Antioxidant Treatment Induces Hyperactivation of the HPA Axis by Upregulating ACTH Receptor in the Adrenal and Downregulating Glucocorticoid Receptors

[Jam]

Abstract​

Glucocorticoid (GC) production is physiologically regulated through a negative feedback loop mediated by the GC, which appear disrupted in several pathological conditions. The inability to perform negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in several diseases is associated with an overproduction of reactive oxygen species (ROS); however, nothing is known about the effects of ROS on the functionality of the HPA axis during homeostasis. This study analyzed the putative impact of antioxidants on the HPA axis activity and GC-mediated negative feedback upon the HPA cascade. Male Wistar rats were orally treated with N-acetylcysteine (NAC) or vitamin E for 18 consecutive days. NAC-treated rats were then subjected to a daily treatment with dexamethasone, which covered the last 5 days of the antioxidant therapy. We found that NAC and vitamin E induced an increase in plasma corticosterone levels. NAC intensified MC2R and StAR expressions in the adrenal and reduced GR and MR expressions in the pituitary. NAC also prevented the dexamethasone-induced reduction in plasma corticosterone levels. Furthermore, NAC decreased HO-1 and Nrf2 expression in the pituitary. These findings show that antioxidants induce hyperactivity of the HPA axis via upregulation of MC2R expression in the adrenal and downregulation of GR and MR in the pituitary.

4. Discussion​

This study investigated the role of antioxidants on the modulation of endogenous glucocorticoid levels. We found that treatment with antioxidants either NAC or vitamin E increases the plasma levels of corticosterone in rats, in association with an overexpression of ACTH receptor and the steroidogenic enzyme StAR in the adrenal glands. NAC also induces a drop in HO-1 and Nrf2 expression in the pituitary and blocked the ability of dexamethasone to perform negative feedback of the HPA axis by decreasing the expression of glucocorticoid receptors in the pituitary. Our findings suggest that antioxidants cause a hyperactivation of the HPA axis with a clear dependency of upregulation of ACTH receptor in adrenals and downregulation of glucocorticoid receptors in the pituitary.

In this study, we showed that both NAC and vitamin E increase circulating levels of corticosterone in rats. NAC and vitamin E are antioxidants that act through distinct mechanisms of action. While NAC provides cysteine, which is a precursor for reduced glutathione production, and scavenges oxidants directly, including hydroxyl radical, −OH, and hypochlorous acid [8]; vitamin E is a peroxyl radical scavenger and due to its lipid solubility plays an important role in maintaining integrity of long-chain polyunsaturated fatty acids in the membranes of cells [6, 7]. The fact that prolonged treatment with two antioxidants with different mechanisms of action can increase circulating levels of corticosterone indicates that this is not an epiphenomenon, but suggests that inhibition of physiological levels of ROS in the HPA axis is responsible for its hyperactivity.

The HPA axis is the main neuroendocrine system that regulates responses to stress [8]. It is well known that the production of high levels of ROS into the glands that comprise the HPA axis is associated with the activation of a stress-response system [13, 14]. Therewith, antioxidant treatment reduces corticosterone levels in several models of diseases, including brain oxidative stress induced by lipopolysaccharide [26]. However, although accumulation of oxidative damage in cellular macromolecules is immensely toxic, ROS products by normal cell metabolism are vital to cell homeostasis maintenance [15, 16]. Our hypothesis is that physiological levels of ROS have a fundamental role in maintaining the homeostasis of the HPA axis. In fact, treatment with NAC in normal rats effectively reduced ROS levels in chondrocytes and Lin−CD45+AnV− marrow cells [27], suggesting that in our model, the antioxidant therapy probably reduces intracellular ROS content in the adrenal and pituitary glands. Thereby, we strongly suggest that any imbalance in the redox system in glands which comprise the HPA axis culminates in its hyperactivation.

In an attempt to elucidate how antioxidants induce the production of glucocorticoids by the HPA axis, we analyzed the expression of adrenal MC2R. Prolonged treatment with NAC increases adrenal MC2R expression. This higher adrenal MC2R expression after treatment can explain, at least partially, the capacity of NAC to increase circulating glucocorticoid levels. Increased expression of MC2R may lead to high activation of this receptor by ACTH and induction of the transcription of several key genes of enzymes involved in steroidogenesis, including StAR [28]. In fact, we showed that NAC induces an upregulation in the expression of StAR into the adrenal glands. StAR rapidly transports cholesterol to the inner mitochondrial membrane, where the conversion of this steroid precursor into pregnenolone, a precursor of steroid hormones, occurs [29]. This metabolic step is crucial to rapid glucocorticoid production into the adrenals in a stress stimulus, once steroidogenic cells store very little amount of glucocorticoids [10].

