COVID-19 And Carbon Monoxide

md_a

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Donnay Detoxicology LLC: humans make more CO naturally in response to lung infections of all kinds.. It comes from Heme oxygenase-1 induced catabolism of heme proteins like hemoglobin, myoglobin, and cytochromes which releases CO along with equal amounts of iron (which is converted to ferritin form) and biliverdin (which reduces to bilirubin). Both ferritin and bilirubin are reported to be high in COVID -19 patients, and ferritin is even considered the primary biomarker of their cytokine storms. But COVID clinicians are not yet testing for CO via blood, breath or skin, which they don't suspect because the pulse oximeters they are using to monitor oxygen saturation are mislabeled with a display says "O2Sat" but is actually the sum of Oxyhemoglobin + Carboxyhemoglobin + Methemoglobin (O2Hb + COHb + MetHb) . Doctors also don't realize that mechanical ventilators cause an increasing level of CO to buildup in the blood and tissues of people who are on them for any reason [see Chawla 2019], which causes an falling level of oxygen [see Ascha 2018] that ends in multi-organ failure and acute hypoxic death [see Simonsen 2018].

Oxygen is extremely toxic, and inhaling high concentration at high flow rate as is typically done in ambulances and EDs via non-rebreather mask that prevents CO2 accumulation actually causes humans to make more CO naturally in response, and it drives this CO from arterial blood into plasma and from there into tissues. Problem is that free CO is much more toxic in tissues, where it causes acute hypoxic multiorgan failure.

CO-oximeter - Wikipedia

....

Title COVID-19 morbidity and mortality caused by endogenous carbon monoxide poisoning, with recommendations for testing and treatment

Abstract

To test our hypothesis that abnormal levels of endogenous carbon monoxide (CO) produced naturally by heme oxygenase-1 (HO-1) in response to infections of all kinds may be contributing to the morbidity and mortality associated with COVID-19, we searched PubMed for peer-reviewed literature on carbon monoxide and each of eleven abnormal blood tests, fourteen signs and symptoms, and five fatal complications of COVID-19 infection reported in a case series from a hospital in Wuhan, China: acute respiratory distress syndrome (ARDS), acute kidney injury, acute cardiac injury, arrhythmia, and shock. We found reports of acute exogenous CO poisoning causing all the same signs, symptoms and complications, and all the abnormal blood tests except D-dimer and procalcitonin. Our search also found endogenous HO-1 and CO levels correlated with these complications, independent of any inhaled CO exposure. In sharp contrast to the CO poisoning literature, most studies of endogenous CO interpret its close positive correlation with these acute conditions as protective, with some going so far as to recommend treating ARDS with inhaled CO. We conclude with new recommendations for testing endogenous CO poisoning in COVID-19 cases using devices approved by the US Food and Drug Administration that can distinguish CO coming from the lungs, arteries, veins, and average of all tissues, unlike current protocols for CO poisoning that only measure CO in arteries or veins but not both. Based on these findings, we appeal to clinicians to start testing CO levels in COVID-19 patients and to stop monitoring oxygen saturation with conventional pulse oximeters that overestimate oxygen saturation by the sum of carboxyhemoglobin and methemoglobin. We conclude by reviewing FDA-approved treatments that may help COVID-19 patients with endogenous CO poisoning.

These include zinc-based drugs that lower the rate of endogenous CO production by inhibiting HO-1, and drug-free devices and methods that reduce the total body burden of CO after exogenous CO poisoning.

Conclusions

We have shown that 14 signs and symptoms and 5 frequently fatal complications of COVID-19 infection reported in a representative series of hospitalized cases from Wuhan, China, are all also reported in the peer-reviewed literature on CO poisoning. All the complications are each also independently associated with increases in endogenous CO. These findings are consistent with the hypotheses that endogenous carbon monoxide is causing the signs, symptoms and complications of COVID-19 but they do not prove it, which will require appropriate testing of cases and controls. Fortunately, FDA-approved devices for non-invasive spot and continuous testing of CO levels in real time are already widely distributed among hospitals and fire departments.

We conclude that people with COVID-19 who have labs, signs, symptoms, and complications consistent with endogenous CO poisoning should be tested for this possibility with any device that can measure CO reproducibly in lungs, blood and tissues.

We also urge clinicians worldwide to stop relying on conventional pulse oximeters to monitor oxygen saturation since the display is always overestimated by unknown fractions of COHb and MetHb.

For people with abnormally high levels of CO in their lungs, blood, and/or tissues, we recommend treatments that either quickly lower the total body burden of CO without drugs, or which quickly reduce the rate of endogenous CO production, while boosting ventilation if needed with carbon dioxide mixtures. This should exclude mechanical ventilation, high-flow hyperoxygenation, and hyperbaric because all increase the level of CO in tissues.

Our approach will not cure COVID-19 infections but we predict it will reduce morbidity and mortality and eliminate the need for mechanical ventilators.

….


From Ray Peat:

“Not all the oxygen we consume is put to good use, and we sometimes produce exhalation of gases other than carbon dioxide and water vapor.

Under stressful conditions, people may exhale measurable amounts of pentane, ethane, isoprene, carbon monoxide, and other substances with potential toxicity.

In hyperventilation, so much carbon dioxide is lost in the breath that our tissue respiration is impaired, creating a partial ‘tissue suffocation.’

If cells consume oxygen without producing carbon dioxide generously, a situation analogous to hyperventilation/tissues suffocation exists.

Oxygen deprivation is one of the signals that stimulates the production of new red blood cells, and this involves the production of porphyrin, heme, and hemoglobin.

The elimination of heme by oxidation produces carbon monoxide, which can block the respiratory production of energy.”


"The exhaled breath is being used to diagnose inflammatory lung disease, since so many of the mediators of inflammation are volatile, but systemic diseases such as cancer and arthritis, and relatively minor stress can be detected by changes in the chemicals found in the breath. Polyunsaturated fats and their breakdown products-- aldehydes, prostaglandins, isoprostanes, hydrocarbons, and free radicals--and carbon monoxide, nitric oxide, nitrite, and hydrogen peroxide are increased in the breath by most stresses."

"The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome c oxidase.

This enzyme is dependent on the thyroid hormone and is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin.”

“The heme group (of hemoglobin and the respinitory enzymes, for example) is the iron-binding oily molecule that interacts with oxygen, and it is called a porphyrin.”

“The presence of porphyrin poisoning, with its associated free radical toxins, can lead to the activation of heme oxygenase, the enzyme which produces carbon monoxide, which I have discussed elsewhere as a cause of the respiratory defect that characterizes cancer. Both ammonia and porphyria have been implicated in the production of cancer.”

“Excess heme is destroyed by the enzyme heme oxygenase, which converts heme into biliverdin and carbon monoxide. Both of these factors have effects on the cell which are characteristic of cancer.”

“Any hypoxic tissue, including inflammations of any sort, will express the heme oxygenase enzyme, producing carbon monoxide.”

“This enzyme degrades the heme molecule, which is released from hemoglobin and other proteins in injured tissues, and which in the free state is toxic (Kumar and Bandyopadhyay, 2005). In degrading heme, this enzyme releases free iron atoms and biliverdin, as well as carbon monoxide. Although free iron atoms can cause harmful oxidation, biliverdin, and the bilirubin that's produced from it, can have beneficial antioxidant effects.”

“Carbon monoxide increases the formation of cortisol, by stimulating ACTH release from the pituitary.

The stress response is self-sustaining on several levels.

For example, stress increases the absorption of bacterial endotoxin from the intestine, which increases the estrogen level and synergizes with biliverdin and cortisol.

Biliverdin (F. Paradisi, 1975) activates betaglucuronidase, one of the main enzymes involved in the local release of estrogen.

