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      Stem cell therapy in COVID-19: Pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review

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          Highlights

          • SARS-CoV-2, SARS-CoV and MERS-CoV shows high homology with each other and the pathophysiology of disease caused by these three coronaviruses are also similar with occurence of Acute respiratory distress syndrome (ARDS) in all the three cases. Stems cells are found to be efficacious against different viral infections and Inteferon stimulating genes (ISGs) are indicated in this protection owing to its capability of reducing the inflammation, decreasing the cell death, secreting cell protective substances, anti-oxidative effects and improving the overall immune function.

          • In in-vitro studies, stem cells showed protective action against ARDS and no in-vitro data have been documented so far for SARS-CoV-2, SARS-CoV and MERS-CoV infection.

          • In preclinical studies protective action was seen in various models of ARDS [lipopolysaccharide, endotoxin, E. coli, Bleomycin induced acute respiratory distress syndrome], including only one study for SARS-CoV-2. But no relevant studies were found for SARS-CoV and MERS CoV.

          • In clinical studies mesenchymal stem cells (MSCs) derived from various sources (bone marrow, umbilical cord, exosomes and even cardiosphere derived cells) showed efficacy in patients with severe COVID-19 infection and it is already under clinical trial in overall severe COVID-19 disease population.

          • Immunomodulating properties, tissue protection and healing properties of stem cells in combination with other anti-viral agents may prove to be a potential therapeuitc strategy for treating severe COVID-19 patients.

          Abstract

          Background

          SARS-CoV-2, which majorly affects the lungs and respiratory tract is thought due to dysregulation of the immune system which causes an immense imbalance of the cytokines. However, till now no standard treatment has been developed in treating the disease. On the other hand, it becomes important to prevent the acute respiratory tract infection due to COVID-19 which is the most dangerous phase leading to increased mortality. Hence this systematic review has been framed by pooling the available data of the use of stem cells in SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS.

          Methods

          6 literature databases (PubMed, EMBASE, Scopus, Google Scholar, Clinicaltrials.gov, and Clinical trial registry of India) were searched for relevant studies till 10th August 2020 using keywords stem cells, mesenchymal stem cells, cell therapy, SARS CoV-2, SARS Coronavirus, Coronavirus 2, COVID-19, nCoV-19, Novel Coronavirus, MERS CoV, ARDS, acute respiratory distress syndrome.

          Results

          The observations of this systematic review suggest capability of MSCs in reducing the systemic inflammation and protecting against SARS-CoV-2 as evidenced by the available clinical data.

          Conclusion

          MSCs can overcome the clinical challenges currently faced by SARS-CoV-2 infected patients, specifically who are seriously ill and not responding to conventional therapies. Though the available clinical data is motivating, still predicting the therapeutic potential of MSCs will be too early in COVID-19. Hence, further studies in a larger cohort of patients becomes a prerequisite to validate their potential efficacy.

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          Most cited references88

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          Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

          Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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            Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

            Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.
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              Is Open Access

              Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

              Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002–2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients’ sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.
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                Author and article information

                Journal
                Biomed Pharmacother
                Biomed Pharmacother
                Biomedicine & Pharmacotherapy
                Published by Elsevier Masson SAS.
                0753-3322
                1950-6007
                28 January 2021
                May 2021
                28 January 2021
                : 137
                : 111300
                Affiliations
                [a ]Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                [b ]Post Graduate Institute of Medical Education and Research, Chandigarh, India
                [c ]PGIMER, Chandigarh, India
                [d ]Dept. of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                Author notes
                [* ]Corresponding author at: Dept. of Pharmacology, Research block B. Postgraduate Institute of Medical Education and Research, Room No: 4044 4th floor, Chandigarh, India.
                [1]

                Indicates first author. In our article both Saniya Mahendiratta and Seema Bansal contributed equally. So, both are designated as first author.

                Article
                S0753-3322(21)00085-8 111300
                10.1016/j.biopha.2021.111300
                7843034
                33529945
                c8f0654c-1e9a-4317-b5f9-bf67e227bc6e
                © 2021 Published by Elsevier Masson SAS.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 8 December 2020
                : 12 January 2021
                : 18 January 2021
                Categories
                Review

                sars-cov-2,stem cell therapy,ards,immunomodulatory,coronavirus

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