the love of God for mankind.” We are dedicated to selling high quality well designed Christian lifestyle apparel. Our message is simple: let your love in the inside shine onto the outside.
The edge 03_connecting with customers_27062008tumlabel
The document discusses improvements being made by Kenya's Immigration Department to better serve its customers. It notes the department had a history of poor customer service, delays, and corruption, frustrating many people seeking services. However, it is now making strides to improve, such as implementing an SMS tracking system to notify people of application statuses and avoid unnecessary visits. While more progress is still needed, these reforms represent remarkable changes for the better in addressing the department's formerly woeful treatment of customers.
Protandim is a dietary supplement created by LifeVantage that activates the Nrf2 pathway in the body. Nrf2 is known as the "master regulator" of the body's antioxidant defenses. By activating Nrf2, Protandim stimulates the body's natural production of antioxidant enzymes like superoxide dismutase, glutathione, and catalase that can neutralize cellular damage from free radicals. Protandim contains a proprietary blend of plant extracts including turmeric, bacopa, ashwagandha, green tea, and milk thistle. Clinical studies show Protandim can significantly increase antioxidant enzyme levels and reduce cellular stress within 30 days.
Our biggest problem in healthcare is efficiency (quality of care per dollar spent) and Obamacare doesn't solve it. Our spending is off the charts by any measure (growth over time, % of GDP, per capita) Consumerism as a force of change in Healthcare is just getting started, but there are many barriers in place that serve to protect existing stakeholders in the industry. Knocking down these barriers to competition is what the GOP should be focusing on, but it's not. "Repeal and replace" seems to be a slogan, not a plan. Do Republican lawmakers have the will to make changes that might upset entrenched players?
Chromatography is a technique used to separate mixtures into individual components. Paper chromatography is a type of chromatography that uses paper as the stationary phase. The mixture is applied to the paper and then placed in a developing chamber with the mobile phase solvent. As the solvent travels up the paper, the different components of the mixture separate based on how strongly they interact with the stationary and mobile phases. This creates discrete spots that can be analyzed to identify the components in the original mixture. Paper chromatography is a simple, inexpensive, and effective technique for separating and analyzing mixtures.
This document summarizes an event about innovative marketing strategies for small businesses with limited budgets. The event included presentations on guerrilla, fusion, affiliate, and joint venture marketing strategies from Dan Storey of Guerrilla Marketing. It also included a session on social media tools for effective lead generation from Andy Poulton of Business West. The event was hosted by Tara Gillam of Business West and the Enterprise Europe Network and provided information on accessing European markets and business opportunities through their partner search services.
Met het hele Mondea team is in de afgelopen 5 maanden gewerkt aan het voedselbank project. Dit om een heldere verlanglijst te maken van wat nodig is om hun wensen in vervulling te laten gaan.
Similar to Nrf2: A Master Regulator of Detoxification and also Antioxidant, Anti-inflammatory, and other Cytoprotective mechanisms is raised by health promoting factors
A perspective on dietary phytochemicals and cancerMonirg
This document discusses the role of oxidative stress and dietary phytochemicals in cancer prevention. It describes how oxidative stress causes an imbalance between reactive oxygen/nitrogen species and antioxidant defenses, potentially leading to DNA damage and cancer. The transcription factor Nrf2 plays a key role in activating antioxidant and detoxification genes. Many dietary phytochemicals have been shown to activate the Nrf2 pathway and protect against cancer by reducing oxidative stress. In addition, some phytochemicals can modify gene expression epigenetically by altering DNA methylation and histone modifications, including reactivating the Nrf2 pathway. Understanding these mechanisms may help develop new strategies for cancer prevention using phytochemicals.
Oxidative Stress in Aging and Human Diseases - Exploring the MechanismsQIAGEN
Many modern diseases, including cancer, cardiovascular disease, diabetes, liver disease, arthritis and neurodegenerative disease are related to aging, and aging is closely linked to oxidative stress. Intensive research is being conducted to understand the antioxidant defense mechanism, the mechanisms of aging itself, as well as their roles in human diseases. This slidedeck provides an update on how oxidative stress is linked to aging and how inflammation leads to aging through DNA damage, telomere dysfunction, cellular senescence and oxidative stress. Recent progress on the health benefits of antioxidants and examination of their potential mechanisms in the prevention and treatment of chronic diseases are also covered. Various assay technologies to tackle the complex signaling pathways in this process will be introduced. Learn how you can apply these advanced tools to your research!
This document discusses neutrophil priming and its implications in periodontal disease. It explains that neutrophils can become "primed" by exposure to inflammatory mediators, making them more reactive. In periodontal disease, neutrophils may become primed by substances released in inflamed tissues. Primed neutrophils are hyperactive and release excessive amounts of destructive enzymes and reactive oxygen species that can damage periodontal tissues. This priming of neutrophils may play a role in the pathogenesis and rapid tissue destruction seen in aggressive periodontitis.
The role of natural products in regulating pyroptosisLucyPi1
This document reviews the role of natural products in regulating pyroptosis. It begins with background on pyroptosis, describing it as a form of inflammatory programmed cell death. It then discusses how pyroptosis is involved in various diseases and its molecular pathways. The document categorizes 14 natural products that have been shown to affect pyroptosis, including flavonoids like dihydromyricetin and terpenoids like andrographolide. These natural products were found to negatively or positively impact pyroptosis pathways by regulating factors like caspase-1, gasdermin D, and cytokines. The review concludes that natural products have potential as sources of new drugs for diseases related to uncontrolled pyroptosis.
Neurodegeneration: Factors Involved and Therapeutic Strategiesinventionjournals
Neurodegenerative disorders are disorders of the nervous system which are characterized by a loss of neuronal structure and function. These changes lead to a loss of several abilities that include cognition and movement as observed in Alzheimer’s and Parkinson’s. Several factors like oxidative stress and protein misfolding have been found to play a vital role in the etiology of common neurological disorders. Whether these factors contribute to the progression of the disorders or are a consequence still remains elusive. Inspite of attempts to elucidate the molecular and pathological mechanisms of these pathways, many aspects still remain unclear. However, newer areas of therapeutic interventions like stem cell therapy and anti-oxidant therapy are now being explored as potential treatments. The aim of this review is to study the various factors that are associated with neurodegeneration along with recent therapeutic strategies that are being employed in an attempt to treat neurodegenerative disorders.
The document summarizes the dual roles of the transcription factor NRF2 in cancer. Traditionally considered a tumor suppressor due to its role in protecting cells from oxidative stress, recent evidence suggests NRF2 can also act as an oncogene by promoting cancer cell survival and resistance to chemotherapy and radiation. The review discusses mechanisms by which NRF2 activation can exert oncogenic functions, including somatic mutations and epigenetic changes affecting NRF2 and its regulator KEAP1. It provides rationale for considering NRF2 as a potential therapeutic target in cancer treatment.
Sofía Morales Del Toro studied the role of the non-coding RNA GAS5 in regulating liver fibrosis. The study examined the interaction between the miR-433–3p/TLR10 axis and NF-κB signaling pathway in relation to liver stellate cell proliferation and inflammation. Various methods were used including cell viability assays, RT-qPCR, western blotting and immunohistochemistry to analyze protein expression levels and reveal the role of GAS5. The results provide insights into the molecular mechanisms of liver fibrosis and the role of long non-coding RNAs.
Natural products as a crucial source of anti-inflammatory drugs: recent trend...LucyPi1
Abstract Natural active molecules are key sources of modern innovative drugs. Particularly, a great amount of natural active molecules have been reported to possess promising therapeutic effects on inflammatory diseases, including asthma, rheumatoid arthritis, hepatitis, enteritis, metabolic disorders and neurodegenerative diseases. However, these natural active molecules with various molecular structures usually exert anti-inflammatory effects through diversiform pharmacological mechanisms, which is necessary to be summarized systematically. In this review, we introduced the current major anti-inflammatory natural active molecules based on their chemical structures, and discussed their pharmacological mechanisms including anti-inflammatory molecular signaling pathways and potential target proteins, which providing a referential significance on the development of novel anti-inflammatory drugs, and also revealing new therapeutic strategies for inflammatory diseases.
This study investigated whether Alpinae Oxyphyllae Fructus (AE), a traditional Chinese medicine, could improve M1 and M2 microglial polarization, inhibit neuroinflammation through the triggering receptor expressed on myeloid cells 2 (TREM2), and exert anti-inflammatory effects. Methods used included cytokine assays, immunofluorescence staining, western blot, and RT-PCR to analyze proteins and genes involved in the TREM2 pathway and neuroinflammation. The findings indicated that AE could improve the polarization response of microglia. TREM2 plays a vital role in the microglial repolarization effects of AE through regulating neuroinflammation signaling pathways.
Cell Signalling and Molecular hydrogenIan Hamilton
Cell signaling involves the release of molecules that transmit signals between cells to maintain homeostasis. Hydrogen gas has been shown to act as a cell signaling molecule by modulating the activity of enzymes involved in cell signaling pathways. Specifically, molecular hydrogen inhibits the phosphorylation of enzymes like ASK1 and JNK that are activated in response to oxidative stress and inflammation. It also attenuates the phosphorylation of enzymes involved in the allergic response. These effects suggest hydrogen gas influences cell signaling pathways indirectly as a modulator, though its specific molecular targets are still unknown.
This document discusses a study aiming to reveal the role of GAS5 in regulating liver fibrosis. The study examines the miR-433–3p/TLR10 axis and its effects on NF-κB signaling and inflammatory reactions in the liver. Methods used include cell viability assays, RNA extraction and PCR to analyze gene expression, western blotting to detect proteins, and immunohistochemistry. Results suggest GAS5 and the miR-433–3p/TLR10 axis may influence liver cell proliferation and fibrosis by modulating inflammation.
Biogen Idec Study: BG-12 (Tecfidera) vs. ProtandimLifeVantage
This study investigated whether activating the Nrf2 pathway using different compounds could boost antioxidant enzyme expression in oligodendrocytes and protect them from reactive oxygen species (ROS)-mediated cell death. The researchers treated primary rat oligodendrocytes and rat and human oligodendrocyte cell lines with various Nrf2 activators including BG-12, tBHQ, SFN, and protandim. They found that all activators strongly induced antioxidant enzyme production, with protandim showing the most potent induction. The activators were also able to protect oligodendrocytes against ROS-induced cell death. Therefore, activating the Nrf2 pathway may be a novel therapeutic strategy to promote oligodendrocy
This document summarizes a study that evaluated the potential of an adeno-associated virus (AAV) vector delivering a peptide derived from the Nrf2 protein to target the Nrf2 signaling pathway in the retina. The Nrf2 peptide was fused to a cell-penetrating peptide sequence (Tat-peptide) and expressed from an AAV vector. In vitro, the TatNrf2mer peptide induced antioxidant gene expression, blocked IL-1β secretion, and protected cells from oxidative injury. In mouse models, TatNrf2mer expression partially protected photoreceptor function and decreased inflammatory cytokines and cells in models of retinal oxidative injury and uveitis. The results suggest this AAV-delivered TatNrf
This document provides an introduction to toxicology and multiple choice questions (MCQs) related to the field. It discusses key topics like dose-response relationships, routes of exposure, biotransformation, bioaccumulation, targets of chemicals, acute vs chronic toxicity, and phases of biotransformation. The document is intended to help students and general audiences improve their knowledge of toxicology through practicing MCQs. It includes 20 MCQs in the first set, with answer keys and brief explanations provided for each.
Molecular mechanism controlling plant growth during Abiotic stressHumnaSajjad1
- Mechanisms that protect against abiotic stress come at the expense of plant growth and productivity. Recent research has improved understanding of how plants balance growth and stress defense.
- At the molecular level, signaling pathways like MAPK, ABF/bZIP, and CBF/DREB allow plants to anticipate stress and regulate growth accordingly. Key players also include hormones like ABA, auxin, and brassinosteroids.
- Chloroplasts play a central role in stress perception and response. Stress can limit growth by disrupting photosynthesis and causing overexcitation that produces damaging ROS. Chloroplast signaling to the nucleus then modulates gene expression and the balance of growth versus stress responses.
Turmeric is referred to as the "Queen of Spices". It contains many health-promoting nutrients and antioxidants that have anti-inflammatory and anti-aging properties. These properties help reduce the risk of dementia and cancer by maintaining cholesterol levels and slowing the signs of normal aging. The antioxidants in turmeric also have anti-thrombotic, cholesterol-lowering, anti-tumor and apoptosis-inducing effects.
This document summarizes a thesis that compares CYP2C19 and CYP2C9 genotypes and phenotypes in healthy Swedish and Korean subjects. The key findings are:
1) Koreans had a higher incidence of CYP2C19 poor metabolizers (14%) compared to Swedes (4%).
