Water Structure, Osmolytes And Cancer

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LLight

LLight

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Hi @yerrag

I think AS10 peptide is a derivative of it, or something similar to it.

I can't find the AS10 on Google search, as I'd like to use it also.

Do you intend to buy and take some AS10, or just study it?

I read some articles where authors say they would like to replace antibiotics (due to resistance to current ones) by such peptides but I don't know if it is sold yet (for scientists at least I guess) or if the safety has been properly assessed :):
 

yerrag

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Hi @yerrag



Do you intend to buy and take some AS10, or just study it?

I read some articles where authors say they would like to replace antibiotics (due to resistance to current ones) by such peptides but I don't know if it is sold yet (for scientists at least I guess) or if the safety has been properly assessed :):
I'd like to buy some. There are some other peptides I've read about that can disrupt the biofilm of p. gingivalis, which is my nemesis:

Bar peptide, Nal-P-113, peptide Pac-525, and agents derived from lactoferrin.

But I think dry fasting for LL-37 would be just as good. And it's free.
 
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I'd like to buy some. There are some other peptides I've read about that can disrupt the biofilm of p. gingivalis, which is my nemesis:

Bar peptide, Nal-P-113, peptide Pac-525, and agents derived from lactoferrin.

But I think dry fasting for LL-37 would be just as good. And it's free.

If you try these, I would be interested to know how much you take and of course, if it works for you!
 

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Aldehyde Dehydrogenase 7A1 (ALDH7A1) Is a Novel Enzyme Involved in Cellular Defense against Hyperosmotic Stress

"Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes."

"ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria, making it unique among the aldehyde dehydrogenase enzymes."

"Initially named “antiquitin,” the ALDH7A1 protein has been highly conserved throughout evolution. Indeed, the degree of homology noted between ALDH7A1 and ALDH7B1 is comparable with that observed between the human and pea histone H2A proteins, which are among the most evolutionarily conserved of all eukaryotic proteins (2, 3). Such a high degree of sequence similarity between species often indicates an essential and functionally conserved role within the cell."​

I wonder if ALDH7A1, which should be produced during osmotic stress, couldn't also be an enzyme that metabolize vitamin A to retinoic acid. The study below provides an answer that but I am not satisfied by their results/conclusions ;)

aldh7a1 regulates eye and limb development in zebrafish

"Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development."

"Knockdown of aldh7a1 in zebrafish leads to uveal coloboma and skeletal abnormalities."

"Because of the strong expression of aldh7a1 in the developing zebrafish eye and the ventral nature of uveal coloboma, we examined expression of genetic markers known to be important in eye ventralization, including nlz1, vax2, pax2.1, nlz2, and vax1 [...] The expression of nlz1 that was seen in the optic fissure and periocular mesenchyme in control embryos was lost in aldh7a1 morphant embryos. This loss of expression led us to hypothesize that nlz1 functions downstream of aldh7a1."

"In zebrafish, blocking RA during development resulted in coloboma. Additionally, RA regulates nlz1 in zebrafish, demonstrated by a significant decrease in nlz1 expression in embryos where RA signaling is blocked."

"co-injection of nlz1 mRNA partially rescued the aldh7a1 morphants"

"These existing connections of RA to coloboma led us to pursue it as a chemical that is potentially involved in the aldh7a1 pathway."

"Thus we conclude that exogenous RA is not able to rescue the aldh7a1 morphant eye phenotype and is less likely to be the endogenous substrate.".​

So we have :
  1. Lack of ALDH1A7 => Uveal coloboma
  2. Lack of RA => Uveal coloboma
  3. ALDH1A7 => nlz1
  4. RA => nlz1
  5. Lack of ALDH1A7 and nlz1 => Partial uveal coloboma
  6. Lack of ALDH1A7 and RA => Uveal coloboma
So they conclude that retinoic acid is not a substrate of ALDH1A7 because a lack of ALDH1A7 leads to coloboma and a lack of ALDH1A7 with retinoic acid infusion does not rescue the uveal coloboma.

But another option is that retinoic acid could be a product of ALDH1A7 but that for example, the production of nlz1 is dependent on ALDH1A7 too and that infusing retinoic acid is not enough to avoid coloboma.

I'm interested to know whether retinoic acid is a product of this enzyme because the ALDH1A7 is upregulated during osmotic stress and to my understanding, osmotic stress/dehydration/NFAT5 upregulation is correlated with an increased immune system response that seem to be able to bypass situations where the immune system could be hijacked by pathogens (for example, VDR inactivation).

