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Too much nrf2

All life is challenged by oxidants -- reactive molecules or compounds that remove electrons from other molecules -- often with adverse effect, commonly referred to as oxidative stress. Consequently, all organisms have evolved specialized antioxidant defenses. NRF2 Nuclear factor erythroid 2-related factor 2 is the master regulator of the antioxidant response. NRF2 levels subsequently build within the cell with the protein entering the nucleus, where it stimulates expression of numerous genes that code for enzymes and other proteins that detoxify harmful oxidants.

Many such compounds are being sold at health food stores as anti-aging remedies. But research in recent years has found that several cancers, including liver and lung cancers, harbor mutations that decouple NRF2 from KEAP1, suggesting that persistent NRF2 activation may not be such a good thing after all. Some researchers now believe cancer cells may actually use NRF2 to protect themselves from radiation and chemotherapeutics. Using a new mouse model whose liver cells express a KEAP1-resistant form of NRF2, Karin and collaborators found that persistent activation of NRF2 in these mice resulted in rapid and dramatic enlargement of the liver, known as hepatomegaly.

In humans, hepatomegaly can appear after insulin overdosing, exposure to various toxins, certain viral and bacterial infections or as an indicator of an underlying disease, such as cirrhosis and liver cancer.

Because NRF2-induced hepatomegaly is similar to insulin-induced hepatomegaly, which relies upon activation of a protein kinase called AKT, the research team investigated the involvement of insulin and AKT in NRF2-induced hepatomegaly. Although no evidence for excessive insulin production was uncovered, the scientists found that AKT otherwise known as Protein kinase B was activated in livers expressing the degradation-resistant form of NRF2. The scientists also discovered that inhibiting AKT produced complete reversal of hepatomegaly and rapid restoration of normal liver size and physiology in the mice.

Working with co-corresponding author Beicheng Sun, MD, a liver surgeon at Nanjing University Medical School in China, the team also reported that human hepatomegaly that is caused by either toxin exposure or autoimmune hepatitis also entails NRF2 activation, enhanced growth factor signaling and stimulation of AKT activity. In addition to liver enlargement, the scientists said persistent NRF2 activation produced excessive fat and glycogen accumulation, suggesting that NRF2 may also be involved in fatty liver disease, such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis -- common metabolic disorders affecting millions of Americans.

The new findings, said Karin, suggest that AKT inhibitors, some of which have already been evaluated in humans for their anti-cancer activity, may be effective in the treatment and reversal of hepatomegaly, which affects more than million persons worldwide.

WeightLifters and Athletes Nrf2 Synergizer

Skip to main content. Too much of a good thing may lead to too much of a liver as well All life is challenged by oxidants -- reactive molecules or compounds that remove electrons from other molecules -- often with adverse effect, commonly referred to as oxidative stress.All life is challenged by oxidants — reactive molecules or compounds that remove electrons from other molecules — often with adverse effect, commonly referred to as oxidative stress.

Consequently, all organisms have evolved specialized antioxidant defenses. NRF2 Nuclear factor erythroid 2-related factor 2 is the master regulator of the antioxidant response.

NRF2 levels subsequently build within the cell with the protein entering the nucleus, where it stimulates expression of numerous genes that code for enzymes and other proteins that detoxify harmful oxidants. Many such compounds are being sold at health food stores as anti-aging remedies.

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But research in recent years has found that several cancers, including liver and lung cancers, harbor mutations that decouple NRF2 from KEAP1, suggesting that persistent NRF2 activation may not be such a good thing after all. Some researchers now believe cancer cells may actually use NRF2 to protect themselves from radiation and chemotherapeutics.

Using a new mouse model whose liver cells express a KEAP1-resistant form of NRF2, Karin and collaborators found that persistent activation of NRF2 in these mice resulted in rapid and dramatic enlargement of the liver, known as hepatomegaly. In humans, hepatomegaly can appear after insulin overdosing, exposure to various toxins, certain viral and bacterial infections or as an indicator of an underlying disease, such as cirrhosis and liver cancer. Because NRF2-induced hepatomegaly is similar to insulin-induced hepatomegaly, which relies upon activation of a protein kinase called AKT, the research team investigated the involvement of insulin and AKT in NRF2-induced hepatomegaly.

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Although no evidence for excessive insulin production was uncovered, the scientists found that AKT otherwise known as Protein kinase B was activated in livers expressing the degradation-resistant form of NRF2. The scientists also discovered that inhibiting AKT produced complete reversal of hepatomegaly and rapid restoration of normal liver size and physiology in the mice. Working with co-corresponding author Beicheng Sun, MD, a liver surgeon at Nanjing University Medical School in China, the team also reported that human hepatomegaly that is caused by either toxin exposure or autoimmune hepatitis also entails NRF2 activation, enhanced growth factor signaling and stimulation of AKT activity.