2) CYP2C19 allele frequencies differed between groups, with Koreans having higher *2 and *3 alleles.
3) Koreans displayed lower CYP2C19 enzyme activity than Swedes when homozygous for *1.
4) Gender and oral contraceptive use influenced CYP2C19 activity levels within groups.
5) A case report identified a patient as an ult
The interaction of Nrf2 and Glyoxalase I in response to lipid loading in Hepa...Farya Mubarik
This document summarizes a study that examined the interaction between Nrf2 and glyoxalase I in response to lipid loading in hepatocytes. The study first optimized the dose and duration of MG132 treatment, a proteasomal inhibitor, to induce accumulation of Nrf2 protein in HepG2 cells. It then examined the effects of oleic acid and palmitic acid on cell viability and found no significant effects. The study aims to determine if inhibition of proteasomal degradation leads to accumulation of Nrf2 and subsequent upregulation of glyoxalase I expression in response to lipid accumulation.
1) The document discusses the relationship between the immune system and brain development/function. Alterations in immune function can impact neurodevelopment and be associated with various neuropsychiatric disorders.
2) Studies show that drugs like fingolimod that modulate sphingosine-1-phosphate receptors and prevent lymphocyte egress from lymph nodes can significantly reduce relapse rates and disability progression in multiple sclerosis patients.
3) Autism disorders may involve abnormalities in certain brain areas and a complex symptomatology related to genetic and environmental factors that can disrupt normal brain growth and the immune situation. The immune status, specific time periods, microenvironment, and genetics may all provide insights into autism pathogenesis.
Similar to Nrf2: A Master Regulator of Detoxification and also Antioxidant, Anti-inflammatory, and other Cytoprotective mechanisms is raised by health promoting factors (20)
Luisetto m, behzad n, ghulam r. brain response in some systemic immune condit...
Nrf2: A Master Regulator of Detoxification and also Antioxidant, Anti-inflammatory, and other Cytoprotective mechanisms is raised by health promoting factors
1. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–18
DOI: 10.13294/j.aps.2015.0001 http://www.actaps.com.cn
1
Review
Nrf2, a master regulator of detoxification and also antioxidant, anti-
inflammatory and other cytoprotective mechanisms, is raised by health
promoting factors
Martin L Pall1,*
, Stephen Levine2
1
Washington State University, Portland, Oregon 97232-3312, USA; 2
Allergy Research Group, Alameda, California 94502, USA
Abstract: The transcription factor Nrf2, nuclear factor erythroid-2-related factor 2, activates the transcription of over 500 genes in the
human genome, most of which have cytoprotective functions. Nrf2 produces cytoprotection by detoxification mechanisms leading to
increased detoxification and excretion of both organic xenobiotics and toxic metals; its action via over two dozen genes increases
highly coordinated antioxidant activities; it produces major anti-inflammatory changes; it stimulates mitochondrial biogenesis and oth-
erwise improves mitochondrial function; and it stimulates autophagy, removing toxic protein aggregates and dysfunctional organelles.
Health-promoting nutrients and other factors act, at least in part by raising Nrf2 including: many phenolic antioxidants; gamma- and
delta-tocopherols and tocotrienols; long chain omega-3 fatty acids DHA and EPA; many carotenoids of which lycopene may be the
most active; isothiocyanates from cruciferous vegetables; sulfur compounds from allium vegetables; terpenoids. Other health promot-
ing, Nrf2 raising factors include low level oxidative stress (hormesis), exercise and caloric restriction. Raising Nrf2 has been found to
prevent and/or treat a large number of chronic inflammatory diseases in animal models and/or humans including various cardiovascu-
lar diseases, kidney diseases, lung diseases, diseases of toxic liver damage, cancer (prevention), diabetes/metabolic syndrome/obesity,
sepsis, autoimmune diseases, inflammatory bowel disease, HIV/AIDS and epilepsy. Lesser evidence suggests that raising Nrf2 may
lower 16 other diseases. Many of these diseases are probable NO/ONOO−
cycle diseases and Nrf2 lowers effects of NO/ONOO−
cycle
elements. The most healthful diets known, traditional Mediterranean and Okinawan, are rich in Nrf2 raising nutrients as apparently
was the Paleolithic diet that our ancestors ate. Modern diets are deficient in such nutrients. Nrf2 is argued to be both lifespan and
healthspan extending. Possible downsides to too much Nrf2 are also discussed. Nrf2 is not a magic bullet but is likely to be of great
importance in health promotion, particularly in those regularly exposed to toxic chemicals.
Key words: electrophiles and oxidants; Keap1; ERK; PI3K; GSK-3β; AMPK; protein kinases C and G; toxic xenobiotics and toxic
metals; detoxification; chronic inflammatory diseases; oxidative and nitrosative stress
Nrf2是调控解毒、抗氧化、抗炎等细胞保护机制的重要转录因子——它的活性
可被保健食物及其他因素增强
Martin L Pall1,*
, Stephen Levine2
1
华盛顿州立大学,波特兰,俄勒冈州 97232-3312,美国;2
Allergy Research Group,阿拉米达,加利福尼亚州 94502,美国
摘 要:转录因子Nrf2 (nuclear factor erythroid-2-related factor 2)可激活人类基因组中500多种基因的转录,这些基因大多数具
有细胞保护功能。Nrf2通过解毒机制产生细胞保护作用,这些机制增强了有害异物和有毒金属的解毒和排泄。Nrf2经20多种
基因的作用来增加高度协调的抗氧化活性;Nrf2也具有重要的抗炎作用;Nrf2促进线粒体的生物合成抑或提高线粒体功能;
Nrf2增强细胞自噬以清除毒性蛋白的聚集体和功能异常的细胞器。有益健康的营养素和其他因素,包括酚类抗氧化剂、γ-和
δ-生育酚和三烯生育酚、长链Ω-3脂肪酸DHA和EPA、类胡萝卜素(其中番茄红素可能活性最强)、十字花科蔬菜中的异硫氰
酸酯、葱蒜类蔬菜中的硫化物、及萜类化合物,至少部分是通过增加Nrf2活性起作用的。其他一些有益健康并增加Nrf2活性
Received 2014-07-28 Accepted 2014-09-22
*
Corresponding author. Tel: +1-503-232-3883; E-mail: martin_pall@wsu.edu
2. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–182
1 Introduction
Nrf2 has been known for over 10 years, to be an im-
portant transcriptional activator of antioxidant genes,
producing important antioxidant protective responses.
It has also been known for about the same time period,
to be activated by many, but not all, phenolic antioxi-
dants, such that much of the antioxidant effects of these
compounds are produced through this regulatory re-
sponse, rather than exclusively through direct chain
breaking antioxidant chemistry.
However Nrf2 has been shown more recently to have
many cytoprotective effects that go far beyond antioxi-
dant effects. These include activation of over two doz-
en genes involved in detoxification of a wide variety of
xenobiotic toxicants. Nrf2 and the system that regulates
Nrf2 lower inflammatory responses, improve mito-
chondrial function and stimulate autophagy, a process
by which both toxic protein aggregates and dysfunc-
tional organelles can be degraded. Three of these ef-
fects, the lowering of oxidative stress, inflammatory
biochemistry and improving mitochondrial function
should lower the pathophysiology involved in dozens
of chronic inflammatory diseases and so may be ex-
pected to be useful in the prevention or treatment of
many common chronic diseases.
It has also been shown, in recent years, that many
health promoting factors other than phenolic antioxi-
dants act to raise Nrf2 activity. Most of these recent find-
ings have been reviewed in a whole series of recent re-
views[1–22]
and it is the role of this paper to summarize
the vast scope of these new findings, including the health-
promoting and disease-preventing effects of Nrf2.
The important detoxification roles of Nrf2 mean that
raising Nrf2 activity is likely to be of particular impor-
tance to the hundreds of millions of people around the
globe who are regularly exposed to toxic chemicals that
cause diseases characterized by oxidative stress, in-
flammation and mitochondrial dysfunction, diseases
which include most of the chronic diseases of 21st
cen-
tury life.
2 Diseases prevented and/or treated by rais-
ing Nrf2, at least in animal models
There are a very large number of chronic diseases, listed
in Table 1 that have been shown to be prevented and/or
treated by raising Nrf2. Conversely, lowering or knocking
out Nrf2 function has often been shown to increase sus-
ceptibility to the same diseases. Most of these studies
have been done in animal models although there are
also an increasing number of human studies being re-
ported.
The finding that raising Nrf2 may be useful in pre-
vention and/or treatment of this list of diseases seems
almost too good to be true. However these diseases all
have both oxidative stress and inflammatory aspects to
them and many of them are also known to involve mi-
tochondrial dysfunction. Protein aggregates have causal
roles of several of them, aggregates that may be re-
moved by Nrf2-dependent autophagy. A number of
these diseases are caused by toxic exposure and may be
lowered by Nrf2-dependent detoxification. The data on
obesity are mixed, but with most data showing that
Nrf2 acts to lower obesity. One of us (Martin L Pall)
has argued that many of these diseases are caused by
the NO/ONOO−
cycle, a vicious cycle mechanism in-
volving oxidative stress, inflammation and mitochon-
drial dysfunction, as well as other factors (discussed
further below). It is therefore quite plausible that be-
cause of the common factors involved in these diseases,
the Nrf2 regulatory response may prevent and/or treat
each of them.
There are reports that still other diseases may be pre-
的因素包括低水平的氧化应激[毒物兴奋效应(hormesis)]、锻炼和热量限制。现已发现,增加Nrf2活性可预防和/或治疗模型
动物和/或人类许多慢性炎症性疾病,包括各种心血管疾病、肾脏疾病、肺脏疾病、中毒性肝损伤疾病、癌症(预防)、糖尿
病/代谢综合征/肥胖、败血症、自身免疫性疾病、炎性肠病、HIV/AIDS及癫痫。较少证据提示增加Nrf2活性可降低其他16种
疾病的风险,这些疾病中的大多数可能是NO/ONOO−
环有关的疾病,而Nrf2可削弱NO/ONOO−
环元素的多种作用。已知最健
康的饮食(地中海和冲绳地区的传统饮食)富含促进Nrf2活性的营养素,这就像我们的祖先在旧石器时代的饮食一样。Nrf2是
否同时具有延长寿命和促进健康的作用是有争议的。Nrf2活性过度的可能负面作用也被讨论。Nrf2不是一个灵丹妙药,但可
能对于促进健康非常重要,特别是对于那些日常暴露于有毒化学药品的人。
关键词:亲电体和氧化剂;Keap1;ERK;PI3K;GSK-3β;AMPK;蛋白激酶C和G;有害异物和有毒金属;解毒;慢性炎
症性疾病;氧化和硝化应激
中图分类号:Q75;R151.4
3. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 3
vented or treated by raising Nrf2, although these other
diseases have been less studied than those listed in Table 1.
These include hemoglobinopathies including sickle cell
disease and β-thalassemia[35]
, malaria[36]
, spinal cord injury[37]
,
traumatic brain injury[38,39]
, altitude sickness[40,41]
, the
three classic psychiatric diseases, major depression,
schizophrenia and bipolar disorder[42–45]
, gastric ulcers[46,47]
,
glaucoma[48]
, age-related macular degeneration[49]
,
cataract[50,51]
, pathophysiological responses to herpes
activation[52]
and benign prostatic hyperplasia[53,54]
.
These diseases all involve oxidative stress and inflam-
matory aspects. Nrf2 is also shown to protect cells from
effects of ionizing radiation[55,56]
. Nrf2 was reported to
lower skin sensitization produced by sensitizing chemi-
cals[57,58]
. Clearly we need much more research on these
Nrf2 activities before any conclusion can be made, but
these studies suggest that the disease spectrum for
which Nrf2 may be protective may be larger than that
covered in Table 1.
3 Gene activation via Nrf2
Nrf2 is most known for its role in activation of genes
having antioxidant effects. It acts by binding in the nu-
cleus, along with some other proteins known as Raf to
what are called antioxidant response elements (AREs)
in the promoter regions of genes. However these AREs
occur not only in promoter regions of antioxidant genes
but also genes involved in other functions, particularly
other cytoprotective functions. While over 500 genes
are activated by Nrf2, there are also genes whose activ-
ity is lowered by Nrf2, some of which may be regulated
by transcription factors regulated by Nrf2 and others
may be regulated through AREs having repressive ef-
fects[4]
. In summary, Nrf2 acts to activate numerous
genes but it can also act via other transcription factors
to increase or decrease transcription of various genes
and may also be able to repress some genes through its
direct effects on transcription.