The study which has me wondered this question is this one:
Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis

"These studies indicate that the vitamin A system plays an important role in mitigating TB; however, the mechanism by which retinol influences the immune response is not a direct effect. Our results here demonstrate that for retinol to trigger an antimicrobial response, it must first be metabolized into ATRA; therefore, since TB lung has lower expression of ALDH1A2, systemic restoration of retinol levels will have minimal effects at the site of infection with a lack of local metabolism-dependent transactivation. Therefore, novel therapeutics that enhance retinol metabolism in the lungs of active TB patients could potentially be used in conjunction with retinol supplementation as an immunotherapy targeting the innate immune response to infection. Alternatively, given that normal lung expresses the vitamin A metabolic machinery, supplementation of retinol-deficient individuals prior to M. tuberculosis exposure provides a strategy that might prevent the spread of disease."​

M. tuberculosis could block the other ALDH enzymes and thus the vitamin A pathway. If these pathogens block the ALDH1A7 enzyme too and that there is osmotic stress, the cell may die because the ALDH1A7 is essential to survive this stress. Again pure speculation but I find it an interesting idea even if the study above seems to induce that this enzyme does not convert retinal to RA.
 

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Citrullination Alters Immunomodulatory Function of LL-37 Essential for Prevention of Endotoxin-Induced Sepsis :

Abstract
Cathelicidin LL-37 plays an essential role in innate immunity by killing invading microorganisms and regulating the inflammatory response. These activities depend on the cationic character of the peptide, which is conferred by arginine and lysine residues. At inflammatory foci in vivo, LL-37 is exposed to peptidyl arginine deiminase (PAD), an enzyme released by inflammatory cells. Therefore, we hypothesized that PAD-mediated citrullination of the arginine residues within LL-37 will abrogate its immunomodulatory functions. We found that, when citrullinated, LL-37 was at least 40 times less efficient at neutralizing the proinflammatory activity of LPS due to a marked decrease in its affinity for endotoxin. Also, the ability of citrullinated LL-37 to quench macrophage responses to lipoteichoic acid and poly(I:C) signaling via TLR2 and TLR3, respectively, was significantly reduced. Furthermore, in stark contrast to native LL-37, the modified peptide completely lost the ability to prevent morbidity and mortality in a mouse model of d-galactosamine–sensitized endotoxin shock. In fact, administration of citrullinated LL-37 plus endotoxin actually exacerbated sepsis due to the inability of LL-37 to neutralize LPS and the subsequent enhancement of systemic inflammation due to increased serum levels of IL-6. Importantly, serum from septic mice showed increased PAD activity, which strongly correlated with the level of citrullination, indicating that PAD-driven protein modification occurs in vivo. Because LL-37 is a potential treatment for sepsis, its administration should be preceded by a careful analysis to ensure that the citrullinated peptide is not generated in treated patients.

Citrullination as a Plausible Link to Periodontitis, Rheumatoid Arthritis, Atherosclerosis and Alzheimer's Disease - PubMed :

Abstract
Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer's disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

@LLight It seems to me that my periodontal bacteria are causing citrullination of arginine. The peptide LL-37 would be rendered ineffective in deactivating LPS as well as in destroying bacteria when its arginine residues are citrullinated by the PPAD secreted by the periodontal bacteria P. gingivalis.

I would have to either find a way to deactivate or inhibit PPAD secretion by p. gingivalis, or destroy p. gingivalis. The latter is much harder to do, given the proliferation of p. gingivalis colonies in my vascular system. I would have to find a way to deactivate the PPAD enzyme, or to inhibit its production first before I could expect to benefit from fasting to induce conditions that favor the production of LL-37.
 
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Citrullination Alters Immunomodulatory Function of LL-37 Essential for Prevention of Endotoxin-Induced Sepsis :

