Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation
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
DOI:
10.1038/s41419-018-1247-9
Publication Date:
2019-01-28T10:03:08Z
AUTHORS (8)
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 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
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