In later stages, anemia and hemolysis are associated with CO and biliverdin production from the release of heme. (Anemia is seen in most patients with advanced cancer.)

Biliverdin, combined with estrogen and hypoxia, alters the cytoskeleton, producing chromosome imbalances, causing mutations and activating the "oncogenes."
 

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  • Donnay 2020 COVID and Carbon Monoxide preprint.pdf
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LLight

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673
Very interesting!

TonEBP Suppresses the HO-1 Gene by Blocking Recruitment of Nrf2 to Its Promoter

"Here, we show that TonEBP suppresses expression of HO-1 by blocking Nrf2 binding to the HO-1 promoter, thereby inducing polarization of macrophages to the M1 phenotype."

But in macrophages and not in erythrocytes...

TonEBP/NFAT5 is upregulated by fluid restriction or dehydration.

Fluid restriction seems to help covid patients:

What's Working for COVID-19 Patients

"Treatment: Fluids
Patients with COVID-19 appear to be very sensitive to fluid overload. We have found success at preventing the need for intubation by keeping patients net negative despite tachycardia and acute kidney injury."
 

LLight

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Messages
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Repost from somewhere else:

A recent preprint on COVID19 is saying that:
"Of particular note, we found the alveolar macrophages with SARS-CoV–2 infection were expressing ACE2, a well-established receptor for both SARS-CoV and SARS-CoV–2 (Extended Data Fig.5). It was reported that SARS-CoV could occasionally be identified in the alveolar macrophages. In COVID–19 patients the extraordinary aggregation and activation of these macrophages could occupy a central position in pathogenesis of the very severe “inflammatory factor storm” or “cytokine storm”.​

Therefore, the spectacular infiltration and activation of alveolar macrophages in COVID–19, especially among patients with severe and critical stages of ARDS, might represent the shift of classically activated phenotype (M1) to alternatively activated phenotype (M2) of alveolar macrophages, whereas this shifted property of alveolar macrophages could contribute to the inflammatory injuries and fibrosis of respiratory tracts."​

If I'm reading this well and that their observations are conclusive, it's M2 macrophages that are involved in the worst cases of COVID19.

Interestingly, the transcription factor NFAT5 which is supposedly increased by dehydration and probably fasting too (also called TonEBP in the literature) tends to suppress the HO-1 enzyme in macrophages.

Moreover, the HO-1 enzyme favor the M2 polarization of macrophages (from the same publication):
"Here, we show that TonEBP suppresses expression of HO-1 by blocking Nrf2 binding to the HO-1 promoter, thereby inducing polarization of macrophages to the M1 phenotype."​

Water restriction has been shown to limit the quantity of water from lungs in mice. Would it be sufficient to prevent edema in lungs and inverse the macrophages polarization?
 

Terma

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I'd say macrophage polarization will have to be interpreted carefully (peer-reviewed) since research is biased to consider M2 activation anti-inflammatory which is not entirely incorrect, but the populations can be mixed into alternative states. Examples: Sci-Hub | IL-6 promotes M2 macrophage polarization by modulating purinergic signaling and regulates the lethal release of nitric oxide during Trypanosoma cruzi infection. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(4), 857–869 | 10.1016/j.bbadis.2017.01.006
One potential regulatory system that could have a role in the IL-6-induced M2 profile is the extracellular levels ofadenosine. After infection, the influx of immune cells consumes large quantities of oxygen, and ischemic cells rapidly respond to the hypoxic and inflammatory environment by releasing ATP [51, 52]. Once released, ATP is converted to AMP and then to adenosine by CD39 and CD73, respectively. Adenosine affects macrophage function through several diverse mechanism [17, 53, 54], in particular inducing cardiac macrophages to adopt an M2-biased phenotype and driving the timely resolution of inflammation [52]. In this study, we found that IL-6 significantly increased the ATP machinery expression in murine and human cells. In pathological conditions, high levels of ATP activate the inflammasome that processes pro-IL-1βinto mature IL-1βin macrophages [55].In this sense, as a consequence of the lower expression of ATP metabolic machinery, the IL-6 deficiency could induce ATP accumulation and inflammasome activation that lead to increased IL-1βproduction. Activation of inflammasome also triggers pyroptosis, a highlyinflammatory form of programmed cell death. In agreement, increased cell death rates occurred within infected IL6KO myocardium

The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of Interleukin-4 receptor alpha (IL4Rα) signaling

http://downloads.hindawi.com/journals/mi/2015/816460.pdf
Apart from IL-4/IL-13, several other stimuli and signalpathways have been recognized as inducers of M2 activation. Based on the applied stimuli and the achieved transcriptional changes, the M2 macrophages have been classified into sub-divisions [4,10]. These are M2a, M2b, and M2c subdivisions(Figure 1). Some authors distinguish the M2d macrophage type also [5,14]. The M2a activation is a response to IL-4 and IL-13, the M2b to immune complexes and bacteriallipopolysaccharide (LPS), and the M2c to glucocorticoids and TGF-. The M2d activation is a response to IL-6 and adenosines [25,26].

https://doi.org/10.1101/2020.03.24.20042655

I think it will determine the correct timing of therapies, such as purines and lipoic acid normally associated with M2 that in principle are opposite to these suggestions and seems important to point that out. These have so many targets you can't total a net effect, so far there's nothing tangibly convincing either way. They were doing a trial with lipoic acid so that might give an idea, if they even dose it correctly. (On the other hand you have NAC)
 
Last edited:

LLight

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Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man - ScienceDirect

"Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of “healthy” versus “unhealthy” obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from “healthy” versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease."

Could this be (even if this study is talking about the liver and adipocytes) why we observe that covid patients with metabolic syndrome have worse outcomes?
 

RealNeat

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Donnay Detoxicology LLC: humans make more CO naturally in response to lung infections of all kinds.. It comes from Heme oxygenase-1 induced catabolism of heme proteins like hemoglobin, myoglobin, and cytochromes which releases CO along with equal amounts of iron (which is converted to ferritin form) and biliverdin (which reduces to bilirubin). Both ferritin and bilirubin are reported to be high in COVID -19 patients, and ferritin is even considered the primary biomarker of their cytokine storms. But COVID clinicians are not yet testing for CO via blood, breath or skin, which they don't suspect because the pulse oximeters they are using to monitor oxygen saturation are mislabeled with a display says "O2Sat" but is actually the sum of Oxyhemoglobin + Carboxyhemoglobin + Methemoglobin (O2Hb + COHb + MetHb) . Doctors also don't realize that mechanical ventilators cause an increasing level of CO to buildup in the blood and tissues of people who are on them for any reason [see Chawla 2019], which causes an falling level of oxygen [see Ascha 2018] that ends in multi-organ failure and acute hypoxic death [see Simonsen 2018].

Oxygen is extremely toxic, and inhaling high concentration at high flow rate as is typically done in ambulances and EDs via non-rebreather mask that prevents CO2 accumulation actually causes humans to make more CO naturally in response, and it drives this CO from arterial blood into plasma and from there into tissues. Problem is that free CO is much more toxic in tissues, where it causes acute hypoxic multiorgan failure.

CO-oximeter - Wikipedia

....