Although the increased expression of MC2R and StAR alone may explain the increase in glucocorticoids levels, other molecular alterations can also participate in the HPA axis hyperactivity noted after antioxidant treatment. Once the HPA axis is finely regulated by a negative feedback response on the hypothalamus and/or pituitary that normalizes circulating corticosterone levels, we hypothesized that antioxidants could induce a defect in the negative feedback regulation in the HPA axis. We observed that treatment with NAC downregulated the expression of Nrf2 in the anterior pituitary gland of rats. Nrf2 is a transcription factor that regulates expression of several antioxidant enzymes, including superoxide dismutase, catalase, glutathione peroxidase, and HO-1 [30]. Although NAC can induce upregulation of Nrf2 expression in phosgene-induced acute lung injury [31], our data is in accordance with others which described that NAC inhibited Nrf2 expression in lymphoid malignant cell lines stimulated with honokiol [32], suggesting that the effect of antioxidant NAC on Nrf2 expression depends on the cell type and condition of the study. Furthermore, we noted that NAC also decreased the expression of HO-1 in the anterior pituitary of rats. The drop in HO-1 levels after treatment with NAC indicates that the low content of Nrf2 is associated with a reduced ability of this transcription factor to induce production of antioxidant enzymes by pituitary cells. We suppose that the downregulation of Nrf2 expression is a strategy of the organism to maintain homeostasis in rats treated for several days with NAC. In fact, it has been shown that exogenous antioxidants can reduce the expression and/or activity of endogenous antioxidant enzymes [33, 34]. These data indicate that the pituitary as well as adrenals is also a direct target of antioxidant drug effects.

Our next approach was to investigate the sensitivity of the HPA axis to negative feedback induced by synthetic glucocorticoid in NAC-treated rats. Dexamethasone decreased plasma corticosterone levels in control rats; however, it did not alter circulating glucocorticoid amount in rats treated with NAC, showing that antioxidants abolish the ability of glucocorticoids to perform negative feedback of the HPA axis. NAC treatment also decreased expression of both GR and MR in the pituitary of rats, indicating that a reduction in glucocorticoid receptor expression in the pituitary of rats can explain the inability of dexamethasone to induce negative feedback of the HPA axis in NAC-treated animals. Our data confirmed the capacity of NAC in inhibiting GR expression, once NAC decreases GR protein levels in the hypothalamus of mice fed with a high-cholesterol diet [35].

Currently, many people consume dietary supplementation with antioxidants to combat diseases associated with aging [36]; however, several clinical trials testing benefits and harms of antioxidant supplements found that antioxidants have been unable to demonstrate beneficial effects and pointed that they seemed to cause an increase in all-cause mortality [37–40]. Once antioxidants induce a HPA axis dysfunction with concomitant increased levels of circulating glucocorticoids, this food supplement is shown as a risk to human health. This occurs because the hyperactivation of the HPA axis, and consequently the glucocorticoid signaling system, may alter the epigenetic landscape and influence genomic regulation and function conducting to the development of aging-related diseases [41]. Some harmful effects of hypercorticoidism, which can culminate with aging-related diseases, are deleterious effects on the central nervous system (CNS), including neuroinflammatory environment, loss of neuronal function, and apoptosis of neuronal cells, causing a decrease in hippocampal neurogenesis and an increase in neuroinflammation and neurodegeneration [42–44]. These deleterious effects of hypercorticoidism on the CNS can lead to the development of a variety of progressive neurodegenerative and psychiatric diseases, including schizophrenia, dementia, depression, Huntington's disease, and Alzheimer's disease [45–49]. Although we showed that antioxidants can induce high production of glucocorticoids, it is well known that chronic stress promotes redox imbalance throughout the body [50], as in blood of humans [51–53], such as in several structures of the CNS of rats including the frontal cortex, hypothalamus, and hippocampus [54]. These data suggest that chronic stress accelerates cellular aging through inducing increased levels of ROS [50]. These observations are conflicting with ours, once we show that antioxidants decreased the expression of Nrf2 and HO-1. However, the induction of ROS production is not the only mechanism related to stress-induced cellular aging. Chronic stress reduces brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex and increases neuroinflammation, an alteration noted in the formation of depression [44]. Furthermore, chronic stress induces prolonged periods of glutamate release in the hippocampus and decreases the ability to clear extracellular glutamate. These alterations in the glutamate transmission may be related to the impairments in the spatial and contextual memory performance and stress-associated psychiatric disorders, including mood and anxiety [55].

In addition, hypercorticoidism can also increase susceptibility to cancer [56], one of the most important aging-related diseases. Although ROS can cause oncogenic mutations and activate oncogenic pathways [57], dietary supplementation with antioxidants promotes increased incidence and death from lung and prostate cancer [58]. Furthermore, antioxidants induce melanoma progression by promoting metastasis [59]. One possibility is that the high incidence of cancer in people which use dietary supplementation with antioxidants can be related to hyperactivation of the HPA axis.

