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All Studies   Meta Analysis       

Potential Mechanism of Curcumin and Resveratrol against SARS-CoV-2

Wu et al., Research Square, doi:10.21203/rs.3.rs-2780614/v1
Apr 2023  
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Curcumin for COVID-19
15th treatment shown to reduce risk in February 2021, now with p = 0.0000000096 from 27 studies.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 112 treatments. c19early.org
In Vitro study showing that curcumin and resveratrol inhibit SARS-CoV-2 infection through multiple mechanisms. Curcumin and resveratrol inhibit SARS-CoV-2 pseudovirus cell entry in HEK293-ACE2 cells with IC50 values of 18.02 μM and 8.76 μM, respectively. Combined treatment further reduces pseudovirus entry. Both compounds also inhibit activity of the SARS-CoV-2 3CL protease with IC50 values around 10-15 μM. Spike protein-induced cytokine storm is alleviated by curcumin or resveratrol through NFKB pathway inhibition in HEK293-ACE2 cells. Similarly, spike protein-mediated oxidative stress is reduced by the compounds via enhanced antioxidant system activity and ROS scavenging. Authors conclude that curcumin and resveratrol may help prevent and treat COVID-19 by inhibiting viral entry, replication, cytokine storm, and oxidative stress.
In Silico study showing potential benefits of curcumin in preventing severe COVID-19 manifestations by protecting mitochondria. Authors identified five mitochondrial dysfunction biomarkers (RECQL4, PYCR1, PIF1, POLQ, GLDC) associated with metabolic and immune dysregulation in severe COVID-19. Curcumin exhibited regulatory effects on these biomarkers and protected cells against SARS-CoV-2 spike protein-induced mitochondrial damage and oxidative stress. The study provides evidence for curcumin's ability to safeguard mitochondrial function, which may help prevent progression to severe disease.
51 preclinical studies support the efficacy of curcumin for COVID-19:
In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,2,7,12,14,20,23,44 (and specifically the receptor binding domainB,10,13,16), MproC,2,7,9,11-13,15,16,18,21,23,24,26,40,44, RNA-dependent RNA polymeraseD,2,13,22,44, PLproE,2, ACE2F,14,15,17, nucleocapsidG,8,25, nsp10H,25, and helicaseI,29 proteins. In Vitro studies demonstrate inhibition of the spikeA,34 (and specifically the receptor binding domainB,43), MproC,19,34,40,42, ACE2F,43, and TMPRSS2J,43 proteins, and inhibition of spike-ACE2 interactionK,27. In Vitro studies demonstrate efficacy in Calu-3L,41, A549M,34, 293TN,3, HEK293-hACE2O,19,32, 293T/hACE2/TMPRSS2P,33, Vero E6Q,9,13,23,32,34,36,37,39,41, and SH-SY5YR,31 cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants10, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells39, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress3, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts45, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity35.
a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
b. The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.
c. The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
d. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
e. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
f. The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
g. The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
h. Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.
i. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
j. Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
k. The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
l. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.
m. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.
n. 293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.
o. HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.
p. 293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.
q. Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.
r. SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.
Wu et al., 13 Apr 2023, preprint, 6 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperCurcuminAll
Potential Mechanism of Curcumin and Resveratrol against SARS-CoV-2
Wei Wu, Junxi Wu, Xuxu Ji, Ji Liu, Fuchang Geng
doi:10.21203/rs.3.rs-2780614/v1
Recently, World Health Organization predicted a near end of COVID-19 pandemic. However, the prediction should be interpreted cautiously. Due to SARS-CoV-2 continuous mutation-evolve, limited durability of infection-acquired protection in individuals with hybrid immunity, and the effects of long COVID-19 or Post-COVID-19 syndrome, COVID-19 may continue to be a worldwide threat. Alternative therapeutics are incorporated into some countries' health guidelines for COVID-19. Qiannan herbal, an ancient medical book of Yi Nationality in China, recorded that grapes and turmeric were often used to treat respiratory diseases. Curcumin and resveratrol are the primary bioactive compounds in turmeric and grapes, respectively. The clinical trials con rmed that curcumin or resveratrol supplementation could cause moderate or marked improvements in COVID-19 patients. Exploring the potential mechanisms is of great signi cance. This study found that curcumin and resveratrol could effectively inhibit SARS-CoV-23CLpro activity and spike protein-mediated cell entry. Curcumin and resveratrol could signi cantly alleviate spike protein-mediated cytokine storm via inhibiting over-activation of NFKB, and effectively ameliorate spike protein-mediated oxidative stress through scavenging ROS and enhancing function of antioxidation system. The combined treatment showed a better effect than alone treatment. Therefore, curcumin and resveratrol could inhibit SARS-CoV-23C-like proteinase activity and Spike protein-mediated cell entry, cytokine storm, and oxidative stress.
In conclusion, curcumin and resveratrol could inhibit SARS-CoV-2 3CLpro activity and spike proteinmediated cell entry, cytokine storm, and oxidative stress. The above conclusions are shown in Supplementary Fig. 5 . Our study provides a reference of nutrient supplementation for preventing and treating COVID-19. Methods Venn analysis and Enrichment analysis Firstly, COVID-19, curcumin, and resveratrol were separately input into Gene or Pubchem database at National Center for Biotechnology Information (NCBI) and ltered with Homo sapiens, and the gene sets were Cell culture and reagents Vero cells and HEK293T-hACE2 cells were obtained from the Laboratory of Biochemistry and Molecular Biology, Sichuan University. Cells were maintained in Dulbecco's Modi ed Eagle's Medium (DMEM) supplemented with 10% FBS and incubated at 37°C with 5% CO2. Fetal bovine serum (FBS), DMEM, and phosphate-buffered saline (PBS) were bought from Gibco (Grand Island, NY, USA). Pyrrolidinedithiocarbamate ammonium (PDTC), curcumin, and resveratrol were obtained from Solarbio. Ebselen was purchased from Beyotime. Cell viability assay Vero E6 cells were..
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