Title COVID-19 morbidity and mortality caused by endogenous carbon monoxide poisoning, with recommendations for testing and treatment

Abstract

To test our hypothesis that abnormal levels of endogenous carbon monoxide (CO) produced naturally by heme oxygenase-1 (HO-1) in response to infections of all kinds may be contributing to the morbidity and mortality associated with COVID-19, we searched PubMed for peer-reviewed literature on carbon monoxide and each of eleven abnormal blood tests, fourteen signs and symptoms, and five fatal complications of COVID-19 infection reported in a case series from a hospital in Wuhan, China: acute respiratory distress syndrome (ARDS), acute kidney injury, acute cardiac injury, arrhythmia, and shock. We found reports of acute exogenous CO poisoning causing all the same signs, symptoms and complications, and all the abnormal blood tests except D-dimer and procalcitonin. Our search also found endogenous HO-1 and CO levels correlated with these complications, independent of any inhaled CO exposure. In sharp contrast to the CO poisoning literature, most studies of endogenous CO interpret its close positive correlation with these acute conditions as protective, with some going so far as to recommend treating ARDS with inhaled CO. We conclude with new recommendations for testing endogenous CO poisoning in COVID-19 cases using devices approved by the US Food and Drug Administration that can distinguish CO coming from the lungs, arteries, veins, and average of all tissues, unlike current protocols for CO poisoning that only measure CO in arteries or veins but not both. Based on these findings, we appeal to clinicians to start testing CO levels in COVID-19 patients and to stop monitoring oxygen saturation with conventional pulse oximeters that overestimate oxygen saturation by the sum of carboxyhemoglobin and methemoglobin. We conclude by reviewing FDA-approved treatments that may help COVID-19 patients with endogenous CO poisoning.

These include zinc-based drugs that lower the rate of endogenous CO production by inhibiting HO-1, and drug-free devices and methods that reduce the total body burden of CO after exogenous CO poisoning.

Conclusions

We have shown that 14 signs and symptoms and 5 frequently fatal complications of COVID-19 infection reported in a representative series of hospitalized cases from Wuhan, China, are all also reported in the peer-reviewed literature on CO poisoning. All the complications are each also independently associated with increases in endogenous CO. These findings are consistent with the hypotheses that endogenous carbon monoxide is causing the signs, symptoms and complications of COVID-19 but they do not prove it, which will require appropriate testing of cases and controls. Fortunately, FDA-approved devices for non-invasive spot and continuous testing of CO levels in real time are already widely distributed among hospitals and fire departments.

We conclude that people with COVID-19 who have labs, signs, symptoms, and complications consistent with endogenous CO poisoning should be tested for this possibility with any device that can measure CO reproducibly in lungs, blood and tissues.

We also urge clinicians worldwide to stop relying on conventional pulse oximeters to monitor oxygen saturation since the display is always overestimated by unknown fractions of COHb and MetHb.

For people with abnormally high levels of CO in their lungs, blood, and/or tissues, we recommend treatments that either quickly lower the total body burden of CO without drugs, or which quickly reduce the rate of endogenous CO production, while boosting ventilation if needed with carbon dioxide mixtures. This should exclude mechanical ventilation, high-flow hyperoxygenation, and hyperbaric because all increase the level of CO in tissues.

Our approach will not cure COVID-19 infections but we predict it will reduce morbidity and mortality and eliminate the need for mechanical ventilators.

….


From Ray Peat:

“Not all the oxygen we consume is put to good use, and we sometimes produce exhalation of gases other than carbon dioxide and water vapor.

Under stressful conditions, people may exhale measurable amounts of pentane, ethane, isoprene, carbon monoxide, and other substances with potential toxicity.

In hyperventilation, so much carbon dioxide is lost in the breath that our tissue respiration is impaired, creating a partial ‘tissue suffocation.’

If cells consume oxygen without producing carbon dioxide generously, a situation analogous to hyperventilation/tissues suffocation exists.

Oxygen deprivation is one of the signals that stimulates the production of new red blood cells, and this involves the production of porphyrin, heme, and hemoglobin.

The elimination of heme by oxidation produces carbon monoxide, which can block the respiratory production of energy.”


"The exhaled breath is being used to diagnose inflammatory lung disease, since so many of the mediators of inflammation are volatile, but systemic diseases such as cancer and arthritis, and relatively minor stress can be detected by changes in the chemicals found in the breath. Polyunsaturated fats and their breakdown products-- aldehydes, prostaglandins, isoprostanes, hydrocarbons, and free radicals--and carbon monoxide, nitric oxide, nitrite, and hydrogen peroxide are increased in the breath by most stresses."

"The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome c oxidase.

This enzyme is dependent on the thyroid hormone and is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin.”

“The heme group (of hemoglobin and the respinitory enzymes, for example) is the iron-binding oily molecule that interacts with oxygen, and it is called a porphyrin.”

“The presence of porphyrin poisoning, with its associated free radical toxins, can lead to the activation of heme oxygenase, the enzyme which produces carbon monoxide, which I have discussed elsewhere as a cause of the respiratory defect that characterizes cancer. Both ammonia and porphyria have been implicated in the production of cancer.”

“Excess heme is destroyed by the enzyme heme oxygenase, which converts heme into biliverdin and carbon monoxide. Both of these factors have effects on the cell which are characteristic of cancer.”

“Any hypoxic tissue, including inflammations of any sort, will express the heme oxygenase enzyme, producing carbon monoxide.”

“This enzyme degrades the heme molecule, which is released from hemoglobin and other proteins in injured tissues, and which in the free state is toxic (Kumar and Bandyopadhyay, 2005). In degrading heme, this enzyme releases free iron atoms and biliverdin, as well as carbon monoxide. Although free iron atoms can cause harmful oxidation, biliverdin, and the bilirubin that's produced from it, can have beneficial antioxidant effects.”

“Carbon monoxide increases the formation of cortisol, by stimulating ACTH release from the pituitary.

The stress response is self-sustaining on several levels.

For example, stress increases the absorption of bacterial endotoxin from the intestine, which increases the estrogen level and synergizes with biliverdin and cortisol.

Biliverdin (F. Paradisi, 1975) activates betaglucuronidase, one of the main enzymes involved in the local release of estrogen.

In later stages, anemia and hemolysis are associated with CO and biliverdin production from the release of heme. (Anemia is seen in most patients with advanced cancer.)

Biliverdin, combined with estrogen and hypoxia, alters the cytoskeleton, producing chromosome imbalances, causing mutations and activating the "oncogenes."
If this is an email exchange with ray could you also post it on the emails thread.
 

md_a

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If this is an email exchange with ray could you also post it on the emails thread.
It's from Donnay Detoxicology LLC, and the rest are collected from older articles written by Ray Peat. I asked for his opinion on this subject and if he answers I will post.
 

md_a

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Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man - ScienceDirect

"Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of “healthy” versus “unhealthy” obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from “healthy” versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease."

Could this be (even if this study is talking about the liver and adipocytes) why we observe that covid patients with metabolic syndrome have worse outcomes?

Obesity Link to Severe COVID-19, Especially in the Under 60s
 

Terma

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Joined
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Messages
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Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man - ScienceDirect

"Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of “healthy” versus “unhealthy” obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from “healthy” versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease."

Could this be (even if this study is talking about the liver and adipocytes) why we observe that covid patients with metabolic syndrome have worse outcomes?

