Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation

• DOI: 10.1038/s41419-018-1247-9
• Publication Date: 2019-01-28T10:03:08Z
• Authors: Venkatesh Pooladanda; Sowjanya Thatikonda; Swarna Bale; Bijay Pattnaik; Dilep Kumar Sigal...; Nagendra Babu Bat...; Shashi Bala Singh; Chandraiah Godugu
• Keywords: Limonins; Male; 0301 basic medicine; Respiratory Distress Syndrome; Azadirachta; Tumor Necrosis Factor-alpha; NF-kappa B; Article; Translocation, Genetic; 3. Good health; Molecular Docking Simulation; Disease Models, Animal; Mice; 03 medical and health sciences; Animals; Humans

Acute respiratory distress syndrome (ARDS) is characterized by an excessive acute inflammatory response in lung parenchyma, which ultimately leads to refractory hypoxemia. One of the earliest abnormalities seen injury elevated levels cytokines, among them, soluble tumor necrosis factor (TNF-α) has a key role, exerts cytotoxicity epithelial and endothelial cells thus exacerbates edema. The bacterial lipopolysaccharide (LPS) was used both vitro (RAW 264.7, THP-1, MLE-12, A549, BEAS-2B) vivo (C57BL/6 mice), as it activates plethora overlapping signaling pathways involved ARDS. Nimbolide chemical constituent Azadirachta indica, contains multiple biological properties, while its role ARDS elusive. Herein, we have investigated protective effects nimbolide abrogating complications associated with We showed that markedly suppressed nitrosative-oxidative stress, chemokines expression suppressing iNOS, myeloperoxidase, nitrotyrosine expression. Moreover, mitigated migration neutrophils mast whilst normalizing LPS-induced hypothermia. Also, modulated epigenetic regulators HDAC inhibitory activity nuclear translocation NF-κB HDAC-3. extended our studies using molecular docking studies, demonstrated strong interaction between TNF-α. Additionally, treatment increased GSH, Nrf-2, SOD-1, HO-1 protein expression; concomitantly abrogated LPS-triggered TNF-α, p38 MAPK, mTOR, GSK-3β Collectively, these results indicate TNF-α-regulated HDAC-3 crosstalk ameliorated promising anti-nitrosative, antioxidant, anti-inflammatory properties