How Artemisia, supplements mitigate COVID-19 severity
• Vitamin C, zinc even in high doses don’t lessen coronavirus symptoms
•Vitamin B6 helps keep pandemic’s cytokine storms at bay, study finds
A team of scientists from Germany and the United States (US) recently explored the effectiveness of traditional plant medicines in treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Their findings reveal that various extracts of two medicinal plants, namely Artemisia annua and Artemisia afra, can potentially inhibit SARS-CoV-2 replication in vitro without causing any cytotoxicity.
The study is currently available on the bioRxiv* preprint server. Various synthetic derivatives (artesunate) of artemisinin, which is a bioactive natural compound found in Artemisia annua plants, are typically being used as antimalarial medicines. The antimicrobial properties of these bioactive compounds have been recognized clinically. Different extracts of Artemisia annua containing high amount of artemisinin are currently undergoing phase 2 clinical trials to treat COVID-19 patients. Since April 2020 in Madagascar, Covid-Organics drinks containing mainly Artemisia annua extracts are being used as a miracle intervention to treat and prevent COVID-19.
In the current study, the scientists have explored the efficacy of Artemisia annua and Artemisia afra extracts and Covid-Organics in preventing SARS-CoV-2 infection in vitro. Using various animal cell lines, they specifically examined whether these plant products are able to inhibit replication of SARS-CoV-2 and feline coronavirus.
Both water and ethanolic extracts of dried leaves of Artemisia annua and Artemisia afra were used in this study. In addition, 500 mg of pure artemisinin and dried form of 50 ml of Covid-Organics were dissolved in dimethyl sulfoxide and tested for activity using various in vitro experimentations.
To determine its antiviral activity, the scientists first incubated feline coronavirus with different concentrations of plant extracts and pure artemisinin solution on a monolayer of feline kidney cells. Using plaque formation assay, they observed that all tested extracts significantly inhibited viral replication in a dose-dependent manner. Specifically, they observed that at a concentration range of 5 – 10 mg/ml, all tested extracts significantly inhibited viral replication, whereas no inhibition was observed at less than 2 mg/ml concentration. Based on these findings, they selected the most potent extracts with the highest antiviral activity for further experimentations on SARS-CoV-2.
A set of experiments conducted using the monkey kidney cell line revealed that the extracts at a concentration of less than 2 mg/ml had potent antiviral activity against SARS-CoV-2. The strongest SARS-CoV-2 inhibitory effects were observed for water extracts of Artemisia annua and Artemisia afra and an ethanolic extract of Artemisia annua. Since Artemisia afra does not contain artemisinin, the scientists believe that other bioactive compounds present in the plant may be responsible for the observed anti-SARS-CoV-2 activity.
Using a separate set of experiments, the scientists estimated that these extracts could induce cytotoxic effects at a concentration range of 10 – 20 mg/ml, which was significantly higher than the concentrations required for antiviral activities. This observation indicates that these extracts can potently inhibit SARS-CoV-2 replication without affecting cell viability.
The preparations made from Covid-Organics drink showed higher antiviral activity against SARS-CoV-2 compared to Feline coronavirus. However, the selectivity index (the window between cytotoxicity and antiviral activity) of Covid-Organics drink was estimated to be 5.2, making it less promising as an antiviral medicine.
The study revealed that various extracts of Artemisia annua and Artemisia afra have potential antiviral activities against SARS-CoV-2. However, the scientists mention that further studies are required to check whether appropriate serum levels of Artemisia compounds needed to inhibit SARS-CoV-2 can be achieved in patients. Moreover, further animal and human clinical trials are required to determine whether these in vitro observations can be translated for actual clinical use.
Also, a new study in shown that nutritional supplements, including several vitamins and the mineral zinc, could be useful in preventing the infection or reducing its severity if caught.
The study titled “Potential Efficacy of Nutrient Supplements for Treatment or Prevention of COVID-19” was published in Journal of Dietary Supplements.
Vaccination appears to be the only safe and effective route to achieve durable and global immunity and end the pandemic. Other short-term preventive methods include behavioral changes and non-pharmaceutical interventions, including mask wearing in public, social distancing and hand washing.
Secondary prevention includes effective therapies that could disrupt the progression of the infection. Treatment options are limited, with remdesivir being among the few drugs to receive early approval for emergency use in COVID-19. Dexamethasone, tocilizumab, and hydroxychloroquine are among other drugs used on empirical grounds, with varying degrees of effectiveness.