In summary, our results indicate that antioxidant therapy can induce an activation of the HPA axis, with an increase in the levels of systemic glucocorticoids by upregulating ACTH receptor in the adrenal and downregulating glucocorticoid receptors in the pituitary. Thereby, indiscriminate use of antioxidant supplements can be a risk to develop several morbidities related to persistent hypercorticoidism, as observed in Cushing's disease.

 

[Dr. B]

so vitamin E and vitamin C supplements can raise cortisol? what about D and K?
is this still in the early stages? its crazy vitamin E can raise cortisol, i thought that was one of the most peaty substances.
what about activated charcoal and olive leaf extract

 

[yerrag]

Abstract​

Glucocorticoid (GC) production is physiologically regulated through a negative feedback loop mediated by the GC, which appear disrupted in several pathological conditions. The inability to perform negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in several diseases is associated with an overproduction of reactive oxygen species (ROS); however, nothing is known about the effects of ROS on the functionality of the HPA axis during homeostasis. This study analyzed the putative impact of antioxidants on the HPA axis activity and GC-mediated negative feedback upon the HPA cascade. Male Wistar rats were orally treated with N-acetylcysteine (NAC) or vitamin E for 18 consecutive days. NAC-treated rats were then subjected to a daily treatment with dexamethasone, which covered the last 5 days of the antioxidant therapy. We found that NAC and vitamin E induced an increase in plasma corticosterone levels. NAC intensified MC2R and StAR expressions in the adrenal and reduced GR and MR expressions in the pituitary. NAC also prevented the dexamethasone-induced reduction in plasma corticosterone levels. Furthermore, NAC decreased HO-1 and Nrf2 expression in the pituitary. These findings show that antioxidants induce hyperactivity of the HPA axis via upregulation of MC2R expression in the adrenal and downregulation of GR and MR in the pituitary.

4. Discussion​

This study investigated the role of antioxidants on the modulation of endogenous glucocorticoid levels. We found that treatment with antioxidants either NAC or vitamin E increases the plasma levels of corticosterone in rats, in association with an overexpression of ACTH receptor and the steroidogenic enzyme StAR in the adrenal glands. NAC also induces a drop in HO-1 and Nrf2 expression in the pituitary and blocked the ability of dexamethasone to perform negative feedback of the HPA axis by decreasing the expression of glucocorticoid receptors in the pituitary. Our findings suggest that antioxidants cause a hyperactivation of the HPA axis with a clear dependency of upregulation of ACTH receptor in adrenals and downregulation of glucocorticoid receptors in the pituitary.

In this study, we showed that both NAC and vitamin E increase circulating levels of corticosterone in rats. NAC and vitamin E are antioxidants that act through distinct mechanisms of action. While NAC provides cysteine, which is a precursor for reduced glutathione production, and scavenges oxidants directly, including hydroxyl radical, −OH, and hypochlorous acid [8]; vitamin E is a peroxyl radical scavenger and due to its lipid solubility plays an important role in maintaining integrity of long-chain polyunsaturated fatty acids in the membranes of cells [6, 7]. The fact that prolonged treatment with two antioxidants with different mechanisms of action can increase circulating levels of corticosterone indicates that this is not an epiphenomenon, but suggests that inhibition of physiological levels of ROS in the HPA axis is responsible for its hyperactivity.

The HPA axis is the main neuroendocrine system that regulates responses to stress [8]. It is well known that the production of high levels of ROS into the glands that comprise the HPA axis is associated with the activation of a stress-response system [13, 14]. Therewith, antioxidant treatment reduces corticosterone levels in several models of diseases, including brain oxidative stress induced by lipopolysaccharide [26]. However, although accumulation of oxidative damage in cellular macromolecules is immensely toxic, ROS products by normal cell metabolism are vital to cell homeostasis maintenance [15, 16]. Our hypothesis is that physiological levels of ROS have a fundamental role in maintaining the homeostasis of the HPA axis. In fact, treatment with NAC in normal rats effectively reduced ROS levels in chondrocytes and Lin−CD45+AnV− marrow cells [27], suggesting that in our model, the antioxidant therapy probably reduces intracellular ROS content in the adrenal and pituitary glands. Thereby, we strongly suggest that any imbalance in the redox system in glands which comprise the HPA axis culminates in its hyperactivation.

In an attempt to elucidate how antioxidants induce the production of glucocorticoids by the HPA axis, we analyzed the expression of adrenal MC2R. Prolonged treatment with NAC increases adrenal MC2R expression. This higher adrenal MC2R expression after treatment can explain, at least partially, the capacity of NAC to increase circulating glucocorticoid levels. Increased expression of MC2R may lead to high activation of this receptor by ACTH and induction of the transcription of several key genes of enzymes involved in steroidogenesis, including StAR [28]. In fact, we showed that NAC induces an upregulation in the expression of StAR into the adrenal glands. StAR rapidly transports cholesterol to the inner mitochondrial membrane, where the conversion of this steroid precursor into pregnenolone, a precursor of steroid hormones, occurs [29]. This metabolic step is crucial to rapid glucocorticoid production into the adrenals in a stress stimulus, once steroidogenic cells store very little amount of glucocorticoids [10].

