Glycyrrhizin prevents 3-nitropropionic acid-induced neurotoxicity by downregulating HMGB1/TLR4/NF-κB p65 signaling, and attenuating oxidative stress, inflammation, and apoptosis in rats.

AIMS: Glycyrrhizin (Glyc) is a saponin triterpenoid that has signified its efficacy against Huntington's disease (HD). Nonetheless, its mechanism has not been fully clarified. Accordingly, this study was designed to evaluate the plausible mechanism of action of Glyc against 3-nitropropionic acid (3-NP)-induced HD. MAIN METHODS: Rats were treated with Glyc (50 mg/kg, i.p.) for 3 weeks and 3-NP (10 mg/kg, i.p.) was administered at the latter 2 weeks alongside to induce HD. KEY FINDINGS: Animals exposed to 3-NP revealed a reduction in body weight, neurobehavioral abnormalities, and various deleterious effects related to overexpression of HMGB1 such as oxidative stress, apoptosis, and inflammation. Promisingly, Glyc administration provided valuable effects by reversing the decline in body weight with improved neurobehavioral deficits. Ameliorating oxidative stress via restoring GSH, SOD, and Nrf2 alongside with MDA suppression was evident. Furthermore, Glyc switched the HMGB1/TLR4/NF-κB p65 signaling off, reduced IL-6, IL-ß, TNF-α, caspase-3, and increased Bcl-2 as well as BDNF. All these beneficial effects were mirrored by a better histopathological picture upon using Glyc that suppressed gliosis by reducing GFAP expression as observed in the immunohistochemistry results. SIGNIFICANCE: Accordingly, the current study demonstrated a promising neuroprotective effect of Glyc against experimentally induced HD through alleviating deleterious events by diverse mechanisms.

Morin alleviates hepatic ischemia/reperfusion-induced mischief: In vivo and in silico contribution of Nrf2, TLR4, and NLRP3.

OBJECTIVE: Morin (MRN), a known natural flavonol, has demonstrated its shielding aptitude against ischemia/reperfusion (I/Re) lesion in various organs. Nonetheless, its potential influence on hepatic I/Re-induced injury modulation has not been fully elucidated. Consequently, the current study strived to investigate the mechanistic maneuvering of MRN against hepatic I/Re. Furthermore, the effects of MRN on Nrf2, TLR4, and NLRP3 proteins were evaluated via molecular docking studies. METHODS: For fulfilling this aim, Sprague-Dawley rats were allotted into 4 groups; Sham-operated (ShG), hepatic I/Re (30 min/24 h), and 10 days orally pre-treated MRN (50 and 100 mg/kg). KEY FINDINGS: MRN mechanistic maneuver disclosed its ability to safeguard the hepatocytes partially due to antioxidant aptitude through intensifying the expression/content of Nrf2/HO-1 trajectory accompanied by total antioxidant capacity boosting besides MDA lessening. In addition, MRN anti-inflammatory attribute was affirmed by downsizing the expression/content of TLR4/NF-κB trajectory accompanied by a sequent lessening of TNF-α, IL-1ß, IL-6, and ICAM-1 content. Moreover, MRN action entangled NLRP3 inhibitory character with subsequent MPO rebating. Furthermore, MRN anti-apoptotic trait verified by diminishing the pro-apoptotic and the executioner markers; Bax and caspase-3 levels, respectively. On the other hand, MRN administration proved its shielding action by improving the histopathological deterioration and lessening the serum ALT and AST levels. Finally, in silico studies exhibited moderate to promising binding affinities of MRN with the selected proteins ranging from -4.23 to -6.09 kcal mol-1. CONCLUSION: Higher and lower doses of MRN purveyed plausible defensive mechanisms and abated episodes concomitant with hepatic I/Re mischief in part, by modifying oxidative status and inflammation by the impact on Nrf2/HO-1, TLR4/ NF-κB, and NLRP3 pathway.