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more on oxidative stress and covid-19

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So, much of this piece will rely on Dr Seheult’s coronavirus update 65. We have this constant set of reactions in the body that reduce oxygen – adding electrons – until we get to water molecules, producing reactive oxygen species (ROS) along the way. This is often described as the oxygen metabolism process. Reactive oxygen species come essentially in three types, superoxides, hydroxy radicals and hydrogen peroxide. The three forms of the enzyme SOD, superoxide dismutase, convert superoxide into oxygen and hydrogen peroxide (H2O2), and then the H2O2 is reduced to H2O by means of glutathione peroxidase (GPx). The GPx, which is broken down in the process is recharged by the enzyme glutathione reductase (GR), which is in turn recharged by other antioxidant products. Also the enzyme catalase, which requires iron, can break H2O2 down into O2 and H2O.

People with diabetes, hypertension and overweight issues, among other things, may have compromised antioxidant systems (too many ROS), linked to angiotensin-converting enzyme 2 (ACE-2) and angiotensin-2. In creating ROS, oxygen is reduced to superoxide by means of the enzyme NADPH oxidase. So, as part of the renin-angiotensin system, angiotensin-2 (AT-2) is converted to angiotensin 1,7 (AT-1,7) by means of angiotensin-converting enzyme 2 (ACE-2). This is important because AT-1,7 effectively blocks superoxide production, while AT-2 promotes it. The virus SARS-CoV2 binds with, and so inactivates, ACE-2, preventing the production of AT-1,7. This action also means that there will be more AT-2 available, and so more superoxides. SARS-CoV2 also, according to Seheult, causes inflammation by recruiting polymorphonuclear neutrophils (PMNs), which stimulate production of superoxides by means of NADPH oxidase. So this, in essence, is why Covid-19 is bringing about oxidative stress.

Seheult next goes on to look at the research evidence for the preceding. A review article from 2005 points out that evidence from animal studies and cell culture studies shows that NADPH oxidase-derived oxidative stress is increased in vascular cells by AT-2, among other ‘agonists’ (chemicals that bind to receptors, thereby producing a response). Another article from 2012 describes several enzyme systems that act to form ROS, including ‘mitochondrial electron leakage from the electron transport chain’ as described in my previous post on the subject, and in Seheult’s update 63. It points out that ROS levels can rise dramatically in older people suffering from oxidative stress due to heart issues such as ischemia-reperfusion (referring to problems with oxygenated blood supply to the heart or other organs). It also points out that it has been shown experimentally that AT-2 stimulates an increase in ROS. A more recent article pertaining to SARS-CoV2 looked at patients in Wuhan and found a substantial increase in neutrophils in the most severe cases. Neutrophils cause ROS to be generated by NADPH oxidase. So Dr Seheult is carefully building up evidence for the case. The last point to deal with is AT-1,7 effects. Seheult has found a 2008 article entitled ‘Angiotensin converting enzyme 2 confers endothelial protection and attenuates atherosclerosis’. Seheult quotes the last line from the abstract:

These data indicate that ACE-2, in an AT-1,7-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE-2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis.

Atherothrombosis involves disruption of atherosclerotic plaques, which can be an immediate cause of heart attacks. Another article from 2015 essentially confirms the findings, as indicated by its title, ‘ACE-2 and AT-1,7 protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response’. A more recent article, from January 2020, describes how AT-1,7 administration improves endothelial function in women who have suffered from preeclampsia (vasoconstriction, high blood pressure and organ damage due to pregnancy). To give more detail, women in the last stages of pregnancy often suffer vasoconstriction and high protein levels, which is believed to be related to AT-2 levels. Researchers administered local AT-1,7, which is ‘an endogenous inhibitor of... AT-2′, to see if this reduced vasodilation and other symptoms of preeclampsia. What they found was that ‘AT-1,7 increased endothelium-dependent vasodilation via nitric oxide synthase-mediated pathways and attenuated AT-2-mediated constriction in women who have had preeclampsia, suggesting that AT-1,7 may be a viable therapeutic target for improve d microvascular function in women who have had a preeclamptic pregnancy’.

