scholarly journals Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1912
Author(s):  
Kaushik Chakravarty ◽  
Victor G. Antontsev ◽  
Maksim Khotimchenko ◽  
Nilesh Gupta ◽  
Aditya Jagarapu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Renin Angiotensin System ◽  
Mechanistic Modeling ◽  
Channel Blockers ◽  
Angiotensin System ◽  
In Silico Modeling ◽  
Site Of Action ◽  
Line Of Therapy

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.

scholarly journals Accelerated repurposing and drug development of pulmonary hypertension therapies for COVID-19 treatment using an AI-integrated biosimulation platform

2020 ◽  
Author(s):  
Kaushik Chakravarty ◽  
Victor Antontsev ◽  
Aditya Jagarapu ◽  
Yogesh Bundey ◽  
Hypatia Hou ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Renin Angiotensin System ◽  
The United States ◽  
Mechanistic Modeling ◽  
World Health ◽  
Channel Blockers ◽  
Health Organization ◽  
Line Of Therapy

Abstract A World Health Organization-declared pandemic, COVID-19, has affected more than 4 million people worldwide with over 100,000 deaths and growing in the United States. Due to the fast-spreading and multi-targeted nature of the virus, it is clear that drugs and/or vaccines need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically Angiotensin converting enzyme (ACE), and Ca2+ -mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors (e.g. benazepril) and calcium channel blockers (CCB, e.g. amlodipine), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCB and ACEI compounds to tissues implicated in COVID-19 pathogenesis.

scholarly journals Accelerated repurposing and drug development of pulmonary hypertension therapies for COVID-19 treatment using an AI-integrated biosimulation platform

2020 ◽  
Author(s):  
Kaushik Chakravarty ◽  
Victor Antontsev ◽  
Aditya Jagarapu ◽  
Yogesh Bundey ◽  
Hypatia Hou ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Renin Angiotensin System ◽  
The United States ◽  
Mechanistic Modeling ◽  
World Health ◽  
Channel Blockers ◽  
Health Organization ◽  
Line Of Therapy

Abstract A World Health Organization-declared pandemic, COVID-19, has affected more than 4 million people worldwide with over 100,000 deaths and growing in the United States. Due to the fast-spreading and multi-targeted nature of the virus, it is clear that drugs and/or vaccines need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically Angiotensin converting enzyme (ACE), and Ca2+ -mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors (e.g. benazepril) and calcium channel blockers (CCB, e.g. amlodipine), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCB and ACEI compounds to tissues implicated in COVID-19 pathogenesis.

The Role of the Renin–Angiotensin System in the Cancer Stem Cell Niche

2021 ◽  
pp. 002215542110262
Author(s):  
Ethan J. Kilmister ◽  
Swee T. Tan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Renin Angiotensin System ◽  
Epidemiological Data ◽  
Malignant Cells ◽  
Angiotensin System ◽  
Renin Angiotensin

Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche, an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin–angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche. Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment:

scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

scholarly journals Galectin-7 Impairs Placentation and Causes Preeclampsia Features in Mice

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1185-1194 ◽  
Author(s):  
Ellen Menkhorst ◽  
Wei Zhou ◽  
Leilani L. Santos ◽  
Sarah Delforce ◽  
Teresa So ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
First Trimester ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Elevated Systolic Blood Pressure ◽  
System Components ◽  
Pregnant Mice ◽  
New Treatment