4 Nrf2-dependent antioxidant effects
Among the antioxidant genes activated by Nrf2, one of
the most commonly studied is the heme oxygenase 1
(HO-1) gene which converts free heme, which has
pro-oxidant effects into iron, carbon monoxide (CO)
and biliverdin, with the last being converted into the
antioxidant bilirubin via an activity also raised by Nrf2,
encoded by the two biliverdin reductase genes[1,2]
. The
iron released by heme oxygenase is sequestered by fer-
ritin, since Nrf2 induces each of 4 ferritin genes, pre-
venting iron-produced oxidative stress [1]
. This coordi-
nate control of multiple genes producing proteins that
are functionally linked in producing an important bio-
logical response has been found repeatedly in Nrf2-
mediated gene regulation. There are also antioxidant
responses produced by CO from its regulatory role.
Heme oxygenase appears to have a very important role
in producing Nrf2 responses, based on studies using
specific enzyme inhibitors or HO-1 gene knockout
mice. A possible explanation for such an important role
is discussed below.
A second commonly studied antioxidant gene activated
by Nrf2 is the quinone oxidoreductase gene (NQO1),
Table 1. Diseases where raising Nrf2 is reported to be useful in prevention and/or treatment in animal models and/or humans
Citations Diseases
2, 4, 9, 16, 22, 23 Cardiovascular diseases including atherosclerosis, ischemic cardiovascular disease, vascular
endothelial dysfunction, and heart failure
2, 4, 5, 6, 12, 13, 19, 23, 24 Neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS, Huntington’s diseases
2, 3, 4, 13, 19 Cancer (prevention)
2, 6, 7, 15, 19, 23 Chronic kidney diseases
2, 8, 10, 20, 23 Metabolic diseases: Type 2 diabetes; metabolic syndrome; obesity
2, 8, 19, 20, 23 Several types of toxic liver disease
2, 6, 16, 21, 23, 25, 27 Chronic lung diseases including emphysema, asthma, and pulmonary fibrosis
4, 14, 26 Sepsis
2, 4, 16, 23, 27–30 Autoimmune diseases
4, 13, 23, 31 Inflammatory bowel disease
4, 32 HIV/AIDS
11, 12 Multiple sclerosis
17, 18, 33, 34 Epilepsy
4. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–184
which produces an enzyme that prevents semiquinone
redox cycling and consequent oxidative stress[2]
. Two
superoxide dismutase genes (SOD1 and SOD2) are ac-
tivated by Nrf2, with each SOD lowering oxidative
stress by lowering superoxide. The functionally linked
catalase and two glutathione peroxidase genes are each
induced by Nrf2, with each of these enzymes acting to
lower H2O2, produced from superoxide by the SODs.
So again, we see Nrf2 mediates coordinate regulation
of multiple antioxidant genes[2]
.
Reduced glutathione (GSH) has often been described
as the most important low molecular weight antioxidant
produced in the human body. Each of the three genes
encoding enzymes required for the de novo synthesis of
GSH is activated by Nrf2, as is the gene for glutathione
reductase [the enzyme that converts oxidized glutathi-
one (GSSG) to GSH][1,2]
. Genes encoding 8 enzymes
that have roles in the synthesis of NADPH, the reduc-
tant needed by glutathione reductase are also activated
by Nrf2. Other genes encoding enzymes that have roles
in using GSH for antioxidant purposes, including two
glutathione peroxidase genes (discussed in the previous
paragraph) and the glutaredoxin 1 gene, are each Nrf2
activated[2]
.
Five genes involved in thioredoxin-related antioxi-
dant responses are activated by Nrf2, including perox-
iredoxin-1 and -6 which destroy peroxides including
peroxynitrite, an extremely reactive oxidant responsible
for nitrosative stress[1]
. The enzymes produced by these
five genes and also glutaredoxin mentioned in the pre-
vious paragraph, represent a set of important and inter-
acting antioxidant enzymes[59]
, each of which is coordi-
nately regulated by Nrf2.
In summary, it can be seen from the above that there
are 23 genes involved in antioxidant protection, each of
which is activated by Nrf2. There are in addition, still
other genes activated by Nrf2. These include genes en-
coding products that act to remove toxic products of
lipid peroxidation, others encoding enzymes that have
roles in removing or repairing protein oxidation prod-
ucts and still others similarly regulated that help re-
move products of oxidative DNA damage in the pro-
cess of DNA repair.
5 Detoxification genes activated by Nrf2
To the hundreds of millions of people around the world
who are exposed daily to substantial levels of toxicants,
detoxification may be the most important Nrf2-depen-
dent cytoprotective mechanisms. Hayes and Dinkova-
Kostova[1]
list a total of 25 different genes that are acti-
vated by Nrf2, each of which encodes an enzyme that
acts in detoxification of various toxic xenobiotics.
Among those 25 genes[1]
are 12 that have roles in me-
tabolism of various carbon-containing xenobiotic toxi-
cants leading up to but not including conjugation. They
also list 5 genes activated by Nrf2 that increase gluta-
thione conjugation, one that increases sulfate conjuga-
tion and two that lead to glucuronidation. Each of these
8 genes have roles in increasing toxicant excretion
which follows upon conjugation. There are also Nrf2-
activated genes that increase transport of xenobiotic
chemicals from the cell, thus increasing subsequent
excretion from the body.
Two potentially important detoxification genes, not
discussed in ref. [1]
are the Mt1 and Mt2 genes for
metallothionein, both of which are induced by Nrf2[60]
.
Metallothionein has roles in chelating, transporting and
excreting both essential and toxic metals, including
cadmium, mercury, lead and arsenic[61]
. However it
should be noted that when metallothionein was studied
in a relatively short-term study of cadmium toxicity, it
was concluded that Nrf2 effects on antioxidant responses
were more important than were metallothionein effects
in producing resistance to cadmium toxicity[60]
. Metal-
lothionein levels have been shown to have a role in
determining lead toxicity[62]
. Toyama et al.[63]
showed
that Nrf2 stimulated mercury excretion with such
excretion attributed by the authors to increased reduced
glutathione. It should be noted that reduced glutathione
is the most common low molecular weight thiol in the
body and because mercury, lead, cadmium and arsenic
all react with thiol groups, Nrf2-dependent raising
reduced glutathione may be expected to increase detox-
ification of each of these toxic metals. The Nrf2 acti-
vating nutrient, curcumin has been shown to lower
hepatotoxicity of arsenic, cadmium, chromium, copper,
lead and mercury with such lowered toxicity attributed
to both Nrf2 activation and direct chelation by curcum-
in[64]
. This paragraph only reviews a fraction of the
available information that relates to Nrf2 and toxic
metal exposure. Nevertheless it suggests that Nrf2
probably has a substantial role in producing resistance
to toxic metal exposure.
Nrf2 has a wide range of detoxification effects, pro-
ducing increased resistance to toxic organic xenobiotics
and toxic metals.
5. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 5
6 Anti-inflammatory effects of Nrf2
Nrf2 activation produces a wide variety of anti-inflam-
matory effects including lowered NF-κB and lowered
activity of a series of inflammatory mediators including
cytokines, chemokines, adhesion molecules, COX-2,
MMP-9 and iNOS[6,15,16]
. The interaction between Nrf2
and NF-κB is very complex, with each having effects
that both increase and decrease the other. However it is
clear that[6]
“NF-κB pathway is inhibited by several
Nrf2 activators” but the specific mechanisms responsi-
ble for Nrf-2 mediated lowering of NF-κB is still some-
what uncertain. However[6]
“Conversely, recent experi-
mental evidence indicates that NF-κB may directly
repress Nrf2 signaling at the transcriptional level.” Two
direct anti-inflammatory effects of Nrf2 are that it stim-
ulates the transcription of the anti-inflammatory cyto-
kine IL-10 gene[5]
and it has also been shown to lower
regulatory responses produced by TGF-β[16]
.
In conclusion, Nrf2 produces a large number of anti-
inflammatory effects, with many mediated by lowering
NF-κB activity and some others mediated through
Nrf2-dependent increases in IL-10. NF-κB acts in turn
to lower Nrf2 activity. The mechanisms involved in
Nrf-2 dependent lowering of NF-κB activity are com-
plex and not completely understood, although it seems
likely that Nrf2-dependent lowering of oxidant levels
has a role.
7 Mitochondrial biogenesis and autophagy
Most of the diseases listed in Table 1 are also charac-
terized by energy metabolism and mitochondrial dys-
function. One of the mechanisms that may be included
as cytoprotective may be increased mitochondrial bio-
genesis. Nrf2 produces such increased mitochondrial
biogenesis acting in part by activating a related gene,
Nrf1[20]
. A large number of other genes involved in en-
ergy metabolism are also activated by Nrf2[1]
and are
thought to contribute to both mitochondrial biogenesis
and improved mitochondrial function. There is a lot of
crosstalk between Nrf2 and the AMPK protein ki-
nase[65]
, which is stimulated by AMP and which there-
fore monitors energy levels. It is possible therefore that
this may be an important interaction in controlling mi-
tochondrial responses.
It is also the case that a number of health-promoting
nutrients that stimulate Nrf2 also act to increase the
process of autophagy by which damaged organelles and
also damaging protein aggregates can be degraded pro-
teolytically, with such autophagy occurring, in part, via
a Nrf2-dependent process[66,67]
. This stimulation of au-
tophagy is useful in removing damaged mitochondria
and other damaged organelles. It is also useful in re-
moving protein aggregates that have roles in neurode-
generative and other diseases and autophagy has anti-
oxidant roles as well. However it should be noted, that
autophagy is inhibited by very high levels of Nrf2. In
summary, Nrf2-dependent autophagy may be useful as
a cytoprotective response in multiple ways, one of
which has roles in improving mitochondrial function.
While most of the health promoting effects of Nrf2
can be understood in terms of its antioxidant, detoxifi-
cation, anti-inflammatory and autophagy effects and its
ability to stimulate mitochondrial biogenesis, still other
health promoting effects may also occur. For example,
in many of the chronic inflammatory diseases, there is
substantial pathophysiological tissue remodeling in-
volving fibrosis. Nrf2 has been reported to have antifi-
brotic effects in the lung, liver and kidney[68–71]
, acting
by stimulating dedifferentiation of fibroblasts. Much of
this antifibrotic effect is thought to be produced by an
anti-inflammatory action of Nrf2 which lowers TGF-β
signaling.
8 Nrf2 activity is raised by many health-promoting
nutrients and other factors
The amazing list of health promoting factors that have
been shown to act, at least in part, by raising Nrf2 are
shown in Table 2.
Each of the nine factors listed in Table 2 have an ex-
tensive literature on their health-promoting effects. Al-
though all nine have been shown to raise Nrf2 activity,
several of these can clearly act in other ways not in-
volving Nrf2 to promote health.
For example, four of the nutritional factors are well
established to act independently of Nrf2 as follows:
Phenolics, including tocopherols/tocotrienols, can act
as chain breaking antioxidants.
Carotenoids can act as scavengers of singlet oxygen
and peroxynitrite.
Fish oil has anti-inflammatory properties by acting as
precursors of eicosanoids.
Exercise can act in ways independent of Nrf2.
The phenolics act via three mechanisms to raise Nrf2,
but some phenolics are completely inactive in this pro-
cess. The ones that appear to act most directly, are or-
6. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–186
tho or para dihydroxyphenols which can get oxidized
to quinones[2]
which then act to raise Nrf2. The role of
the phenol ring structures are also seen in the second
type of chemical listed in Table 2, the different forms
of vitamin E. These are also phenolic forms, but the
phenol ring structures in the γ & δ forms are much
more active than that in α-tocopherol in raising
Nrf2[72,73]
. α-tocopherol, the common form of vitamin E
used in supplements, has modest activity in raising
Nrf2; it may decrease Nrf2 activity in vivo, however,
because it increases the degradation in the body of the
other forms of vitamin E, including the γ & δ tocopher-
ols and tocotrienols[81]
.
However each of these 9 factors, when tested in
Nrf2−/−
mouse knockout mutants have been shown to
have lost most of their health-promoting properties as
compared with their activity in Nrf2+/+
mice (see, for
example, refs [82–89]
). This shows, therefore that much of
their health promotion requires the presence of a func-
tional Nrf2 gene, at least in the mouse. Other cell cul-
ture studies on these nutritional factors have also sup-
ported an important role for Nrf2 elevation in response
to these factors, as well.
Caloric restriction, another health-promoting factor,
acts in part by raising Nrf2[90–92]
. There are traditional
Chinese, Ayurvedic, European and Native American
herbals that have been shown to act by raising Nrf2.
Two of these were discussed earlier[93]
but a full consid-
eration of such herbals goes beyond the scope of this
review.
There are still other phytochemical Nrf2 raising fac-
tors, some of which are harder to characterize than the
categories listed in Table 2. For example, a number of
plant-derived acetylenic compounds also raise Nrf2[2]
.
