ABSTRACT
Despite being an effective chemotherapeutic agent, the clinical use of doxorubicin (DOX) is limited by several organ toxicities including hepatic injury. Pentoxifylline (PTX) is a methylxanthine derivative with marked anti-inflammatory and anti-apoptotic features. It is unknown, however, whether PTX can mitigate DOX-evoked hepatotoxicity. This study aims to explore the potential hepatoprotective impact of PTX in DOX-induced hepatic injury and the underlying molecular mechanisms. Histopathology, immunohistochemistry, and ELISA were used to examine liver tissues. The current findings revealed that PTX administration to DOX-intoxicated rats mitigated the pathological manifestations of hepatic injury, reduced microscopical damage scores, and improved serum ALT and AST markers, revealing restored hepatic cellular integrity. These favorable effects were attributed to PTX's ability to mitigate inflammation by reducing hepatic IL-1ß and TNF-α levels and suppressing the pro-inflammatory HMGB1/TLR4/NF-κB axis. Moreover, PTX curtailed the hepatic apoptotic abnormalities by suppressing caspase 3 activity and lowering the Bax/Bcl-2 ratio. In tandem, PTX improved the defective autophagy events by lowering hepatic SQSTM-1/p62 accumulation and enhancing the AMPK/mTOR pathway, favoring autophagy and hepatic cell preservation. Together, for the first time, our findings demonstrate the ameliorative effect of PTX against DOX-evoked hepatotoxicity by dampening the hepatic HMGB1/TLR4/NF-κB pro-inflammatory axis and augmenting hepatic AMPK/mTOR-driven autophagy. Thus, PTX could be utilized as an adjunct agent with DOX regimens to mitigate DOX-induced hepatic injury.
ABSTRACT
Topiramate, a promising drug classically used for the management of neurological disorders including epilepsy and migraine, has demonstrated marked anti-inflammatory and anti-apoptotic actions in murine models of cardiac post-infarction inflammation, wound healing, and gastric/intestinal injury. However, its potential impact on cadmium-induced testicular injury remains to be elucidated. Herein, the present study aimed to explore the effect of topiramate against cadmium-invoked testicular impairment with emphasis on the molecular mechanisms linked to inflammation, apoptosis, and autophagy. Herein, administration of topiramate (50 mg/kg/day, by gavage) continued for 60 days and the testes were examined by histology, immunohistochemistry, and biochemical assays. The present data demonstrated that serum testosterone, sperm count/abnormalities, relative testicular weight, and histopathological aberrations were improved by topiramate administration to cadmium-intoxicated rats. The rescue of testicular dysfunction was driven by multi-pronged mechanisms including suppression of NLRP3/caspase-1/IL-1ß cascade, which was evidenced by dampened caspase-1 activity, lowered IL-1ß/IL-18 production, and decreased nuclear levels of activated NF-κBp65. Moreover, curbing testicular apoptosis was seen by lowered Bax expression, decreased caspase-3 activity, and upregulation of Bcl-2. In tandem, testicular autophagy was activated as seen by diminished p62 SQSTM1 accumulation alongside Beclin-1 upregulation. Autophagy activation was associated with AMPK/mTOR pathway stimulation demonstrated by decreased mTOR (Ser2448) phosphorylation and increased AMPK (Ser487) phosphorylation. In conclusion, combating inflammation/apoptosis and enhancing autophagic events by topiramate were engaged in ameliorating cadmium-induced testicular impairment.
ABSTRACT
The present investigation was designed to examine the possible additive hypolipidemic effect of carvacrol (CARV) in combination with simvastatin (SIM) on poloxamer 407 (P407)-induced hyperlipidemia. Rats were injected with P407, (500 mg/ kg; i.p.), twice a week, for 30 days. Treatment was carried out by administration of SIM (20 mg/kg/day; p.o.) or CARV (50 mg/kg/day; p.o.) or combination of them. Treatment with CARV significantly decreased total cholesterol, triglycerides, low-density lipoprotein, atherogenic index, leptin, and increased high-density lipoprotein and adiponectin. Moreover, CARV potentiated the hypolipidemic effect of SIM. Both SIM and CARV alleviated the oxidative stress induced by P407. Interestingly, CARV, when combined with SIM, significantly ameliorated SIM-induced liver and muscle injury by reducing the level of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and myoglobin and restoring the normal histological picture of both liver and muscle as well as apoptosis.