In addition to liver enlargement, the scientists said persistent NRF2 activation produced excessive fat and glycogen accumulation, suggesting that NRF2 may also be involved in fatty liver disease, such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis — common metabolic disorders affecting millions of Americans.

The new findings, said Karin, suggest that AKT inhibitors, some of which have already been evaluated in humans for their anti-cancer activity, may be effective in the treatment and reversal of hepatomegaly, which affects more than million persons worldwide. Scott LaFee. JavaScript must be enabled to view this email address. Search News Search Search. Search Faculty and Staff Search Search.

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too much nrf2

Posted 27 April - AM. This is an old post but if any of the members are still interested in this topic, Sulforaphane is my research specialty area and I am happy to answer questions. The paper addresses all the issues raised above and more.

Posted 29 April - PM. Eat a radish with the sprouts. It supposedly only takes a little of the radish so even a few small slices might do the job. Community Forum Software by IP. Board Licensed to: ImmInst. Google Sign in options Remember me This is not recommended for shared computers Sign in anonymously Don't add me to the active users list Privacy Policy.

Donate Join Sponsors Store. Started by joelcairoMay 05 AM. Please log in to reply. Isothiocyanates, sulphoraphane and SGS may only be part of the equation? Posted 05 May - PM I can understand your concern and desire to take the supplement, but maybe it would be better just to eat more broccoli and other veggies that have sulphoraphane.

Posted 05 May - PM I do eat cruciferous vegetables every day, but that's a lotta broccoli. Eating broccoli sprouts would be somewhat more efficient, but would still require a certain amount of dedication to the task.

Then there's still the question of how much to eat to register a clinically measurable effect. Indole 3 carbinol and apigenin also look healthful, but based on what I've read my primary interest is sulforaphane. Posted 21 November - AM This is an old post but if any of the members are still interested in this topic, Sulforaphane is my research specialty area and I am happy to answer questions. Informative x 2. Posted 21 November - PM One of the better articles on sulforaphane bioavailability and kinetics is Vermeulen, Martijn, et al.

Its behind a paywall, but here's the graph showing typical uptake from g broccoli containing about Note the near 0. When 0. See Fig 2 in: Kensler, Thomas W. Cruciferous plants likely evolved sulforaphane and the other isothiocyanates to deter insect predation, and at very high doses adverse effects are possible. Shapiro, Theresa A.

Broccoli and broccoli sprout concentrations can vary, but that high dose is equivalent to about 27 cups of broccoli, or a cup of broccoli sprouts.

Sestili, Piero, et al.All life is challenged by oxidants -- reactive molecules or compounds that remove electrons from other molecules -- often with adverse effect, commonly referred to as oxidative stress. Consequently, all organisms have evolved specialized antioxidant defenses. NRF2 Nuclear factor erythroid 2-related factor 2 is the master regulator of the antioxidant response.

NRF2 levels subsequently build within the cell with the protein entering the nucleus, where it stimulates expression of numerous genes that code for enzymes and other proteins that detoxify harmful oxidants. Many such compounds are being sold at health food stores as anti-aging remedies.

But research in recent years has found that several cancers, including liver and lung cancers, harbor mutations that decouple NRF2 from KEAP1, suggesting that persistent NRF2 activation may not be such a good thing after all. Some researchers now believe cancer cells may actually use NRF2 to protect themselves from radiation and chemotherapeutics.

Using a new mouse model whose liver cells express a KEAP1-resistant form of NRF2, Karin and collaborators found that persistent activation of NRF2 in these mice resulted in rapid and dramatic enlargement of the liver, known as hepatomegaly.

In humans, hepatomegaly can appear after insulin overdosing, exposure to various toxins, certain viral and bacterial infections or as an indicator of an underlying disease, such as cirrhosis and liver cancer. Because NRF2-induced hepatomegaly is similar to insulin-induced hepatomegaly, which relies upon activation of a protein kinase called AKT, the research team investigated the involvement of insulin and AKT in NRF2-induced hepatomegaly.

Although no evidence for excessive insulin production was uncovered, the scientists found that AKT otherwise known as Protein kinase B was activated in livers expressing the degradation-resistant form of NRF2. The scientists also discovered that inhibiting AKT produced complete reversal of hepatomegaly and rapid restoration of normal liver size and physiology in the mice.