The odds of severe COVID-19 are higher in people with risk factors such as cardiovascular disease, obesity, diabetes mellitus and lung disease, besides advancing age. The mechanism of severity operating to produce heightened risk in these conditions ranges from exaggerated inflammation to airway damage.
The association of severe COVID-19 with inflammatory conditions and weakened or altered immunity suggests that these are intrinsic to the clinical course.
Since dietary and nutritional measures are linked to marked changes in immunity, many have explored the effects of macro- and micronutrients in erecting a defense against this virus. Moreover, nutritional approaches are safe and possibly effective by their positive impact on immunity.
Old age is associated with immune-senescence as well as frailty, which in turn are linked to nutritional deficiencies of calcium, vitamin C, vitamin D, folate and zinc. Vitamin B3 deficiency could also be key to immune decline, since it is a precursor of nicotinamide adenine dinucleotide (NAD), a fundamental metabolic mediator.
Some researchers have therefore explored the possible advantages of using nutritional supplements, especially vitamin C, vitamin D, zinc, and B3 vitamins, as part of primary and secondary COVID-19 prevention.
Meanwhile, who would have thought that a small basic compound like vitamin B6 in the banana or fish you had this morning might be key to your body’s robust response against COVID-19?
Studies have so far explored the benefits of vitamins D and C and minerals like zinc and magnesium in fortifying immune response against COVID-19. But research on vitamin B6 has been mostly missing. Food scientist Thanutchaporn Kumrungsee hopes their paper published in Frontiers in Nutrition can be the first step in showing vitamin B6’s potential in lowering the odds of patients becoming seriously ill with the coronavirus.
“In addition to washing your hands, food and nutrition are among the first lines of defense against Covid-19 virus infection. Food is our first medicine and kitchen is our first pharmacy,” Kumrungsee, an associate professor at Hiroshima University’s Graduate School of Integrated Sciences for Life, said.
“Recently, many scientists have published papers regarding the role of diets and nutrients in the protection against COVID-19. However, very few scientists are paying attention to the important role of vitamin B6,” she added.
In their paper, she and her fellow researchers pointed out growing evidence showing that vitamin B6 exerts a protective effect against chronic illnesses such as cardiovascular diseases and diabetes by suppressing inflammation, inflammasomes, oxidative stress, and carbonyl stress.
“Coronaviruses and influenza are among the viruses that can cause lethal lung injuries and death from acute respiratory distress syndrome worldwide. Viral infections evoke a ‘cytokine storm,’ leading to lung capillary endothelial cell inflammation, neutrophil infiltration, and increased oxidative stress,” they said.
Kumrungsee explained that thrombosis (blood clotting) and cytokine storm (hyper inflammation) might be closely linked to the graveness of COVID-19. Cytokine storms happen when the immune system dangerously goes into overdrive and starts attacking even the healthy cells. Meanwhile, blood clots linked to COVID-19 can block capillaries, damaging vital organs like the heart, lungs, liver, and kidneys.
Vitamin B6 is a known anti-thrombosis and anti-inflammation nutrient. Deficiency in this vitamin is also associated with lower immune function and higher susceptibility to viral infections.
“Vitamin B6 has a close relationship with the immune system. Its levels always drop in people under chronic inflammation such as obesity, diabetes, and heart diseases. We can see from the news that obese and diabetic people are at high risk for COVID-19,” Kumrungsee said.
“Thus, our attempt in this paper is to shed light on the possible involvement of vitamin B6 in decreasing the severity of COVID-19.”The associate professor said she is looking forward to clinical trials that would test their hypothesis.
“It is of great interest to examine if vitamin B6 exerts protection against novel types of virus infection and pneumonia which will be encountered in the future. At present, there is few information regarding the protective role of nutrients against pneumonia and lung diseases,” she said.
“After COVID-19, we should develop the area of nutrition for lung diseases such as pneumonia and lung cancer.” Indeed, viral infections lead to cell damage and death through various mechanisms: hijacking the cellular energy metabolism pathways; suppressing cellular synthesis of biomolecules; competing for ribosomes; and competing for transcription factors. As the cell detects this process, it reacts with innate immune responses, which leads to more powerful and specific adaptive immunity eventually.
THE work of Linus Pauling indicated the potential for vitamin C to reduce the severity of the common cold, as well as its duration. This has been confirmed by a meta-analysis of almost 30 studies. Moreover, vitamin C may also reduce or prevent other infections, including those caused by bacteria, viruses and protozoa, being a potent immune-modulator.
However, the benefits of vitamin C may be obvious only in those who are vitamin C deficient, and in children, and those with infections that cause metabolic complications resulting in a lowering of vitamin C levels.
