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    Adhatoda Vasica attenuates inflammatory and hypoxic MESHD responses in preclinical  mouse models: potential for repurposing in COVID-19 MESHD-like conditions

    Authors: Atish Prabhakar Gheware; Dhwani Dholakia; S Kanan; Lipsa Panda; Ritu Rani; Bijay Ranjan Pattnaik; Vaibhav Jain; Yash Parekh; M.Ghalib Enayathullah; Kiran Kumar Bokara; V Subramanian; Mitali Mukerji; Anurag Agrawal; Bhavana Prasher

    doi:10.21203/rs.3.rs-105233/v2 Date: 2020-11-09 Source: ResearchSquare

    Background:   COVID-19 MESHD pneumonia MESHD has been associated with severe acute hypoxia MESHD, sepsis MESHD-like states, thrombosis MESHD and chronic sequelae including persisting hypoxia MESHD and fibrosis MESHD. The molecular hypoxia MESHD response pathway has been associated with such pathologies and   our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract  of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. Methods: In this study, we tested the effect of whole aqueous extract of AV , in murine models of bleomycin induced pulmonary fibrosis MESHD, Cecum Ligation and Puncture ( CLP MESHD) induced sepsis MESHD, and siRNA induced hypoxia-thrombosis MESHD phenotype. The effect on lung of AV treated naïve mice was also studied at  transcriptome level. We also determined if the extract may have any direct effect on SARS-CoV2 replication   Results: Oral administration AV extract attenuates increased airway inflammation MESHD,  levels of  transforming growth factor-b1 (TGF-b1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis MESHD and   sepsis MESHD and rescues the siRNA induced inflammation MESHD and associated blood coagulation MESHD phenotypes in mice. We observed downregulation of  hypoxia MESHD, inflammation MESHD, TGF-b1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome . AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2.  Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation MESHD features and highlights the repurposing potential of AV  in COVID-19 MESHD-like conditions. 

    Adhatoda Vasica: a potential ayurvedic intervention against COVID-19 MESHD associated impaired immune response and hypoxia-inflammation phenotype

    Authors: Atish Gheware; Dhwani Dholakia; S. Kannan; Lipsa Panda; Vivek Anand; Ritu Rani; Bijay Ranjan Pattnaik; Vaibhav Jain; V Subramanian; Mitali Mukerji; Anurag Agrawal; Bhavana Prasher

    doi:10.21203/rs.3.rs-92502/v1 Date: 2020-10-14 Source: ResearchSquare

    Background: The importance of hypoxia MESHD inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation MESHD is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia MESHD and inflammatory diseases. Increased hypoxia MESHD is being reported to  be an important modifier for several pathological features of COVID-19 MESHD such as impaired immunity, hyper-inflammation MESHD, thrombosis MESHD, lung injury MESHD and sepsis MESHD. Methods: In this study we tested the effect of whole aqueous extract Adhatoda Vasica (AV), that our group has shown to have anti-hypoxic and anti-inflammatory effects, on various outcomes of hypoxic response. Effects of AV were assessed in preclinical mouse models of pulmonary fibrosis MESHD, bacterial sepsis MESHD and siRNA induced hypoxia-thrombosis MESHD phenotype. Therapeutic relevance of AV in current pandemic were also examined through transcriptome and molecular docking analysis. Results:  Oral administration AV extract attenuated the increased levels of airway inflammation MESHD, collagen content, transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improved the overall survival rate in bleomycin treated  and Cecum Ligation  and Puncture ( CLP MESHD) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α MESHD and associated blood coagulation MESHD phenotypes in mice. Transcriptome analysis of lungs of AV MESHD treated naïve mice reveal downregulation of   hypoxia MESHD, inflammation MESHD, TGF-β1 and angiogenesis and upregulation of adaptive immunity related genes. These genes and pathways show opposite expression in transcriptome of  BALF and PBMCs of SARS-CoV2 infected MESHD patient. Molecular docking of AV constituents presents in extract  reveal many molecules with low binding energy (≤ -8)  to multiple SARS-CoV2 and host target proteins that are relevant in viral entry and replication. Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the anti-inflammatory and anti-HIF-1α effect for potential use in management of COVID19 MESHD patients.

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MeSH Disease
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