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      Ursolic acid and SARS-CoV-2 infection: a new horizon and perspective

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          Abstract

          SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) has been identified as the source of a world coronavirus pandemic in 2019. Covid-19 is considered a main respiratory disease-causing viral pneumonia and, in severe cases, leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Although, extrapulmonary manifestations of Covid-19 like neurological, cardiovascular, and gastrointestinal have been confirmed. Exaggerated immune response and release of a high amount of pro-inflammatory cytokines may progress, causing a cytokine storm. Consequently, direct and indirect effects of SARS-CoV-2 infection can evolve into systemic complications due to the progression of hyper inflammation, oxidative stress and dysregulation of the renin-angiotensin system (RAS). Therefore, anti-inflammatory and antioxidant agents could be efficient in alleviating these disorders. Ursolic acid has anti-inflammatory, antioxidant, and antiviral effects; it reduces the release of pro-inflammatory cytokines, improves anti-inflammatory cytokines, and inhibits the production of reactive oxygen species (ROS). In virtue of its anti-inflammatory and antioxidant effects, ursolic acid may minimize SARS-CoV-2 infection-induced complications. Also, by regulating RAS and inflammatory signaling pathways, ursolic acid might effectively reduce the development of ALI in ARDS in Covid-19. In this state, this perspective discusses how ursolic acid can mitigate hyper inflammation and oxidative stress in Covid-19.

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          How COVID-19 induces cytokine storm with high mortality

          The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.
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            COVID-19: Current understanding of its Pathophysiology, Clinical presentation and Treatment

            Background The severe acute respiratory syndrome (SARS) coronavirus-2 is a novel coronavirus belonging to the family Coronaviridae and is now known to be responsible for the outbreak of a series of recent acute atypical respiratory infections originating in Wuhan, China. The disease caused by this virus, termed coronavirus disease 19 or simply COVID-19, has rapidly spread throughout the world at an alarming pace and has been declared a pandemic by the WHO on March 11, 2020. In this review, an update on the pathophysiology, clinical presentation and the most recent management strategies for COVID-19 has been described. Materials and Methods A search was conducted for literature and various articles/case reports from 1997 to 2020 in PUBMED/MEDLINE for the keywords coronavirus, SARS, Middle East respiratory syndrome and mRNA virus. Results and Conclusions COVID-19 has now spread globally with increasing morbidity and mortality among all populations. In the absence of a proper and effective antibody test, the diagnosis is presently based on a reverse-transcription PCR of nasopharyngeal and oropharyngeal swab samples. The clinical spectrum of the disease presents in the form of a mild, moderate or severe illness. Most patients are either asymptomatic carriers who despite being without symptoms have the potential to be infectious to others coming in close contact, or have a mild influenza-like illness which cannot be differentiated from a simple upper respiratory tract infection. Moderate and severe cases require hospitalisation as well as intensive therapy which includes non-invasive as well as invasive ventilation, along with antipyretics, antivirals, antibiotics and steroids. Complicated cases may require treatment by immunomodulatory drugs and plasma exchange therapy. The search for an effective vaccine for COVID-19 is presently in full swing, with pharmaceutical corporations having started human trials in many countries.
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              p38 MAPK inhibition: A promising therapeutic approach for COVID-19

              COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1–7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1–7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.
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                Author and article information

                Contributors
                hayderm36@yahoo.com
                Dr.alialgareeb78@yahoo.com
                walaa.negm@pharm.tanta.edu.eg
                gaberbatiha@gmail.com , dr_gaber_batiha@vetmed.dmu.edu.eg
                Journal
                Inflammopharmacology
                Inflammopharmacology
                Inflammopharmacology
                Springer International Publishing (Cham )
                0925-4692
                1568-5608
                3 August 2022
                : 1-9
                Affiliations
                [1 ]Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
                [2 ]GRID grid.412258.8, ISNI 0000 0000 9477 7793, Department of Pharmacognosy, Faculty of Pharmacy, , Tanta University, ; Tanta, 31527 Egypt
                [3 ]Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW Australia
                [4 ]AFNP Med, Vienna, Austria
                [5 ]GRID grid.449014.c, ISNI 0000 0004 0583 5330, Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, , Damanhour University, AL Beheira, ; Damanhour, 22511 Egypt
                Author information
                http://orcid.org/0000-0003-0463-8047
                http://orcid.org/0000-0002-7817-425X
                Article
                1038
                10.1007/s10787-022-01038-3
                9362167
                35922738
                4a6bd073-a4cf-4e4f-bd52-ff954c463013
                © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 26 June 2022
                : 14 July 2022
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                acute lung injury,antiviral,covid-19,immunity,oxidative stress,pandemics

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