Dithiolethiones from cruciferous plants also act to raise
Nrf2[2]
as does α-lipoic acid. It has also been reported
that butyrate produced from dietary fiber fermentation
in the colon, acts to raise Nrf2 in colonocytes[94]
; this
butyrate action may have implications regarding
dietary fiber and Nrf2 control in the lower gastrointesti-
nal (GI) tract.
Three of these classes of chemicals act via their oxi-
dation products to raise Nrf2 levels. The long chain
omega-3 fatty acids DHA and EPA act via their oxida-
tion product 4-hydroxyhexenal and other oxidation
products to raise Nrf2[26,27,95]
. The carotenoids act, pri-
marily and possibly entirely, via their oxidation prod-
ucts to raise Nrf2[76,77]
. Many of the phenolic antioxi-
dants that raise Nrf2 are thought to act via their quinone
oxidation products in raising Nrf2[1–6]
. Sandberg et al.[5]
have argued that chronically inflamed tissues may be-
come less susceptible to agents raising Nrf2. Similarly,
Kumar et al.[2]
state that “Unfortunately, long-term in-
flammatory signaling can result in decreased Nrf2 ac-
tivity and decreased antioxidant and defense capacity”.
It may be useful in therapy of diseases of chronic in-
flammation to use these three classes of Nrf2 raising
nutrients, because the higher rates of oxidation of these
nutrients in inflamed, oxidative stressed tissues may act
to counteract otherwise lowered Nrf2 responses in such
tissues.
9 The two most healthful known diets, the
traditional Mediterranean diet and the tra-
ditional Okinawan diet, are both rich in Nrf2
activating nutrients
The traditional Mediterranean diet which is thought to
be ideally the Cretan diet and perhaps the southern
Greek and southern Italian diets of the 1960s and the
traditional Okinawan diet of the same time period, are
thought to be the most healthful human diets known,
Table 2. Health-promoting factors that raise Nrf2 activity
Citations Health-promoting factors
2, 3, 4, 5, 8, 15 Many but not all phenolic antioxidants
74, 75 γ, δ-tocopherols and tocotrienols (but α-tocopherol has little activity)
2, 3, 4, 5, 7, 8, 15 Isothiocyanates from broccoli, cabbage and other cruciferous foods
2, 4, 5, 8, 15, 19, 20 Triterpenoids and other terpenes
2, 23, 74, 75 Sulfur compounds including allyl sulfides in garlic/onion/allium foods
2, 76, 77 Many carotenoids with lycopene apparently the most active
3, 78, 79 Fish oil (long chain omega-3 fatty acids DHA and EPA)
3, 80 Modest oxidative stress (hormesis)
4, 9, 22 Exercise, works in part via modest oxidative stress; may also work in the vasculature via laminar shear stress
7. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 7
with high overall lifespans, large numbers of centenari-
ans and low incidences of cancer and cardiovascular
disease[96–103]
. Diets in both of these locations are
thought to have become much less healthful in recent
decades, but studies of these two traditional diets are
still important parts of our understanding of dietary
factors that may influence human health. The question
being raised here is whether it is likely that nutrients
raising Nrf2 activity in these diets have an important
role in producing the health promoting properties of
these two diets.
The dietary factors listed in Table 2 which raise Nrf2
are all of plant origin except for the long chain omega-
3 fatty acids which are best obtained from seafood.
Consequently, it may be argued that the best diets for
raising Nrf2 are diets with regular seafood consumption
but otherwise containing large amounts of foods de-
rived from plants, particular plants with low calorie
densities which are likely to be consumed in larger
quantities and therefore provide, in general more phy-
tochemicals. Both the traditional Mediterranean and
Okinawan diets clearly fit this description[96–103]
. Fur-
thermore several of the nutrient categories known to
raise Nrf2 listed in Table 2 are thought to be high in
each of these diets (see Table 3).
It can be seen from Table 3 that each of these health-
promoting diets are very rich in nutritional components
that raise Nrf2, including five of the six types of Nrf2
activating components listed in Table 3. The traditional
Mediterranean diet is most characterized by high con-
sumption of olives and olive oil, which are known to
contain very high levels of phenolics and terpenoids;
both olive-derived phenolics and terpenoids have been
shown to raise Nrf2. The main caloric source in the tra-
ditional Okinawan diet is the sweet potato, often
including purple sweet potatoes [96]
. All sweet potatoes
are very high in carotenoids and purple sweet potatoes
are very high in anthocyanin phenolics which are
potent Nrf2 activators. Murakami et al.[97]
showed that
a large number of specific vegetables in the traditional
Okinawan diet are potent agents that lower the produc-
tion of both superoxide and nitric oxide in leukocytes,
suggesting that these vegetables act in part by raising
Nrf2. In some cases, they[97]
implicated both phenolics
and terpenoids in producing these responses, again sug-
gesting a possible Nrf2 effect. While it is unlikely that
all of the phytochemicals that may produce health-
promoting effects in these two diets are acting mainly
or solely via Nrf2, it is likely in our opinion, that Nrf2
has a major role in the health promotion in each of
these two diets.
The Okinawan diet is thought to be very similar to
what is often called the Paleolithic diet[103]
, the diet that
our ancestors ate during much of human evolution. The
only substantial difference is that in the Paleolithic diet,
most of the omega-3 fatty acids came from wild terres-
trial animals and plants, both of which are quite rich in
omega-3 fatty acids[104]
, rather than primarily from fish.
Table 3. Estimated Nrf2 raising nutritional components in the two most healthful diets known
Nutrient component Traditional Mediterranean Diet Traditional Okinawan Diet
Phenolic antioxidants High consumption from olives and olive oil, High consumption from soy, many green
herbs, legumes, eggplant, many leafy green vegetables and herbs; also provided by purple
vegetables sweet potato varieties; “Okinawan spinach”
(Perilla, major source of rosmarinic acid)
Carotenoids High consumption, especially from tomatoes Very high consumption from sweet potatoes and
and leafy green vegetables many leafy green vegetables
Long-chain omega-3 High consumption from fish; also purslane High consumption from fish; also leafy green
fatty acids and walnuts provide fatty acid precursors to vegetables provide some fatty acid precursors to
the human body the human body
Isothiocyanates Probably average for European diets High from cruciferous vegetables and daikon
radish, but no higher than other East Asian diets
Terpenoids High from Mediterranean herbs, olives, peel Uncertain; substantial levels in Perilla and some
of fruits and eggplant other herbs; may be high[97]
Allium-derived sulfur High consumption of garlic and onions Relatively high (onions, other allium), probably
compounds similar to Chinese diet
Information derived from[96–103]
.
8. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–188
Specifically, the Okinawan diet is thought to closely re-
semble the Paleolithic diet in having very high levels of
phenolic and carotenoid antioxidants as well as high
omega-3 levels, probably also terpenoids and essentially
no grain consumption[103]
, all of which may be relevant
to Nrf2 control. It seems likely, therefore, that we
evolved with much higher levels of Nrf2 raising nutri-
ents in our diets and that almost all of us are currently
in a dietary deficiency state for Nrf2 raising nutrients.
This may be responsible for much of the extraordinary
predominance of chronic diseases afflicting modern
populations, characterized by oxidative stress, inflam-
mation and mitochondrial dysfunction.
10 Is Nrf2 a master regulator of longevity
and healthspan?
The concept that Nrf2 is a master regulator of not only
longevity, but also more importantly of healthspan was
suggested by Lewis et al.[105]
in their paper entitled
“Nrf2, a guardian of healthspan and gatekeeper of spe-
cies longevity.” They state[105]
that “There is mounting
evidence across evolutionarily distant species that
Nrf2-ARE-dependent components are associated with
both longevity and extension of healthspan.” These
studies include a number of genetic studies in the
mouse and in several other species, showing that rais-
ing Nrf2 activity produces prolonged lifespans and
healthspans and that lowering Nrf2 produces shorter
lifespans and healthspans. The mouse studies are par-
ticularly important here because genetic manipulation
in transgenic mice allows one to easily determine ef-
fects of both raised and lowered Nrf2 activity. One
change that may contribute to determining lifespans
and healthspans is replicative senescence of cells which
has been reported to be delayed by Nrf2[106]
. Converse-
ly, a knockout of the Nrf2 gene leads to premature cel-
lular senescence[107]
. These roles of Nrf2 in determining
cellular senescence rates should not be surprising, giv-
en the roles of oxidative stress in producing cellular se-
nescence[108]
.
This general notion regarding Nrf2, longevity and
healthspan is, of course, strongly supported by the
many diseases including diseases of aging that are low-
ered, at least in animal studies by raising Nrf2 (Table
1). It is also strongly supported by the various health
promoting nutritional and other factors that all raise
Nrf2 and act, at least in part through the raising of Nrf2
(Table 2). It is supported as well by the high levels of
Nrf2-raising nutrients found in the two most healthful
diets known, the traditional Mediterranean diet and the
traditional Okinawan diet (Table 3).
11 How is Nrf2 regulated by the health pro-
moting factors listed in Table 2?
Each of refs[1–22]
has reviewed the mechanisms by
which Nrf2 is regulated and each provides some infor-
mation on how various factors raise Nrf2. Their discus-
sions on mechanisms of Nrf2 regulation are, in general,
much more detailed than is the discussion here. Conse-
quently, the reader is encouraged to go to them and in
particularly to[1–4]
for more detailed information than is
provided here.
Nrf2 protein under what have been called noninduced
situations is mostly contained in an inactive complex
with another protein known as Keap1. Keap1 has five
reactive cysteine residues, in each of which reaction of
inducing chemicals with the cysteine thiol, can start a
process leading to release of Nrf2 from Keap1. Follow-
ing release, Nrf2 can move into the nucleus, complex
with other proteins called Maf, bind to ARE sequences
on DNA and stimulate transcription of adjacent genes.
The agents that react with these thiols are electrophilic
and/or oxidative and the reaction with these thiols is
thought to be the most important mechanism of regula-
tion of Nrf2. The five different cysteine thiols differ
from one another in what compounds they react with.
However there are many other mechanisms that come
into play, making the Nrf2 control system very com-
plex. There are several protein kinases that have roles
in regulating Nrf2, including the ERK/JNK pathway,
PI3K/Akt/GSK-3β pathway, protein kinase C, AMPK[65]
and protein kinase G. In addition, when Nrf2 is bound
to Keap1, Nrf2 tends to be targeted for proteasomal
degradation, so that its levels are kept low. Release
from Keap1 increases the stability of Nrf2 roughly
7-fold, leading to substantially increased levels. Fur-
thermore, Nrf2 stimulates the transcription of its own
gene and also the MafG gene, thus further stimulating
Nrf2-dependent transcription. The P62 protein involved
in autophagy that is activated by Nrf2 also is involved
in a positive feedback loop, increasing Nrf2 activity[66]
.
While the mechanisms in the previous three sentences
act to amplify Nrf2 activation, there is also two mecha-
nisms that lower Nrf2 activation. Nrf2 also stimulates
transcription of the Keap1 gene, lowering Nrf2 eleva-
tion. Furthermore Nrf2 also stimulates the transcription
9. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 9
of a gene encoding INrf2, a protein that also lowers
Nrf2 activity[109]
.
Nrf2 is also regulated by microRNAs, including miR-
200a, that lower the translation of the Nrf2 mRNA or
mRNAs of Nrf2 related proteins[110,111]
. Because levels
of miR-200a are regulated by histone acetylation[111]
,
such acetylation may bring in another level of control;
this may explain part of the action of the histone
deacetylase inhibitor butyrate, discussed above, in rais-
ing Nrf2[94]
. Furthermore, the protein designated p300/
CBP is an acetyltransferase that acetylates both his-
tones and Nrf2 itself, with Nrf2 acetylation stimulating
its activity in ARE-mediated gene transcription[112]
.
Consequently, the histone deacetylase inhibitor butyr-
ate may also act by increasing Nrf2 acetylation to in-
crease Nrf2 transcriptional activity.
Another regulatory linkage is that agents that stimu-
late the aryl hydrocarbon receptor (AhR) increase Nrf2
transcription, leading to increases in Nrf2 activity, a
subject that has only fairly recently attracted much at-
tention[113]
.
Protein kinase G has recently been shown to have a
substantial role in activating Nrf2[114–117]
. Its role may
explain one of the long-standing puzzles about Nrf2,
why does HO-1 induction have such an important role
in the action of Nrf2? This has been shown in a number
of studies of Nrf2 action, where a specific inhibitor of
heme oxygenase has been shown to greatly lower the
biological effects of Nrf2 activation. Why then should
HO-1 be so important in the action of Nrf2? One of the
products of HO-1 enzymatic activity is CO, which acts,
as does NO, to greatly stimulate the production of
cGMP and therefore of protein kinase G stimulation of
Nrf2[117,118]
. It follows from this that HO-1 induction by
Nrf2 may be an important positive feedback loop, pro-
ducing a much more rapid increase in Nrf2 activity and
therefore Nrf2-dependent responses over time follow-
ing any initial steps raising Nrf2 activity, than will oc-
cur in the absence of increased HO-1 activity. It is our
opinion, that substantial indirect effects of Nrf2 may be
produced via increased cGMP/protein kinase G, effects
that are distinct from this positive feedback loop.