All of this is interesting in itself, of course, and is a little crash course in how research is helping us to tweak our immune systems, but in relation to Covid-19 these finding are of importance due to the comorbidities and general characteristics of patients being hospitalised with Covid-19. Dr Seheult, in his update 65 video, shows that, contrary to what was initially thought, i.e that Covid-19 is primarily a virus affecting the lungs and respiratory system, it may be much more of a problem for those with hypertension, cardiovascular issues and obesity – all of which are related to oxidative stress, as are diabetes and many forms of cancer. They contribute to endothelial dysfunction, which inevitably leads to oxidative stress, and may lead to thrombosis. Seheult here refers to a lengthy 2018 review article, ‘nutrients and oxidative stress: friend or foe?’, which among other things makes useful dietary suggestions for the combatting of oxidative stress – whole grains, nuts, fruit and vegetables, fish and legumes.

It’s been known for some time that endothelial cell dysfunction (ECD) can lead to thrombosis, as it is a major function of these cells to prevent thrombosis. The abstract from a 2002 study finds that ECD ‘is associated with decreased synthesis and oxidative inactivation of nitric oxide (NO)’ and it lists four types of antioxidant enzymes ‘essential for eliminating ROS that can inactivate NO’. It seems that the promotion of these enzymes can be associated with diet as above and with the reduction of risk factors such as hypertension, hypercholesterolaemia (high blood cholesterol), hyperhomocysteinaemia (homocysteine is an amino acid which can contribute to arterial damage and blood clots, and the condition is often associated with lack of vitamin B-12 or folate), cigarette smoking and diabetes mellitus. NO is the key molecule in maintaining endothelial function through these enzymes.

Now I’m having a look at Dr Seheult’s update 66 on blood pressure medications known as ACE inhibitors or ARBs. He cites an editorial article for the New England Journal of Medicine, on ‘inhibitors of the renin-angiotensin-aldosterone system and Covid-19’. This is a triple hormone system responsible for blood pressure regulation and fluid balance. Now, to return to what was outlined before, angiotensin-2 (AT-2) is converted to AT-1,7 by an angiotensin-converting enzyme (ACE-2). The SARS-CoV2 virus binds to the ACE-2 receptor and inhibits the enzyme’s production. This is problematic because AT-2 stimulates superoxide production (that’s bad), while the antioxidant AT-1,7 blocks it, so reducing oxidative stress. SARS-CoV2 also stimulates the production of PMNs, as above, which activates oxidative stress. Another part of this picture is that AT-1 is converted to AT-2 by ACE. There are blood pressure lowering medications, such as benazepril and lisinopril, aka ACE inhibitors, which reduce the production of AT-2. There are also angiotensin receptor blockers (ARBs), which may up-regulate ACE-2 (it isn’t clear, apparently). ACE inhibitors may do the same. The question being asked is, assuming these medications produce more ACE-2, will this lead to more infections because SARS-CoV2 has more ACE-2 to work with? Clearly it would be important to know whether to maintain these medications or not, that’s to say, whether these medications are a risk factor for contracting the virus or recovering from it. The above-mentioned article discusses three studies from different parts of the world, each involving thousands of participants. They all found no risks associating ACE inhibitors and ARBs with a higher risk of infection, severity of illness or death from Covid-19. One of the studies found that ACE inhibitors and statins were associated with a decreased risk of mortality, but these are observational studies and further research would need to be done.

So the above is a rather technical piece, highly reliant on the experts. I write to inform myself, and I’ve certainly been informed by writing this one. Apologies for its laboriousness, but I’ll be continuing… Please consult the references yourself if there’s anything you don’t understand.


