Madhuri Basak1, Tarun Mahata1, Sreemoyee Chakraborti1, Pranesh Kumar2, Bolay Bhattacharya3, Sandip Kumar Bandyopadhyay4, Madhusudan Das5, Adele Stewart6, Sudipta Saha2, Biswanath Maity1. 1. Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Lucknow, India. 2. Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India. 3. Department of Pharmacy, Geethanjali College of Pharmacy, Cheeryala, India. 4. Department of Biochemistry, KPC Medical College and Hospital, Kolkata, India. 5. Department of Zoology, University of Calcutta, Kolkata, India. 6. Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, Florida.
Abstract
Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs), among the most commonly used drugs worldwide, are associated with gastrointestinal (GI) complications that severely limit the clinical utility of this essential class of pain medications. Here, we mechanistically dissect the protective impact of a natural product, malabaricone C (Mal C), on NSAID-induced gastropathy. Results: Mal C dose dependently diminished erosion of the stomach lining and inflammation in mice treated with NSAIDs with the protective impact translating to improvement in survival. By decreasing oxidative and nitrative stress, Mal C treatment prevented NSAID-induced mitochondrial dysfunction and cell death; nuclear factor κ-light-chain enhancer of activated B cell induction, release of proinflammatory cytokines and neutrophil infiltration; and disruptions in the vascular endothelial growth factor/endostatin balance that contributes to mucosal autohealing. Importantly, Mal C failed to impact the therapeutic anti-inflammatory properties of multiple NSAIDs in a model of acute inflammation. In all assays tested, Mal C proved as or more efficacious than the current first-line therapy for NSAID-dependent GI complications, the proton pump inhibitor omeprazole. Innovation: Given that omeprazole-mediated prophylaxis is, itself, associated with a shift in NSAID-driven GI complications from the upper GI to the lower GI system, there is a clear and present need for novel therapeutics aimed at ameliorating NSAID-induced gastropathy. Mal C provided significant protection against NSAID-induced gastric ulcerations impacting multiple critical signaling cascades contributing to inflammation, cell loss, extracellular matrix degradation, and angiogenic autohealing. Conclusion: Thus, Mal C represents a viable lead compound for the development of novel gastroprotective agents.
Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs), among the most commonly used drugs worldwide, are associated with gastrointestinal (GI) complications that severely limit the clinical utility of this essential class of pain medications. Here, we mechanistically dissect the protective impact of a natural product, malabaricone C (Mal C), on NSAID-induced gastropathy. Results: Mal C dose dependently diminished erosion of the stomach lining and inflammation in mice treated with NSAIDs with the protective impact translating to improvement in survival. By decreasing oxidative and nitrative stress, Mal C treatment prevented NSAID-induced mitochondrial dysfunction and cell death; nuclear factor κ-light-chain enhancer of activated B cell induction, release of proinflammatory cytokines and neutrophil infiltration; and disruptions in the vascular endothelial growth factor/endostatin balance that contributes to mucosal autohealing. Importantly, Mal C failed to impact the therapeutic anti-inflammatory properties of multiple NSAIDs in a model of acute inflammation. In all assays tested, Mal C proved as or more efficacious than the current first-line therapy for NSAID-dependent GI complications, the proton pump inhibitor omeprazole. Innovation: Given that omeprazole-mediated prophylaxis is, itself, associated with a shift in NSAID-driven GI complications from the upper GI to the lower GI system, there is a clear and present need for novel therapeutics aimed at ameliorating NSAID-induced gastropathy. Mal C provided significant protection against NSAID-induced gastric ulcerations impacting multiple critical signaling cascades contributing to inflammation, cell loss, extracellular matrix degradation, and angiogenic autohealing. Conclusion: Thus, Mal C represents a viable lead compound for the development of novel gastroprotective agents.
Authors: Melanie Schirmer; Sanne P Smeekens; Hera Vlamakis; Martin Jaeger; Marije Oosting; Eric A Franzosa; Rob Ter Horst; Trees Jansen; Liesbeth Jacobs; Marc Jan Bonder; Alexander Kurilshikov; Jingyuan Fu; Leo A B Joosten; Alexandra Zhernakova; Curtis Huttenhower; Cisca Wijmenga; Mihai G Netea; Ramnik J Xavier Journal: Cell Date: 2016-12-15 Impact factor: 41.582
Authors: John L Wallace; Stephanie Syer; Emmanuel Denou; Giada de Palma; Linda Vong; Webb McKnight; Jennifer Jury; Manlio Bolla; Premysl Bercik; Stephen M Collins; Elena Verdu; Ennio Ongini Journal: Gastroenterology Date: 2011-07-13 Impact factor: 22.682