Vitamin C is a very safe molecule. Its antioxidant activity is particularly effective in light of the high inflammatory and oxidative markers in COVID-19, especially hsCRP, and the cytokine storm, which is another marker of oxidative stress.
In one study of patients in an intensive care unit (ICU), and patients on mechanical ventilation because of acute inflammatory lung disease associated with oxidant damage, the use of vitamin C reduced the duration spent in the ICU and the outcome in ventilated patients.
One Chinese study showed that boluses of vitamin C given by intravenous infusion to COVID-19 patients, with repeated boluses if the condition was critical, improved the oxygenation status. All patients under treatment were discharged to home. Controlled trials of vitamin C therapy in patients hospitalized with severe COVID-19 are underway.
VITAMIN D also has a vital role in immunity, as its active form interacts with the vitamin D receptor (VDR) on the nucleus of immune cells. It stimulates the generation of antimicrobial peptides, such as cathelicidins and defensins, broad-spectrum agents against a range of pathogens, thus bolstering innate immune responses.
On the other hand, it modulates the adaptive immune response, including inflammatory cytokine release. This could tone down cytokine levels in COVID-19, and thus prevent the cytokine storm that underlies severe COVID-19 presentations.
It also helps maintain epithelial integrity via tight junctions, gap junctions and adherens junctions, reducing the odds that pathogens can pass through to the underlying tissues.
Vitamin D deficiency is thought to be a risk factor for COVID-19 among older people, Black individuals, those with a higher body mass index and smokers. Other immune disorders, including autoimmune conditions like rheumatoid arthritis, multiple sclerosis (MS), and inflammatory bowel disease, are found to be associated with low vitamin D levels.
Again, vitamin D deficiency is more common at regions farther to the north of the globe, where solar radiation is relatively less intense. MS sets in earlier in such regions, while type I diabetes and inflammatory bowel diseases are more common. Moreover, the type of MS called relapsing-remitting MS is partially improved with supplemental vitamin D.
The case fatality rate in the 1918 influenza pandemic dropped as sunlight increased (specifically, ultraviolet B radiation). Other studies show that the number of cases of infectious diseases like the flu or septic shock varies with the season.
Recent studies indicate that in vitamin D-deficient people, vitamin D supplementation may help reduce the risk of respiratory infections. With COVID-19, the risk of being diagnosed with this condition was 1.8 times higher with vitamin D deficiency relative to adequate vitamin D status. The risk of hospitalization may also be higher in the former group.
Vitamin D reduces angiotensin-converting enzyme 2 (ACE2) levels. This molecule acts as an entry receptor for SARS-CoV-2, and at higher levels, it may increase vulnerability to more severe manifestations.
The first outbreak of the pandemic occurred, as did its spread, during the winter when vitamin D levels were likely to be reduced. During the first wave, the higher toll taken on dark-skinned people in the developed world could be due to their lower vitamin D levels. If so, the disparity would be expected to be less obvious as summer set in, and this has indeed occurred.
Vitamin D deficiency is also a risk factor for acute respiratory distress syndrome (ARDS), a common fatal complication of critical COVID-19.
Based on these findings, vitamin D intake has been advised in COVID-19 patients to push the serum concentrations above 40–60 ng/mL. Trials are ongoing to investigate the role of vitamin D.
Zinc is commonly present in every tissue and metallo-enzyme in the body but is deficient in about a third of human beings worldwide. Insufficient zinc intake has been linked to many health conditions, including skin disorders and cognitive issues. Immune function is also impaired. Phytate and fiber in the diet can reduce zinc absorption, putting those on a strictly vegetarian diet at a higher risk of zinc deficiency. This is also found in several chronic disease conditions.
Zinc is involved in innate and adaptive immune responses, from immune cell development onwards, through mucosal integrity. Supplementation with zinc has been found to reduce respiratory infections in children, and to cut short colds by a day.Studies are ongoing to test the effects of zinc supplementation in COVID-19.
Vitamin B3 is a complex of three vitamins, namely, nicotinamide riboside (NR), nicotinamide (NAM), and nicotinic acid (NA), which are precursors of NAD+, a central catalyst of metabolism. NAD depletion is associated with poor immunity since cellular immune responses consume NAD.
Two components of the cell response to coronavirus infection include SIRT and PARP molecules, both of which compete for NAD. Reduced SIRT activation due to hyperactivation of PARPs leads to hyperinflammation, and a cytokine storm, with added oxidative stress due to viral activation.
