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Breakthroughs in cures for COVID-19

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*Chemical compounds in foods, keto diet can help mitigate severe disease
*Novel cannabis plant extracts could protect against virus, study confirms

Can a combination of chemical compounds in foods such as phycobilins and resveratrol, keto diet, novel cannabis plant extracts and steam inhalation therapy prevent and cure COVID-19?

According to a new study by plant biologists at North Carolina State University, United States, chemical compounds in foods or beverages like green tea, muscadine grapes and dark chocolate can bind to and block the function of a particular enzyme, or protease, in the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) virus. SARS-CoV-2 causes COVID-19.

Proteases are important to the health and viability of cells and viruses, says De-Yu Xie, professor of plant and microbial biology at NC State and the corresponding author of the study. If proteases are inhibited, cells cannot perform many important functions — like replication, for example.

“One of our lab’s focuses is to find nutraceuticals in food or medicinal plants that inhibit either how a virus attaches to human cells or the propagation of a virus in human cells,” Xie said.

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In the study, the NC State researchers performed both computer simulations and lab studies showing how the so-called “main protease” (Mpro) in the SARS-CoV-2 virus reacted when confronted with a number of different plant chemical compounds already known for their potent anti-inflammatory and antioxidant properties.

“Mpro in SARS-CoV-2 is required for the virus to replicate and assemble itself,” Xie said. “If we can inhibit or deactivate this protease, the virus will die.”

Computer simulations showed that the studied chemical compounds from green tea, two varieties of muscadine grapes, cacao powder and dark chocolate were able to bind to different portions of Mpro.

“Mpro has a portion that is like a ‘pocket’ that was ‘filled’ by the chemical compounds,” Xie said. “When this pocket was filled, the protease lost its important function.”

In vitro lab experiments completed by Yue Zhu, an NC State Ph.D. student in Xie’s lab, showed similar results. The chemical compounds in green tea and muscadine grapes were very successful at inhibiting Mpro’s function; chemical compounds in cacao powder and dark chocolate reduced Mpro activity by about half.

“Green tea has five tested chemical compounds that bind to different sites in the pocket on Mpro, essentially overwhelming it to inhibit its function,” Xie said. “Muscadine grapes contain these inhibitory chemicals in their skins and seeds. Plants use these compounds to protect themselves, so it is not surprising that plant leaves and skins contain these beneficial compounds.”

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The paper was published in the journal Frontiers in Plant Science. Zhu is the paper’s first author. The research was supported by the U.S. Department of Agriculture.

Also, researchers from Tennesee State University and Meharry Medical College in the United States have released an interesting new study on the preprint bioRxiv server in November 2020 that describes the broad-spectrum of antiviral activity that phycobilins can have. Phycobilins, which are bioactive plant compounds, were found to inhibit two coronavirus enzymes.

The current study focuses on phytochemicals, which are less toxic than synthetic drugs in many cases, and have been reported to have antiviral activity against multiple viruses, including coronaviruses. Selecting 15 phytochemicals of various chemical classes based on existing knowledge of their antiviral activity, the researchers studied their binding interactions with the SARS-CoV-2 MPro and PLPro.

These compounds include flavonols like quercetin, flavins like riboflavins, isoflavones such as daidzein and genistein, phenolic ketones like gingerol, and phenolic alkaloids such as capsaicin, all of which are well-known plant compounds.

Their interactions with the viral enzymes were examined by docking studies. These showed that the phycobilins (PCB) docked with the best score or binding energy for MPro, followed by riboflavin, cyanidin, daidzein and genistein in a close cluster. There were 12 important residues at the active site involved in these interactions with the phytochemicals.

When other phycobilins, such as phycourobilin (PUB), Phycoerythrobilin (PEB) and Phycoviolobilin (PVB), were explored, they all bound strongly to the binding pockets of these enzymes at specific amino acids, with PCB having the highest or almost the highest docking score for both enzymes. It is notable that these compounds also have other powerful therapeutic properties such as scavenging oxidative radicals, inhibiting cancer cell division and platelet aggregation. They can also be used orally in the form of the phycobilin-protein complex, phycobiliprotein. Once ingested, it is digested in the human gut, and free PCB is released there, which may account for the therapeutic properties of this complex.