Although the increased expression of MC2R and StAR alone may explain the increase in glucocorticoids levels, other molecular alterations can also participate in the HPA axis hyperactivity noted after antioxidant treatment. Once the HPA axis is finely regulated by a negative feedback response on the hypothalamus and/or pituitary that normalizes circulating corticosterone levels, we hypothesized that antioxidants could induce a defect in the negative feedback regulation in the HPA axis. We observed that treatment with NAC downregulated the expression of Nrf2 in the anterior pituitary gland of rats. Nrf2 is a transcription factor that regulates expression of several antioxidant enzymes, including superoxide dismutase, catalase, glutathione peroxidase, and HO-1 [30]. Although NAC can induce upregulation of Nrf2 expression in phosgene-induced acute lung injury [31], our data is in accordance with others which described that NAC inhibited Nrf2 expression in lymphoid malignant cell lines stimulated with honokiol [32], suggesting that the effect of antioxidant NAC on Nrf2 expression depends on the cell type and condition of the study. Furthermore, we noted that NAC also decreased the expression of HO-1 in the anterior pituitary of rats. The drop in HO-1 levels after treatment with NAC indicates that the low content of Nrf2 is associated with a reduced ability of this transcription factor to induce production of antioxidant enzymes by pituitary cells. We suppose that the downregulation of Nrf2 expression is a strategy of the organism to maintain homeostasis in rats treated for several days with NAC. In fact, it has been shown that exogenous antioxidants can reduce the expression and/or activity of endogenous antioxidant enzymes [33, 34]. These data indicate that the pituitary as well as adrenals is also a direct target of antioxidant drug effects.

Our next approach was to investigate the sensitivity of the HPA axis to negative feedback induced by synthetic glucocorticoid in NAC-treated rats. Dexamethasone decreased plasma corticosterone levels in control rats; however, it did not alter circulating glucocorticoid amount in rats treated with NAC, showing that antioxidants abolish the ability of glucocorticoids to perform negative feedback of the HPA axis. NAC treatment also decreased expression of both GR and MR in the pituitary of rats, indicating that a reduction in glucocorticoid receptor expression in the pituitary of rats can explain the inability of dexamethasone to induce negative feedback of the HPA axis in NAC-treated animals. Our data confirmed the capacity of NAC in inhibiting GR expression, once NAC decreases GR protein levels in the hypothalamus of mice fed with a high-cholesterol diet [35].

Currently, many people consume dietary supplementation with antioxidants to combat diseases associated with aging [36]; however, several clinical trials testing benefits and harms of antioxidant supplements found that antioxidants have been unable to demonstrate beneficial effects and pointed that they seemed to cause an increase in all-cause mortality [37–40]. Once antioxidants induce a HPA axis dysfunction with concomitant increased levels of circulating glucocorticoids, this food supplement is shown as a risk to human health. This occurs because the hyperactivation of the HPA axis, and consequently the glucocorticoid signaling system, may alter the epigenetic landscape and influence genomic regulation and function conducting to the development of aging-related diseases [41]. Some harmful effects of hypercorticoidism, which can culminate with aging-related diseases, are deleterious effects on the central nervous system (CNS), including neuroinflammatory environment, loss of neuronal function, and apoptosis of neuronal cells, causing a decrease in hippocampal neurogenesis and an increase in neuroinflammation and neurodegeneration [42–44]. These deleterious effects of hypercorticoidism on the CNS can lead to the development of a variety of progressive neurodegenerative and psychiatric diseases, including schizophrenia, dementia, depression, Huntington's disease, and Alzheimer's disease [45–49]. Although we showed that antioxidants can induce high production of glucocorticoids, it is well known that chronic stress promotes redox imbalance throughout the body [50], as in blood of humans [51–53], such as in several structures of the CNS of rats including the frontal cortex, hypothalamus, and hippocampus [54]. These data suggest that chronic stress accelerates cellular aging through inducing increased levels of ROS [50]. These observations are conflicting with ours, once we show that antioxidants decreased the expression of Nrf2 and HO-1. However, the induction of ROS production is not the only mechanism related to stress-induced cellular aging. Chronic stress reduces brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex and increases neuroinflammation, an alteration noted in the formation of depression [44]. Furthermore, chronic stress induces prolonged periods of glutamate release in the hippocampus and decreases the ability to clear extracellular glutamate. These alterations in the glutamate transmission may be related to the impairments in the spatial and contextual memory performance and stress-associated psychiatric disorders, including mood and anxiety [55].

