scholarly journals Adhatoda Vasica: A Potential Ayurvedic Intervention Against COVID-19 Associated Impaired Immune Response and Hypoxia-Inflammation Phenotype

2020 ◽  
Author(s):  
Atish Prabhakar Gheware ◽  
Dhwani Dholakia ◽  
S Kanan ◽  
Lipsa Panda ◽  
Vivek Anand ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Viral Entry ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Adhatoda Vasica ◽  
Hypoxia Inducible Factor 1 ◽  
Infection And Inflammation ◽  
Impaired Immune Response ◽  
Host Target

Abstract Background: The importance of hypoxia inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia and inflammatory diseases. Increased hypoxia is being reported to be an important modifier for several pathological features of COVID-19 such as impaired immunity, hyper-inflammation, thrombosis, lung injury and sepsis. 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, bacterial sepsis and siRNA induced hypoxia-thrombosis 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, collagen content, transforming growth factor-b1 (TGF-b1), IL-6, HIF-1α and improved the overall survival rate in bleomycin treated and Cecum Ligation and Puncture (CLP) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α and associated blood coagulation phenotypes in mice. Transcriptome analysis of lungs of AV treated naïve mice reveal downregulation of hypoxia, inflammation, TGF-b1 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 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 hypoxia-hyperinflammation features which could be useful against SARS-CoV-2 infection.

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

2020 ◽  
Author(s):  
Atish Gheware ◽  
Dhwani Dholakia ◽  
S. Kannan ◽  
Lipsa Panda ◽  
Vivek Anand ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Viral Entry ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β1 ◽  
Infection And Inflammation ◽  
Impaired Immune Response ◽  
Anti Inflammatory ◽  
Tgf Β1

Abstract Background: The importance of hypoxia inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia and inflammatory diseases. Increased hypoxia is being reported to be an important modifier for several pathological features of COVID-19 such as impaired immunity, hyper-inflammation, thrombosis, lung injury and sepsis. 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, bacterial sepsis and siRNA induced hypoxia-thrombosis 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, 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) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α and associated blood coagulation phenotypes in mice. Transcriptome analysis of lungs of AV treated naïve mice reveal downregulation of hypoxia, inflammation, 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 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 patients.

scholarly journals HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3343-3354 ◽  
Author(s):  
Marzia Scortegagna ◽  
Christophe Cataisson ◽  
Rebecca J. Martin ◽  
Daniel J. Hicklin ◽  
Robert D. Schreiber ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cancer Metastasis ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Local Environment ◽  
Inflammatory Cells ◽  
Hypoxia Inducible Factor 1 ◽  
Inflammatory Protein ◽  
Multiple Cell ◽  
Epithelial Inflammation

AbstractHypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.

scholarly journals Molecular Docking and Drug-Likeness for the Identification of Inhibitory Action of Acetogenins from Annona muricata as Potential Anticancer against Hypoxia Inducible Factor 1 Alpha

2018 ◽  
Vol 11 (3) ◽  
pp. 1301-1307
Author(s):  
Supri I. Handayani ◽  
Rahmiati Rahmiati ◽  
Lisnawati Rahmadi ◽  
Rosmalena Rosmalena ◽  
Vivitri D. Prasasty
Keyword(s):  
Molecular Docking ◽  
Hypoxia Inducible Factor ◽  
Binding Energies ◽  
Binding Modes ◽  
Annona Muricata ◽  
Chemical Structures ◽  
Hypoxia Inducible Factor 1 ◽  
Human Cancers

Hypoxia inducible factor 1 alpha (HIF-1α) regulates cell growth and differentiation which is implicated in human cancers. HIF-1α activates its cascade carcinogenesis mechanism in cancer cells. It is well-understood that signaling is initiated by HIF-1α receptor. Overexpression of HIF-1α is associated with several different human cancers, including breast cancer, lung cancer and colon cancer. Thus, HIF-1α becomes potential target of therapeutic approach in developing HIF-1α inhibitors. The aim of this research is to investigate potential inhibitors which are known as Acetogenins (AGEs) isolated from Annona muricata against HIF-1α. In order to achieve this goal, chemical structures of all compounds were retrieved from PubChem database. Molecular docking was performed by AutoDock Vina program and the resulting binding modes were analyzed with AutoDock Tools program. Among all the compounds, murihexocin A showed the best binding modes compared to other two inhibitors based on the lowest binding energies (LBE = -7.9 kcal/mol) as high as gefitinib. This was indicating that murihexocin A has favorable interaction with the essential amino acid residues at catalytic site of HIF-1α. Drug-likeness calculation of AGEs were also performed. These in silico results could be beneficial as a compound model for further studies in-vitro and in-vivo.

scholarly journals Inherited/Genetically-Associated Pheochromocytoma/ Paraganglioma Syndromes and COVID-19