How then do the agents listed in Table 2 stimulate
Nrf2 activity? Isothiocyanates[2,7]
, H2O2 and other oxi-
dants, phenolic antioxidants, long chain omega-3 fatty
acids and carotenoids act by reaction with Keap1 reac-
tive thiols with the last three of these acting through
their oxidation products. Allium sulfur compounds,
isothiocyanates and carotenoids act via ERK stimula-
tion[119,120]
, with the latter two acting via two distinct
mechanisms to raise Nrf2. Some flavonoids and other
phenolics, including some that are inactive in the
Keap1 reactions act as AhR agonists[121]
, some act via
protein kinase signaling[122]
and some act via their qui-
none oxidation products directly on Keap1 thiols[2]
.
Terpenoids are thought to act via three distinct mecha-
nisms, directly on the Keap1/Nrf2 protein complex,
through protein kinase regulation and also via miRNA
regulation[2,19]
.
It follows from all this that phytochemicals and other
agents can increase Nrf2 activity by reacting either di-
rectly or through their oxidation products with different
cysteine residues on Keap1, by regulating the activity
of a number of different protein kinases, by stimulating
the AhR receptors or by acting via histone acetylation
or other mechanisms to influence microRNA synthesis
and therefore Nrf2 activity. It follows from this that
phytochemicals and other agents that act in different
ways to raise Nrf2 may be expected to act synergisti-
cally together. An example of such synergism was re-
ported by Saw et al.[123]
who showed that the carotenoid
astaxanthin and the fish oil fatty acids DHA and EPA
acted synergistically with each other in raising Nrf2.
The components of Protandim were shown in cell cul-
ture to act synergistically in raising Nrf2 responses,
probably due to the role of multiple signaling pathways
in their actions in raising Nrf2[93]
.
Consequently phytochemically rich diets such as the
traditional Mediterranean diet and the traditional Oki-
nawan diet may be expected to be more active in Nrf2
activation than may be suggested from just looking at
the activities of their individual Nrf2 raising nutrients,
due to such synergisms.
11 Can too much Nrf2 over extensive time pe-
riods be toxic?
In general as indicated in ref.[105]
raising Nrf2 produces
prolonged lifespans and healthspans in animal studies.
In addition, human diets rich in nutrients that raise Nrf2
including the traditional Mediterranean and Okinawan
diets produce longer lifespans and lowered disease in-
cidences. However, there are situations where chronic
high-level Nrf2 stimulation produces pathophysiologi-
cal responses in the body. Perhaps the clearest, well-
documented example of this is where high level chronic
raising of Nrf2 levels by TCDD (dioxin) leads to chlor-
acne[124,125]
. TCDD also has other, Nrf2 independent
10. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–1810
toxic effects but these acne-like changes in skin proper-
ties are clearly caused by excessive, long-term levels of
Nrf2, such that chloracne may serve as a marker for
excessive Nrf2 stimulation. Arsenite and other arseni-
cals can also produce similar skin responses, acting via
excessive Nrf2 activity[125]
, but again arsenite has other
Nrf2 independent toxic effects. Both the TCDD and the
arsenite effects act through AhR stimulation to produce
elevated Nrf2 activity. These skin effects of excessive
Nrf2 appear to be caused in part by the elevated sensi-
tivity of keratinocytes to Nrf2.
This keratinocyte role also shows up in perhaps the
most dramatic effect of excessive Nrf2. It was shown
that Keap1 transgenic mouse knockout mutants devel-
oped hyperkeratosis in the esophagus and forestomach
during gestation, which led to death from malnutrition
after birth[126]
. This was shown to be caused by exces-
sive Nrf2 activity[126]
.
Months long, high level chronic elevation of Nrf2 is
produced by certain conditions in the mouse, condi-
tions that produce cardiac dysfunction[127,128]
. While it is
unclear how much of this dysfunction is caused by
Nrf2, this may be another example where chronic, high
level Nrf2 elevation may produce pathophysiological
responses.
It is generally accepted that steady high level Nrf2
activity is much more likely to be damaging than is
variable activation[2,129]
. As stated earlier[129]
, “Pharma-
cologic induction of the pathway, however, allows for
pulsed induction rather than permanent induction of the
Keap1-Nrf2-signaling axis, which may reduce any un-
toward effects of constant pathway activation.” The
same reasoning applies to Nrf2 raising nutrients con-
sumed at certain times of the day.
The possibility of what may appear to be paradoxical
Nrf2 effects may occur where there is no Nrf2 at all, in
Nrf2 knockout mutant cells. For example, it has been
reported that such knockout cells are deficient in the
activation of inflammasomes, showing that some Nrf2
activity may be required for some inflammatory re-
sponses[130]
.
In conclusion, it may be expected that levels of Nrf2
raising nutrients that occur in the Mediterranean or
Okinawan diets will produce predominantly health-pro-
moting effects. Nevertheless, very high chronic, long-
term Nrf2 elevation can produce pathophysiological ef-
fects like almost any regulatory effect taken to extreme.
Therefore, one needs to take care not to raise Nrf2 lev-
els too high for too long. It is possible that some indi-
viduals may be much more susceptible to such patho-
physiological effects, given the great amount of genetic
heterogeneity in the human population. One way of
minimizing any pathophysiological effects is to vary
the levels of Nrf2-raising agents in the body at different
times of the day. The acne-like skin responses to exces-
sive, chronic long-term elevation of Nrf2 activity may
serve as a visual indication of whether such excessive
Nrf2 activity is occurring in humans in response to
Nrf2 raising agents.
12 Summary
Gao et al.[4]
state that “Nrf2 activation or inhibition re-
sponding to oxidative or electrophilic stress, and de-
signed to restore redox homeostasis, paves a new way
to understand prevent or even cure complex diseases.”
The list of diseases in Table 1 where raising Nrf2 acts
to prevent and/or treat the disease, at least in animal
models is truly stunning. The regulation of Nrf2 and
the regulatory responses produced by it are summarized
in Fig. 1.
The actions of 7 classes of health-promoting nutrients
(box, inner left side, Fig. 1) are each known to act to a
great extent by raising Nrf2, as are 3 other health pro-
moting factors. The two most healthful diets known,
the traditional Mediterranean and Okinawan diets, and
the Paleolithic diet are all thought to be rich in Nrf2
raising nutrients, whereas modern diets are deficient in
such nutrients (Fig. 1, left). These findings strongly
suggest that health-promotion by these diets acts, to a
great extent via Nrf2 but that most of us are currently
deficient in Nrf2 raising nutrients. Nrf2 acts, in turn via
transcription of roughly 500 genes, to raise antioxidant
responses, mitochondrial biogenesis and energy metab-
olism, detoxification of carbon-containing xenobiotics
and toxic metals, autophagy of toxic protein aggregates
and dysfunctional organelles and greatly lowering
many inflammatory responses (Fig. 1, lower right). It is
not surprising, therefore, that a large number of chronic
diseases characterized by oxidative stress, inflamma-
tion and often mitochondrial function can be treated
and/or prevented by raising Nrf2, at least in animal
models (Fig. 1, right). Nor should it be surprising that
Nrf2 has been proposed to produce both lifespan and
healthspan extension, given the many diseases of aging
characterized by oxidative stress, inflammation and mi-
tochondrial dysfunction (Fig. 1, upper right).
There are 16 other diseases that are reported to be
11. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 11
prevented and/or treated by raising Nrf2[35–58]
, with each
Nrf2-linked disease based on one or two studies. One
would tend to ignore these, except for the fact that each
of these diseases are diseases of oxidative stress and in-
flammation and therefore may plausibly be impacted
by Nrf2; and also except for the fact that these are all
based on recent and rapidly increasing numbers of
studies (Table 4), suggesting that we are still in the ear-
ly stages of findings about disease impacts of Nrf2.
While no doubt it is too early to make a conclusion, it
is difficult to escape the suggestion, from Tables 1 and
4, that we may be on the verge of a new literature on
health effects of Nrf2 which may well become the most
extraordinary therapeutic and most extraordinary pre-
ventive breakthrough in the history of medicine.
It is our opinion that raising Nrf2 is likely to be the
most important health promoting approach into the
foreseeable future. That is not to say that it is a magic
bullet. More is not always better and other health pro-
moting nutrients and other agents acting in other ways
are likely to act along with Nrf2. Agents that lower NF-
κB via Nrf2-independent ways are likely to be useful.
So are agents or diets that lower the production of ad-
vanced glycation end products with their RAGE recep-
tor-mediated inflammatory responses. Nutrients that are
health promoting in other ways, such as B vitamins and
vitamin C, magnesium and some trace elements are
likely to be useful, as are agents like high doses of the
hydroxocobalamin form of B-12 which lowers per-
oxynitrite by lowering its two precursors. Other agents
that act to improve mitochondrial function independent
of Nrf2 are also likely to be useful, as well.
Many of the diseases that are thought to be prevented
and/or treated by raising Nrf2 activity are also thought
to be caused by what is called the NO/ONOO–
cycle.
These apparent NO/ONOO–
cycle diseases that respond
to Nrf2 include several cardiovascular and neurodegen-
erative diseases, asthma, multiple sclerosis, epilepsy,
spinal cord injury and glaucoma[131–135]
. Heart failure is
now the best documented NO/ONOO–
cycle disease[136]
.
The 23rd
and most recent disease to be proposed to be
caused by the local impact of the cycle is glaucoma[135]
.
Because the cycle involves oxidative stress including
peroxynitrite elevation, inflammatory aspects and mito-
chondrial dysfunction, it should not be surprising that
apparent NO/ONOO–
cycle diseases may be prevented
and/or treated by raised Nrf2. Because the NO/ONOO–
cycle is primarily local, localized in different tissues in
different individuals, it may cause a variety of different
diseases, depending on where it is localized in the
body[131–135]
. One question that should be asked here is
Fig. 1. Outline of the Nrf2 regulatory system.
Table 4. Nrf2 & other diseases cited in citations [37–60]
Year Numbers of citations
2006 2
2007 1
2008 1
2009 1
2010 1
2011 4
2012 4
2013 6
2014 (5 months) 4
12. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–1812
whether this notion that the Nrf2 regulatory system
may be nature’s way of preventing NO/ONOO–
cycle
diseases holds up in looking at other aspects of the cy-
cle. While clearly increased Nrf2 activity may be ex-
pected to lower the oxidative/nitrosative stress, inflam-
matory and mitochondrial dysfunction parts of the
cycle, and the majority of the cycle elements are part of
these three aspects of the cycle[131–135]
, there are other
cycle elements that are not involved with oxidative/ni-
trosative stress, inflammation or mitochondrial dys-
function. Does Nrf2 also lower pathophysiological
consequences of these other parts of the cycle? Here,
the data are limited, but what data we have are support-
ive of this prediction. Pathophysiological consequences
of excessive NMDA activity[136–138]
and excessive intra-
cellular calcium levels[138,139]
are both lowered by Nrf2.
Tetrahydrobiopterin oxidation and depletion, another
part of the cycle, have been shown to be elevated in a
Nrf2 knockout mouse[140]
, suggesting but not proving
that raising Nrf2 will lower this part of the cycle. Clear-
ly we need more studies on these issues, but the data
available to date support the view that Nrf2 may well
be nature’s way of preventing NO/ONOO–
cycle dis-
eases. It follows that our dietary deficiencies of Nrf2
raising nutrients may well be the central cause of the
high incidence and prevalence of these diseases in the
modern world.
The stunning apparent breadth of the effects of Nrf2
on diverse diseases produces a challenge for medicine.
Medicine has historically focused mainly on the ways
in which these various diseases differ from one another,
as a way of understanding their differences. However it
is possible that these diverse chronic inflammatory dis-
eases all have a similar underlying mechanism and dif-
fer from one another primarily in their localization in
the body, with the differences in localization being re-
sponsible for any differences in their etiologies. That
does not necessarily mean that all these diseases are
NO/ONOO–
cycle diseases, but that may well be the
most apparent available explanation.