Working with co-corresponding author Beicheng Sun, MD, a liver surgeon at Nanjing University Medical School in China, the team also reported that human hepatomegaly that is caused by either toxin exposure or autoimmune hepatitis also entails NRF2 activation, enhanced growth factor signaling and stimulation of AKT activity.

In addition to liver enlargement, the scientists said persistent NRF2 activation produced excessive fat and glycogen accumulation, suggesting that NRF2 may also be involved in fatty liver disease, such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis -- common metabolic disorders affecting millions of Americans.

The new findings, said Karin, suggest that AKT inhibitors, some of which have already been evaluated in humans for their anti-cancer activity, may be effective in the treatment and reversal of hepatomegaly, which affects more than million persons worldwide. Skip to main content All life is challenged by oxidants -- reactive molecules or compounds that remove electrons from other molecules -- often with adverse effect, commonly referred to as oxidative stress. T2K insight into the origin of the universe Lancaster University Mouse study shows how advancing glioma cells scramble brain function, blood flow The Zuckerman Institute at Columbia University Unusually clear skies drove record loss of Greenland ice in Earth Institute at Columbia University Researchers develop synthetic scaffolds to heal injured tendons and ligaments University of Sydney View all latest news releases.February 25, All life is challenged by oxidants—reactive molecules or compounds that remove electrons from other molecules—often with adverse effect, commonly referred to as oxidative stress.

Consequently, all organisms have evolved specialized antioxidant defenses. In a new study, published February 24, in the Journal of Hepatologya team of scientists, led by postdoctoral fellows Feng He, Ph.

NRF2 Nuclear factor erythroid 2-related factor 2 is the master regulator of the antioxidant response.

too much nrf2

NRF2 levels subsequently build within the cell with the protein entering the nucleus, where it stimulates expression of numerous genes that code for enzymes and other proteins that detoxify harmful oxidants. Many such compounds are being sold at health food stores as anti-aging remedies. But research in recent years has found that several cancers, including liver and lung cancers, harbor mutations that decouple NRF2 from KEAP1, suggesting that persistent NRF2 activation may not be such a good thing after all.

Some researchers now believe cancer cells may actually use NRF2 to protect themselves from radiation and chemotherapeutics. Using a new mouse model whose liver cells express a KEAP1-resistant form of NRF2, Karin and collaborators found that persistent activation of NRF2 in these mice resulted in rapid and dramatic enlargement of the liver, known as hepatomegaly.

In humans, hepatomegaly can appear after insulin overdosing, exposure to various toxins, certain viral and bacterial infections or as an indicator of an underlying disease, such as cirrhosis and liver cancer. Because NRF2-induced hepatomegaly is similar to insulin-induced hepatomegaly, which relies upon activation of a protein kinase called AKT, the research team investigated the involvement of insulin and AKT in NRF2-induced hepatomegaly.

Although no evidence for excessive insulin production was uncovered, the scientists found that AKT otherwise known as Protein kinase B was activated in livers expressing the degradation-resistant form of NRF2. The scientists also discovered that inhibiting AKT produced complete reversal of hepatomegaly and rapid restoration of normal liver size and physiology in the mice.

Working with co-corresponding author Beicheng Sun, MD, a liver surgeon at Nanjing University Medical School in China, the team also reported that human hepatomegaly that is caused by either toxin exposure or autoimmune hepatitis also entails NRF2 activation, enhanced growth factor signaling and stimulation of AKT activity. In addition to liver enlargement, the scientists said persistent NRF2 activation produced excessive fat and glycogen accumulation, suggesting that NRF2 may also be involved in fatty liver disease, such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis—common metabolic disorders affecting millions of Americans.

The new findings, said Karin, suggest that AKT inhibitors, some of which have already been evaluated in humans for their anti-cancer activity, may be effective in the treatment and reversal of hepatomegaly, which affects more than million persons worldwide. Explore further. Your feedback will go directly to Science X editors.

too much nrf2

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E-mail the story Too much of a good thing may lead to too much of a liver as well Your friend's email Your email I would like to subscribe to Science X Newsletter. Learn more Your name Note Your email address is used only to let the recipient know who sent the email.These direct acting enzymes and nutrients are great at fighting the fire of oxidative stress, but where this is a chronic condition, understanding how best to activate these antioxidants in the body is of great interest.

Most compounds and molecules in our body exist in a relatively stable state, this is why we need enzymes think of them as molecular power tools to break them down or turn them into other more useful molecules.

However, some reactions in the body lead to the formation of molecules called free radicals including reactive oxygen species and peroxidesmost notably those involved in energy generation within the cell. Put another way, the byproduct of energy metabolism are damaging free radicals. These free radicals are chemically unstable, and highly reactive. Two common examples are O 2 — sometimes called superoxide and H 2 O 2 or hydrogen peroxide.