It fits these:
Ferritin Is a Marker of Inflammation rather than Iron Deficiency in Overweight and Obese People
Increased Body Mass Index may lead to Hyperferritinemia Irrespective of Body Iron Stores
but KO studies are like ablating circadian rhythm. My guess is low HO-1 expression at right times can be desirable (hormetic, infections, preventing worse damage) while high or extended HO-1 is destructive - like NO, CO in circumstances - ferritin production has to be a factor, and tons of things can increase Nrf2/HO-1 (vit D, AMPK) so situations that increase it significantly in macrophages have to be the pivot, but macrophages are associated with obesity enough to suspect their link even prior to this.
https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.116.016165
Circadian clock disruption by selective removal of endogenous carbon monoxide
Sleep Apnea Patients Have High Carbon Monoxide Levels After Sleep
The thyroid hormone triiodothyronine controls macrophage maturation and functions: protective role during inflammation. - PubMed - NCBI
 

Gone Peating

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Donnay Detoxicology LLC: humans make more CO naturally in response to lung infections of all kinds.. It comes from Heme oxygenase-1 induced catabolism of heme proteins like hemoglobin, myoglobin, and cytochromes which releases CO along with equal amounts of iron (which is converted to ferritin form) and biliverdin (which reduces to bilirubin). Both ferritin and bilirubin are reported to be high in COVID -19 patients, and ferritin is even considered the primary biomarker of their cytokine storms. But COVID clinicians are not yet testing for CO via blood, breath or skin, which they don't suspect because the pulse oximeters they are using to monitor oxygen saturation are mislabeled with a display says "O2Sat" but is actually the sum of Oxyhemoglobin + Carboxyhemoglobin + Methemoglobin (O2Hb + COHb + MetHb) . Doctors also don't realize that mechanical ventilators cause an increasing level of CO to buildup in the blood and tissues of people who are on them for any reason [see Chawla 2019], which causes an falling level of oxygen [see Ascha 2018] that ends in multi-organ failure and acute hypoxic death [see Simonsen 2018].

Oxygen is extremely toxic, and inhaling high concentration at high flow rate as is typically done in ambulances and EDs via non-rebreather mask that prevents CO2 accumulation actually causes humans to make more CO naturally in response, and it drives this CO from arterial blood into plasma and from there into tissues. Problem is that free CO is much more toxic in tissues, where it causes acute hypoxic multiorgan failure.

CO-oximeter - Wikipedia

....

Title COVID-19 morbidity and mortality caused by endogenous carbon monoxide poisoning, with recommendations for testing and treatment

Abstract

To test our hypothesis that abnormal levels of endogenous carbon monoxide (CO) produced naturally by heme oxygenase-1 (HO-1) in response to infections of all kinds may be contributing to the morbidity and mortality associated with COVID-19, we searched PubMed for peer-reviewed literature on carbon monoxide and each of eleven abnormal blood tests, fourteen signs and symptoms, and five fatal complications of COVID-19 infection reported in a case series from a hospital in Wuhan, China: acute respiratory distress syndrome (ARDS), acute kidney injury, acute cardiac injury, arrhythmia, and shock. We found reports of acute exogenous CO poisoning causing all the same signs, symptoms and complications, and all the abnormal blood tests except D-dimer and procalcitonin. Our search also found endogenous HO-1 and CO levels correlated with these complications, independent of any inhaled CO exposure. In sharp contrast to the CO poisoning literature, most studies of endogenous CO interpret its close positive correlation with these acute conditions as protective, with some going so far as to recommend treating ARDS with inhaled CO. We conclude with new recommendations for testing endogenous CO poisoning in COVID-19 cases using devices approved by the US Food and Drug Administration that can distinguish CO coming from the lungs, arteries, veins, and average of all tissues, unlike current protocols for CO poisoning that only measure CO in arteries or veins but not both. Based on these findings, we appeal to clinicians to start testing CO levels in COVID-19 patients and to stop monitoring oxygen saturation with conventional pulse oximeters that overestimate oxygen saturation by the sum of carboxyhemoglobin and methemoglobin. We conclude by reviewing FDA-approved treatments that may help COVID-19 patients with endogenous CO poisoning.

These include zinc-based drugs that lower the rate of endogenous CO production by inhibiting HO-1, and drug-free devices and methods that reduce the total body burden of CO after exogenous CO poisoning.

Conclusions

We have shown that 14 signs and symptoms and 5 frequently fatal complications of COVID-19 infection reported in a representative series of hospitalized cases from Wuhan, China, are all also reported in the peer-reviewed literature on CO poisoning. All the complications are each also independently associated with increases in endogenous CO. These findings are consistent with the hypotheses that endogenous carbon monoxide is causing the signs, symptoms and complications of COVID-19 but they do not prove it, which will require appropriate testing of cases and controls. Fortunately, FDA-approved devices for non-invasive spot and continuous testing of CO levels in real time are already widely distributed among hospitals and fire departments.

We conclude that people with COVID-19 who have labs, signs, symptoms, and complications consistent with endogenous CO poisoning should be tested for this possibility with any device that can measure CO reproducibly in lungs, blood and tissues.

We also urge clinicians worldwide to stop relying on conventional pulse oximeters to monitor oxygen saturation since the display is always overestimated by unknown fractions of COHb and MetHb.

For people with abnormally high levels of CO in their lungs, blood, and/or tissues, we recommend treatments that either quickly lower the total body burden of CO without drugs, or which quickly reduce the rate of endogenous CO production, while boosting ventilation if needed with carbon dioxide mixtures. This should exclude mechanical ventilation, high-flow hyperoxygenation, and hyperbaric because all increase the level of CO in tissues.

Our approach will not cure COVID-19 infections but we predict it will reduce morbidity and mortality and eliminate the need for mechanical ventilators.

….


From Ray Peat:

“Not all the oxygen we consume is put to good use, and we sometimes produce exhalation of gases other than carbon dioxide and water vapor.

Under stressful conditions, people may exhale measurable amounts of pentane, ethane, isoprene, carbon monoxide, and other substances with potential toxicity.

In hyperventilation, so much carbon dioxide is lost in the breath that our tissue respiration is impaired, creating a partial ‘tissue suffocation.’

If cells consume oxygen without producing carbon dioxide generously, a situation analogous to hyperventilation/tissues suffocation exists.

Oxygen deprivation is one of the signals that stimulates the production of new red blood cells, and this involves the production of porphyrin, heme, and hemoglobin.

The elimination of heme by oxidation produces carbon monoxide, which can block the respiratory production of energy.”


"The exhaled breath is being used to diagnose inflammatory lung disease, since so many of the mediators of inflammation are volatile, but systemic diseases such as cancer and arthritis, and relatively minor stress can be detected by changes in the chemicals found in the breath. Polyunsaturated fats and their breakdown products-- aldehydes, prostaglandins, isoprostanes, hydrocarbons, and free radicals--and carbon monoxide, nitric oxide, nitrite, and hydrogen peroxide are increased in the breath by most stresses."

"The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome c oxidase.

This enzyme is dependent on the thyroid hormone and is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin.”

“The heme group (of hemoglobin and the respinitory enzymes, for example) is the iron-binding oily molecule that interacts with oxygen, and it is called a porphyrin.”

“The presence of porphyrin poisoning, with its associated free radical toxins, can lead to the activation of heme oxygenase, the enzyme which produces carbon monoxide, which I have discussed elsewhere as a cause of the respiratory defect that characterizes cancer. Both ammonia and porphyria have been implicated in the production of cancer.”

“Excess heme is destroyed by the enzyme heme oxygenase, which converts heme into biliverdin and carbon monoxide. Both of these factors have effects on the cell which are characteristic of cancer.”

“Any hypoxic tissue, including inflammations of any sort, will express the heme oxygenase enzyme, producing carbon monoxide.”

“This enzyme degrades the heme molecule, which is released from hemoglobin and other proteins in injured tissues, and which in the free state is toxic (Kumar and Bandyopadhyay, 2005). In degrading heme, this enzyme releases free iron atoms and biliverdin, as well as carbon monoxide. Although free iron atoms can cause harmful oxidation, biliverdin, and the bilirubin that's produced from it, can have beneficial antioxidant effects.”

“Carbon monoxide increases the formation of cortisol, by stimulating ACTH release from the pituitary.

The stress response is self-sustaining on several levels.

For example, stress increases the absorption of bacterial endotoxin from the intestine, which increases the estrogen level and synergizes with biliverdin and cortisol.

Biliverdin (F. Paradisi, 1975) activates betaglucuronidase, one of the main enzymes involved in the local release of estrogen.