It has become commonplace for some physicians and
some other scientists to argue against the importance of
oxidative stress in human disease despite the extensive
and repeated evidence for the existence of and impor-
tance of protein changes produced by oxidative/nitrosa-
tive chemistry in dozens of chronic diseases. Watson,
in his recent paper[141]
, shows that he knows about the
existence of Nrf2, but is apparently completely un-
aware of its activation by oxidants and its role in pro-
ducing complex and extraordinarily well coordinated
enzymatic antioxidant responses. The complexity and
coordination of these responses could not possibly have
evolved without strong genetic selection based on the
pathophysiological roles of oxidative/nitrosative stress
in the etiology of many diseases. The Nrf2-controlled
antioxidant mechanisms are telling us, therefore, that
antioxidant mechanisms are among the most important
mechanisms in metazoan evolution. While it is a major
mistake to ignore the other Nrf2 cytoprotective mecha-
nisms, it is also a major mistake to ignore the compel-
ling evidence that the Nrf2 studies give us on the im-
portance of enzymatic antioxidant mechanisms.
This paper started out emphasizing the special impor-
tance of Nrf2 to the hundreds of millions of people
around the world who are exposed on a daily basis to
toxic chemicals. The role of Nrf2 in producing complex
and well coordinated detoxification mechanisms allows
us to focus on raising Nrf2 as a way of substantially
lowering the pathophysiological effects of such expo-
sures by detoxification of the body, lowering levels of
both organic, carbon-containing xenobiotic toxicants
and also toxic metals.
REFERENCES
1 Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory net-
work provides and interface between redox and intermedi-
ary metabolism. Trends Biochem Sci 2014; 39: 199–218.
2 Kumar H, Kim IS, More SV, Kim BW, Choi DK. Natural
product-derived pharmacological modulators of Nrf2/ARE
pathway for chronic disease. Nat Prod Rep 2014; 31: 109–
139.
3 Baird L, Dinkova-Kostova AT. The cytoprotective role of
the Keap1-Nrf2 pathway. Arch Toxicol 2011; 85: 241–272.
4 Gao B, Doan A, Hybertson BM. The clinical potential of
Nrf2 signaling in degenerative and immunological disor-
ders. Clin Pharmacol 2014; 6: 19–34.
5 Sandberg M, Patil J, D’Angelo B, Weber SG, Mallard C.
NRF2-regulation in brain health and disease: Implication
of cerebral inflammation. Neuropharmacology 2014; 79:
298–306.
6 Buelna-Chontal M, Zazueta C. Redox activation of Nrf2
and NF-κB: A double end sword? Cell Signal 2013; 25:
2548–2557.
7 Saito H. Toxico-pharmacological perspective of the Nrf2-
Keap1 defense system against oxidative stress in kidney
diseases. Biochem Pharmacol 2013; 85: 865–872.
8 Seo HA, Lee IK. The role of Nrf2: Adipocyte differentia-
tion, obesity, and insulin resistance. Oxid Med Cell Longev
2013; 2013: 184598
13. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 13
9 Mann GE, Niehueser-Saran J, Watson A, Gao L, Ishii T, de
Winter P, Siow RC. Nrf2-ARE regulated antioxidant gene
expression in endothelial and smooth muscle cells in oxi-
dative stress: implications for atherosclerosis and pre-
eclampsia. Acta Physiol Sin (生理学报) 2007; 59: 117–
127.
10 Bocci V, Zanardi I. An integrated medical treatment for
type-2 diabetes. Diabetes Metab Syndr 2014; 8: 57–61.
11 Arnold P, Mojumder D, Detoledo J, Lucius R, Wilms H.
Pathophysiological processes in multiple sclerosis: focus
on nuclear factor erythroid-2-related factor 2 and emerging
pathways. Clin Pharmacol 2014; 6: 35–42.
12 Lee DH, Gold R, Linker RA. Mechanisms of oxidative
damage in multiple sclerosis and neurodegenerative diseas-
es: Therapeutic modulation via fumaric acid esters. Int J
Mol Sci 2012; 13: 11783–11803.
13 Zhuang C, Miao Z, Sheng C, Zhang W. Updated research
and applications of small molecule inhibitors of Keap1-
Nrf2 protein-protein interaction: a review. Curr Med Chem
2014; 16. DOI: 10.2174/0929867321666140217104648.
14 Lee JW, Bae CJ, Choi YJ, Kim SI, Kwon YS, Lee HJ, Kim
SS, Chun W. 3,4,5-Trihydroxycinnamic acid inhibits lipo-
polysaccharide (LPS)-induced inflammation by Nrf2 acti-
vation in vitro and improves survival of mice in LPS-in-
duced endotoxemia model in vivo. Mol Cell Biochem
2014; 390: 143–153.
15 Pedruzzi LM, Stockler-Pinto MB, Leite M Jr, Mafra D.
Nrf2-keap1 system versus NF-κB: the good and the evil in
chronic kidney disease? Biochimie 2012; 94: 2461–2466.
16 Kim J, Cha YN, Surh YJ. A protective role of nuclear fac-
tor-erythroid 2-related factor-2 (Nrf2) in inflammatory dis-
orders. Mutat Res 2010; 690: 12–23.
17 Wang W, Wu Y, Fang H, Wang H, Zang H, Xie T, Wang W.
Activation of Nrf2-ARE signal pathway protects the brain
from damage induced by epileptic seizure. Brain Res 2014;
1544: 54–61.
18 Mazzuferi M, Kumar G, van Eyll J, Danis B, Foerch P, Ka-
minski RM. Nrf2 defense pathway: Experimental evidence
for its protective role in epilepsy. Ann Neurol 2013; 74:
560–568.
19 Loboda A, Rojczyk-Golebiewska E, Bednarczyk-Cwynar
B, Lucjusz Z, Jozkowicz A, Dulak J. Targeting Nrf2-medi-
ated gene transcription by triterpenoids and their deriva-
tives. Biomol Ther (Seoul) 2012; 20: 499–505.
20 Vomhof-Dekrey EE, Picklo MJ Sr. The Nrf2-antioxidant
response element pathway: a target for regulating energy
metabolism. J Nutr Biochem 2012; 23: 1201–1206.
21 Cho HY, Kleeberger SR. Nrf2 protects against airways dis-
orders. Toxicol Appl Pharmacol 2010; 244: 43–56.
22 Reuland DJ, McCord JM, Hamilton KL. The role of Nrf2
in the attenuation of cardiovascular disease. Exerc Sport
Sci Rev 2013; 41: 162–168.
23 Liby KT, Sporn MB. Synthetic oleanane triterpenoids:
multifunctional drugs with a broad range of applications
for prevention and treatment of chronic disease. Pharmacol
Rev 2012; k64: 972–1003.
24 Bergström P, von Otter M, Nilsson S, Nilsson AC, Nilsson
M, Andersen PM, Hammarsten O, Zetterberg H. Associa-
tion of NFE2L2 and KEAP1 haplotypes with amyotrophic
lateral sclerosis. Amyotroph Lateral Scler Frontotemporal
Degener 2014; 15: 130–137.
25 Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fry-
er AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN,
Biswal S. Disruption of Nrf2 enhances susceptibility to se-
vere airway inflammation and asthma in mice. J Exp Med
2005; 202: 47–59.
26 Kim JH, Choi YK, Lee KS, Cho DH, Baek YY, Lee DK,
Ha KS, Choe J, Won MH, Jeoung D, Lee H, Kwon YG,
Kim YM. Functional dissection of Nrf2-dependent phase II
genes in vascular inflammation and endotoxic injury using
Keap1 siRNA. Free Radic Biol Med 2012; 53: 629–640.
27 Jiang T, Tian F, Zheng H, Whitman SA, Lin Y, Zhang Z,
Zhang N, Zhang DD. Nrf2 suppresses lupus nephritis
through inhibition of oxidative injury and the NF-κB-me-
diated inflammatory response. Kidney Int 2014; 85: 333–
343.
28 Fragoulis A, Laufs J, Müller S, Soppa U, Siegl S, Reiss
LK, Tohidnezhad M, Rosen C, Tenbrock K, Varoga D, Lip-
pross S, Pufe T, Wruck CJ. Sulforaphane has opposing ef-
fects on TNF-alpha stimulated and unstimulated synov-
iocytes. Arthritis Res Ther 2012; 27;14(5): R220.
29 Tsai PY, Ka SM, Chang JM, Lai JH, Dai MS, Jheng HL,
Kuo MT, Chen P, Chen A. Antroquinonol differentially
modulates T cell activity and reduces interleukin-18 pro-
duction, but enhances Nrf2 activation, in murine accelerat-
ed severe lupus nephritis. Arthritis Rheum 2012; 64: 232–
242.
30 Li B, Cui W, Liu J, Li R, Liu Q, Xie XH, Ge XL, Zhang J,
Song XJ, Wang Y, Guo L. Sulforaphane ameliorates the
development of experimental autoimmune encephalomy-
elitis by antagonizing oxidative stress and Th17-related in-
flammation in mice. Exp Neurol 2013; 250: 239–249.
31 Yalniz M, Demirel U, Orhan C, Bahcecioglu IH, Ozercan
IH, Aygun C, Tuzcu M, Sahin K. Nadroparin sodium acti-
vates Nrf2/HO-1 pathway in acetic acid-induced colitis in
rats. Inflammation 2012; 35: 1213–1221.
32 Scofield VL, Yan M, Kuang X, Kim SJ, Wong PK. The
drug monosodium luminol (GVT) preserves crypt-villus
epithelial organization and allows survival of intestinal T
cells in mice infected with the ts1 retrovirus. Immunol Lett
14. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–1814
2009; 122: 150–158.
33 Wang W, Wang WP, Zhang GL, Wu YF, Xie T, Kan MC,
Fang HB, Wang HC. Activation of Nrf2-ARE signal path-
way in hippocampus of amygdala kindling rats. Neurosci
Lett 2013; 543: 58–63.
34 Milder JB, Liang LP, Patel M. Acute oxidative stress and
systemic Nrf2 activation by the ketogenic diet. Neurobiol
Dis 2010; 40: 238–244.
35 Macari ER, Lowrey CH. Induction of human fetal hemo-
globin via the NRF2 antioxidant response signaling path-
way. Blood 2011; 117: 5987–5997.
36 Olagnier D, Lavergne RA, Meunier E, Lefèvre L,
Dardenne C, Aubouy A, Benoit-Vical F, Ryffel B, Coste A,
Berry A, Pipy B. Nrf2, a PPARγ alternative pathway to
promote CD36 expression on inflammatory macrophages:
implication for malaria. PLoS Pathog 2011; 7(9):
e1002254.
37 Jin W, Ming X, Hou X, Zhu T, Yuan B, Wang J, Ni H, Ji-
ang J, Wang H, Liang W. Protective effects of erythropoie-
tin in traumatic spinal cord injury by inducing the Nrf2
signaling pathway activation. J Trauma Acute Care Surg
2014; 76: 1228–1234.
38 Jin W, Wang H, Yan W, Zhu L, Hu Z, Ding Y, Tang K. Role
of Nrf2 in protection against traumatic brain injury in mice.
J Neurotrauma 2009; 26: 131–139.
39 Jin W, Zhu L, Guan Q, Chen G, Wang QF, Yin HX, Hang
CH, Shi JX, Wang HD. Influence of Nrf2 genotype on pul-
monary NF-kappaB activity and inflammatory response af-
ter traumatic brain injury. Ann Clin Lab Sci 2008; 38: 221–
227.
40 Sharma NK, Sethy NK, Meena RN, Ilavazhagan G, Das M,
Bhargava K. Activity-dependent neuroprotective protein
(ADNP)-derived peptide (NAP) ameliorates hypobaric hy-
poxia induced oxidative stress in rat brain. Peptides 2011;
32: 1217–1224.
41 Lisk C, McCord J, Bose S, Sullivan T, Loomis Z,
Nozik-Grayck E, Schroeder T, Hamilton K, Irwin DC. Nrf2
activation: a potential strategy for the prevention of acute
mountain sickness. Free Radic Biol Med 2013; 63: 264–
273.
42 Martín-de-Saavedra MD, Budni J, Cunha MP, Gómez-Ran-
gel V, Lorrio S, Del Barrio L, Lastres-Becker I, Parada E,
Tordera RM, Rodrigues AL, Cuadrado A, López MG. Nrf2
participates in depressive disorders through an anti-inflam-
matory mechanism. Psychoneuroendocrinology 2013; 38:
2010–2022.
43 Maes M, Fišar Z, Medina M, Scapagnini G, Nowak G,
Berk M. New drug targets in depression: inflammatory,
cell-mediated immune, oxidative and nitrosative stress, mi-
tochondrial, antioxidant, and neuroprogressive pathways.
And new drug candidates--Nrf2 activators and GSK-3 in-
hibitors. Inflammopharmacology 2010; 2012; 20: 127–150.
44 Shirai Y, Fujita Y, Hashimoto K. Effects of the antioxidant
sulforaphane on hyperlocomotion and prepulse inhibition
deficits in mice after phencyclidine administration. Clin
Psychopharmacol Neurosci 2012; 10: 94–98.
