Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells
Biomedicines 2020, 8(5), 129; https://doi.org/10.3390/biomedicines8050129
by Gennadi V. Glinsky email@example.com
Institute of Engineering in Medicine, University of California, San Diego, 9500 Gilman Dr. MC 0435, La Jolla, CA 92093-0435, USA
The risk of 44 diseases at least double with poor Vitamin D Receptor as of Oct 2019
Vitamin D Receptor activation can be increased by any of: Resveratrol, Omega-3, Magnesium, Zinc, Quercetin, non-daily Vit D, Curcumin, intense exercise, Ginger, Essential oils, etc Note: The founder of VitaminDWiki uses 10 of the 12 known VDR activators
Vitamin D Receptor category has the following
Vitamin D tests cannot detect Vitamin D Receptor (VDR) problems
A poor VDR restricts Vitamin D from getting in the cells
It appears that 30% of the population has a poor VDR (40% of the Obese )
A poor VDR increases the risk of 55 health problems click here for details
The risk of 44 diseases at least double with poor Vitamin D Receptor as of Oct 2019
VDR at-home test $29 - results not easily understood in 2016
There are hints that you may have inherited a poor VDR
Compensate for poor VDR by increasing one or more:
|1) Vitamin D supplement|
Sun, Ultraviolet -B
| Vitamin D in the blood |
and thus in the cells
|2) Magnesium||Vitamin D in the blood |
AND in the cells
|3) Omega-3||Vitamin D in the cells|
|4) Resveratrol||Vitamin D Receptor|
|5) Intense exercise||Vitamin D Receptor|
|6) Get prescription for VDR activator|
|Vitamin D Receptor|
|7) Quercetin (flavonoid)||Vitamin D Receptor|
|8) Zinc is in the VDR||Vitamin D Receptor|
|9) Boron||Vitamin D Receptor ?, |
|10) Essential oils e.g. ginger, curcumin||Vitamin D Receptor|
|11) Progesterone||Vitamin D Receptor|
|12) Infrequent high concentration Vitamin D|
Increases the concentration gradient
|Vitamin D in the cells|
|13) Sulfroaphone and perhaps sulfur||Vitamin D Receptor|
Note: If you are not feeling enough benefit from Vitamin D, you might try increasing VDR activation. You might feel the benefit within days of adding one or more of the above
Far healthier and stronger at age 72 due to supplements Includes 6 supplements which help the VDR
Items in both categories Virus and Vitamin D Receptor are listed here:
- Dengue viral production decreased 1000X if activate Vitamin D Receptor (in lab) – July 2020
- Vitamin D, Quercetin, and Estradiol all increase vitamin D in cells and increase genes which reduce COVID-19 – May 21, 2020
- Quercetin and Vitamin D —possible Allies Against Coronavirus - March 2020
- Risk of enveloped virus infection is increased 50 percent if poor Vitamin D Receptor - meta-analysis Dec 2018
- Hand, foot, and Mouth disease is 14X more likely if poor Vitamin D Receptor – Oct 2019
- Treating herpes reduced incidence of senile dementia by 10 X (HSV1 reduces VDR by 8X) – 2018
- Severe hand, foot, and mouth virus is 2.9 X more likely if poor Vitamin D receptor – Oct 2018
- Hepatitis B virus reduced by 5X the Vitamin D getting to liver cells in the lab – Oct 2018
- Some enveloped virus are 1.2 X more likely if have a poor Vitamin D Receptor -Aug 2018
- Severe Pertussis is 1.5 times more likely if poor vitamin D receptor – Feb 2016
- Dengue Fever associated with poor vitamin D receptor – July 2002
- Dengue virus 2X to 4X more likely if vitamin D receptor gene problems
Resveratrol improves health (Vitamin D receptor, etc.) has the following
- The Vitamin D Receptor can restrict how much of the Vitamin D in the blood actually gets to cells
- Resveratrol is one of 11 ways to negate the Vitamin D Receptor restrictions
- Resveratrol is produced by several plants in response to injury or, when the plant is under attack by pathogens such as bacteria or fung
- Benefits of Reseveratrol, like Vitamin D, appears to be increased when used with other things
- Quercetin and Curcumin in the case of Resveratro
The articles in both of the categories Resveratrol and Vitamin D Receptor
- Cognitive decline not helped by daily vitamin D getting to just 30 ng – RCT July 2019
- Resveratrol prevented bone loss associated with T2DM (probably via VDR) – RCT Sept 2018
- Effects of Resveratrol against Lung Cancer in mice – Nov 2017
- Resveratrol Role in Autoimmune Disease-A Mini-Review. – Dec 2016
- Lifespan and healthspan extension by resveratrol - Jan 2015
- Resveratrol and Cardiovascular Diseases – May 2016
- Resveratrol improves health (Vitamin D receptor, etc.)
- Bone density improved with resveratrol (which improves Vitamin D Receptor) – RCT Sept 2018
- Natural Ways to Increase Calcitriol and Activate The Vitamin D Receptor Gene – Oct 2017
- Immune system is aided by red grapes, blueberries, both of which increase Vitamin D receptor – 2013
- Resveratol helps vitamin D bind to cells – Dec 2014
- Resveratrol gets vitamin D to cells even if poor vitamin D receptor
Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomic-guided molecular maps of upstream regulatory elements, their expression and functions in the human body, and pathophysiologically -relevant cell types. Repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1; RUNX1; HNF4a; JNK1/c-FOS) were then employed to identify existing drugs manifesting in their effects on gene expression signatures of potential coronavirus infection mitigation agents. Using this strategy, vitamin D and quercetin have been identified as putative 2019 coronavirus disease (COVID-19) mitigation agents.
Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses (GSEA) of expression profiling experiments (EPEs), indicating that highly structurally similar quercetin, luteolin, and eriodictyol could serve as scaffolds for the development of efficient inhibitors of SARS-CoV-2 infection. In agreement with this notion, quercetin alters the expression of 98 of 332 (30%) of human genes encoding protein targets of SARS-CoV-2, thus potentially interfering with functions of 23 of 27 (85%) of the SARS-CoV-2 viral proteins in human cells. Similarly, Vitamin D may interfere with functions of 19 of 27 (70%) of the SARS-CoV-2 proteins by altering expression of 84 of 332 (25%) of human genes encoding protein targets of SARS-CoV-2. Considering the potential effects of both quercetin and vitamin D, the inference could be made that functions of 25 of 27 (93%) of SARS-CoV-2 proteins in human cells may be altered. GSEA and EPEs identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of testosterone versus estradiol impacts on SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during the coronavirus pandemic.
Estradiol, in contrast with testosterone, affects the expression of the majority of human genes (203 of 332; 61%) encoding SARS-CoV-2 targets, thus potentially interfering with functions of 26 of 27 SARS-CoV-2 viral proteins. A hypothetical tripartite combination consisting of quercetin/vitamin D/estradiol may affect expression of 244 of 332 (73%) human genes encoding SARS-CoV-2 targets.
Of major concern is the ACE2 and FURIN expression in many human cells and tissues, including immune cells, suggesting that SARS-CoV-2 may infect a broad range of cellular targets in the human body. Infection of immune cells may cause immunosuppression, long-term persistence of the virus, and spread of the virus to secondary targets.
Present analyses and numerous observational studies indicate that age-associated vitamin D deficiency may contribute to the high mortality of older adults and the elderly. Immediate availability for targeted experimental and clinical interrogations of potential COVID-19 pandemic mitigation agents, namely vitamin D and quercetin, as well as of the highly selective (Ki, 600 pm) intrinsically specific FURIN inhibitor (a1-antitrypsin Portland (a1-PDX), is considered an encouraging factor. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically viable interventions to combat the COVID-19 pandemic.
Specifically, gene expression profiles of vitamin D and quercetin activities and their established safety records as over-the-counter medicinal substances strongly argue that they may represent viable candidates for further considerations of their potential utility as COVID-19 pandemic mitigation agents.
In line with the results of present analyses, a randomized interventional clinical trial evaluating effects of estradiol on severity of the coronavirus infection in COVID19+ and presumptive COVID19+ patients and two interventional randomized clinical trials evaluating effects of vitamin D on prevention and treatment of COVID-19 were listed on the ClinicalTrials.gov website.
Keywords: COVID-19; SARS-CoV-2 coronavirus; genomics; mitigation approaches; drugs and medicinal substance repurposing; vitamin D; quercetin; luteolin; eriodictyol; estradiol
The main motivation of this work was to identify human genes implicated in regulatory cross
talks affecting expression and functions of the ACE2 and FURIN genes to build a model of genomic
regulatory interactions potentially affecting SARS-CoV-2 infection. A panel of genes acting as
activators and/or repressors of the ACE2 and/or FURIN expression then could be employed to search
for existing drugs and medicinal substances that, based on their mechanisms of action, could be
defined as candidate coronavirus infection mitigation agents. After experimental and clinical
validation, these existing drugs and/or medicinal agents could be utilized to ameliorate the clinical
severity of the pandemic. This knowledge could also be exploited in an ongoing effort to discover
novel targeted therapeutics tailored to prevent SARS-CoV-2 infection and block the entry of the virus
into human cells. Observations reported in this contribution are in agreement with recent studies
describing numerous beneficial clinical effects of the vitamin D supplementations, emphasizing
many detrimental effects of the vitamin D insufficiency and deficiency, and underscoring the
significant COVID-19 mitigation potential of vitamin D [29,30]. Importantly, two recent
interventional randomized clinical trials aiming to evaluate effects of vitamin D on the prevention
and treatment of COVID-19 were listed on the ClinicalTrials.gov website
One of the important findings documented herein is that identified medicinal compounds with
potential coronavirus infection-mitigating effects also appear to induce cell type-specific patterns of
gene expression alterations. Therefore, based on all observations reported in this study, it has been
concluded that any definitive recommendations regarding the potential clinical utility of the herein
identified putative coronavirus infection-mitigating agents, namely vitamin D, quercetin, and
estradiol, should be made only after preclinical studies and randomized controlled clinical trials have
been appropriately designed, carefully executed, and the desired outcomes have been reached.
A supercomputer modeling study using the world’s most powerful supercomputer, SUMMIT,
identified several candidate small molecule drugs which bind to either the isolated SARS-CoV-2 Viral
S-protein at its host receptor region or to the S protein-human ACE2 interface . Interestingly, in
this study, quercetin was identified among the top five scoring ligands for viral S-protein-human
ACE2 receptor interface. Thus, quercetin also appears to be a potentially promising therapeutic
molecule that may directly interfere with the binding of SARS-CoV-2 to human cells. Previously
reported experiments demonstrated that quercetin appears to inhibit SARS-CoV entry into host cells
. Since SARS-CoV-2 utilizes, for the entry into human cells, the same receptor (ACE2) and the
accessory protease FURIN as the SARS-CoV coronavirus , these observations suggest that
quercetin may, indeed, possess antiviral activity against SARS-CoV-2 as well. Significantly, both
quercetin and luteolin have been identified among the top five ligands for the viral S-protein–human
ACE2 receptor interface–ligand-binding complex , suggesting that these highly structurally
similar compounds (Figure 7) could serve as efficient inhibitors of SARS-CoV-2 infection. Consistent
with this hypothesis, it has been reported that both quercetin and luteolin significantly inhibit the
SARS-CoV virus infection 
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