Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation
Open Access
- 28 January 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 10 (2), 1-17
- https://doi.org/10.1038/s41419-018-1247-9
Abstract
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 in lung injury is the elevated levels of inflammatory cytokines, among them, the soluble tumor necrosis factor (TNF-α) has a key role, which exerts cytotoxicity in epithelial and endothelial cells thus exacerbates edema. The bacterial lipopolysaccharide (LPS) was used both in vitro (RAW 264.7, THP-1, MLE-12, A549, and BEAS-2B) and in vivo (C57BL/6 mice), as it activates a plethora of overlapping inflammatory signaling pathways involved in ARDS. Nimbolide is a chemical constituent of Azadirachta indica, which contains multiple biological properties, while its role in ARDS is elusive. Herein, we have investigated the protective effects of nimbolide in abrogating the complications associated with ARDS. We showed that nimbolide markedly suppressed the nitrosative-oxidative stress, inflammatory cytokines, and chemokines expression by suppressing iNOS, myeloperoxidase, and nitrotyrosine expression. Moreover, nimbolide mitigated the migration of neutrophils and mast cells whilst normalizing the LPS-induced hypothermia. Also, nimbolide modulated the expression of epigenetic regulators with multiple HDAC inhibitory activity by suppressing the nuclear translocation of NF-κB and HDAC-3. We extended our studies using molecular docking studies, which demonstrated a strong interaction between nimbolide and TNF-α. Additionally, we showed that treatment with nimbolide increased GSH, Nrf-2, SOD-1, and HO-1 protein expression; concomitantly abrogated the LPS-triggered TNF-α, p38 MAPK, mTOR, and GSK-3β protein expression. Collectively, these results indicate that TNF-α-regulated NF-κB and HDAC-3 crosstalk was ameliorated by nimbolide with promising anti-nitrosative, antioxidant, and anti-inflammatory properties in LPS-induced ARDS.Keywords
This publication has 52 references indexed in Scilit:
- Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in ratsActa Pharmacologica Sinica, 2013
- The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κBNucleic Acids Research, 2012
- CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4Cell, 2011
- Biomarkers in Acute Lung Injury: Insights into the Pathogenesis of Acute Lung InjuryCritical Care Clinics, 2011
- TLR signalling augments macrophage bactericidal activity through mitochondrial ROSNature, 2011
- Acute Lung Injury: Epidemiology, Pathogenesis, and TreatmentJournal of Aerosol Medicine and Pulmonary Drug Delivery, 2010
- Histone Deacetylase-3 Activation Promotes Tumor Necrosis Factor-α (TNF-α) Expression in Cardiomyocytes during Lipopolysaccharide StimulationOnline Journal of Public Health Informatics, 2010
- The Antioxidant Role of Glutathione and N-Acetyl-Cysteine Supplements and Exercise-Induced Oxidative StressJournal of the International Society of Sports Nutrition, 2005
- Acute Respiratory Failure from Abused SubstancesJournal of Intensive Care Medicine, 2004
- THE EFFECTS OF CYCLOSPORINE AND DEXAMETHASONE ON AN ALVEOLAR MACROPHAGE CELL LINE (NR8383)Transplantation, 1992