Prediction models based on miRNA-disease relationship: Diagnostic relevance to multiple diseases including COVID-19.

BACKGROUND: Small, non-coding microRNAs, usually of 20-25 nucleotides, are known to regulate the post-transcriptional gene expression, which has a significant role in human biological processes, including immune-biogenesis, homeostasis and infection control as differential expression of such miRNAs is responsible for fine-tuning the organismic development. METHODS: A search of bibliographic databases was carried out with a focused question on microRNA-Disease Prediction. A deductive qualitative content analysis approach was further employed to assess the research's overall outcomes, review articles on prediction tools in miRNA-Diseases, and analyse the interventions. RESULTS: Diagnosis and therapeutics of diseases and miRNA prediction methods hold importance in identifying the regulatory mechanisms. Collections of efficient miRNA prediction methods to identify miRNA-mRNA-disease regulatory relationships have been presented through this review, consolidating the potential of miRNAs as a diagnostic and prognostic biomarker of multiple diseases, including COVID-19. CONCLUSIONS: The role of miRNA in the aetiology and pathogenesis of wide-range of pathologies, including viral, bacterial to chronic diseases such as cancer, is quite feasible through the modern tools in bioinformatics which has been elaborated focusing upon miRNA-disease prediction methods and their application potential establishing miRNAs as a robust and reliable biomarker in clinico-medical studies.

Effects of the SARS-CoV-2 Spike protein on in vitro aggregation of alpha synuclein- probable molecular interactions and clinical implications

There have been reports of neurodegenerative diseases including Parkinsonism, Alzheimer's disease and Creutzfeldt Jakob disease following COVID-19. The exact pathogenesis of these has not been elucidated yet though authors have proposed the possibility of the hyper-inflammatory state of COVID-19 acting as a trigger through cytokine-induced inflammatory response of brain microglia and astrocytes, as well as damage resulting from the central nervous system hypoxia of severe COVID-19, or even the direct pathogenetic actions of SARS-CoV-2 on the brain. There have also been reports of worsening of Parkinsonian symptoms, new onset movement disorders and even rapidly progressive dementia following COVID-19 vaccination using different vaccine types. The occurrence of protein-aggregation mediated neurodegenerative syndromes following both COVID-19 and vaccination led us to explore the common thread of the Spike (S) protein as a potential mediator. In the current study, we investigated the interactions of S protein of SARS-CoV-2 with α-synuclein.

The Pathogenetic Dilemma of Post-COVID-19 Mucormycosis in India.

There has been a surge of mucormycosis cases in India in the wake of the second wave of COVID-19 with more than 40000 cases reported. Mucormycosis in patients of COVID-19 in India is at variance to other countries where Aspergillus, Pneumocystis, and Candida have been reported to be the major secondary fungal pathogens. We discuss the probable causes of the mucormycosis epidemic in India. Whereas dysglycaemia and inappropriate steroid use have been widely suggested as tentative reasons, we explore other biological, iatrogenic, and environmental factors. The likelihood of a two-hit pathogenesis remains strong. We propose that COVID-19 itself provides the predisposition to invasive mucormycosis (first hit), through upregulation of GRP78 and downregulation of spleen tyrosine kinase involved in anti-fungal defense, as also through inhibition of CD8+ T-cell mediated immunity. The other iatrogenic and environmental factors may provide the second hit which may have resulted in the surge.

Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms.

The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors - CX3CR1 and L-selectin - were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.

Vitamin D and immuno-pathology of COVID-19: many interactions but uncertain therapeutic benefits.

Introduction: COVID-19 pandemic has caused huge loss of human lives and extensive socio-economic damages. The immuno-pathology of this disease is neither clearly understood nor there are effective drugs for severe cases of COVID-19. Repurposing of available drugs for the treatment of COVID-19 is imperative.Areas Covered: This review has gathered the evidence from PubMed, Google Scholar, WHO, and other reliable websites on COVID-19 and summarized the existing knowledge of the immuno-pathology of COVID-19. We elucidated how vitamin D through its diverse actions on immune effector cells, epithelial cells, or renin-angiotensin-aldosterone system could have a modulatory role on the pathogenic mechanisms of COVID-19. The epidemiological evidence associating vitamin D deficiency with the severity and incidence of COVID-19 is also presented. However, the evidence of clinical benefit to patients of COVID-19 from randomized controlled trials with vitamin D has not come as yet.Expert opinion: It is now established that fatality of COVID-19 is primarily determined by hyperactivation of the host's innate immune system in response to SARS-CoV-2 invasion, and thus the research on the immuno-modulatory and other roles of vitamin D against viral infections should be pursued vigorously. This would be also useful for future pandemics caused by other novel viruses.

Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia.

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2.

The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 28 million cases of COVID-19 (Corona virus disease-2019) and more than 900000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1-7) axes, that can be utilized against COVID-19 disease progression.