In addition, hypercorticoidism can also increase susceptibility to cancer [56], one of the most important aging-related diseases. Although ROS can cause oncogenic mutations and activate oncogenic pathways [57], dietary supplementation with antioxidants promotes increased incidence and death from lung and prostate cancer [58]. Furthermore, antioxidants induce melanoma progression by promoting metastasis [59]. One possibility is that the high incidence of cancer in people which use dietary supplementation with antioxidants can be related to hyperactivation of the HPA axis.

In summary, our results indicate that antioxidant therapy can induce an activation of the HPA axis, with an increase in the levels of systemic glucocorticoids by upregulating ACTH receptor in the adrenal and downregulating glucocorticoid receptors in the pituitary. Thereby, indiscriminate use of antioxidant supplements can be a risk to develop several morbidities related to persistent hypercorticoidism, as observed in Cushing's disease.

I can't find a link to the study.

I'm very leery though of such studies that link to the HPA axis as it's often the case that readers like me brush through the details because the subject is a bit on the level of studying quantum physics. So it's easy for the study to count on people who don't understand what the writer is talking about to think this is all science and not propaganda and just submit to believing the conclusions beause "an expert has spoken."

I don't know the state of the rats. I don't know the kind of vitamin E that was used, and if there is any excipients included in the NAC that would be a confounder. And it's misleading to terms vitamin E and NAC as representative of all antioxidants, which vary in their uses, but hearing from the authors it's as if al antioxidants can be painted with one broad brush as bad.

And so, because of this study which does not talk about vitamin C, I am supposed to be careful about vitamin C supplementation?

 

[Jam]

I can't find a link to the study.

I'm very leery though of such studies that link to the HPA axis as it's often the case that readers like me brush through the details because the subject is a bit on the level of studying quantum physics. So it's easy for the study to count on people who don't understand what the writer is talking about to think this is all science and not propaganda and just submit to believing the conclusions beause "an expert has spoken."

I don't know the state of the rats. I don't know the kind of vitamin E that was used, and if there is any excipients included in the NAC that would be a confounder. And it's misleading to terms vitamin E and NAC as representative of all antioxidants, which vary in their uses, but hearing from the authors it's as if al antioxidants can be painted with one broad brush as bad.

And so, because of this study which does not talk about vitamin C, I am supposed to be careful about vitamin C supplementation?

Sorry. Click on "Abstract".

 

[yerrag]

The dosage were 150mg/kg of NAC and 400mg/kg of alpha-tocopherol vitamin E for the Wistar rats. However, I don't see the HED. Do you have it?

I have no idea how much equivalent human dosage this translates to. If they are insanely huge amounts, then I would have to not take such insanely huge amounts to avoid the effects of increased cortisone production and suppression of endogenous antioxidant production.

 

[yerrag]

The HED is 0.162, so this translates to a dosage of 24mg/kg for NAC and 65mg/kg for alpha-tocopherol.

For a 70kg human, that comes out to 1,680mg NAC, and 4,500mg alpha-tocopherol, which is equivalent to 1.48IU/mg, for 6,600 IU of vitamin E daily supplementation.

I take 1200mg NAC daily, and I take it because I have a use, a sink, for it. It gets used because I have albumin being oxidized which NAC can recycle back (though not all of it). Whereas the rat has no real need for it, and the amount it's taking is slightly more, which could probably be no issue except that I don't know why any rat of human would be taking NAC when there's no need for it.

As for vitamin E, 6600 IU/day is really excessive. 2,000 IU/day would be useful as a therapy, but 400IU/day suffices as maintenance.

I think the study is being too liberal with its use of antioxidants in order to get more funding for its next project from its sponsor.

1 mg alpha-tocopherol is equivalent to 1.48IU (https://enerex.ca/en/articles/new-old-findings-on-unique-vitamin-e)

Not a coincidence that the study chose to use mg instead of IU for vitamin E, and that it choose to use alpha-tocopherols. A subtle attempt at preying on people's lack of omniscience.

 

[Jam]

The HED is 0.162, so this translates to a dosage of 24mg/kg for NAC and 65mg/kg for alpha-tocopherol.

For a 70kg human, that comes out to 1,680mg NAC, and 4,500mg alpha-tocopherol, which is equivalent to 10IU/mg, for 45,000 IU of vitamin E daily supplementation.

I take 1200mg NAC daily, and I take it because I have a use, a sink, for it. It gets used because I have albumin being oxidized which NAC can recycle back (though not all of it). Whereas the rat has no real need for it, and the amount it's taking is slightly more, which could probably be no issue except that I don't know why any rat of human would be taking NAC when there's no need for it.

As for vitamin E, 45,000 IU/day is really excessive. 2,000 IU/day would be useful as a therapy, but 400IU/day suffices as maintenance.

I think the study is being too liberal with its use of antioxidant in order to get more funding for its next project from its sponsor.

Well, I'll have to drill deeper into that study, but it does support the idea that reductive stress can have catastrophically negative effects on health. This is a fundamental concept around here, and in Peat's work, and is something I definitely subscribe to. That reductive stress, and not oxidative stress, is what is often driven by chronic inflammation, is something to keep very much in mind, in my opinion.