Coronavirus Pandemic Update 65: COVID-19 and Oxidative Stress (Prevention & Risk Factors)

Coronavirus Pandemic Update 66: ACE-Inhibitors and ARBs – Hypertension Medications with COVID-1

Written by stewart henderson

July 16, 2020 at 4:21 pm

on appetite suppressants

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just add water and you get stuffed, apparently

The ‘obesity epidemic’ has been big news in the west for some time now. Increasing affluence, increased food production, the popularity of junk food and sugar-laden soft drinks, the pressure of advertising, not to mention the popularity of computer games and activities that exercise only the finger muscles, all have contributed to the rise and rise of western flab, and associated health problems.

Naturally, all sorts of solutions, of varying quality, are being offered, from lap banding to any number of diets, from crash fads to the more or less scientific. Clearly there’s the potential for a lot of money to be made in this area. Crisis can always be spelt as ‘opportunity’.

So it was with some interest that I noted an ad on TV the other day, from the company Swisse. From memory [that very unreliable source] it featured an attractive thirty-something woman, telling us of her busy day and how it was important to stay in trim, and recommending the use of Swisse ‘appetite suppressant’ pills. She also mentioned that the pills, or their active ingredients, were derived from a cactus plant which was used for this purpose for thousands of years by the natives of wherever the cactus grew. I don’t think the location was specified.

Well, I fell to wondering. A pill that suppresses your appetite, so that you’re less hungry and therefore eat less on a daily basis. Isn’t this the solution to the obesity crisis? Well, maybe not the solution, as there’s still the matter of what you eat, and how active you are, but certainly a general purpose appetite suppressant would be a great weapon in the fight against flab, and probably the primary weapon. Surely this is nothing short of sensational. Worthy of headline news at least.

So let’s see what I can learn about this appetite suppressant and how it works. As a seasoned researcher, I accessed that unmatchable research tool, google, and clicked the first link to come up in the list under ‘Swisse appetite suppressant’. It took me, of course, to the Swisse website, where I found a useful summary, from their perspective:

Swisse Ultiboost Appetite Suppressant contains Slimaluma®, a premium quality ingredient to help reduce hunger levels. Slimaluma® is a naturally derived extract of the cactus plant which has been used for centuries in India for its appetite suppressant qualities when food was scarce. Swisse Ultiboost Appetite Suppressant can be used to help control hunger levels and is best combined with healthy eating and as part of a regular exercise regime.

The advice at the end is admirable, though I do wonder whether people who engage in healthy eating and regular exercise are in need of an appetite suppressant. Healthy eating presumably already excludes over-eating. I was also interested in, and on reflection, slightly disturbed by the offhand remark ‘when food was scarce’. After all, to take away or reduce the pangs of hunger when you’re hungry, or even starving, is a bit like giving a painkiller. It reduces the symptoms but doesn’t solve the problem. It could even exacerbate it, when you consider that feeling hungry is nature’s or evolution’s way of telling you that you need to eat. I wondered how such a product could translate to use in an over-indulgent food-abundant society.

In any case we now find that the cactus plant hails from India and that the active ingredient extracted from it is called ‘Slimaluma’. So how effective is Slimaluma and how does it work?

My search took me to the website of Gencor Pacific, the makers of Slimaluma, and here’s what they have to say:

SLIMALUMA™ is a proprietary standardized extract of Caralluma Fimbriata, an edible plant used for centuries in India as a famine food and appetite suppressant. Gencor Pacific has developed a unique patented process to extract the essential constituents of the whole herb without chemical alteration to any of the key constituents, ensuring that the full benefits of the herb are delivered in concentrated form.

Caralluma fimbriata

Sounds impressive, and there’s more. They describe the results of clinical testing of the product, which is a great sign at least:

SLIMALUMA™ has undergone two double blind, randomized, placebo controlled human clinical trials, one in India and the other in California, USA. Many participants experienced significant loss in appetite and some lost inches off their waist and hips. Participants also experienced reduction in body weight and body fat.

They then link to a more detailed description of the studies and their findings, which again is excellent, and much more than we’ve learned to expect from the sellers of ‘natural’ health products. However, for obvious reasons it would be unwise to simply accept the description and interpretation of the studies of a health product by the makers of that product. So we need to look at more than one, possibly multiple descriptions and interpretations of the studies, and at whether other studies have been conducted.