The researchers call for “in-vivo studies on inhibition of CoVs infectivity using human cells and animal models.” Moreover, they suggest that more phycobilin lead compounds could be developed by structure-guided development to “rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-associated diseases.”

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Also, researchers in Canada have conducted a study suggesting that novel Cannabis sativa extracts may decrease levels of the host cell receptor that SARS-CoV-2 uses to gain viral entry to target tissues.

The team – from the University of Lethbridge and Pathway Rx Inc., Lethbridge – developed hundreds of new C. sativa cultivars and tested 23 extracts in artificial 3D human models of the oral, airway and intestinal tissues.

As recently reported in the journal Aging, 13 of the extracts downregulated expression of the SARS-CoV-2 host cell receptor angiotensin-converting enzyme 2 (ACE2).

“The observed down-regulation of ACE2 gene expression by several tested extracts of new C. sativa cultivars is a novel and crucial finding,” say the researchers.

“While our most effective extracts require further large-scale validation, our study is important for future analyses of the effects of medical cannabis on COVID-19,” write Olga Kovalchuk and colleagues.

Numerous studies have also reported high levels of ACE2 expression in the lower respiratory tract of patients with chronic obstructive pulmonary disease (COPD). This patient group is associated with increased susceptibility to COVID-19 and more severe disease.

Cannabis sativa, particularly cultivars rich in cannabidiol (CBD), have previously been shown to alter gene expression and to possess anti-inflammatory and anti-cancer properties.

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However, the effects of C. sativa on ACE2 expression are not known, says the team.

“Using artificial 3D human models of oral, airway and intestinal tissues, we identified 13 high-CBD C. sativa extracts that decrease ACE2 protein levels,” writes the team.

The researchers say the findings provide a foundation for further analyses of the effects C. sativa may have on the pathogenesis of COVID-19 and other viral diseases where the ACE2 receptor is used as a molecular gateway.

“The extracts of our most successful novel high-CBD C. sativa lines, pending further investigation, may become a useful and safe addition to the prevention and treatment of COVID-19 as an adjunct therapy,” concludes the team.

Also, a recent study published in the journal Phytotherapy Research reveals that resveratrol, a phenolic compound produced by spermatophytes, can inhibit the replication of SARS-CoV-2.

The scientists from Shenzhen Third People’s Hospital, China, conducted the study to investigate how resveratrol, a phenolic plant compound, can modulate the replication of SARS-CoV-2 in Vero cells. They chose resveratrol as an experimental compound because of its proven efficacy in inhibiting replication of several viruses, including dengue virus, Zika virus, influenza virus, and more importantly, Middle East respiratory syndrome coronavirus (MERS-CoV), which is a betacoronavirus in the same family as SARS-CoV-2.

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The current study identifies resveratrol as a potential antiviral candidate that is capable of inhibiting SARS-CoV-2 replication. Previously, it has been reported that resveratrol reduces cellular inflammation by decreasing the production of nitric oxide. Moreover, there is much evidence showing that resveratrol acts as a potent antioxidant. Another benefit of resveratrol is that it does not cause any serious adversity even when used at a very high concentration. Because oxidative stress and inflammation are common consequences of any viral infection, the scientists believe that resveratrol holds the potency to be used as an effective therapeutic agent to treat COVID-19 patients.

Meanwhile, Italian researchers at the Biochemistry and Pharmacology Laboratory, Meyer Children’s University Hospital, Florence, Italy, have published a study on the efficacy of steam inhalations as another possible treatment to help mitigate SARS-CoV-2 infection. Their study was published in the latest issue of the journal Life Sciences.

Early on in the virus’s outbreak, it was found that soapy water could help break down the viral envelope and thus denature it. Researchers added that heat has also been seen to denature the proteins that lead to loss of infectivity of the SARS-CoV that caused the 2002 SARS outbreak. The researchers have shown that heat can also denature the SARS-CoV-2 virion’s proteins.