The presence of highly reactive oxygen species (ROS) leads to further oxidative damage to DNA and cell membranes, with further PARP activation for repair processes to proceed. Type I interferons are triggered by some viruses, activating CD38, which further consumes NAD and also promotes further inflammation.
Vitamin B3 deficiency causes pellagra, and its supplementation could help avoid age-related frailty. Coronaviruses encode enzymes that oppose PARP pathway activation, thus preventing NAD depletion
Lymphocytopenia is a unique clinical feature of COVID-19 infection, unlike the rise that occurs in the lymphocyte count with other viral infections. One reason could be the high PARP activation levels during the innate immune response that depletes NAD and further modulates the adaptive immune response. Indeed, PARP upregulation with coronavirus infection has been confirmed in a recent paper.
Supplementation with B3 may thus boost both innate and adaptive immunity in COVID-19. NR appears to be the most suited for this purpose, with better pharmacological properties and a safety profile to match.
One recent trial showed that a combined nutritional supplement including NR with standard care shortened the recovery period in COVID-19 by a third, and larger studies are warranted with these findings.
What are the implications?
“Vitamins B3, C and D and Zinc have been shown to impact the initial innate immune response and/or modulate subsequent downstream processes related to viral infection.”
These early preclinical and clinical study findings form a solid grounding for further exploring the potential benefit of supplementation on COVID-19 incidence and severity.
Some important caveats apply. First, the Food and Drug Administration (FDA) in the U.S. do not regulate supplements with the same rigor as prescription drugs. They require only that the agency be satisfied with the safety of New Dietary Ingredients (NDI, those ingredients brought to market after October, 1994).
Thus, quality and safety challenges may exist, and all claims made by the manufacturer may not be true. Their over-the-counter status may pose a problem if too much is ingested with some supplements. And thirdly, some conditions or sensitivities may rule out supplement use in some cases, as with those that thin the blood or interact with prescription drugs.
Another set of issues unique to COVID-19 is the difficulty of obtaining data from ambulatory patients due to the mandatory quarantine, which leaves home visits by the investigators as the only way out. Secondly, funding for nutritional approaches can be very costly, while this avenue is not a high priority.
“Data support the model that essential nutrients may aid cellular defense and repair mechanisms and thus promote recovery and/or control of symptoms in late-stage disease, such approaches may be just as beneficial as pharmaceutical products.”
But, according to the first randomized clinical trial to test the two supplements under medical supervision, vitamin C and zinc even at high doses do not.
Despite the popular use of vitamin C and zinc to fight off or lessen the severity of viral colds and flu, the new study, published in JAMA Network Open, found the two supplements were of no benefit to people isolating at home with COVID-19.
In fact, the findings were so unimpressive that the study was stopped early.
“Unfortunately, these 2 supplements failed to live up to their hype,” wrote Dr. Erin Michos of John Hopkins and Houston Methodist’s Dr. Miguel Cainzos-Achirica, in an accompanying editorial.
The clinical trial gave high doses of each supplement alone and in combination to one of three groups of 214 adults who were recovering at home. A fourth group got standard care, such as rest, hydration and fever-reducing medications, but no supplements.
“High-dose zinc gluconate (zinc), ascorbic acid (vitamin C), or both supplements did not reduce SARS-CoV-2 symptoms,” according to Cleveland Clinic cardiologist Dr. Milind Desai and a team from Cleveland Clinic.
The high doses, however, did cause some unpleasant side effects for patients taking the supplements.
“More adverse effects (nausea, diarrhea, and stomach cramps) were reported in the supplement groups than in the usual care group,” wrote Michos, an associate professor of medicine at Johns Hopkins University School of Medicine, and Cainzos-Achirica, an assistant professor of preventive cardiology at Houston Methodist.
Vitamin C is a recognized antioxidant, and plays an essential role in supporting the immune system. Even though it has not been shown to prevent illness, other research has found vitamin C can shorten colds by eight per cent in adults and 14 per cent in kids.
Zinc may help a cell’s ability to fight infection, the study said, “while there is evidence that zinc deficiency increases pro-inflammatory cytokines and decreases the production of antibodies.”
But what does that mean in real life? If taken within 24 hours of the very first signs of a cold, zinc may reduce the length of a cold by only one day, a review of 13 studies found.
There is a down side, too. Taking over 2,000 milligrammes of vitamin C a day can cause heartburn, stomach cramps, nausea, vomiting, diarrhea and headaches. The average daily recommended amount of vitamin C is 75 milligrams for adult women and 90 milligrams for men.
Over 40 milligrammes of zinc each day can cause dry mouth, nausea, loss of appetite and diarrhea, plus it can have a nasty metallic taste.
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