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1033
Author(s):  
Ioannis Ilias ◽  
Gregory Kaltsas ◽  
Konstantinos Barkas ◽  
George P. Chrousos
Keyword(s):  
Protective Effect ◽  
Viral Entry ◽  
Binding Sites ◽  
Hypoxia Inducible Factor ◽  
Therapeutic Interventions ◽  
Spike Protein ◽  
Hypoxia Inducible Factor 1 ◽  
Stimulation Of ◽  
Angiotensin Converting Enzymes

In some subjects with inherited pheochromocytoma/paraganglioma (PPG) syndromes, hypoxia-inducible factor 1 alpha (HIF1α) stabilization/activation could lead to an increase in angiotensin converting enzymes (ACE). This would result in the stimulation of angiotensin (AT) II production and, hence, reduce the availability of ACE 2. The latter would provide decreased numbers of binding sites for the spike protein of SARS-CoV-2 and, therefore, result in less points of viral entry into cells. Thus, subjects with HIF1α-associated PPG syndromes may benefit from an inherent protective effect against COVID-19. Such an implication of HIF1α vis-à-vis COVID-19 could open ways of therapeutic interventions.

scholarly journals Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts

2000 ◽  
Vol 350 (1) ◽  
pp. 307-312 ◽  
Author(s):  
Ruth D. THORNTON ◽  
Pamela LANE ◽  
Ruth C. BORGHAEI ◽  
Elizabeth A. PEASE ◽  
Jaime CARO ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Consensus Sequence ◽  
Hypoxia Inducible Factor ◽  
Synovial Fibroblasts ◽  
Consensus Binding Site ◽  
Hypoxia Inducible Factor 1 ◽  
Aryl Hydrocarbon ◽  
Factor Α ◽  
Endothelial Growth Factor

Rheumatoid arthritis and periodontitis are inflammatory diseases modulated by proinflammatory cytokines [e.g. interleukin (IL-1) 1 and tumour necrosis factor α], which activate local fibroblasts to do the following: (1) proliferate, (2) induce gene expression and (3) produce destructive metalloproteinases. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor (composed of HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear transporter) that is modulated by hypoxia. HIF-1 binds to and induces several genes containing an HIF-1 consensus-binding site, including vascular endothelial growth factor and several glycolytic enzymes. Through differential screening of a human synovial fibroblast cDNA library, we identified HIF-1α as a clone up-regulated by IL-1. The mRNA for HIF-1α subunit was increased 3–4-fold by Northern blot analysis after cells had been incubated for 3h in the presence of IL-1. In addition, IL-1 increased the binding of the heterodimer HIF-1 to the HIF consensus sequence. These results suggest that HIF-1 might have a role in inflammation, possibly in attempting to re-establish homoeostasis.

scholarly journals Transforming Growth Factor β1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression

2006 ◽  
Vol 281 (34) ◽  
pp. 24171-24181 ◽  
Author(s):  
Stephanie McMahon ◽  
Martine Charbonneau ◽  
Sebastien Grandmont ◽  
Darren E. Richard ◽  
Claire M. Dubois
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Selective Inhibition ◽  
Transforming Growth Factor Β1 ◽  
Hypoxia Inducible Factor 1

scholarly journals Hypoxia-Inducible Factor-1 Transactivates Transforming Growth Factor-β3 in Trophoblast

Endocrinology ◽  
2004 ◽  
Vol 145 (9) ◽  
pp. 4113-4118 ◽  
Author(s):  
Hirotaka Nishi ◽  
Toshihide Nakada ◽  
Mitsuyasu Hokamura ◽  
Yumi Osakabe ◽  
Osamu Itokazu ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
First Trimester ◽  
Vital Role ◽  
Low Oxygen ◽  
Mobility Shift ◽  
Trophoblast Differentiation ◽  
Hypoxia Inducible Factor 1 ◽  
Electrophoretic Mobility Shift Assays

Abstract Hypoxia occurs during the development of placenta in the first trimester and is implicated in trophoblast differentiation. Intervillous blood flow increases after 10 wk of gestation and results in exposure of trophoblast cells to oxygen. Before this time, low oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. The oxygen-regulated early events of trophoblast differentiation are mediated by TGF-β3. TGF-β3 plays a vital role in trophoblast differentiation, and its overexpression can be found in preeclamptic placenta. We sought to determine the mechanism of TGF-β3 expression through hypoxia-inducible factor (HIF)-1. We show that HIF-1α and TGF-β3 are overexpressed in preeclamptic placenta. Hypoxia not only transactivates the TGF-β3 promoter activity but also enhances endogenous TGF-β3 expression. Using the TGF-β3 promoter deletion mutants, we show that the region between −90 and −60, which contains a putative HIF-1 consensus motif, is crucial for HIF-1-mediated transactivation. Electrophoretic mobility shift assays show that HIF-1 binds to the oligonucleotide containing the HIF-1 motif. Also, introduction of an antisense oligonucleotide for HIF-1 diminishes TGF-β3 expression during hypoxia, indicating that the up-regulation of TGF-β3 by hypoxia is mediated through HIF-1. Our results provide evidence that regulation of TGF-β3 promoter activity by HIF-1 represents a mechanism for trophoblast differentiation during hypoxia.

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