In later stages, anemia and hemolysis are associated with CO and biliverdin production from the release of heme. (Anemia is seen in most patients with advanced cancer.)

Biliverdin, combined with estrogen and hypoxia, alters the cytoskeleton, producing chromosome imbalances, causing mutations and activating the "oncogenes."

So how can we prevent porphyrin poisoning and stop all the terrible effect that result from it?
 

LLight

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tons of things can increase Nrf2/HO-1 (vit D, AMPK) so situations that increase it significantly in macrophages have to be the pivot
What do you mean by "have to be the pivot"? I'm not sure to understand :):
 

Terma

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The point where the products of HO-1 are high enough that effects aren't reversible within the timeframe or no longer buffered sufficiently by things like ferritin - maybe other cells contribute, but hard to imagine without the macrophages to concentrate/localize production, biased also by the ACE2 factor. Mostly an analogy with eNOS (non-defective) vs iNOS (macrophages). (I guess there's HO-2 to factor in, but eh)
 

LLight

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If it happens to be related to M. tuberculosis, it does increase HO-1 (maybe it's the case for all infections as it has been said):

Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes - PubMed

"In both HIV-1 coinfected and Mtb monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by Mtb, we performed a series of in vitro experiments using mouse and human macrophages. We found that Mtb-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early-secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2."

By the way:
Regulation of Mycobacterium Tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway - PubMed
"Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages."
 

yerrag

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But COVID clinicians are not yet testing for CO via blood, breath or skin, which they don't suspect because the pulse oximeters they are using to monitor oxygen saturation are mislabeled with a display says "O2Sat" but is actually the sum of Oxyhemoglobin + Carboxyhemoglobin + Methemoglobin (O2Hb + COHb + MetHb) . Doctors also don't realize that mechanical ventilators cause an increasing level of CO to buildup in the blood and tissues of people who are on them for any reason [see Chawla 2019], which causes an falling level of oxygen [see Ascha 2018] that ends in multi-organ failure and acute hypoxic death [see Simonsen 2018].

Ray Peat, in a recent interview, where he mentioned the right way of interpreting and using pulse oximeters, talked about the poor quality on readings in the current crop oximeters that are widely available, but he didn't elaborate. Now, we know what he meant. So, where can we buy pulse oximeters that are better? I'm failing to find good oximeters in my search. Amazon doesn't seem to carry anything where the description would tout the product as distinctive, especially when it comes to giving accurate oxyhemoglobin saturation values, and if available, the ability to measure carboxyhemoglobin values as well.

@LifeGivingStore do you have any such product in the pipeline? I'd be very interested in getting one.

In this day and age where we're flooded with sensors of all sorts off-the-shelf, I find it ludicrous to believe that no oximeter with a specialized and useful sensor is available readily. Is this kind of sensor not available because of "national security" issues? I wonder what excuse the apparitchik in Langley has ginned up.

I think a good oximeter would be a very good tool. Perhaps too good that it would expose the scam of ventilators. They would be exposed as death machines - of the gas chamber variety. Their use should be banned, and they can be reassigned to prisons to execute death sentences for hardened criminals, such as those who set up the protocols in place for the modern medical hospital system.
 
Last edited:

yerrag

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Ray Peat, in a recent interview, where he mentioned the right way of interpreting and using pulse oximeters, talked about the poor quality on readings in the current crop oximeters that are widely available, but he didn't elaborate. Now, we know what he meant. So, where can we buy pulse oximeters that are better? I'm failing to find good oximeters in my search. Amazon doesn't seem to carry anything where the description would tout the product as distinctive, especially when it comes to giving accurate oxyhemoglobin saturation values, and if available, the ability to measure carboxyhemoglobin values as well.

@LifeGivingStore do you have any such product in the pipeline? I'd be very interested in getting one.

In this day and age where we're flooded with sensors of all sorts off-the-shelf, I find it ludicrous to believe that no oximeter with a specialized and useful sensor is available readily. Is this kind of sensor not available because of "national security" issues? I wonder what excuse the apparitchik in Langley has ginned up.

I think a good oximeter would be a very good tool. Perhaps too good that it would expose the scam of ventilators. They would be exposed as death machines - of the gas chamber variety. Their use should be banned, and they can be reassigned to prisons to execute death sentences for hardened criminals, such as those who set up the protocols in place for the modern medical hospital system.
This one from Masimo costs $3,500:

Masimo - Rad-57
 

md_a

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So how can we prevent porphyrin poisoning and stop all the terrible effect that result from it?

“Porphyrins are the pigment molecules that include the heme of hemoglobin, of the respiratory cytochromes, the peroxidases including thyroid peroxidase, and of the P450 enzymes which, among other things, produce steroid hormones.” RP

“The heme group (of hemoglobin and the respiratory enzymes, for example) is the iron-binding oily molecule that interacts with oxygen, and it is called a porphyrin.”RP


“Besides the frequently discussed interactions of excessively accumulated iron with the unsaturated fatty acids, producing lipid peroxides and other toxins, the accumulated calcium very probably forms some insoluble soaps with the free fatty acids which are released even from intracellular fats during stress. The growth of new mitochondria probably occasionally leaves behind such useless materials, combining soaps, iron, and porphyrins remaining from damaged respiratory enzymes.

When the background of carbon dioxide is high, circulation and oxygenation tend to prevent the anaerobic glycolysis that produces toxic lactic acid, so that a given level of activity will be harmful or helpful, depending on the level of carbon dioxide being produced at rest.” Mitonchondria and mortality

“Sensitivity to the harmful effects of light can be increased by some drugs and by excess porphyrins produced in the body (and by the porphyrin precursor, delta-amino levulinic acid), leading to rosacea, so those factors should be considered, but too often alcohol (which can cause porphyrin to increase) is blamed for rosacea and rhinophyma, without justification. There are many ways in which poor health can increase light sensitivity. Some types of excitation produced by metabolites (or by the failure of inhibitory metabolites) can produce vasodilation, involving the release of nitric oxide (Cardenas, et al., 2000), setting off a series of potentially pathological reactions, including fibrosis. The nitric oxide increases glycolysis while lowering energy production. The excitatory metabolite glutamate, and nitric oxide, are both inhibited by aspirin (Moro, et al., 2000).



Estrogen's most immediate effect on cells is to alter their oxidative metabolism. It promotes the formation of lactic acid. In the long run, it increases the nutritional requirements for the B vitamins, as well as for other vitamins. It also increases the formation of aminolevulinic acid, a precursor of porphyrin, and increases the risk of excess porphyrin increasing light sensitivity. Both aminolevulinic acid and excess porphyrins are toxic to mitochondria, apart from their photosensitizing actions. Nitric oxide, glutamate, and cortisol all tend to be increased by estrogen.



Lactate, glutamate, ammonium, nitric oxide, quinolinate, estrogen, histamine, aminolevulinate, porphyrin, ultraviolet light, polyunsaturated fatty acids and endotoxin contribute to excitatory and excitotoxic processes, vasodilation, angioneogenesis, and fibrosis.” Rosacea, inflammation, and aging: The inefficiency of stress

“My results, in which estrogen interfered with respiration, made me think of Warburg's description of cancer metabolism. He saw cancer's,respiratory defect’; as depriving it of the energy it needed to function as a useful tissue, leaving it only the primitive function of growth. I considered many ways in which estrogen might be a cancer hormone, including its promotion of the oxygen-wasting age pigment, and its stimulation of porphyrin metabolism, since some researchers had seen an association between cancer and porphyrins. At that time, it wasn't known that the breakdown of the porphyrin, heme, produced carbon monoxide.

