md_a
Member
- Joined
- Aug 31, 2015
- Messages
- 468
Your reasoning is correct. Emodin can also be obtained from aloe vera, as a drink without side effects. I gave this example with emodin, but there are several substances in their natural state that have this effect. The sun, vitamin B1, cocoa, ... decrease Ang II. I don't know anything about pine needle tea.Thanks for this @md_a! I haven’t spoken to you in a while but you have always got such great finds. I for one appreciate the help in understanding.
So what I am getting from this (and please do correct if I am wrong as an expert on this I am not by any stretch of the imagination this is what I feel I am contributing to the forum the average guy who knows very little but is not afraid to ask questions)
Cascara segrada would provide a source of emotion which would help prevent the spike proteins spread via transmission bind to the ACE2 receptor and perhaps detox (for lack of a better term) it from our system or at least help move it on the ejection side of things?
Is there a reference to possibly the pine needle tea mentioned earlier in another thread the word polygonaceae seems familiar but I could be wrong.
The most common complication leading to the CoV-induced mortality can be justified through ACE-AngII-AT1-Spike protein overactivation caused by virus / toxin / antiviral drugs
The spikes protein have high affinity to ACE2, uses ACE2 to enter a cell.
It is suggested that this “occupation” of the virus of ACE2 might reduce the ability of Ang II to bind to ACE2.
Accumulated Ang II result in an increased activation of AT1.
Activation of AT1 results in vasoconstriction, increased pro-inflammatory response.
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Ray:
The virus uses ACE2 (angiotensin converting enzyme 2) as receptor and enters cells by the angiotensin receptor. Losartan (recommended in China), an angiotensin blocker, is effective protection, and has many other antiinflammatory effects. The Chinese also have good results with cinanserin, a serotonin blocker. I think cyproheptadine might help, too. Progesterone lowers the angiotensin receptor, but doesn’t act immediately as losartan does.
“The virus activates the angiotensin receptor (AT1), so the receptor blockers are protective—losartan, telmisartan, etc. Progesterone is a natural inhibitor of that receptor. Also the usual antiinflammatory things, aspirin, eggnog, orange juice would be helpful.” Ray Peat
...the angiotensin converting enzyme is one of the early parts of our immune system that sets up an inflammatory reaction that will set in action a whole chain of events, if the pathogen gets trough and is actually a treat, then you activate this proteolytic protein that create angiotensin witch is like a transmitter of a panic reaction to the organism, and it happens this coronavirus is able to bind to one of this angiotensin converting enzymes, there is one with is only pro-inflammatory and the other one that backs that up, which undoes, inhibits the inflammatory damage done by the first angiotensin producing enzyme, this is called ACE2, and ACE2 happens to be attacked by this particular virus witch binds to that enzyme, and that’s receptor its vulnerable point of organism as far this fire is concern, and binding to that ACE2 means that it leaves the ACE1 which produces angiotensin, it leaves that free to act, and ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme, and that enzyme combined with the virus, than acts to enter the cell by way of the angiotensin receptor which is called the AT1, that are two known receptors by which angiotensin can do damage. Angiotensin 1 is strictly an inflammation producing system, the angiotensin 2 produces somewhat defensive reactions, but it happens that the virus enzyme combination entering the cell by way of angiotensin receptor 1, AT1, and that turns on a whole range of destructive processes, nitric oxide, serotonin for example. And, so, just looking at the effects, its obvious you can defend by anything that defends you against nitric oxide and serotonin, so anti-inflammatory things are the known treatment for this kind of virus that Chinese for years have been using, cinanserin which is a serotonin blocker for other treatments, and they find that is helpful for people with the established respiratory corona infection, and losartan witch is high blood pressure drug is the most well-known blocker of angiotensin 1 receptor.. losartan is cheap and widely available. - Ray Peat
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The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin–angiotensin system
Abstract
The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2.