Of Cross-immunity, Herd Immunity and Country-specific Plans: Experiences from COVID-19 in India.

India has witnessed a high number of COVID-19 cases, but mortality has been quite low, and most cases have been asymptomatic or mild. In early April, we had hypothesized a low COVID-19 mortality in India, based on the concept of cross-immunity. The presence of cross-immunity is presumed to lead to a milder course of disease and allow the time necessary for the development of adaptive immunity by the body to eliminate the virus. Evidence supporting our hypothesis has started showing up. Multiple studies have shown the generation of different T cell subsets and B cells responding to epitopes of viral proteins, especially of the spike protein, as a part of adaptive immunity against SARS-CoV-2. Cross-reactive T-cells have been demonstrated in patients who have been previously exposed to endemic coronaviruses. The interplay of cross-immunity and herd immunity is apparent in the COVID-19 scenario in India from the presence of a large number of asymptomatic or mild cases, a low infection-fatality ratio and a generally flat curve of percentage positivity of cases with respect to total testing, both in periods of strict lock-down and step-wise unlocking. It seems that cross-immunity resulted in faster generation of herd immunity. Although the initial restrictive measures such as lockdown prevented the rapid spread of the outbreak, further extension of such measures and overly expensive ones such as enhanced testing in India will result in a huge burden on the health economics as well as the society. Hence, we propose a restructuring of the health services and approach to COVID-19. The restructured health services should move away from indiscriminate testing, isolation and quarantine, and instead, the emphasis should be on improving facilities for testing and management of only critical COVID cases and the replacement of complete lockdowns by the selective isolation and quarantine of susceptible persons such as the aged and those with co-morbidities. In the process of describing India-specific plans, we emphasize why the development of country-specific plans for tackling epidemics is important, instead of adopting a "one policy fits all" approach.

Targeting Host Cell Proteases to Prevent SARS-CoV-2 Invasion.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.

Repurposing of SARS-CoV nucleocapsid protein specific nuclease resistant RNA aptamer for therapeutics against SARS-CoV-2.

COVID-19 pandemic is rapidly advancing among human population. Development of new interventions including therapeutics and vaccines against SARS-CoV-2 will require time and validation before it could be made available for public use. Keeping in view of the emergent and evolving situation the motive is to repurpose and test the immediate efficacy of available drugs and therapeutics against COVID-19. Through this article we propose and discuss the possibility of repurposing the available nuclease resistant RNA aptamer against the nucleocapsid protein of SARS-CoV as a potential therapeutic agent for COVID-19.

Physiological Relevance of Angiotensin Converting Enzyme 2 As a Metabolic Linker and Therapeutic Implication of Mesenchymal Stem Cells in COVID-19 and Hypertension.

Severe acute respiratory syndrome corona virus - 2 (SARS-CoV-2) is a single stranded RNA virus and responsible for infecting human being. In many cases the individual may remain asymptomatic. Some recently reported studies revealed that individuals of elderly age group and with pre-existing medical conditions such as hypertension, diabetes mellitus had severe consequences, even may lead to death. However, it is not clearly delineated whether hypertension itself or associated comorbidities or antihypertensive therapy contributes to the grave prognosis of COVID-19 infections. This review is aimed to decipher the exact mechanisms involved at molecular level from existing evidence and as reported. It has been reported that SARS-CoV-2 enters into the host cell through interaction between conserved residues of viral spike protein and angiotensin converting enzyme 2 (ACE2) receptor which is highly expressed in host's cardiac and pulmonary cells and finally transmembrane protease, serine-2 (TMPRSS2), helps in priming of the surface protein. Subsequently, symptom related to multi organ involvement is primarily contributed by cytokine storm. Although various clinical trials are being conducted on renin- angiotensin- system inhibitor, till to date there is no standard treatment protocol approved for critically ill COVID-19 positive cases with pre-existing hypertension. Recently, several studies are carried out to document the safety and efficacy outcome of mesenchymal stem cell transplantation based on its immunomodulatory and regenerative properties. Therefore, identification of future novel therapeutics in the form of mesenchymal stem cell either alone or in combination with pharmacological approach could be recommended for combating SARS-CoV-2 which might be dreadful to debilitating elderly people. Graphical Abstract.

COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?

The ongoing Corona virus (COVID-19) pandemic has witnessed global political responses of unimaginable proportions. Many nations have implemented lockdowns that involve mandating citizens not to leave their residences for non-essential work. The Indian government has taken appropriate and commendable steps to curtail the community spread of COVID-19. While this may be extremely beneficial, this perspective discusses the other reasons why COVID-19 may have a lesser impact on India. We analyze the current pattern of SARS-CoV-2 transmission, testing, and mortality in India with an emphasis on the importance of mortality as a marker of the clinical relevance of COVID-19 disease. We also analyze the environmental and biological factors which may lessen the impact of COVID-19 in India. The importance of cross-immunity, innate immune responses, ACE polymorphism, and viral genetic mutations are discussed.