SARS‐CoV‐2 infection has now become the world's most significant health hazard, with the World Health Organization declaring a pandemic on March 11, 2020. COVID‐19 enters the lungs through angiotensin‐converting enzyme 2 (ACE2) receptors, alters various signaling pathways, and causes immune cells to overproduce cytokines, resulting in mucosal inflammation, lung damage, and multiple organ failure in COVID‐19 patients. Although several antiviral medications have been effective in managing the virus, they have not been effective in lowering the inflammation and symptoms of the illness. Several studies have found that epigallocatechin‐3‐gallate and melatonin upregulate sirtuins proteins, which leads to downregulation of pro‐inflammatory gene transcription and NF‐κB, protecting organisms from oxidative stress in autoimmune, respiratory, and cardiovascular illnesses. As a result, the purpose of this research is to understand more about the molecular pathways through which these phytochemicals affect COVID‐19 patients' impaired immune systems, perhaps reducing hyperinflammation and symptom severity.
Practical applications
Polyphenols are natural secondary metabolites that are found to be present in plants. EGCG a polyphenol belonging to the flavonoid family in tea has potent anti‐inflammatory and antioxidative properties that helps to counter the inflammation and oxidative stress associated with many neurodegenerative diseases. Melatonin, another strong antioxidant in plants, has been shown to possess antiviral function and alleviate oxidative stress in many inflammatory diseases. In this review, we propose an alternative therapy for COVID‐19 patients by supplementing their diet with these nutraceuticals that perhaps by modulating sirtuin signaling pathways counteract cytokine storm and oxidative stress, the root causes of severe inflammation and symptoms in these patients.
Background
Organic cation transporter 1 primarily governs the action of metformin in the liver. There are considerable inter-individual variations in metformin response. In light of this, it is crucial to obtain a greater understanding of the influence of OCT1 expression or polymorphism in the context of variable responses elicited by metformin treatment.
Results
We observed that the variable response to metformin in the responders and non-responders is independent of isoform variation and mRNA expression of OCT-1. We also observed an insignificant difference in the serum metformin levels of the patient groups. Further, molecular docking provided us with an insight into the hotspot regions of OCT-1 for metformin binding. Genotyping of these regions revealed SNPs 156T>C and 1222A>G in both the groups, while as 181C>T and 1201G>A were found only in non-responders. The 181T>C and 1222A>G changes were further found to alter OCT-1 structure in silico and affect metformin transport in vitro which was illustrated by their effect on the activation of AMPK, the marker for metformin activity.
Conclusion
Taken together, our results corroborate the role of OCT-1 in the transport of metformin and also point at OCT1 genetic variations possibly affecting the transport of metformin into the cells and hence its subsequent action in responders and non-responders.
Follicle‐stimulating hormone receptor (FSHR) belongs to the family of G‐protein coupled receptors and acts as a cognate receptor for follicle‐stimulating hormone (FSH). Among the various polymorphic changes reported in FSHR, rs6165 polymorphism leading to Ala307Thr variation in the extracellular domain of the FSHR (FSHRED) is widely reported. Therefore we attempted to evaluate the functional implications of this variation by studying its effects on FSHRED structure as well as FSH binding. Our atomic‐scale investigations reveal that the hinge region, a key hormone interaction site in the extracellular domain of Wt FSHR, exhibits significantly more flexibility compared with the variant structure. Moreover, the Wt receptor in complex with FSH was observed to form a pocket‐like structure in its hinge region whereas such a structure was not detected in the variant. The study further reveals that the key residue, sTyr335, required for FSH recognition and FSHR activation, exhibits lower binding free energy in the variant structure as compared to the Wt. In conclusion, our results point out that Ala307Thr variation leads to structural and conformational anomalies in FSHRED which may alter its FSH binding and affect its activation.
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