Reductive Stress in Inflammation-Associated Diseases and the Pro-Oxidant Effect of Antioxidant Agents​

Abstract​

Reductive stress (RS) is the counterpart oxidative stress (OS), and can occur in response to conditions that shift the redox balance of important biological redox couples, such as the NAD+/NADH, NADP+/NADPH, and GSH/GSSG, to a more reducing state. Overexpression of antioxidant enzymatic systems leads to excess reducing equivalents that can deplete reactive oxidative species, driving the cells to RS. A feedback regulation is established in which chronic RS induces OS, which in turn, stimulates again RS. Excess reducing equivalents may regulate cellular signaling pathways, modify transcriptional activity, induce alterations in the formation of disulfide bonds in proteins, reduce mitochondrial function, decrease cellular metabolism, and thus, contribute to the development of some diseases in which NF-κB, a redox-sensitive transcription factor, participates. Here, we described the diseases in which an inflammatory condition is associated to RS, and where delayed folding, disordered transport, failed oxidation, and aggregation are found. Some of these diseases are aggregation protein cardiomyopathy, hypertrophic cardiomyopathy, muscular dystrophy, pulmonary hypertension, rheumatoid arthritis, Alzheimer’s disease, and metabolic syndrome, among others. Moreover, chronic consumption of antioxidant supplements, such as vitamins and/or flavonoids, may have pro-oxidant effects that may alter the redox cellular equilibrium and contribute to RS, even diminishing life expectancy.

 

[yerrag]

Well, I'll have to drill deeper into that study, but it does support the idea that reductive stress can have catastrophically negative effects on health. This is a fundamental concept around here, and in Peat's work, and is something I definitely subscribe to. That reductive stress, and not oxidative stress, is what is often driven by chronic inflammation, is something to keep very much in mind, in my opinion.

Reductive Stress in Inflammation-Associated Diseases and the Pro-Oxidant Effect of Antioxidant Agents​

Abstract​

Reductive stress (RS) is the counterpart oxidative stress (OS), and can occur in response to conditions that shift the redox balance of important biological redox couples, such as the NAD+/NADH, NADP+/NADPH, and GSH/GSSG, to a more reducing state. Overexpression of antioxidant enzymatic systems leads to excess reducing equivalents that can deplete reactive oxidative species, driving the cells to RS. A feedback regulation is established in which chronic RS induces OS, which in turn, stimulates again RS. Excess reducing equivalents may regulate cellular signaling pathways, modify transcriptional activity, induce alterations in the formation of disulfide bonds in proteins, reduce mitochondrial function, decrease cellular metabolism, and thus, contribute to the development of some diseases in which NF-κB, a redox-sensitive transcription factor, participates. Here, we described the diseases in which an inflammatory condition is associated to RS, and where delayed folding, disordered transport, failed oxidation, and aggregation are found. Some of these diseases are aggregation protein cardiomyopathy, hypertrophic cardiomyopathy, muscular dystrophy, pulmonary hypertension, rheumatoid arthritis, Alzheimer’s disease, and metabolic syndrome, among others. Moreover, chronic consumption of antioxidant supplements, such as vitamins and/or flavonoids, may have pro-oxidant effects that may alter the redox cellular equilibrium and contribute to RS, even diminishing life expectancy.

No doubt wanton use of antioxidants can backfire, but the other extreme is not good either.

It comes down to understanding the context, so as to be able to make antioxidants and oxidants work in your favor.

A lot of times it is about letting the body decide when to make the oxidant, or the antioxidant, as the body produces it fresh for the moment of need - at the right time and the right place. Providing the body the nutrition so that it has the precursors to make them is important. But when the body needs some help in the form of exogenous antioxidants (and oxidants), depriving it of such help isn't going to help.

 

[Dave Clark]

Maybe I am understanding it wrong, but oxidation the way it is embraced on this forum is for cellular oxidation that is part of energy metabolism. Oxidative stress should not be conflated with oxygen metabolism for energy. ROS are behind every disease state, and antioxidants help keep that at bay. Too many members here on this forum think that pro-oxidation is good in all its forms, which is a bad theory to get behind, if you want to stay healthy. I take notice that hospitals are not lined up with antioxidant/vitamin users waiting to get in. I understand that some of the oxidative stress can trigger internal antioxidants, like what ozone therapy does, but there is a limit to how much is good, and how much crosses the line. To me, moral of the story is to not go overboard on antioxidants...........or oxidants.

 

[Jam]

Maybe I am understanding it wrong, but oxidation the way it is embraced on this forum is for cellular oxidation that is part of energy metabolism. Oxidative stress should not be conflated with oxygen metabolism for energy. ROS are behind every disease state, and antioxidants help keep that at bay. Too many members here on this forum think that pro-oxidation is good in all its forms, which is a bad theory to get behind, if you want to stay healthy. I take notice that hospitals are not lined up with antioxidant/vitamin users waiting to get in. I understand that some of the oxidative stress can trigger internal antioxidants, like what ozone therapy does, but there is a limit to how much is good, and how much crosses the line. To me, moral of the story is to not go overboard on antioxidants...........or oxidants.