Steam inhalation cycles are thus considered to be useful in damaging the capsid of the SARS-CoV-2 envelope and prevent infection, write the researchers. They write that the European Pharmacopoeia VI edition has recommended steam inhalations as a procedure to treat respiratory diseases.

This study, although a small one, shows the beneficial effects of steam inhalation in reducing viral shedding from infected patients. The team writes that this could be an “easily accessible, non-invasive and inexpensive procedure” which has been proven to be effective. It should be subjected to larger clinical trials, the team wrote.

They concluded, “Should our preliminary observations be confirmed, the protocol could be used against COVID19 or other viral infections using vapotherm masks, where temperature, time of exposure and size of steam particles can be set and monitored.”

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Meanwhile, could the keto diet help prevent or mitigate severe COVID-19?
There is much evidence that obesity, hypertension and cardiovascular disease contribute significantly to adverse outcomes following COVID-19. It is rational to apply the principles of primary prevention in the attempt to contain this pandemic, by mitigating these risk factors.

A new study published in the journal of Translational Medicine reports that the ketogenic diet (KD) may be useful in this area, with its track history of effectual reduction of fat mass, anti-inflammatory and immune-modulatory effects, and consequent improvement of cardiovascular health.

The state of sarcopenic obesity is a combination of poor muscle mass with high fatty tissue mass, and involves poor nutrition, reduced antiviral immunity, as well as dysregulated metabolism and inflammatory pathways. The authors note that this state in patients with critical COVID-19 is more commonly associated with a poor outcome than obesity without sarcopenia. Secondly, obesity is known to shift the individual to a high-risk COVID-19 group at a relatively younger age.

Ketogenic diets (KDs) are a lifestyle intervention that aims at changing the metabolic state in the host from one that utilizes primarily carbohydrates to ketone-based metabolism, by a high-fat, low-carbohydrate dietary pattern. Interestingly, one researcher has previously suggested using intermittent fasting along with supplementary medium-chain triglycerides as a possible method to prevent or reduce the severity of SARS-CoV-2 infection. The expected benefits are increased mitochondrial resistance to stress, better antioxidant activity, greater DNA repair and autophagy of damaged cells, and insulin sensitivity. These chime in with the health benefits of keto diets.

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KDs have been widely used to reduce body mass in severe obesity, metabolic disorders, migraine, and cancers, with adjustments in the composition of the overall pattern. In one particular group of very obese individuals who are at risk of cardiovascular disease, a very-low-calorie ketogenic diet (VLCKD) has been found to be very useful, supplying adequate nutrition while restricting carbohydrates to 30 g/day, making up the energy deficit by fat and protein. The daily caloric intake is reduced to 800kcal/day or less. These individuals have been shown to regain insulin sensitivity, good glycemic control and normal blood pressure, as they lose primarily fat mass, preserving muscle mass.

KD also treats metabolic (dysfunction) associated fatty liver disease (MAFLD), with a healthy reduction in the liver fat content and insulin resistance in the liver within a week of treatment. Short VLCKD regimens also improve glycemic control in type 2 diabetes mellitus, since the very low carbohydrate intake not only promotes weight loss, and prevents blood sugar spikes, but also promotes hepatic insulin sensitivity, thus preventing the synthesis of glucose in the liver. These changes cause a marked improvement in beta-cell function. The extremely rapid pace of change requires such diets be followed under strict medical supervision.

VLCKD also helps lower blood pressure via increased sodium losses through urine in combination with ketonuria. Physical exercise would further increase the favorable effects of such a diet. Attention should be paid to setting up properly customized KDs to produce a permanent lifestyle modification in obese patients, reducing multiple risk factors for severe COVID-19 through multiple mechanisms. A study comparing severe COVID-19 incidence among obese patients on a KD versus those on an ordinary diet may throw more light on the validity of this hypothesis.

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