Conclusion
Because SARS-CoV-2 enters the cell bound to ACE2, which induces ACE2 deficiency at the cell membrane, AngII is persistently activated. Increased AngII induces activation of AT1R, causing more uptake of SARS-CoV-2 and increasing ACE2 deficiency, thus maintaining and exacerbating a non-specific immune response, consisting of cytokine-induced inflammation. This non-specific immune response is an attempt to reduce the viral load, while the specific immune response is mounted. Unrestrained AngII eventually causes death by respiratory distress induced by excessive inflammation and its deleterious effects on other organs. Therefore, SARS-CoV-2-induced mortality is promoted by three mechanisms: (i) increased AngII induces endocytosis of ACE2-bound SARS-CoV-2, leading to ACE2 deficiency and viral replication; (ii) ACE2 deficiency prevents the priming of an adaptive immune response by lack of NO; and (iii) Ang II induces an increase in viral load leading to an increased innate immune response and a further increase in AngII levels. Therefore, treatments should aim at preventing the AngII ‘storm’ in an early phase of the infection, restoring the modulation of NO, and preventing the entry of SARS-CoV-2 into the cell. All these mechanisms are targeted by AT1R antagonists. They may reduce morbid inflammatory distress and provide an environment to facilitate an effective, virus-specific adaptive immune response.
The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin–angiotensin system
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[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease
Abstract
Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.
[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease - PubMed
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Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2
Hesperidin is a major flavonoid compound, present in orange and lemon fruits. 470–761 mg/L of Hesperidin is normally present in orange juice31. This phytochemical exhibit various medicinal properties. According to oral toxicity study of hesperidin, it can be concluded that this phytochemical can be safely used in herbal formulations with its LD50 value more than 2000 mg/kg31. This flavanone glycoside, has a long medicinal history in both Indian and Chinese herbal medications32. This phytochemical alone or in combination with other chemicals, is often used to treat various diseases.
Emodin is a polyphenol found in the roots, bark and leaves of several plants including aloe vera, cascara, rhubarb, senna etc. In traditional medicine, emodin has been used for cardiovascular diseases and osteoporosis. It has been suggested earlier that emodin can inhibit influenza A virus replication33 via several cell signaling pathways.
Chrysin a natural flavonoid, is commonly found in propolis and honey. As reported earlier, chrysin can act as an inhibitor during enterovirus 71 (EV71) growth and replication34. Similarly, Song et al.35described antiviral activity of chrysin against coxsackievirus B3 (CVB3).
Considering the results obtained from molecular docking studies, phytochemicals hesperidin, emodin and chrysin can be used for COVID-19 treatment, after in-silico mutagenesis study and experimental verification. These phytochemicals have shown comparable spike protein inhibiting efficacy as that of known inhibitors such as chloroquine and hydroxychloroquine. From the molecular dynamics and QSAR study, it can be concluded that for ACE2 receptor protein, ligand binding activity of spike protein fragment, will be decreased noncompetitively by modulator hesperidin. So, this natural compound can show antiviral activity by destabilizing spike protein binding with human host ACE2 receptor. The modulation of hesperidin of ACE2 protein try to prevent its interaction with spike protein. It has been proved by a simple in silico experiment and the result of this experiment in shown in Supplementary Information S3.
Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2
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Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19
As far as clinical applications, one promising indication comes from a report of a cohort of 2,500 French patients treated with MeBlu as part of their cancer care none of whom developed influenza like illness during the COVID-19 epidemics (Henry et al., 2020). MeBlu has also been explored in one Phase one clinical trial (NCT04370288) for treatment of critically ill COVID-19 patients in Iran as part of a three-drug last therapeutic option add-on cocktail (MeBlu 1 mg/kg, vitamin C 1500 mg/kg, and N-acetyl cysteine 2000 mg/kg) based on the hypothesis that this combination could rebalance NO, methemoglobin, and oxidative stress. Four of the five patients responded well to treatment (Alamdari et al., 2020).
In conclusion, screening of our organic dye-based library identified MeBlu as a low-micromolar inhibitor of the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, a PPI that is the first critical step initiating the viral entry of this coronavirus. While MeBlu shows strong polypharmacology and might be a somewhat promiscuous PPI inhibitor, its ability to inhibit this PPI could contribute to the antiviral activity of MeBlu against SARS-CoV-2 even in the absence of light making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.
Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19