I think Wikipedia states it fairly well: "In a biological context, ROS are formed as a natural byproduct of the normal aerobic metabolism of oxygen and have important roles in cell signaling and homeostasis.[5][6] ROS are intrinsic to cellular functioning, and are present at low and stationary levels in normal cells."

Too much ROS is bad, just like too much water, or too much of anything, really. We're not really confusing anything here, I merely wanted to post a warning that reductive stress is an oft overlooked state that is much more common than many people think.

 

[Jam]

ROS are behind every disease state, and antioxidants help keep that at bay.

But this is not the full story, as the studies I posted clearly show. If you are already in a reduced state, guzzling down anti-oxidants produces even more reductive stress, which can have serious consequences, including a paradoxical increase of ROS.

Excess reducing equivalents may regulate cellular signaling pathways, modify transcriptional activity, induce alterations in the formation of disulfide bonds in proteins, reduce mitochondrial function, decrease cellular metabolism, and thus, contribute to the development of some diseases in which NF-κB, a redox-sensitive transcription factor, participates.

 

[yerrag]

I think Wikipedia states it fairly well: "In a biological context, ROS are formed as a natural byproduct of the normal aerobic metabolism of oxygen and have important roles in cell signaling and homeostasis.[5][6] ROS are intrinsic to cellular functioning, and are present at low and stationary levels in normal cells."

Too much ROS is bad, just like too much water, or too much of anything, really. We're not really confusing anything here, I merely wanted to post a warning that reductive stress is an oft overlooked state that is much more common than many people think.

That is true. The problem is that it's hard to tell when countering oxidative stress become too much that it starts to produce reductive stress. Ray Peat talks about reductive stress, but he says it in a very vague and general manner without so much as giving specific examples. It is hard to find such instances on one's own, especially as the literature is scant on it. And if one were to count on experience to learn about it, that would be a path lined with remains.

Good article though. Thanks for sharing. This puts some filling into the donut.

 

[Dave Clark]

I am still convinced that most people just speculate as to what state they are in. Not to mention that these states may be isolated in different organs or systems and not reflect the entire body's state. You can have an overabundance of ROS in the brain for instance, but not other areas of the body, based on oxidative stress localized in that area due to iron or copper accumulation causing the Fenton reaction. And, you may not be confusing it, but many members of the forum think that if some oxidation is good, than more oxidation is better. The same criticism with antioxidants can be said of oxidants. Balance is a fantasy that we all chase, but rarely catch. Just how reductive are most people? I question that.

 

[Dr. B]

That is true. The problem is that it's hard to tell when countering oxidative stress become too much that it starts to produce reductive stress. Ray Peat talks about reductive stress, but he says it in a very vague and general manner without so much as giving specific examples. It is hard to find such instances on one's own, especially as the literature is scant on it. And if one were to count on experience to learn about it, that would be a path lined with remains.

Good article though. Thanks for sharing. This puts some filling into the donut.

I dont think Ray generally advises supplementing antioxidants to begin with, besides vitamin E right. and even that i think his article said antioxidant isnt its primary function or whatever

 

[Makrosky]

Well I think the Redox balance has to be... in balance. Too much oxidation or too much antioxidation is bad.

That oxidation is good is not a Peat discovery, it is on mainstream science and books.

 

[Makrosky]

I am still convinced that most people just speculate as to what state they are in. Not to mention that these states may be isolated in different organs or systems and not reflect the entire body's state. You can have an overabundance of ROS in the brain for instance, but not other areas of the body, based on oxidative stress localized in that area due to iron or copper accumulation causing the Fenton reaction. And, you may not be confusing it, but many members of the forum think that if some oxidation is good, than more oxidation is better. The same criticism with antioxidants can be said of oxidants. Balance is a fantasy that we all chase, but rarely catch. Just how reductive are most people? I question that.

+1

 

[Dr. B]

Well I think the Redox balance has to be... in balance. Too much oxidation or too much antioxidation is bad.

That oxidation is good is not a Peat discovery, it is on mainstream science and books.

whats issue with too much antioxidation, does it apply to antioxidation of fats too?
btw do antioxidants reduce oxidation of all systems of the body, like fats/sugars?

 

[yerrag]

Well, I'll have to drill deeper into that study, but it does support the idea that reductive stress can have catastrophically negative effects on health. This is a fundamental concept around here, and in Peat's work, and is something I definitely subscribe to. That reductive stress, and not oxidative stress, is what is often driven by chronic inflammation, is something to keep very much in mind, in my opinion.