O 2 is the normal stable form of oxygen, however when involved in some reactions in the body O 2 — is formed. That little — sign means that an extra electron has been added. Superoxide is therefore highly reactive as it is trying to find a way to lose that extra electron, and the only way to do that is to transfer it to another molecule or compound. This mopping up occurs constantly in the body, however, when antioxidant function in the body becomes overwhelmed by free radicals, oxidative stress can occur.

It is important to understand that free radicals in themselves are not bad, their formation is part and parcel of cellular energy generation, and they serve a vital role in other functions such as bacterial killing.

In the short term, oxidative stress is unlikely to be harmful, as whilst the body may be temporarily overwhelmed it will usually respond and clear any harmful compounds. Other major areas of interest are dietary and environmental exposures. At a base level things like alcohol and tobacco or a meat rich diet can increase oxidative stress.

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There are other factors however which are more difficult to avoid such as air pollution, excessive exposure to pesticides, herbicides, or heavy metals. So we know that molecules such as glutathione are great at mopping up free radicals on a one to one basis, and that enzymes such as the SOD or glutathione peroxidase GPX enzyme families can rapidly reduce oxidative stress.

But what happens in a chronic system where these defenses have been overwhelmed? Nuclear factor erythroid 2 [NF-E2]-related factor 2, known by the much easier to remember acronym Nrf2 is a transcription factor which is a major regulator of cell protective, including antioxidant, responses.

Table 1 — Genes activated by NRF2. Adapted from: Baird, L. In health, Nrf2 exists in the cytosol of a cell, or the region outside of the nucleus where it cannot interact with DNA. It is held here by another protein called Keap1, which prevents it moving into the nucleus. Keap1 contains several sensors for reactive oxygen species, along with receptor regions for other cell proteins associated with cell stress. Both of these proteins exhibit potent antioxidant capacity and can rapidly clear oxidative stress.

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The important role for Nrf2 has been shown by several studies with a particular focus on animal models. Mice which have been genetically engineered to lack Nrf2 protein are considerably more sensitive to chemical carcinogens, and also chemical toxins leading to increased inflammation in the lung and brain, all major markers of oxidative stress.

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All are complex in name and structure, but they share a common function in that they support increased and prolonged expression of Nrf2 gene targets.Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging.

The sooner these treatments arrive, the more lives will be saved. The transcription factor nrf2 regulates levels of antioxidant proteins, a part of the response to everyday cellular stress, such as that induced by raised mitochondrial activity and greater generation of reactive oxygen species ROS during exercise.

Greater nrf2 activity shows up in long-lived species and in the modest slowing of aging that can be achieved via hormesis in some species. Here is an open access review paper on this topic:.

Support for the role of Nrf2 in regulation of lifespan comes from Nrf2 gain of function and loss of function studies. For example, experimental deletion of the antielectrophilic gene glutathione transferase gGsta4 activated Nrf2 and significantly extended lifespan in mice. The authors propose that deletion of this glutathione transferase gene resulted in chronic moderate Nrf2 activation and presumably elevated downstream Nrf2 signaling throughout the mouse lifespan.

Upon activation, SKN-1 upregulates genes involved in the oxidative stress response, including many orthologs to those regulated by mammalian Nrf2. Similar to mouse Nrf2 knockouts, SKN-1 mutants show diminished resistance to oxidative stress and shortened lifespan.

On the other hand, moderate overexpression of a constitutively active SKN-1 increases lifespan, alongside increased resistance to oxidative stress. The naked mole rat is an exceptionally long-lived species, with a lifespan four times longer than similarly sized rodents, thus making the naked mole rat an important model for longevity studies.

Naked mole rats do not have typical lifespan curves in which mortality rates increase with age, but rather they experience few of the biological changes typically associated with aging.

Nrf2: friend or foe for chemoprevention?

Naked mole rats also have significantly elevated proteasome quality control mechanisms. The high breakdown and clearance of damaged proteins is suspected to be largely due to increased Nrf2 expression.

In support of the hypothesized role of Nrf2 in naked mole rat longevity, under nonstressed conditions, naked mole rats have greater protein levels of Nrf2 and greater expression of Nrf2-regulated enzymes in fibroblasts and liver. These data suggest Nrf2 may be responsible for the heightened quality control mechanisms in naked mole rats and may be associated with their exceptional longevity.

For me Nrf2 is something good and bad, I read so many studies of how it is highly protective and great overall; and it is. But then, I just take in some Nrf2 activators and think, ok, this is not going to make me live that longer; healthier for a bit longer yes though definitely a good thing Something doesn't gel.

How so?


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