Abstract
Cathelicidin LL-37 plays an essential role in innate immunity by killing invading microorganisms and regulating the inflammatory response. These activities depend on the cationic character of the peptide, which is conferred by arginine and lysine residues. At inflammatory foci in vivo, LL-37 is exposed to peptidyl arginine deiminase (PAD), an enzyme released by inflammatory cells. Therefore, we hypothesized that PAD-mediated citrullination of the arginine residues within LL-37 will abrogate its immunomodulatory functions. We found that, when citrullinated, LL-37 was at least 40 times less efficient at neutralizing the proinflammatory activity of LPS due to a marked decrease in its affinity for endotoxin. Also, the ability of citrullinated LL-37 to quench macrophage responses to lipoteichoic acid and poly(I:C) signaling via TLR2 and TLR3, respectively, was significantly reduced. Furthermore, in stark contrast to native LL-37, the modified peptide completely lost the ability to prevent morbidity and mortality in a mouse model of d-galactosamine–sensitized endotoxin shock. In fact, administration of citrullinated LL-37 plus endotoxin actually exacerbated sepsis due to the inability of LL-37 to neutralize LPS and the subsequent enhancement of systemic inflammation due to increased serum levels of IL-6. Importantly, serum from septic mice showed increased PAD activity, which strongly correlated with the level of citrullination, indicating that PAD-driven protein modification occurs in vivo. Because LL-37 is a potential treatment for sepsis, its administration should be preceded by a careful analysis to ensure that the citrullinated peptide is not generated in treated patients.

Citrullination as a Plausible Link to Periodontitis, Rheumatoid Arthritis, Atherosclerosis and Alzheimer's Disease - PubMed :

Abstract
Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer's disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

@LLight It seems to me that my periodontal bacteria are causing citrullination of arginine. The peptide LL-37 would be rendered ineffective in deactivating LPS as well as in destroying bacteria when its arginine residues are citrullinated by the PPAD secreted by the periodontal bacteria P. gingivalis.

I would have to either find a way to deactivate or inhibit PPAD secretion by p. gingivalis, or destroy p. gingivalis. The latter is much harder to do, given the proliferation of p. gingivalis colonies in my vascular system. I would have to find a way to deactivate the PPAD enzyme, or to inhibit its production first before I could expect to benefit from fasting to induce conditions that favor the production of LL-37.

Interesting information! I wonder whether I could have periodontal issues myself so P. Gingivalis is in my scope too.

Additionnaly, it shows how the immune system and microorganisms seem to be in a "constant fight". In my opinion, it shows that the germ theory of diseases is consistent and that microorganisms are not passive bystanders at all.

The immune system seems to feature redundancies and, even if LL-37 potency is decreased by P. Gingivalis, there might be other peptides or mechanisms that help dealing with them. I have no concrete proof for that claim but I think that, as we are in contact with these pathogens for a long time, there must be a way so that the immune system is able to get rid of them.
 
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yerrag

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Interesting information! I wonder whether I could have periodontal issues myself so P. Gingivalis is in my scope too.

Additionnaly, it shows how the immune system and microorganisms seem to be in a "constant fight". In my opinion, it shows that the germ theory of diseases is consistent and that microorganisms are not passive bystanders at all.

The immune system seems to feature redundancies and, even if LL-37 potency is decreased by P. Gingivalis, there might be other peptides or mechanisms that help dealing with them. I have no concrete proof for that claim but I think that, as we are in contact with these pathogens for a long time, there must be a way so that the immune system is able to get rid of them.
It's a possibility I can't discount, but I'd like to see the p. gingivalis colony weakened enough by exhausting it of its supporting ecosystem. Throwing everything I can get my hands on at it right now. It's a war of attrition, to see who lasts longer.
 

yerrag

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Citrullination as a Plausible Link to Periodontitis, Rheumatoid Arthritis, Atherosclerosis and Alzheimer's Disease - PubMed :

Abstract
Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer's disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

I came up with some studies and reviews on deactivating or inhibiting the PPAD secreted by P. Gingivalis. I came up only with studies that keep the substances a secret, such as in their names being withheld and being called A, B, C, D. I had given up hope but then I decided to look up the constituents of a Chinese herbal blend called Si Wu Tang, Si Wu Tang Pian (Tonics4™) , and as I was looking into the properties of each, Chinese Peony Root caught my eye. Chinese peony root is used for rheumatoid arthritis, and it is possible (my guess only) that it is effective against arthritis because it arrests the citrullination process. With no protein citrullinated and no modification of proteins that would cause the immune system to identify them as a foreign substance, there would be no autoimmune reaction directed at these proteins that causes the symptom of arthritis. Since I only have the si wu tang pill now, I'm trying out this blend that contains the Chinese Peony Root in its formula.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022223/pdf/zjom-10-1487742.pdf
Anti-Inflammatory and Immunomodulatory Effects of Paeonia Lactiflora Pall., a Traditional Chinese Herbal Medicine

This is just one of the many ways I hope to get my body back to be able to produce the LL-37 antimicrobial peptide.