But beyond the possibility that estrogen was deeply involved in the nature of cancer, I felt that its biological role had to do with its interference with oxidative metabolism. Selye had characterized estrogen's effect as ‘like the shock phase of the stress reaction’. Estrogen does act in conjunction with histamine, and histamine alone tends to cause circulatory collapse by allowing fluid to leak out of blood vessels. Lack of oxygen probably relates more generally to the shock reaction than does histamine.The reduction of cellular energy is probably estrogen's central action, and in Warburg's scheme, this would be the way to turn on cell division and growth. In the absence of oxygen, cells take up water, and when water-logged (even from being placed in a hypotonic fluid), they begin to divide.” Ray Peat - From PMS To Menopause Females Hormones In Context

“The increased energy deficiency produced by accumulated toxins and fibrosis can stimulate the production of porphyrins for the heme enzymes that control respiration and detoxification, and this can lead to the production of carbon monoxide and other anti-respiratory factors. Increasing amounts of ammonia and lactic acid circulate through the tissues.” Ray Peat - FIBROSIS

...

“Almost any sort of liver disease increases the systemic ammonia level. Estrogen can cause a large variety of liver diseases, including fatty liver and cholestasis; ammonia, which is toxic in itself, also links into another potentially toxic system, the porphyrin synthetic system.

Porphyria (acute intermittent porphyria, hepatic porphyria) is a disease that can cause nerve damage, hypertension, and connective tissue damage. It typically involves an excess of two precursors of heme, and sometimes a deficiency of heme (needed for respiratory enzymes), and it is often triggered by hypoglycemia, by exercise, and by estrogen or by certain poisons. Although it is usually described as a strictly genetic disease, it is higly susceptible to environmental influences, and a proper reevaluation of the evidence might show that it is more often environmental than genetic. Most of the evidence for a genetic cause consists of measurements that show low activity of certain enzymes. Since the conditions prevailing when a protein is synthesized can affect its structure and functions, the simple measurement of enzyme activity is hardly an appropriate argument.

The two substances that accumulate happen to be in a synthetic sequence, subsequent to a step in which C02 is removed, and before a step in which NH3, ammonia, is removed. The principle of mass action indicates that a reaction will slow or stop when there is a certain concentration of the product of the reaction. High C02 and low NH3 will prevent an accumulation of these chemicals, one of which is a potent neurotoxin. The opposite situation, low C02 and high NH3 (ammonia), will tend to cause an accumulation of these substances. Therefore, a simple metabolic shift that predictably happens in stress and malnutrition, can explain the main type of porphyria, independently of specific genetic problems. Everyone's genetic constitution is unique, and in a metabolically complex condition such as porphyria, there will be a spectrum of susceptibility. To draw a line across the spectrum, dividing people with "genetic defects" from the normal, is a purely arbitary and illogical procedure. It is much more important to identify and eliminate "porphyriogenic" environments.

Since porphyria attacks commonly occur premenstrually or after skipping a meal, the food cravings caused by increased estrogen ·and lowered blood sugar, are probably reinforced in many people by dread of the terrible symptoms that can be produced by not eating enough, resulting from the increased ammonia and porphyrins or porphyrin precursors. Calorie restriction can be dangerous when porphyria is developing. The presence of porphyrin poisoning, with its associated free radical toxins, can lead to the activation of heme oxygenase, the enzyme which produces carbon monoxide, which I have discussed elsewhere as a cause of the respiratory defect that characterizes cancer. Both ammonia and porphyria have been implicated in the production of cancer.

Acetazolamide, a drug that causes carbon dioxide to be retained in the tissues, tends to block the formation of ammonia. This is probably a confirmation of the importance of carbon dioxide as an anti-ammonia factor. High altitude also causes increased retention of carbon dioxide in the tissues, because of the Haldane-Bohr effect, and the reduction of ammonia (production, serum concentration, and excretion) at high altitude is probably even greater than the reduction of lactate production.” Ray Peat -Estrogen, Aging, Radiation, Migraine & Energy

...

“THE ORIGINAL ARGUMENT:

Cancer is the result of ordinary physiological processes which become autonomous because of regulatory weaknesses in the organism. Respiration is essential for the maintenance of the higher forms of life, and it is a respiratory 'defect, on both the cellular and the organismic levels, which allows cancer to persist and develop.

The heme group, because it serves many respiratory functions--hemoglobin, mitochondrial respiratory enzymes, steroid synthesizing enzymes, formation of thyroid hormone, detoxifying enzymes--is regulated in relatively primitive ways within each cell, and in more complex ways at higher organismic levels.

When the cell needs more respiratory energy, some fuel is diverted into the production of porphyrin, which is then turned into heme, which would normally provide for the efficient production of energy and protective factors.

When the efficient energy-producing systems are blocked, by injury, oxygen deficiency, toxins, or by the lack of one or more essential nutritional factors, heme production is activated.

Excess heme is destroyed by the enzyme heme oxygenase, which converts heme into biliverdin and carbon monoxide. Both of these factors have effects on the cell which are characteristic of cancer.

Estrogen, radiation, chemical carcinogens, and other forms of stress, activate the heme oxygenase enzyme.

Estrogen causes both porphyria and jaundice and is associated with increased formation of carbon monoxide. It inhibits many types of liver function, including detoxification.

The production of carbon monoxide by cancer cells can account for cancer's self-sustaining, "hereditary," property, without invoking genetic mutations which are now known to be consequences, rather than causes of cancer.

The production of carbon monoxide and biliverdin can account for many of the structural and biochemical abnormalities of cancer cells, and for their induction of abnormalities in adjacent cells.

"Genetic" theories of cancer have now reached a dead end, and the epigenetic, developmental physiological approach remains as the only plausible description of cancer.” Carbon monoxide, estrogen, and the medical cancer cult

...

“THE ARGUMENT:

Cancer is the result of ordinary physiological processes which become autonomous because of regulatory weaknesses in the organism. Respiration is essential for the maintenance of the higher forms of life, and it is a respiratory defect, on both the cellular and the organismic levels, which allows cancer to persist and develop. The heme group, because it serves many respiratory functions--hemoglobin, mitochondrial respiratory enzymes, steroid synthesizing enzymes, formation of thyroid hormone, detoxifying enzymes--is regulated in relatively primitive ways within each cell, and in more complex ways at higher organismic levels. When the cell needs more respiratory energy, some fuel is diverted the production of porphyrin which is then turned i which would normal provide for the efficient production of energy and protective factors.

When the efficient energy-producing systems are blocked by injury, oxygen deficiency, toxins, or by the lack of one or more nutritional factors, heme production is activated. Excess heme is destroyed by the enzyme heme oxygenase which converts heme into biliverdin and monoxide. Both of these factors have effects on the cell wich are characteristic of cancer. Estrogen, radiation, chemical carcinogens and other forms of stress, activate the heme oxygenase enzyme.

Estrogen causes both porphyria and jaundice and is associated with increased formation of carbon monoxide. It inhibits types of liver function, including detoxification.

The production of carbon monoxide by cancer cells can account for cancer's self-sustaining, "hereditary," property, without invoking genetic mutations which are now known to be consequences, rather than causes of cancer.

The production of carbon monoxide and biliverdin can account for many of the structural and biochemical abnormalities of cancer cells, and for their induction of abnormalities in adjacent cells. "Genetic" theories of cancer have now reached a dead end, and the epigenetic, developmental physiological approach remains as the only plausible description of cancer.



Strong discovered that and poor nutrition lead to overproduction of the porphyrin pigment, and contribute to the development of cancer. He showed that the liver was involved in the control of cancer. The Shutes, the Biskinds, and Alexander Lipshutz were at this time revealing other effects of estrogen that illuminated Strong's discoveries.” Ray Peat ‘Carbon Monoxide, Stress, and Cancer: 1999 status’

...

