TY - JOUR T1 - Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. JF - Nat Commun Y1 - 2019 A1 - Singh, Rajbir A1 - Chandrashekharappa, Sandeep A1 - Bodduluri, Sobha R A1 - Baby, Becca V A1 - Hegde, Bindu A1 - Kotla, Niranjan G A1 - Hiwale, Ankita A A1 - Saiyed, Taslimarif A1 - Patel, Paresh A1 - Vijay-Kumar, Matam A1 - Langille, Morgan G I A1 - Douglas, Gavin M A1 - Cheng, Xi A1 - Rouchka, Eric C A1 - Waigel, Sabine J A1 - Dryden, Gerald W A1 - Alatassi, Houda A1 - Zhang, Huang-Ge A1 - Haribabu, Bodduluri A1 - Vemula, Praveen K A1 - Jala, Venkatakrishna R KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Caco-2 Cells KW - Coumarins KW - Epithelial Cells KW - Gene Expression Regulation KW - HT29 Cells KW - Humans KW - Intestinal Mucosa KW - Macrophages KW - Mice KW - Mice, Inbred C57BL KW - Mice, Knockout KW - NF-E2-Related Factor 2 KW - Receptors, Aryl Hydrocarbon KW - Specific Pathogen-Free Organisms KW - Tight Junction Proteins AB -

The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.

VL - 10 IS - 1 ER - TY - JOUR T1 - Prevention of pesticide-induced neuronal dysfunction and mortality with nucleophilic poly-Oxime topical gel. JF - Sci Adv Y1 - 2018 A1 - Thorat, Ketan A1 - Pandey, Subhashini A1 - Chandrashekharappa, Sandeep A1 - Vavilthota, Nikitha A1 - Hiwale, Ankita A A1 - Shah, Purna A1 - Sreekumar, Sneha A1 - Upadhyay, Shubhangi A1 - Phuntsok, Tenzin A1 - Mahato, Manohar A1 - Mudnakudu-Nagaraju, Kiran K A1 - Sunnapu, Omprakash A1 - Vemula, Praveen K AB -

Organophosphate-based pesticides inhibit acetylcholinesterase (AChE), which plays a pivotal role in neuromuscular function. While spraying in the field, farmworkers get exposed to pesticides through the dermal route. Internalized pesticide inhibits AChE, which leads to neurotoxicity, cardiotoxicity, cognitive dysfunction, loss of endurance, and death in severe cases. Here, we present a nucleophilic pyridine-2-aldoxime-functionalized chitosan-based topical gel (-Oxime gel) that rapidly deactivates organophosphates, methyl parathion (MPT), on the skin of rats, which leads to reduced AChE inhibition in the blood and tissues. Testing the robustness of -Oxime gel, we report reduction in AChE inhibition following repeated dermal administration of MPT in the presence of -Oxime gel. Furthermore, -Oxime gel prevented MPT-induced neuromuscular dysfunction, loss of endurance, and locomotor coordination. We observe a 100% survival in rats following topical MPT administration in the presence of -Oxime gel. This prophylactic gel may therefore help farmworkers by limiting pesticide-induced toxicity and mortality.

VL - 4 IS - 10 ER -