Another way is to deprive P. Gingivalis of its food. This bacteria secretes gingipains that break down protein to proteolytic fragments that the bacteria feeds on. Intake of berberine helps puts this process in check.

Role of Gingipains in Growth of Porphyromonas Gingivalis in the Presence of Human Serum Albumin - PubMed
Berberine Promotes Osteogenic Differentiation of Mesenchymal Stem Cells With Therapeutic Potential in Periodontal Regeneration - PubMed

P. Gingivalis also expresses DPP4, an enzyme which degrades incretins that disturbs the regulation of blood glucose through insulin.

https://iai.asm.org/content/iai/85/9/e00277-17.full.pdf

In my experience, it causes me to become more insulin-resistant. Instead of blood sugar falling within a normal healthy range, it would swing high and then low, and it affects by energy levels. Berberine inhibits DPP4, as well.

Inhibition of Dipeptidyl Peptidase IV (DPP IV) Is One of the Mechanisms Explaining the Hypoglycemic Effect of Berberine - PubMed





Another way is to continue to kill my body store of P. Gingivalis bacteria. This is quite involved as I'm not just directing the firepower at P. Gingivalis, but at the ecosystem it has built around it to maintain its resiliency. For example, there are fungi that support p. gingivalis in a symbiotic relationship. Killing these fungi also weakens P. Gingivalis. It gets involved and I'll save that for a different thread in the future. For now, I'm just throwing the sink at the problem.
 

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It's a possibility I can't discount, but I'd like to see the p. gingivalis colony weakened enough by exhausting it of its supporting ecosystem. Throwing everything I can get my hands on at it right now. It's a war of attrition, to see who lasts longer.

How did you figure out which strain you are infected with?
 

yerrag

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How did you figure out which strain you are infected with?
Good question. It is an assumption I make. There would be other strains for sure, but P. Gingivalis is a keystone bacteria, which I believe to mean that without it my pathology won't be as severe and hard to overcome, given the way P. Gingivalis operates. How it has evolved and adapted over time makes it a very potent foe especially when it reaches an advanced stage of colonization.

I imagine that difficult pathogens such as candida albicans would be as evolved and as difficult to overcome. Knowing their m. o. and their surrogates and vassals and how they work together allows us to beat them at their own game.
 
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Deuterium Depletion as a Possible New Strategy to Combat SARS-CoV-2

"Considering all available data on the effect of deuterium depletion on cell function and metabolism, and over 20 years’ experience with Vetera-DDW-25 deuterium-depleted veterinary medicinal anti-cancer product, which showed anti-viral effect of deuterium depletion in pets"

Mitochondrial deuterium depletion restrains prokaryote proliferation and virus hosting cellular events thus may alleviate the use of biologics

Burn (saturated) fat, create water, drink less and be immune?
 
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Sulfate’s Critical Role for Maintaining Exclusion Zone Water: Dietary Factors Leading to Deficiencies

"Biological water exists in at least two distinct forms: bulk and interfacial. While the former possesses widely understood properties, little has been written about the formation, maintenance, and functional role of interfacial water in living systems. In this paper we equate interfacial water with Exclusion Zone (EZ) water described by Pollack and propose that it is the sulfate molecule that plays a fundamental role in providing the interfacial negative charge that builds and maintains the EZ in biological systems. We further propose novel roles for endothelial nitric oxide synthase (eNOS), erythrocytes, and cobalamin in sulfate production and ongoing regulation. Two exogenous agents, the diabetes drug metformin and the herbicide glyphosate, and one lifestyle factor, vegetarianism/veganism, can contribute to reduced sulfate production and subsequent loss of EZ water. A set of compensatory changes in the body, often normally considered to be discrete pathologies, serve to reestablish adequate sulfate supply in the face of these and other detrimental impacts on sulfate production. Finally, we review additional pathologies associated with cobalamin deficiency and suggest that they, too, can be linked to the restoration of sulfate metabolism."
 
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Characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan, China

"Lymphopenia, anemia, hypoproteinemia, and abnormal serum sodium were presented in 52.6%, 54.6%, 69.8%, and 21.8% cases, respectively."
Half of COVID19 patients had anemia.