45 Rizak J, Tan H, Zhu H, Wang JF. Chronic treatment with
the mood-stabilizing drug lithium up-regulates nuclear fac-
tor E2-related factor 2 in rat pheochromocytoma PC12
cells in vitro. Neuroscience 2014; 256: 223–229.
46 Shibuya A, Onda K, Kawahara H, Uchiyama Y, Nakayama
H, Omi T, Nagaoka M, Matsui H, Hirano T. Sofalcone, a
gastric mucosa protective agent, increases vascular endo-
thelial growth factor via the Nrf2-heme-oxygenase-1 de-
pendent pathway in gastric epithelial cells. Biochem Bio-
phys Res Commun 2010; 398: 581–584.
47 Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M,
Kamiya Y, Fujita H, Hasegawa S, Takagi T, Wang FY, Hi-
rata I, Nakano H. The relationship between Helicobacter
pylori infection and promoter polymorphism of the Nrf2
gene in chronic gastritis. Int J Mol Med 2007; 19: 143–148.
48 Himori N, Yamamoto K, Maruyama K, Ryu M, Taguchi K,
Yamamoto M, Nakazawa T. Critical role of Nrf2 in oxida-
tive stress-induced retinal ganglion cell death. J Neuro-
chem 2013; 127: 669–680.
49 Wang L, Cano M, Handa JT. p62 provides dual cytoprotec-
tion against oxidative stress in the retinal pigment epitheli-
um. Biochim Biophys Acta 2014; 1843: 1248–1258.
50 Varma SD, Chandrasekaran K, Kovtun S. Sulforaphane-in-
duced transcription of thioredoxin reductase in lens: possi-
ble significance against cataract formation. Clin Ophthal-
mol 2013; 7: 2091–2098.
51 Liu H, Smith AJ, Lott MC, Bao Y, Bowater RP, Reddan JR,
Wormstone IM. Sulforaphane can protect lens cells against
oxidative stress: implications for cataract prevention. In-
vest Ophthalmol Vis Sci 2013; 54: 5236–5248.
52 Schachtele SJ, Hu S, Lokensgard JR. Modulation of exper-
imental herpes encephalitis-associated neurotoxicity
through sulforaphane treatment. PLoS One 2012; 7(4):
e36216.
53 Clarke JD, Hsu A, Yu Z, Dashwood RH, Ho E. Differential
effects of sulforaphane on histone deacetylases, cell cycle
arrest and apoptosis in normal prostate cells versus hyper-
plastic and cancerous prostate cells. Mol Nutr Food Res
2011; 55: 999–1009.
54 Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E. Sul-
foraphane inhibits histone deacetylase activity in BPH-1,
LnCaP and PC-3 prostate epithelial cells. Carcinogenesis
2006; 27: 811–819.
55 Mathew ST, Bergström P, Hammarsten O. Repeated Nrf2
15. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 15
stimulation using sulforaphane protects fibroblasts from
ionizing radiation. Toxicol Appl Pharmacol 2014; 276:
188–194.
56 Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST,
Ward KW. Topical application of the synthetic triterpenoid
RTA 408 protects mice from radiation-induced dermatitis.
Radiat Res 2014; 181: 512–520.
57 El Ali Z, Gerbeix C, Hemon P, Esser PR, Martin SF, Pal-
lardy M, Kerdine-Römer S. Allergic skin inflammation in-
duced by chemical sensitizers is controlled by the tran-
scription factor Nrf2. Toxicol Sci 2013; 134: 39–48.
58 van der Veen JW, Gremmer ER, Vermeulen JP, van Lov-
eren H, Ezendam J. Induction of skin sensitization is aug-
mented in Nrf2-deficient mice. Arch Toxicol 2013; 87:
763–766.
59 Lu J, Holmgren A. The thioredoxin antioxidant system.
Free Radic Biol Med 2014; 66: 75–87.
60 Wu KC, Liu JJ, Klaassen CD. Nrf2 activation prevents
cadmium-induced acute liver injury. Toxicol Appl Pharma-
col 2012; 263: 14–20.
61 Sears ME. Chelation: harnessing and enhancing heavy
metal detoxification--a review. ScientificWorldJournal
2013; 2013: 219840.
62 Yang CC, Chen HI, Chiu YW, Tsai CH, Chuang HY.
Metallothionein 1A polymorphisms may influence urine
uric acid and N-acetyl-beta-D-glucosaminidase (NAG) ex-
cretion in chronic lead-exposed workers. Toxicology 2013;
306: 68–73.
63 Toyama T, Shinkai Y, Yasutake A, Uchida K, Yamamoto M,
Kumagai Y. Isothiocyanates reduce mercury accumulation
via an Nrf2-dependent mechanism during exposure of mice
to methylmercury. Environ Health Perspect 2011; 119:
1117–1122.
64 García-Niño WR, Pedraza-Chaverrí J. Protective effect of
curcumin against heavy metals-induced liver damage. Food
Chem Toxicol 2014; 69: 182–201
65 Mo C, Wang L, Zhang J, Numazawa S, Tang H, Tang X,
Han X, Li J, Yang M, Wang Z, Wei D, Xiao H. The cross-
talk between Nrf2 and AMPK signal pathways is important
for the anti-inflammatory effect of berberine in LPS-stimu-
lated macrophages and endotoxin-shocked mice. Antioxid
Redox Signal 2014; 20: 574–588.
66 Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øver-
vatn A, McMahon M, Hayes JD, Johansen T. p62/SQSTM1
is a target gene for transcription factor NRF2 and creates a
positive feedback loop by inducing antioxidant response
element-driven gene transcription. J Biol Chem 2010; 285:
22576–22591.
67 Nezis IP, Stenmark H. p62 at the interface of autophagy,
oxidative stress signaling, and cancer. Antioxid Redox Sig-
nal 2012; 17: 786–793.
68 Artaud-Macari E, Goven D, Brayer S, Hamimi A, Besnard
V, Marchal-Somme J, Ali ZE, Crestani B, Kerdine-Römer
S, Boutten A, Bonay M. Nuclear factor erythroid 2-related
factor 2 nuclear translocation induces myofibroblastic de-
differentiation in idiopathic pulmonary fibrosis. Antioxid
Redox Signal 2013; 18: 66–79.
69 Oh CJ, Kim JY, Min AK, Park KG, Harris RA, Kim HJ,
Lee IK. Sulforaphane attenuates hepatic fibrosis via
NF-E2-related factor 2012; 2-mediated inhibition of trans-
forming growth factor-β/Smad signaling. Free Radic Biol
Med 2012; 52: 671–682.
70 Ryoo IG, Ha H, Kwak MK. Inhibitory role of the KEAP1-
NRF2 pathway in TGFβ1-stimulated renal epithelial transi-
tion to fibroblastic cells: a modulatory effect on SMAD
signaling. PLoS One 2014; 9(4): e93265.
71 Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Ber-
nard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ.
Reversal of persistent fibrosis in aging by targeting Nox4-
Nrf2 redox imbalance. Sci Transl Med 2014; 6(231):
231ra47.
72 Hsieh TC, Elangovan S, Wu JM. Differential suppression
of proliferation in MCF-7 and MDA-MB-231 breast cancer
cells exposed to alpha-, gamma- and delta-tocotrienols is
accompanied by altered expression of oxidative stress
modulatory enzymes. Anticancer Res 2010; 30: 4169–
4176.
73 Smolarek AK, So JY, Thomas PE, Lee HJ, Paul S, Dom-
browski A, Wang CX, Saw CL, Khor TO, Kong AN, Reuhl
K, Lee MJ, Yang CS, Suh N. Dietary tocopherols inhibit
cell proliferation, regulate expression of ERα, PPARγ, and
Nrf2, and decrease serum inflammatory markers during the
development of mammary hyperplasia. Mol Carcinog
2013; 52: 514–525.
74 Ho CY, Cheng YT, Chau CF, Yen GC. Effect of diallyl sul-
fide on in vitro and in vivo Nrf2-mediated pulmonic antiox-
idant enzyme expression via activation ERK/p38 signaling
pathway. J Agric Food Chem 2012; 60: 100–107.
75 Colín-González AL, Santana RA, Silva-Islas CA,
Chánez-Cárdenas ME, Santamaría A, Maldonado PD. The
antioxidant mechanisms underlying the aged garlic extract-
and S-allylcysteine-induced protection. Oxid Med Cell
Longev 2012; 2012: 907162
76 Yang CM, Huang SM, Liu CL, Hu ML. Apo-8’-lycopenal
induces expression of HO-1 and NQO-1 via the ERK/p38-
Nrf2-ARE pathway in human HepG2 cells. J Agric Food
Chem 2012; 60: 1576–1585.
77 Linnewiel K, Ernst H, Caris-Veyrat C, Ben-Dor A, Kampf
A, Salman H, Danilenko M, Levy J, Sharoni Y. Structure
activity relationship of carotenoid derivatives in activation
16. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–1816
of the electrophile/antioxidant response element transcrip-
tion system. Free Radic Biol Med 2009; 47: 659–667.
78 Zhang M, Wang S, Mao L, Leak RK, Shi Y, Zhang W, Hu
X, Sun B, Cao G, Gao Y, Xu Y, Chen J, Zhang F. Omega-3
fatty acids protect the brain against ischemic injury by acti-
vating Nrf2 and upregulating heme oxygenase 1. J Neuros-
ci 2014; 34: 1903–1915.
79 Nakagawa F, Morino K, Ugi S, Ishikado A, Kondo K, Sato
D, Konno S, Nemoto K, Kusunoki C, Sekine O, Sunagawa
A, Kawamura M, Inoue N, Nishio Y, Maegawa H. 4-Hy-
droxy hexenal derived from dietary n-3 polyunsaturated
fatty acids induces anti-oxidative enzyme heme oxygen-
ase-1 in multiple organs. Biochem Biophys Res Commun
2014; 443: 991–996.
80 Maher J, Yamamoto M. The rise of antioxidant signaling—
The evolution and hormetic actions of Nrf2. Toxicol Appl
Pharmacol 2010; 244: 4–15.
81 Sontag TJ, Parker RS. Influence of major structural fea-
tures of tocopherols and tocotrienols on their omega-oxida-
tion by tocopherol-omega-hydroxylase. J Lipid Res 2007;
48: 1090–1098.
82 Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Ya-
mamoto M, Biswal S. Identification of Nrf2-regulated
genes induced by the chemopreventive agent sulforaphane
by oligonucleotide microarray. Cancer Res 2002; 62:
5196–5203.
83 Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yama-
moto M, Kensler TW. Modulation of gene expression by
cancer chemopreventive dithiolethiones through the
Keap1-Nrf2 pathway. Identification of novel gene clusters
for cell survival. J Biol Chem 2003; 278: 8135–8145.
84 McMahon M, Itoh K, Yamamoto M, Chanas SA, Hender-
son CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD. The
Cap ‘n’Collar basic leucine zipper transcription factor Nrf2
(NF-E2 p45-related factor 2) controls both constitutive and
inducible expression of intestinal detoxification and gluta-
thione biosynthetic enzymes. Cancer Res 2001; 61: 3299–
3307.
85 Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto
M, Zhang LY, Kleeberger SR. Role of NRF2 in protection
against hyperoxic lung injury in mice. Am J Respir Cell
Mol Biol 2002; 26: 175–182.
86 Itoh K, Tong K, Yamamoto M. Molecular mechanism acti-
vating Nrf2-Keap1 pathway in regulation of adaptive re-
sponse to electrophiles. Free Radic Biol Med 2004; 36:
1208–1213.
87 Nair S1, Xu C, Shen G, Hebbar V, Gopalakrishnan A, Hu
R, Jain MR, Liew C, Chan JY, Kong AN. Pharmacogenom-
ics of phenolic antioxidant butylated hydroxyanisole
(BHA) in the small intestine and liver of Nrf2 knockout
and C57BL/6J mice. Pharm Res 2006; 23: 2621–2637.
88 Wang H, Khor TO, Saw CL, Lin W, Wu T, Huang Y, Kong
AN. Role of Nrf2 in suppressing LPS-induced inflamma-
tion in mouse peritoneal macrophages by polyunsaturated
fatty acids docosahexaenoic acid and eicosapentaenoic
acid. Mol Pharm 2010; 7: 2185–2193.
89 Gerhäuser C, Klimo K, Hümmer W, Hölzer J, Petermann
A, Garreta-Rufas A, Böhmer FD, Schreier P. Identification
of 3-hydroxy-beta-damascone and related carotenoid-de-
rived aroma compounds as novel potent inducers of
Nrf2-mediated phase 2 response with concomitant anti-in-
flammatory activity. Mol Nutr Food Res 2009; 53: 1237–
1244.
