The COVID-19-diabetes mellitus molecular tetrahedron.

Accumulating molecular evidence suggests that insulin resistance, rather than SARS-CoV-2- provoked beta-cell impairment, plays a major role in the observed rapid metabolic deterioration in diabetes, or new-onset hyperglycemia, during the COVID-19 clinical course. In order to clarify the underlying complexity of COVID-19 and diabetes mellitus interactions, we propose the imaginary diabetes-COVID-19 molecular tetrahedron with four lateral faces consisting of SARS-CoV-2 entry via ACE2 (lateral face 1), the viral hijacking and replication (lateral face 2), acute inflammatory responses (lateral face 3), and the resulting insulin resistance (lateral face 4). The entrance of SARS-CoV-2 using ACE2 receptor triggers an array of multiple molecular signaling beyond that of the angiotensin II/ACE2-Ang-(1-7) axis, such as down-regulation of PGC-1 α/irisin, increased SREBP-1c activity, upregulation of CD36 and Sirt1 inhibition leading to insulin resistance. In another arm of the molecular cascade, the SARS-CoV-2 hijacking and replication induces a series of molecular events in the host cell metabolic machinery, including upregulation of SREBP-2, decrement in Sirt1 expression, dysregulation in PPAR-É£, and LPI resulting in insulin resistance. The COVID-19-diabetes molecular tetrahedron may suggest novel targets for therapeutic interventions to overcome insulin resistance that underlies the pathophysiology of worsening metabolic control in patients with diabetes mellitus or the new-onset of hyperglycemia in COVID-19.

Immunopathology and Immunopathogenesis of COVID-19, what we know and what we should learn.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) directly interacts with host's epithelial and immune cells, leading to inflammatory response induction, which is considered the hallmark of infection. The host immune system is programmed to facilitate the clearance of viral infection by establishing a modulated response. However, SARS-CoV-2 takes the initiative and its various structural and non-structural proteins directly or indirectly stimulate the uncontrolled activation of injurious inflammatory pathways through interaction with innate immune system mediators. Upregulation of cell-signaling pathways such as mitogen-activate protein kinase (MAPK) in response to recognition of SARS-CoV-2 antigens by innate immune system receptors mediates unbridled production of proinflammatory cytokines and cells causing cytokine storm, tissue damage, increased pulmonary edema, acute respiratory distress syndrome (ARDS), and mortality. Moreover, this acute inflammatory state hinders the immunomodulatory effect of T helper cells and timely response of CD4+ and CD8+ T cells against infection. Furthermore, inflammation-induced overproduction of Th17 cells can downregulate the antiviral response of Th1 and Th2 cells. In fact, the improperly severe response of the innate immune system is the key to conversion from a non-severe to severe disease state and needs to be investigated more deeply. The virus can also modulate the protective immune responses by developing immune evasion mechanisms, and thereby provide a more stable niche. Overall, combination of detrimental immunostimulatory and immunomodulatory properties of both the SARS-CoV-2 and immune cells does complicate the immune interplay. Thorough understanding of immunopathogenic basis of immune responses against SARS-CoV-2 has led to developing several advanced vaccines and immune-based therapeutics and should be expanded more rapidly. In this review, we tried to delineate the immunopathogenesis of SARS-CoV-2 in humans and to provide insight into more effective therapeutic and prophylactic strategies.

Virtual Screening on Marine Natural Products for Discovering TMPRSS2 Inhibitors.

Although SARS-CoV-2 entry to cells strictly depends on angiotensin-converting enzyme 2 (ACE2), the virus also needs transmembrane serine protease 2 (TMPRSS2) for its spike protein priming. It has been shown that the entrance of SARS-CoV-2 through ACE2 can be blocked by cellular TMPRSS2 blockers. The main aim of this study was to find potential inhibitor(s) of TMPRSS2 through virtual screening against a homology model of TMPRSS2 using the library of marine natural products (MNPs). The homology modeling technique for generating a three-dimensional structure of TMPRSS2 was applied. Molecular docking, MM-GBSA and absorption, distribution, metabolism, excretion (ADME) evaluations were performed to investigate the inhibitory activity of marine natural products (MNPs) against TMPRSS2 and their pharmacokinetic properties. Camostat and nafamostat mesylate were used as the standard inhibitory molecules. Seven MNPs were able to inhibit TMPRSS2 better than the standard compounds. MNP 10 with CAS number 107503-09-3, called Watasenia ß-D- Preluciferyl glucopyrasoiuronic acid, was found to be the best inhibitor of TMPRSS2 with acceptable pharmacokinetic properties. Herein, for the first time, a new marine natural product was introduced with potent inhibitory effects against TMPRSS2. MNP 10 exhibited favorable drug-like pharmacokinetic properties and it promises a novel TMPRSS2 blocker to combat SARS-CoV-2.

