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

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.

%B Nat Commun %V 10 %P 89 %8 2019 01 09 %G eng %N 1 %R 10.1038/s41467-018-07859-7 %0 Journal Article %J Sci Adv %D 2018 %T Prevention of pesticide-induced neuronal dysfunction and mortality with nucleophilic poly-Oxime topical gel. %A Thorat, Ketan %A Pandey, Subhashini %A Chandrashekharappa, Sandeep %A Vavilthota, Nikitha %A Hiwale, Ankita A %A Shah, Purna %A Sreekumar, Sneha %A Upadhyay, Shubhangi %A Phuntsok, Tenzin %A Mahato, Manohar %A Mudnakudu-Nagaraju, Kiran K %A Sunnapu, Omprakash %A Vemula, Praveen K %X

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.

%B Sci Adv %V 4 %P eaau1780 %8 2018 Oct %G eng %N 10 %R 10.1126/sciadv.aau1780