Conceptual Framework for SARS-CoV-2-Related Lymphopenia.

The emerging of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is associated with high morbidity and mortality rates globally. One of the most prominent characteristics of coronavirus disease-19 (COVID-19) is lymphopenia, which is in contrast to other viral infections. This controversy might be explained by the evaluation of impaired innate and adaptive immune responses, during the SARS-CoV-2 infection. During the innate immune response, poly-ADP-ribose polymerase hyperactivated due to virus entry and extensive DNA damage sequentially, leading to nicotinamide adenine dinucleotide (NAD)+ depletion, adenosine triphosphate depletion, and finally cell death. In contrast to the immune response against viral infections, cytotoxic T lymphocytes decline sharply in SARS-CoV-2 infection which might be due to infiltration and trapping in the lower respiratory tract. In addition, there are more factors proposed to involve in lymphopenia in COVID-19 infection such as the role of CD38, which functions as NADase and intensifies NAD depletion, which in turn affects NAD+-dependent Sirtuin proteins, as the regulators of cell death and viability. Lung tissue sequestration following cytokine storm supposed to be another reason for lymphopenia in COVID-19 patients. Protein 7a, as one of the virus-encoded proteins, induces apoptosis in various organ-derived cell lines. These mechanisms proposed to induce lymphopenia, although there are still more studies needed to clarify the underlying mechanisms for lymphopenia in COVID-19 patients.

The Molecular Basis of COVID-19 Pathogenesis, Conventional and Nanomedicine Therapy.

In late 2019, a new member of the Coronaviridae family, officially designated as "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.

Vitamin D can be effective on the prevention of COVID-19 complications: A narrative review on molecular aspects

The widespread COVID-19 pandemic has been, currently, converted to a catastrophic human health challenge. Vitamin D (VD) and its metabolites have been used as a palliative treatment for chronic inflammatory and infectious diseases from ancient times. In the current study, some molecular aspects of the potential effects of VD against COVID-19 side-effects have been discussed. An arguable role in autophagy or apoptosis control has been suggested for VD through calcium signaling at the mitochondrial and ER levels. 1,25(OH)2D3 is also an immunomodulator that affects the development of B-cells, T-cells, and NK cells in both innate and acquired immunity. The production of some anti-microbial molecules such as defensins and cathelicidins is also stimulated by VD. The overexpression of glutathione, glutathione peroxidase, and superoxide dismutase, and down-regulation of NADPH oxidase are induced by VD to reduce the oxidative stress. Moreover, the multi-organ failure due to a cytokine storm induced by SARS-CoV2 in COVID-19 may be prevented by the immunomodulatory effects of VD. It can also downregulate the renin-angiotensin system which has a protective role against cardiovascular complications induced by COVID-19. Given the many experimental and molecular evidences due to the potential protective effects of VD on the prevention of the COVID-19-induced morbidities, a VD supplementation is suggested to prevent the lethal side-effects of the infection. It is particularly recommended in VD-deficient patients or those at greater risk of serious or critical effects of COVID-19, including the elderly, and patients with pre-existing chronic diseases, especially those in nursing homes, care facilities, and hospitals.