Preeclampsia is a serious pregnancy-induced disorder unique to humans. The etiology of preeclampsia is poorly understood; however, poor placental formation is thought causal. Galectin-7 is produced by trophoblast and is elevated in first-trimester serum of women who subsequently develop preeclampsia. We hypothesized that elevated placental galectin-7 may be causative of preeclampsia. Here, we demonstrated increased galectin-7 production in chorionic villous samples from women who subsequently develop preterm preeclampsia compared with uncomplicated pregnancies. In vitro, galectin-7 impaired human first-trimester trophoblast outgrowth, increased placental production of the antiangiogenic sFlt-1 splice variant, sFlt-1-e15a , and reduced placental production and secretion of ADAM12 (a disintegrin and metalloproteinase12) and angiotensinogen. In vivo, galectin-7 administration (E8–E12) to pregnant mice caused elevated systolic blood pressure, albuminuria, impaired placentation (reduced labyrinth vascular branching, impaired decidual spiral artery remodeling, and a proinflammatory placental state demonstrated by elevated IL1β, IL6 and reduced IL10), and dysregulated expression of renin-angiotensin system components in the placenta, decidua, and kidney, including angiotensinogen, prorenin, and the angiotensin II type 1 receptor. Collectively, this study demonstrates that elevated galectin-7 during placental formation contributes to abnormal placentation and suggests that it leads to the development of preeclampsia via altering placental production of sFlt-1 and renin-angiotensin system components. Targeting galectin-7 may be a new treatment option for preeclampsia.

Erythropoietin in COVID-19-Induced Neuroinflammation; EPO Plus Losartan Might be Promising

2020 ◽  
Author(s):  
Reza Nejat ◽  
Ahmad Shahir Sadr ◽  
David Najafi
Keyword(s):  
Inflammatory Mediators ◽  
Renin Angiotensin System ◽  
Oxygen Species ◽  
Ang Ii ◽  
Angiotensin System ◽  
Intracellular Messengers ◽  
The Central Nervous System ◽  
Harmful Effects

Introduction: Neuroinflammation is the inflammatory reaction in the central nervous system (CNS) provoked by diverse insults. This phenomenon results in a cascade of release of inflammatory mediators and intracellular messengers such as reactive oxygen species. The elicited responses are the cause of many neurological and neurodegenerative disorders. Erythropoietin (EPO) has been considered effective in attenuating this inflammatory process in the CNS, yet its administration in COVID-19 needs meticulously designed studies. Discussion: Neuroinflammation in COVID-19 due to probable contribution of renin-angiotensin system dysregulation resulting in surplus of Ang II and owing to the synergistic interaction between this octapeptide and EPO needs special consideration. Both of these compounds increase intracellular Ca2+ which may induce release of cytokine and inflammatory mediators leading to aggravation of neuroinflammation. In addition, Ang II elevates HIF even in normoxia which by itself increases EPO. It is implicated that EPO and HIF may likely increase in patients with COVID-19 which makes administration of EPO to these patients hazardous. Furthermore, papain-like protease of SARS-CoV2 as a deubiquitinase may also increase HIF. Conclusion: It is hypothesized that administration of EPO to patients with COVID-19-induced neuroinflammation may not be safe and in case EPO is needed for any reason in this disease adding of losartan may block AT1R-mediated post-receptor harmful effects of Ang II in synergism with EPO. Inhibition of papain-like protease might additionally decrease HIF in this disease. More in vitro, in vivo and clinical studies are needed to validate these hypotheses.

scholarly journals Benzbromarone Attenuates Oxidative Stress in Angiotensin II- and Salt-Induced Hypertensive Model Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Nanako Muraya ◽  
Daisuke Kadowaki ◽  
Shigeyuki Miyamura ◽  
Kenichiro Kitamura ◽  
Kohei Uchimura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Radical Scavenging ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Scavenging Effect ◽  
Stress Markers ◽  
Radical Scavenging Effect

Oxidative stress induced by hyperuricemia is closely associated with the renin-angiotensin system, as well as the onset and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD). It is therefore important to reduce oxidative stress to treat hyperuricemia. We previously found that benzbromarone, a uricosuric agent, has a direct free radical scavenging effect in vitro. The antioxidant effects of benzbromarone were evaluated in vivo via oral administration of benzbromarone for 4 weeks to model rats with angiotensin II- and salt-induced hypertension. Benzbromarone did not alter plasma uric acid levels or blood pressure but significantly reduced the levels of advanced oxidation protein products, which are oxidative stress markers. Furthermore, dihydroethidium staining of the kidney revealed a reduction in oxidative stress after benzbromarone administration. These results suggest that benzbromarone has a direct antioxidant effect in vivo and great potential to prevent CVD and CKD.

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