Moreover, it is thought that SARS-COV-2 could infect cells via the Basignin / CD147 receptor:

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

Basigin - Wikipedia

"Basigin (BSG) also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147) is a protein that in humans is encoded by the BSG gene.[4][5][6] This protein is a determinant for the Ok blood group system. Basigin has been shown to be an essential receptor on red blood cells for the human malaria parasite, Plasmodium falciparum."​

Now, vasopressin, an hormone/neuropeptide which should be increased when water is restricted, seems to boost the production of red blood cells:

Vasopressin stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia

"In mouse models of anemia (induced by bleeding, irradiation, or increased destruction of circulating RBCs), AVP increased the number of circulating RBCs independently of EPO. In these models, AVP appears to jump-start peripheral blood cell replenishment until EPO can take over."
Increased Production of Erythropoietin After Application of Antidiuretic Hormone. A Consequence of Renal Vasoconstriction?

"The renal glycoprotein hormone erythropoietin (Epo) is the key element in the feedback control of the production of red blood cells (RBC) in bone marrow. Excess of antidiuretic hormone (ADH) increases the RBC mass by increasing the synthesis of Epo."​
 
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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?
 
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Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response - PubMed

Mitochondrial function has been increasingly implicated in regulation of immune responses.
While studies examining the effects of OXT and/or AVP on mitochondrial function remain limited, a growing literature suggests that these neurohormones may directly interact with mitochondria, and that these interactions could have vast effects on mitochondrial bioenergetic functioning, signaling, interaction with the unfolded protein response, and production of reactive oxygen species. These multitudes of neurohormone-mitochondrial interactions may play a significant role in regulating immune responses to a variety of homeostatic challenges, and are a vital area of future research.
Intermittent drinking, oxytocin and human health. - PubMed - NCBI
 
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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."
 

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Watering tropical plants with seawater near the equator with redlight sounds awesome
 
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Reduction of Virus Infectivity in the Presence of Protecting Osmolytes

Protecting osmolytes have the ability to reduce the infectivity by 4-logs of a model non-enveloped virus, porcine parvovirus (PPV) in cell culture. Osmolytes are natural, organic compounds that stabilize intracellular proteins against environmental stresses, such as severe temperature or high osmotic pressure by changing the water content of cells. Protecting osmolytes have the ability to fold proteins by structuring water around the protein surface, therefore stabilizing the protein. We are currently working with PPV, a non-enveloped, icosahedral, single-strand DNA virus, to demonstrate the ability of osmolytes to attenuate non-nenveloped viruses. We have discovered that both glycine and trimethylamine N-oxide (TMAO) reduce the initial 50% infectious dose of PPV from 8-logs to 4-logs. This was quantified by the MTT assay, a cell viability assay that measured the cytopathic effects of PPV virus in susceptible pig kidney cells (PK-13 cells). The reduction in infectivity decreased over time and approached 1 log reduction when the osmolyte was added 20 hours after initial virus infection. We hypothesize that the osmolytes are disrupting the PPV infection cycle. The PPV infection cycle starts with virus attachment to susceptible host cells, and then the virus penetrates the cells through the endosomal pathway to uncoat its genetic material. The virus then uses the host cell’s replication machinery to produce viral DNA. After replication, the virus assembles a protein coat, enveloping the nucleic acids, and then breaks open the cell to release progeny PPV particles. It is possible that the osmolytes inhibit virus infectivity by disruption of either the virus interaction with receptors, the endosomal trafficking of virus through the cell or the transport of virus to the nucleus. It appears that protecting osmolytes stabilize intracellular proteins in the initial stages of the PPV infection cycle. We propose that the presence of protecting osmolytes can reduce virus infectivity of other non-enveloped viruses, such as the rhinovirus, which is known to cause the common cold in humans.​
 
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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."

I'm not sure how it's related but this new preprint seems to make a link between covid19 and water homeostasis:

SARS-CoV-2 selectively mimics a cleavable peptide of human ENaC in a strategic hijack of host proteolytic machinery

"We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site (RRARSVAS), absent in any previous coronavirus sequenced, that results in mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic truncation at this ENaC-α cleavage site causes aldosterone dysregulation in patients, highlighting the functional importance of the mimicked SARS-CoV-2 peptide."

"ENaC regulates Na+ and water homeostasis and its expression levels are controlled by aldosterone and the associated Renin-Angiotensin-Aldosterone System (RAAS)."

"Mimicry of human ENaC-ɑ by the S1/S2 site raises the specter that SARS-CoV-2 may be
hijacking the protease network of ENaC-ɑ for viral activation."

Too complex for my understanding :dead:
I post that for the record.
 

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