Reductive Stress in Inflammation-Associated Diseases and the Pro-Oxidant Effect of Antioxidant Agents​

Abstract​

Reductive stress (RS) is the counterpart oxidative stress (OS), and can occur in response to conditions that shift the redox balance of important biological redox couples, such as the NAD+/NADH, NADP+/NADPH, and GSH/GSSG, to a more reducing state. Overexpression of antioxidant enzymatic systems leads to excess reducing equivalents that can deplete reactive oxidative species, driving the cells to RS. A feedback regulation is established in which chronic RS induces OS, which in turn, stimulates again RS. Excess reducing equivalents may regulate cellular signaling pathways, modify transcriptional activity, induce alterations in the formation of disulfide bonds in proteins, reduce mitochondrial function, decrease cellular metabolism, and thus, contribute to the development of some diseases in which NF-κB, a redox-sensitive transcription factor, participates. Here, we described the diseases in which an inflammatory condition is associated to RS, and where delayed folding, disordered transport, failed oxidation, and aggregation are found. Some of these diseases are aggregation protein cardiomyopathy, hypertrophic cardiomyopathy, muscular dystrophy, pulmonary hypertension, rheumatoid arthritis, Alzheimer’s disease, and metabolic syndrome, among others. Moreover, chronic consumption of antioxidant supplements, such as vitamins and/or flavonoids, may have pro-oxidant effects that may alter the redox cellular equilibrium and contribute to RS, even diminishing life expectancy.

It's a good read, and has many references, although I find some of the references have little to do with what the article is saying.

It does make me think about how many alternative therapies for cancer based on using antioxidants liberally does not work, and it's possible but unknowingly both the practitioner and the patient, far from getting into a healing modality, may be driving into a deeper level of disease.

I personally think that getting a good feel of the terrain is the first thing that needs to be done, as defined by acid-base balance. Being too acidic is just as bad as being too alkaline. But many healers are, for example, too vitamin C -centric, and have the mistaken idea that it will do everything. I have a friend die from lung cancer and while he indulged in many expensive things like stem cells, he wasn't able to stay focused on what's important as he believed in an orthomolecular biochemist who sells vitamin C as a cure. That didn't help. He finally died in a hospital after the first cancer doctor he consulted with refused his decision to go back to him. He had no strategy to heal. I don't know if he had listened to me if he would have made it alive and well, but I think his chances would have been better. Instead, he played it safe, and did hybrid therapy, which I liken to worshipping Buddhism, Zoroastrianism, Christianity, Judaism, and Islam all together. In short, no underlying root cause analysis, but a failed strategy of "take this take that" from friends and family. The same people who believed in COVID-19 hoax.

Smart and successful people not smart enough to keep themselves alive. All too common when you count the carcasses in the ICU of modern medicine.

 

[Dave Clark]

It's a good read, and has many references, although I find some of the references have little to do with what the article is saying.

It does make me think about how many alternative therapies for cancer based on using antioxidants liberally does not work, and it's possible but unknowingly both the practitioner and the patient, far from getting into a healing modality, may be driving into a deeper level of disease.

I personally think that getting a good feel of the terrain is the first thing that needs to be done, as defined by acid-base balance. Being too acidic is just as bad as being too alkaline. But many healers are, for example, too vitamin C -centric, and have the mistaken idea that it will do everything. I have a friend die from lung cancer and while he indulged in many expensive things like stem cells, he wasn't able to stay focused on what's important as he believed in an orthomolecular biochemist who sells vitamin C as a cure. That didn't help. He finally died in a hospital after the first cancer doctor he consulted with refused his decision to go back to him. He had no strategy to heal. I don't know if he had listened to me if he would have made it alive and well, but I think his chances would have been better. Instead, he played it safe, and did hybrid therapy, which I liken to worshipping Buddhism, Zoroastrianism, Christianity, Judaism, and Islam all together. In short, no underlying root cause analysis, but a failed strategy of "take this take that" from friends and family. The same people who believed in COVID-19 hoax.

Smart and successful people not smart enough to keep themselves alive. All too common when you count the carcasses in the ICU of modern medicine.

Lung cancer is not a good example of a cancer that people cure themselves of, regardless of therapy or mindset.

 

[yerrag]

Lung cancer is not a good example of a cancer that people cure themselves of, regardless of therapy or mindset.

What is, anyway?

You're saying then for lung cancer go to an oncologist as he knows best as maybe his track record is stellar?

Or go to an alternative practitioner?

Why do you think lung cancer is so hard to treat that sets it apart from other cancers?

And why do you think self treating is a bad idea if one understands cancer and its causes and also understands to fix the identified problem? Don't you think it's because it's the ignorant people who don't understand cancer that fail at it?

Believe in the individual and his capacity to understand and to cure if he can discard the baggage of falsehoods that surround the curing of cancer.

Most of the science that guides doctors are false, and they don't really have an edge. More often than not, it's a liability. It's a handicap designed to make them fail by the medical establishment as for the establishment, cure is a failing business model.