“Estrogen promotes lactic acid formation, and promotes porphyrin synthesis, providing the material for forming heme and carbon monoxide. Besides causing porphyria, estrogen causes many other liver diseases, including chole"stasis, the failure to release bile; the inhibition of carbon monoxide formation has been found to promote bile flow. Estrogen promotes the formation of the enzyme heme oxygenase, which forms carbon monoxide from heme. Carbon monoxide increases the formation of cortisol, by stimulating ACTH release from the pituitary.

The stress response is self-sustaining on several levels.

For example, stress increases the absorption of bacterial endotoxin from the intestine, which increases the estrogen level and synergizes with biliverdin and cortisol.

While estrogen does cause direct DNA damage, its clearest effect in carcinogenesis is on the cytoskeleton which regulates cell division, and defective cell division, rather than "gene mutation," is one of the important steps in the progression of cancer (Rubin, Duesberg).

Cancer cells are protected against the body's ability to destroy them, by the antioxidant functions of carbon dioxide and biliverdin.



This would include antiestrogen regimes, antiinflammatory and antihistamine factors (histamine interacts closely with nitric oxide and carbon monoxide), adequate nutrition, carbon dioxide, and specific anti-carbon monoxide therapies (such as light, alcohol, and possibly the minerals which convert porphyrin into compounds that inhibit the production of carbon monoxide), and methods to decrease nitric oxide formation and to restrain cortisol production, since these promote the formation of carbon monoxide. One of the most interesting approaches to inhibiting carbon monoxide production is to use vitamin B12, as hydroxocobalamin, as an antidote to nitric oxide, preventing the nitric oxide from stimulating the formation of heme oxygenase.

Wherever carbon monoxide mediates a biological malfunction, as in aquired immunodeficiency, Alzheimer's disease, and cancer, vitamin B12 seems to have a place as a detoxicant.

Progesterone and thyroid have several desirable properties that make them generally useful in cancer prevention and therapy. The shorter-chain saturated fatty acids contained in coconut oil have several beneficial effects. Aspirin and vitamin E and simultaneously destabilizing normal cellular phenotypes.” Ray Peat

...

When something interferes with the normal, productive use of oxygen, there is a great increase in the destructive forms of oxidation, such as lipid peroxidation, and the antioxidative reserves become crucial. That is, decreased respiration of the productive sort tends to increase the destructive use of oxygen.

In 1895 Magnus-Levy demonstrated that hypothyroid people have abnormally low heat production,

and that their heat production could be brought up to normal by giving them thyroid substance.

In 1926, Otto Warburg showed that the respiratory enzyme, containing the heme group, is inhibited by carbon monoxide, which binds to that enzyme, as it does to hemoglobin. Warburg also showed that visible light restores the activity of the respiratory enzyme by dissociating it from the carbon monoxide.

The heme group (of hemoglobin and the respiratory enzymes, for example) is the iron-binding oily molecule that interacts with oxygen, and it is called a porphyrin. There is a long history of investigating the interactions of porphyrin metabolism with estrogen with diet, and with excess iron. Estrogens are known to cause porphyria and to exacerbate the symptoms and biochemical disturbances in· people with subclinical porphyria.

Sometimes symptoms occur premenstrually, during the time of increased estrogen production—the term "ovulocyclic porphyria" has been in use for a long time. Puberty therefore increases the susceptibility to symptomatic episodes. Jaundice in pregnancy and in oral contraceptive users is probably a closely related phenomenon.

Porphyrin synthesis begins at an important cross-over point of protein and carbohydrate metabolism.

Succinyl CoA and amino levulinic acid can enter the Krebs cycle or the porphyrin pathway.

Protein catabolism feeds into these pathways. Increased protein catabolism or blockage of oxidative consumption of Krebs cycle fuel--for example by poisoning--makes these precursors available to enter the porphyrin pathway. Stress-induced oxidation of heme can eliminate feedback control, but the specific outcome can be modified in many ways...

Low blood sugar, most often caused by hypothyroidism, and diabetes--which involves poor absorption of sugar by cells--both tend to lower the respiratory quotient, the amount of carbon dioxide produced in relation to the amount of oxygen used.

High carbohydrate diets, sometimes with insulin have been used to treat porphyria. The use of carbon dioxide inhalation in psychiatry has many metabolic justifications, one of which might be the importance of carbon dioxide in glucose regeneration. It is also essential for detoxifying ammonia.

Whenever a symptom is relieved by glucose, I think we should suspect that thyroid and carbon dioxide might be deficient.

Many serious long-range consequences of excess heme/porphyrin production and metabolism are currently being investigated, suggesting that the criterion of "twice the upper limit of normal" excretion that was recently proposed by a government agency, for recognizing that a problem exists, could allow far more serious problems to develop over time, that on the surface might seem unrelated to porphyria. I consider any porphyrin excess to be a serious indicator of physiological stress. The ramifications of disturbed heme metabolism, resulting from exogenous factors, are far-reaching. For example, G. Y. Kennedy, at the Cancer Research Laboratory, University of Sheffield, observed that a porphyrin shortened the time required to induce tumors, and porphyrin derivatives have been proposed to be “cancer hormones."

The carbon monoxide produced in the breakdown of heme inhibits many enzymes. The consequences of slight excesses in porphyrin metabolism just haven't been investigated, because of the genetic dogmatism that denies that the person's environment could be at fault.

The synthesis of heme/porphyrin, and the production of red blood cells, are stimulated by a lack of oxygen, or by toxins such as arsenic and iron, which cause oxidative stress. Emphysema, high elevation, sluggish circulation, and nocturnal breathing problems can cause enough oxygen deficiency to stimulate the formation of new red blood cells. Newborn babies often have polycythemia, as a result of limited prenatal oxygen supply. At a certain point, the continued production of red blood cells can make the blood so viscous that this viscosity impairs circulation through capillaries, and creates a vicious circle, stimulating the formatjon of more red blood cells. Men are more likely than women to have polycythemia rubra vera, possibly because testosterone is anabolic to the bone marrow, and estrogen tends to slow blood cell formation (females of all species are relatively "anemic" compared to males, partly because their blood is more dilute), but I think the greater ability of men's marrow to respond proliferatively to hypoxia is influenced by many factors.” Ray Peat – ‘Optimizing respiration’

...


“Oxygen deprivation causes tissues to retain calcium (and iron), as does estrogen in many cases, being similar to aging in promoting cellular uptake of calcium. Since the porphyrins strongly bind metals, it has been suggested that they may have a role in mediating the deposition of metals in stressed tissues. Paroxysmal vasospasm occurs in about 90% of scleroderma patients, and estrogen and adrenalin are known to synergize in producing vascular spasm; hypothyroidism normally involves elevations of both estrogen and adrenalin.

The porphyrins break down into bilirubin, which also poisons mitochondrial respiration (Zetterstrom and Ernster).”



“When extracts of cancers were injected into healthy animals, some of them became sick, and were inclined to develop cancer. Several lines of investigation led to the belief that pyrroles and porphyrins, related to heme (the iron-binding pigment in hemoglobin and various oxidative enzymes), might be a "cancer hormone," but the idea lacked charm, and didn't catch on.

I made extracts from aged uterine tissue, thinking it might contain estrogen, and found that when I injected it into a hamster, it seemed to cause secretion of porphyrin from the animal's eye. This led me to get interested in the hormonal significance of the porphyrin pigment, and it was known to be related to estrogen excess and cancer susceptibility. Two of cancer's most mysterious features are its respiratory defect, identified by Otto Warburg, in which it converts glucose to lactic acid even in the presence of oxygen, and its resistance to lipid peroxidation. Lipid peroxidation is intimately involved in the control of cell division and aging, and in susceptibility of cells to elimination by the immune system, so cancer's antioxidative capacity seems to be closely related to its "immortal" nature. Iron (either free or bound to heine) is known to catalyze lipid peroxidation, but its presence in cancer cells simply supports their growth, rather than causing peroxidation.