90 Martín-Montalvo A, Villalba JM, Navas P, de Cabo R.
NRF2, cancer and calorie restriction. Oncogene 2011; 30:
505–520.
91 Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cas-
cajo MV, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z,
Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram
DK, Navas P, de Cabo R. Nrf2 mediates cancer protection
but not prolongevity induced by caloric restriction. Proc
Natl Acad Sci U S A 2008; 105: 2325–2330.
92 Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R.
Mechanisms underlying caloric restriction and lifespan
regulation: implications for vascular aging. Circ Res 2008;
102: 519–528.
93 Velmurugan K, Alam J, McCord JM, Pugazhenthi S. Syn-
ergistic induction of heme oxygenase-1 by the components
of the antioxidant supplement Protandim. Free Radic Biol
Med 2009; 46: 430–440.
94 Yaku K, Enami Y, Kurajyo C, Matsui-Yuasa I, Konishi Y,
Kojima-Yuasa A. The enhancement of phase 2 enzyme ac-
tivities by sodium butyrate in normal intestinal epithelial
cells is associated with Nrf2 and p53. Mol Cell Biochem
2012; 370: 7–14.
95 Cipollina C, Salvatore SR, Muldoon MF, Freeman BA,
Schopfer FJ. Generation and dietary modulation of anti-in-
flammatory electrophilic omega-3 Fatty Acid derivatives.
PLoS One 2014; 9(4): e94836.
96 Willcox DC, Willcox BJ, Todoriki H, Suzuki M. The Oki-
nawan diet: health implications of a low-calorie, nutri-
ent-dense, antioxidant-rich dietary pattern low in glycemic
load. J Am Coll Nutr 2009; 28 Suppl: 500S-516S.
97 Murakami A, Ishida H, Kobo K, Furukawa I, Ikeda Y, Yo-
naha M, Aniya Y, Ohigashi H. Suppressive effects of Oki-
nawan food items on free radical generation from stimu-
lated leukocytes and identification of some active
constituents: implications for the prevention of inflamma-
tion-associated carcinogenesis. Asian Pac J Cancer Prev
2005; 6: 437–448.
17. Martin L Pall et al.: Nrf2, Master Cytoprotection & Detoxification Regulator, is Raised by Many Health Promoting Factors 17
98 Suzuki M, Wilcox BJ, Wilcox CD. Implications from and
for food cultures for cardiovascular disease: longevity. Asia
Pac J Clin Nutr 2001; 10: 165–171.
99 Kafatos A, Verhagen H, Moschandreas J, Apostolaki I, Van
Westerop JJ. Mediterranean diet of Crete: foods and nutri-
ent content. J Am Diet Assoc 2000; 100: 1487–1493.
100 Manios Y, Detopoulou V, Visioli F, Galli C. Mediterranean
diet as a nutrition education and dietary guide: misconcep-
tions and the neglected role of locally consumed foods and
wild green plants. Forum Nutr 2006; 59: 154–170.
101 Willett WC, Sacks F, Trichopoulou A, Drescher G, Fer-
ro-Luzzi A, Helsing E, Trichopoulos D. Mediterranean diet
pyramid: a cultural model for healthy eating. Am J Clin
Nutr 1995; 1(6 Suppl): 1402S–1406S.
102 Simopoulos AP. 2001 The Mediterranean diets: What is so
special about the diet of Greece? The scientific evidence. J
Nutr 2001; 131(11 Suppl): 3065S-3073S.
103 Salen P, de Lorgeril M. The Okinawan diet: a modern view
of an ancestral healthy lifestyle. World Rev Nutr Diet 2011;
102: 114–123.
104 Simopoulos AP. Omega-3 fatty acids and antioxidants in
edible wild plants. Biol Res 2004; 37: 263–277.
105 Lewis KN, Mele J, Hayes JD, Buffenstein R. Nrf2, a
guardian of healthspan and gatekeeper of species longevity.
Integr Comp Biol 2010; 50: 829–843.
106 Kapeta S, Chondrogianni N, Gonos ES. Nuclear erythroid
factor 2-mediated proteasome activation delays senescence
in human fibroblasts. J Biol Chem 2010; 285: 8171–8184.
107 Jódar L, Mercken EM, Ariza J, Younts C, González-Reyes
JA, Alcaín FJ, Burón I, de Cabo R, Villalba JM. Genetic
deletion of Nrf2 promotes immortalization and decreases
life span of murine embryonic fibroblasts. J Gerontol A
Biol Sci Med Sci 2011; 66: 247–256.
108 Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H,
Nakayama K, Nakayama KI, Ide T, Saya H, Hara E. Mito-
genic signalling and the p16INK4a-Rb pathway cooperate
to enforce irreversible cellular senescence. Nat Cell Biol
2006; 8: 1291–1297.
109 Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2-an
update. Free Radic Biol Med 2014; 66: 36–44.
110 Narasimhan M, Patel D, Vedpathak D, Rathinam M, Hen-
derson G, Mahimainathan L. Narasimhan M1, Patel D,
Vedpathak D, Rathinam M, Henderson G, Mahimainathan
L. PLoS One 2012; 7(12): e51111.
111 Eades G, Yang M, Yao Y, Zhang Y, Zhou Q. miR-200a reg-
ulates Nrf2 activation by targeting Keap1 mRNA in breast
cancer cells. J Biol Chem 2011; 286: 40725–40733.
112 Sun Z, Chin YE, Zhang DD. Acetylation of Nrf2 by p300/
CBP augments promoter-specific DNA binding of Nrf2
during the antioxidant response. Mol Cell Biol 2009; 29:
2658–2672.
113 Seymour EM, Bennink MR, Bolling SF. Diet-relevant phy-
tochemical intake affects the cardiac AhR and Nrf2 tran-
scriptome and reduces heart failure in hypertensive rats. J
Nutr Biochem 2013; 24: 1580–1586.
114 Astort F, Mercau M, Giordanino E, Degese MS, Caldareri
L, Coso O, Cymeryng CB. Nitric oxide sets off an antioxi-
dant response in adrenal cells: involvement of sGC and
Nrf2 in HO-1 induction. Nitric Oxide 2014; 37: 1–10.
115 Kim SK, Joe Y, Zheng M, Kim HJ, Yu JK, Cho GJ, Chang
KC, Kim HK, Han J, Ryter SW, Chung HT. Resveratrol in-
duces hepatic mitochondrial biogenesis through the se-
quential activation of nitric oxide and carbon monoxide
production. Antioxid Redox Signal 2014; 20: 2589–2605.
116 Liu XM, Peyton KJ, Wang X, Durante W. Sildenafil stimu-
lates the expression of gaseous monoxide-generating en-
zymes in vascular smooth muscle cells via distinct signal-
ing pathways. Biochem Pharmacol 2012; 84: 1045–1054.
117 Chung HT, Choi BM, Kwon YG, Kim YM. Interactive re-
lations between nitric oxide (NO) and carbon monoxide
(CO): heme oxygenase-1/CO pathway is a key modulator
in NO-mediated antiapoptosis and anti-inflammation.
Methods Enzymol 2008; 441: 329–338.
118 Rochette L, Cottin Y, Zeller M, Vergely C. Carbon monox-
ide: mechanisms of action and potential clinical implica-
tions. Pharmacol Ther 2013; 137: 133–152.
119 Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme
oxygenase-1 through MAPK pathway. Arch Biochem Bio-
phys 2004; 432: 252–260.
120 Ho CY, Cheng YT, Chau CF, Yen GC. Effect of diallyl sul-
fide on in vitro and in vivo Nrf2-mediated pulmonic antiox-
idant enzyme expression via activation ERK/p38 signaling
pathway. J Agric Food Chem 2012; 60: 100–107.
121 Amakura Y1, Tsutsumi T, Nakamura M, Kitagawa H, Fuji-
no J, Sasaki K, Toyoda M, Yoshida T, Maitani T. Activation
of the aryl hydrocarbon receptor by some vegetable con-
stituents determined using in vitro reporter gene assay. Biol
Pharm Bull 2003; 26: 532–539.
122 Mansuri ML, Parihar P, Solanki I, Parihar MS. Flavonoids
in modulation of cell survival signalling pathways. Genes
Nutr 2014; 9(3): 400.
123 Saw CL, Yang AY, Guo Y, Kong AN. Astaxanthin and
omega-3 fatty acids individually and in combination pro-
tect against oxidative stress via the Nrf2-ARE pathway.
Food Chem Toxicol 2013; 62: 869–875.
124 Schäfer M, Willrodt AH, Kurinna S, Link AS, Farwanah H,
Geusau A, Gruber F, Sorg O, Huebner AJ, Roop DR, Sand-
hoff K, Saurat JH, Tschachler E, Schneider MR, Langbein
L, Bloch W, Beer HD, Werner S. Activation of Nrf2 in ke-
ratinocytes causes chloracne (MADISH)-like skin disease
18. Acta Physiologica Sinica, February 25, 2015, 67(1): 1–1818
in mice. EMBO Mol Med 2014; 6: 442–457.
125 Tan NS, Wahli W. The emerging role of Nrf2 in dermato-
toxicology. EMBO Mol Med 2014; 6: 431–433.
126 Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H,
Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F,
Roop DR, Harada T, Engel JD, Yamamoto M. Keap1-null
mutation leads to postnatal lethality due to constitutive
Nrf2 activation. Nat Genet 2003; 35: 238–245.
127 Rajasekaran NS, Varadharaj S, Khanderao GD, Davidson
CJ, Kannan S, Firpo MA, Zweier JL, Benjamin IJ. Sus-
tained activation of nuclear erythroid 2-related factor 2/an-
tioxidant response element signaling promotes reductive
stress in the human mutant protein aggregation cardiomy-
opathy in mice. Antioxid Redox Signal 2011; 14: 957–971.
128 Rajasekaran NS, Connell P, Christians ES, Yan LJ, Taylor
RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leo-
pold JA, Barry WH, Loscalzo J, Odelberg SJ, Benjamin IJ.
Human alpha Β-crystallin mutation causes oxido-reductive
stress and protein aggregation cardiomyopathy in mice.
Cell 2007; 130: 427–439.
129 Slocum SL, Kensler TW. Nrf2: control of sensitivity to
carcinogens. Arch Toxicol 2011; 85: 273–284.
130 Zhao C, Gillette DD, Li X, Zhang Z, Wen H. Nuclear fac-
tor E2-related factor-2 (Nrf2) is required for NLRP3 and
AIM2 inflammasome activation. J Biol Chem 2014;
289(24): 17020–17009.
131 Pall ML. Explaining ‘Unexplained Illness’: Disease Para-
digm for Chronic Fatigue Syndrome, Multiple Chemical
Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder,
Gulf War Syndrome and Others. New York: Harrington
Park (Haworth) Press, 2007.
132 Pall ML. Teufelskreis NO/ONOO–
-Zyklus, oxidaver stress,
mitochondriale, inflammatorische und neurologische dys-
funktion. Umw Med Ges 2010; 23: 281–293.
133 Pall ML. Pulmonary hypertension is a probable NO/
ONOO–
cycle disease: A review. ISRN Hypertension 2013:
Article ID 742418, 27 pages.
134 Pall ML. The NO/ONOO−
cycle as the central cause of
heart failure. Int J Mol Sci 2013; 14: 22274–22330.
135 Pall ML. Is open-angle glaucoma caused by the NO/
ONOO−
cycle acting at two locations in the eye? Med Hy-
pothesis Discov Innov Ophthalmol 2014; 4 : 1–2.
136 Nada SE, Shah ZA. Preconditioning with Ginkgo biloba
(EGb 761®) provides neuroprotection through HO1 and
CRMP2. Neurobiol Dis 2012; 46: 180–189.
137 Shah ZA, Li RC, Ahmad AS, Kensler TW, Yamamoto M,
Biswal S, Doré S. The flavanol (−)-epicatechin prevents
stroke damage through the Nrf2/HO1 pathway. J Cereb
Blood Flow Metab 2010; 30: 1951–1961.
138 Nakamura T, Lipton SA. Preventing Ca2+
-mediated nitrosa-
tive stress in neurodegenerative diseases: possible pharma-
cological strategies. Cell Calcium 2010; 47: 190–197.
139 Lee JM, Shih AY, Murphy TH, Johnson JA. NF-E2-related
factor-2 mediates neuroprotection against mitochondrial
complex I inhibitors and increased concentrations of intra-
cellular calcium in primary cortical neurons. J Biol Chem
2003; 278: 37948–37956.
140 Mukhopadhyay S, Sekhar KR, Hale AB, Channon KM,
Farrugia G, Freeman ML, Gangula PR. Loss of NRF2 im-
pairs gastric nitrergic stimulation and function. Free Radic
Biol Med 2011; 51: 619–625.
141 Watson JD. Type 2 diabetes as a redox disease. Lancet
2014; 383: 841–843.