Role of myeloid-derived suppressor cells in viral respiratory infections; Hints for discovering therapeutic targets for COVID-19.

The expansion of myeloid-derived suppressor cells (MDSCs), known as heterogeneous population of immature myeloid cells, is enhanced during several pathological conditions such as inflammatory or viral respiratory infections. It seems that the way MDSCs behave in infection depends on the type and the virulence mechanisms of the invader pathogen, the disease stage, and the infection-related pathology. Increasing evidence showing that in correlation with the severity of the disease, MDSCs are accumulated in COVID-19 patients, in particular in those at severe stages of the disease or ICU patients, contributing to pathogenesis of SARS-CoV2 infection. Based on the involved subsets, MDSCs delay the clearance of the virus through inhibiting T-cell proliferation and responses by employing various mechanisms such as inducing the secretion of anti-inflammatory cytokines, inducible nitric oxide synthase (iNOS)-mediated hampering of IFN-γ production, or forcing arginine shortage. While the immunosuppressive characteristic of MDSCs may help to preserve the tissue homeostasis and prevent hyperinflammation at early stages of the infection, hampering of efficient immune responses proved to exert significant pathogenic effects on severe forms of COVID-19, suggesting the targeting of MDSCs as a potential intervention to reactivate T-cell immunity and thereby prevent the infection from developing into severe stages of the disease. This review tried to compile evidence on the roles of different subsets of MDSCs during viral respiratory infections, which is far from being totally understood, and introduce the promising potential of MDSCs for developing novel diagnostic and therapeutic approaches, especially against COVID-19 disease.

Potential Natural Products Against Respiratory Viruses: A Perspective to Develop Anti-COVID-19 Medicines.

The emergence of viral pneumonia caused by a novel coronavirus (CoV), known as the 2019 novel coronavirus (2019-nCoV), resulted in a contagious acute respiratory infectious disease in December 2019 in Wuhan, Hubei Province, China. Its alarmingly quick transmission to many countries across the world and a considerable percentage of morbidity and mortality made the World Health Organization recognize it as a pandemic on March 11, 2020. The perceived risk of infection has led many research groups to study COVID-19 from different aspects. In this literature review, the phylogenetics and taxonomy of COVID-19 coronavirus, epidemiology, and respiratory viruses similar to COVID-19 and their mode of action are documented in an approach to understand the behavior of the current virus. Moreover, we suggest targeting the receptors of SARS-CoV and SARS-CoV-2 such as ACE2 and other proteins including 3CLpro and PLpro for improving antiviral activity and immune response against COVID-19 disease. Additionally, since phytochemicals play an essential role in complementary therapies for viral infections, we summarized different bioactive natural products against the mentioned respiratory viruses with a focus on influenza A, SARS-CoV, MERS, and COVID-19.Based on current literature, 130 compounds have antiviral potential, and of these, 94 metabolites demonstrated bioactivity against coronaviruses. Interestingly, these are classified in different groups of natural products, including alkaloids, flavonoids, terpenoids, and others. Most of these compounds comprise flavonoid skeletons. Based on our survey, xanthoangelol E (88), isolated from Angelica keiskei (Miq.) Koidz showed inhibitory activity against SARS-CoV PLpro with the best IC50 value of 1.2 µM. Additionally, hispidulin (3), quercetin (6), rutin (8), saikosaponin D (36), glycyrrhizin (47), and hesperetin (55) had remarkable antiviral potential against different viral infections. Among these compounds, quercetin (6) exhibited antiviral activities against influenza A, SARS-CoV, and COVID-19 and this seems to be a highly promising compound. In addition, our report discusses the obstacles and future perspectives to highlight the importance of developing screening programs to investigate potential natural medicines against COVID-19.

Clinical characteristics of outpatients and inpatients with COVID-19 in Bushehr: a report from the south of Iran

Aim: To investigate clinical, laboratory and imaging features of COVID-19 patients in Bushehr, a southern province of Iran. Materials & methods: A total of 148 COVID-19 patients were enrolled. The patients were categorized into four groups including inpatients, outpatients, elderly and nonelderly. Clinical, laboratory and computed tomography characteristics were analyzed and compared. Results: Levels of erythrocyte sedimentation rate, CRP, lactate dehydrogenase and aspartate aminotransferas among inpatients were higher than outpatients. There were significant differences in the levels of creatinine and blood urine nitrogen between elderly and nonelderly patients. The incidence of ground-glass opacities in inpatients was significantly higher than in outpatients. Conclusion: COVID-19 is associated with more severe renal failure in elderly patients. Elderly patients with underlying conditions are at increased risk of severe progression of COVID-19.

COVID-19 cytokine storm: The anger of inflammation.

Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.