So let’s look at clinical trial number one. It was conducted at the Division of Nutrition, St John’s National Academy of Health Sciences, Bangalore India during January to August 2003, and it involved 50 subjects. The Wikipedia article on Caralluma fimbriata [and I find Wikipedia quire reliable on these matters in spite of its reputation in some circles] reports on this trial rather differently:

In a small clinical trial conducted in India, modest benefits of Caralluma fimbriata extracts were observed. In the study, 50 overweight individuals were given either a placebo or one gram of extract each day for 60 days. Compared to the placebo group, individuals receiving the extract showed no significant change in body weight, body mass index, hip circumference, body fat or energy intake; however, both appetite and waist circumference were reduced

The difference in these descriptions of the same trial naturally demands that we examine those descriptions more closely. In Slimaluma’s description we’re told that ‘many’ participants experienced ‘significant loss in appetite’. Two questions here – first, how many is many? Fifteen, thirty-five? What about a percentage? And second, how do you measure ‘significant loss of appetite’? Weight loss and BMI are easy to measure objectively, but not appetite loss. I can only imagine that it’s measured through reporting, which, however unreliable, can at least be measured against the reporting of the placebo group. So, while the term ‘significant’ here is a bit tricksy, let’s accept that there was discernible appetite loss. Fine, but the findings were that this change did not lead to reduction in ‘energy intake’, meaning that the Slimaluma consumers didn’t eat less, in spite of having reduced appetite. An odd finding. Not only that, they didn’t reduce body weight or BMI, though there was a reduction in waist circumference. In other words the results seem to be all over the place, and of course the Slimaluma manufacturers only reported, and hyped, the positive findings.

The Indian study was quite small, and its results were hardly definitive. Shannon Moffett, in her book about the brain, The Three-Pound Enigma, which I just happened to be reading today, makes a general statement about research which fits nicely here:

..when you make a generalisation from the sample you study to the population at large, there is a chance – bigger or smaller depending on factors like the size of your sample compared to the size of the population as a whole, how well you controlled for other variables, and so forth – that the trend or trait you observed is characteristic only of that sample and not of the population at large

I seem to remember Steven Novella saying that 50 was an okay number for a study of this kind, if a bit on the small side. It would certainly be useful if it was backed up by further research, but really the initial findings are so underwhelming that further funding might be hard to find. One might expect that there would be some weight loss for the whole group over the six-month research period, as they were all obese and knew they were being studied for weight loss. They were advised not to change their diets, but it’s likely they would have. I haven’t been able to find the precise data on the study, as it’s behind a paywall [why?], but there was a further study done. However, it involved only 26 subjects, only 7 of whom were given placebos. This study only lasted for four weeks [an absurdly short period, it seems to me, given the notorious ‘rebound effects’ of people on diets]. As presented in this Gencor gloss on both studies, it produced ‘excellent’ results, but the sample was too small and the research period too short to produce reliable data.

The gloss mentioned above does attempt some science on the action of Caralluma fimbriata’s phytochemical constituents – pregnane glycosides, fIavone glycosides, megastigmane glycosides and saponins – in suppressing appetite, but I can find very little in the mainstream literature on these specific phytochemicals. The fact is, there’s very little scientific evidence for the efficacy of this product, and the Wikipedia article mentioned above makes this very important point.

Various diet pills claiming to contain Caralluma fimbriata extracts are marketed for weight loss. However there is no independent evidence to suggest that the amount of extract found in these products is sufficient to obtain the same results as the clinical trial. The FTC cautions against the use of “miracle diet” products.

This is a major problem with all so-called allopathic products. There is no control or oversight to their manufacture, as there is with all prescription medication. And, let’s face it, if these appetite suppressants really were efficacious, they would become prescription treatments. That’s what happens with evidence-based medicine. So chuck out those pills, eat less, eat healthily, and make sure you get plenty of exercise. There really is no alternative.

Written by stewart henderson

November 4, 2012 at 12:43 am