Warburg discovered that light desorbs carbon monoxide and cyanide from respiratory pigments. In trying to understand light's effects on respiration, it occurred to me that it might be desorbing those, or other toxins that bind to and inhibit the respiratory enzymes. Cancer cells lack the ability to detoxify cyanide, so it has seemed possible that cyanide might contribute to the respiratory defect of cancer; bowel bacteria can produce small amounts.

But carbon monoxide is always being produced in the body, by the enzyme heme oxygenase, which is involved in the breakdown of hemoglobin. Carbon monoxide, by binding to heme-iron, inhibits lipid peroxidation, as well as inhibiting the respiratory pigments in the mitochondria.

Warburg observed that depriving growing cells of oxygen was sufficient to cause some of them to turn into cancer cells.

Anything which causes oxygen deprivation stimulates the formation of heme.

If the breakdown of heme occurs in cancer cells, that is, if heme oxygenase can be demonstrated in them, then the conditions exist for a stable, heritable but non-genetic state which, as a result of the carbon monoxide which is produced in heme metabolism, combines a respiratory defect with resistance to lipid peroxidation. Heme oxygenase is induced by a variety of stresses, especially oxidative stress, and is known to exist in at least some cancers. I think it will turn out to be a universal feature of cancer. Heme could function as a systemic toxin, if produced in cancer cells in abundance, since it would be metabolized in the liver, with production there of abnormally large amounts of carbon monoxide. Liver abnormalities have long been recognized as an important feature of cancer. And carbon monoxide, produced by a large tumor, would certainly be a systemic toxin. It could also account for the "regional cancerization" which has been reported to occur in the area immediately around a tumor, in which normal cells seem to be modified by the cancer as if by an inductive agent. These observations have always been discounted by the genetic dogmatists.

The relation between estrogen and porphyrin (which can be seen in some types of porphyria), and their association with cancer susceptibility, probably is a consequence of estrogen's interference with blood oxygenation, which would tend to cause exaggerated production of heine in various tissues. A sensitive instrument is now available, which can measure carbon monoxide in the breath; this could become an important diagnostic instrument.

Besides using light to desorb toxins from the heme group, there are probably various ways to directly inhibit the formation of heme. For example, ethyl alcohol inhibits heme formation (the "hemeless" ring sideroblast is often considered to be a sign of alcoholism). Alcohol is superior in many ways to morphine for pain control in cancer patients, and if carbon monoxide produced by heme breakdown turns out to be a factor in cancer's persistence, alcohol might become an important factor in the prevention or treatment of cancer. It would be necessary to use a highly purified form of vodka, free of estrogen and other carcinogens. Except for bowel and liver cancer, the alcohol should be taken transdermally or intravenously. Anti-inflammatory and antihistamine agents, magnesium, progesterone, pregnenolone and other substances could be used to support oxidative metabolism.

The material used in heme synthesis is diverted from energy production. Useless heme production would contribute to cancer's energy-depleting effect on the organism.

Although carbon monoxide production by cancer cells will seem merely an incidental feature to the genetic dogmatists, I think it offers the opportunity for a unifying perspective on cancer, explaining both its systemic effects (immune suppression, wasting, and adrenal activation, for example) and its cellular features, including the respiratory defect, dedifferentiation, resistance to killing by lipid peroxidation, and – in some ways the most important feature - its stability, which has led so many people to call it a "genetic disease." Metabolic stress does cause chromosomal damage and mutations, but without the intrinsic resistance to lipid peroxidation, these defects would lead to the cells' death.” - Ray Peat ‘Carbon Monoxide: Cancer Hormone?’
 

md_a

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New Insight into the Mechanism of Anaerobic Heme Degradation.

Abstract
ChuW, ChuX, and ChuY are contiguous genes downstream from a single promoter that are expressed in the enteric pathogen Escherichia coli O157:H7 when iron is limiting. These genes, and the corresponding proteins, are part of a larger heme uptake and utilization operon that is common to several other enteric pathogens, such as Vibrio cholerae. The aerobic degradation of heme has been well characterized in humans and several pathogenic bacteria, including E. coli O157:H7, but only recently was it shown that ChuW catalyzes the anaerobic degradation of heme to release iron and produce a reactive tetrapyrrole termed "anaerobilin". ChuY has been shown to function as an anaerobilin reductase, in a role that parallels biliverdin reductase. In this work we have employed biochemical and biophysical approaches to further interrogate the mechanism of the anaerobic degradation of heme. We demonstrate that the iron atom of the heme does not participate in the catalytic mechanism of ChuW and that S-adenosyl-l-methionine binding induces conformational changes that favor catalysis. In addition, we show that ChuX and ChuY have synergistic and additive effects on the turnover rate of ChuW. Finally, we have found that ChuS is an effective source of heme or protoporphyrin IX for ChuW under anaerobic conditions. These data indicate that ChuS may have dual functionality in vivo. Specifically, ChuS serves as a heme oxygenase during aerobic metabolism of heme but functions as a cytoplasmic heme storage protein under anaerobic conditions, akin to what has been shown for PhuS (45% sequence identity) from Pseudomonas aeruginosa.

New Insight into the Mechanism of Anaerobic Heme Degradation. - PubMed - NCBI
 

md_a

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From Host Heme To Iron: The Expanding Spectrum of Heme Degrading Enzymes Used by Pathogenic Bacteria

Iron is an essential nutrient for many bacteria. Since the metal is highly sequestered in host tissues, bound predominantly to heme, pathogenic bacteria often take advantage of heme uptake and degradation mechanisms to acquire iron during infection. The most common mechanism of releasing iron from heme is through oxidative degradation by heme oxygenases (HOs). In addition, an increasing number of proteins that belong to two distinct structural families have been implicated in aerobic heme catabolism. Finally, an enzyme that degrades heme anaerobically was recently uncovered, further expanding the mechanisms for bacterial heme degradation. In this analysis, we cover the spectrum and recent advances in heme degradation by infectious bacteria. We briefly explain heme oxidation by the two groups of recognized HOs to ground readers before focusing on two new types of proteins that are reported to be involved in utilization of heme iron. We discuss the structure and enzymatic function of proteins representing these groups, their biological context, and how they are regulated to provide a more complete look at their cellular role.

Conclusion
In many pathogenic bacteria, heme catabolism is carried out by HOs similar to either HO-1 or IsdG. Other bacteria encode enzymes that bind and degrade heme in vitro. These proteins fall into two families based on structure: enzymes that contain HemS motif and those with PNPOx domains. Proteins from these families are regulated by iron, support bacterial growth on heme iron, and/or aid in tolerance of heme and oxidative stress. It seems possible that proteins from these families might have evolved to serve separate functions in different bacteria. Already, PhuS was shown in vivo to shuttle heme to the HO, PigA/HemO. While in vitro degradation and additional investigations link proteins from these families to iron/heme metabolism, more work is required to determine their physiological role. Genetic studies suggest that even in bacteria with recognized HOs there are additional (likely non-homologous) enzymes that aid in heme degradation. This redundancy emphasizes the importance of this mechanism for bacterial physiology. For 50 years, this area has challenged both researchers and technology. While much has been learned about how pathogenic bacteria obtain iron, the complexity and diverse strategies employed by the bacteria could easily fascinate researchers for many more years.

From Host Heme To Iron: The Expanding Spectrum of Heme Degrading Enzymes Used by Pathogenic Bacteria
 
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