Heena Agarwal1,2, Santosh Reddy Sukka1,2, Vishal Singh1, Madhu Dikshit1,3, Manoj Kumar Barthwal4,5. 1. Pharmacology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. 2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. 3. Translational Health Science and Technology Institute, Faridabad, Haryana, 121001, India. 4. Pharmacology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. manojbarthwal@cdri.res.in. 5. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. manojbarthwal@cdri.res.in.
Abstract
OBJECTIVE: Present study investigates the effect of Xylocarpus moluccensis (Lamk.) M. Roem fruit fraction (CDR) on endotoxemia and explores the underlying mechanisms. MATERIALS AND METHODS: The effect of CDR (1-100 µg/ml) was assessed on cytokines, MAPKs, ROS, and metabolic reprogramming in LPS-induced cells (J774.2 and THP-1) by the conventional methodology of ELISA, PCR, and Western blotting. The effect of CDR (1-50 mg/kg, p.o.) was also evaluated in the mice model of endotoxemia and sepsis. RESULTS: CDR prevents LPS-induced cytokine production from murine and human whole blood and cell lines. CDR suppressed total cellular and mitochondrial superoxide generation and preserved mitochondrial function in LPS-stimulated phagocytes. Additionally, CDR abrogated LPS-induced MAPK's phosphorylation and IκBα degradation in J774.2 cells. Moreover, CDR suppressed LPS-induced glycolytic flux as indicated from PKM2, HK-2, PDK-2, and HIF-1α expression in J774.2 cells. In vivo, CDR pre-treatment inhibited pro-inflammatory cytokines release, metabolic reprogramming from oxidative phosphorylation to glycolysis in both LPS-induced endotoxemia and cecal slurry-induced sepsis mice model. CONCLUSION: Present study demonstrates the protective effect of CDR on LPS-induced inflammation and sepsis and identifies MAPK-NFκB and ROS-HIF1α-PKM2 as the putative target axis.
OBJECTIVE: Present study investigates the effect of Xylocarpus moluccensis (Lamk.) M. Roem fruit fraction (CDR) on endotoxemia and explores the underlying mechanisms. MATERIALS AND METHODS: The effect of CDR (1-100 µg/ml) was assessed on cytokines, MAPKs, ROS, and metabolic reprogramming in LPS-induced cells (J774.2 and THP-1) by the conventional methodology of ELISA, PCR, and Western blotting. The effect of CDR (1-50 mg/kg, p.o.) was also evaluated in the mice model of endotoxemia and sepsis. RESULTS: CDR prevents LPS-induced cytokine production from murine and human whole blood and cell lines. CDR suppressed total cellular and mitochondrial superoxide generation and preserved mitochondrial function in LPS-stimulated phagocytes. Additionally, CDR abrogated LPS-induced MAPK's phosphorylation and IκBα degradation in J774.2 cells. Moreover, CDR suppressed LPS-induced glycolytic flux as indicated from PKM2, HK-2, PDK-2, and HIF-1α expression in J774.2 cells. In vivo, CDR pre-treatment inhibited pro-inflammatory cytokines release, metabolic reprogramming from oxidative phosphorylation to glycolysis in both LPS-induced endotoxemia and cecal slurry-induced sepsis mice model. CONCLUSION: Present study demonstrates the protective effect of CDR on LPS-induced inflammation and sepsis and identifies MAPK-NFκB and ROS-HIF1α-PKM2 as the putative target axis.
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