Protocatechuic acid ameliorates lipopolysaccharide-induced kidney damage in mice via downregulation of TLR-4-mediated IKBKB/NF-κB and MAPK/Erk signaling pathways.

Acute kidney injury (AKI) is a very critical cause of death in the whole world. Lipopolysaccharide (LPS) induces kidney damage by activating various deleterious inflammatory and oxidative pathways. Protocatechuic acid, a natural phenolic compound, has shown to exert beneficial effects against oxidative and inflammatory responses. The study aimed to clarify the nephroprotective activity of protocatechuic acid in LPS-induced acute kidney damage in mice. Forty male Swiss mice were allocated in four groups as follows: normal control group; LPS (250 µg/kg, ip)-induced kidney injury group; LPS-injected mice treated with protocatechuic acid (15 mg/kg, po), and LPS-injected mice treated with protocatechuic acid (30 mg/kg, po). Significant toll-like receptor 4 (TLR-4)-mediated activation of IKBKB/NF-κB and MAPK/Erk/COX-2 inflammatory pathways has been observed in kidneys of mice treated with LPS. Oxidative stress was revealed by inhibition of total antioxidant capacity, catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and NAD(P)H quinone oxidoreductase (NQO1) enzyme along with increased nitric oxide level. In parallel, focal inflammatory effects were shown in between the tubules and glomeruli as well as in the perivascular dilated blood vessels at the cortex affecting the normal morphology of the kidney tissues of LPS-treated mice. However, treatment with protocatechuic acid reduced LPS-induced changes in the aforementioned parameters and restored normal histological features of the affected tissues. In conclusion, our study uncovered that protocatechuic acid has nephroprotective effects in mice with AKI through opposing different inflammatory and oxidative cascades.

Rosuvastatin and co-enzyme Q10 improve high-fat and high-fructose diet-induced metabolic syndrome in rats via ameliorating inflammatory and oxidative burden.

The prevalence of metabolic syndrome (MetS) has been rising alarmingly and it has now become a global concern causing an enormous economic burden on the health care system. MetS is generally linked to complications in lipid metabolism, oxidative stress and low grade inflammation. The aim of the current study was to evaluate the effect of rosuvastatin, co-enzyme Q10 (CoQ10), and their combination on blood pressure, blood sugar, dyslipidemia, and liver function in rats with MetS induced by high fructose and high fat diet (HF-HFD) and the possible underlying mechanism. Oral administration of rosuvastatin (10 mg/kg/day), CoQ10 (10 mg/kg/day) and their combination for 4 weeks in HF-HFD-fed rats elevated serum high density lipoprotein and reduced glutathione. On the other hand, treatment with rosuvastatin, CoQ10 or their combination decreased the serum levels of malondialdehyde, triglycerides, total cholesterol, and low density lipoprotein-cholesterol as well as systolic blood pressure, body weight and fasting blood glucose level. In addition, the drugs or their combination declined serum pro-inflammatory cytokines, namely tumor necrosis factor-α and interleukin-1ß. In conclusion, our results showed that rosuvastatin or CoQ10 protected against HF-HFD-induced MetS through the regulation of dyslipidemia, elevated blood glucose, elevated blood pressure, antioxidant defenses and inflammatory response. Rosuvastatin or CoQ10 also alleviated the impairment of liver function that was induced by HF-HFD. Interestingly, CoQ10 augmented rosuvastatin's effect in ameliorating MetS, via exerting synergistic modulatory effects on oxidative stress and inflammation. Thus, rosuvastatin and CoQ10 combination therapy may have possible applications in ameliorating metabolic disorders.

Nateglinide Exerts Neuroprotective Effects via Downregulation of HIF-1α/TIM-3 Inflammatory Pathway and Promotion of Caveolin-1 Expression in the Rat's Hippocampus Subjected to Focal Cerebral Ischemia/Reperfusion Injury.

Ischemic stroke is a major cause of death and motor disabilities all over the world. It is a muti-factorial disorder associated with inflammatory, apoptotic, and oxidative responses. Nateglinide (NAT), an insulinotropic agent used for the treatment of type 2 diabetes mellitus, recently showed potential anti-inflammatory and anti-apoptotic effects. The aim of our study was to elucidate the unique neuroprotective role of NAT in the middle cerebral artery occlusion (MCAO)-induced stroke in rats. Fifty-six male rats were divided to 4 groups (n = 14 in each group): the sham-operated group, sham receiving NAT (50 mg/kg/day, p.o) group, ischemia/reperfusion (IR) group, and IR receiving NAT group (50 mg/kg/day, p.o). MCAO caused potent deficits in motor and behavioral functions of the rats. Significant increase in inflammatory and apoptotic biomarkers has been observed in rats' hippocampi. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was significantly stimulated causing activation of series inflammatory biomarkers ending up neuro-inflammatory milieu. Pretreatment with NAT preserved rats' normal behavioral and motor functions. Moreover, NAT opposed the expression of hypoxia-inducible factor-1α (HIF-1α) resulting in downregulation of more inflammatory mediators namely, NF-κB, tumor necrosis factor-ß (TNF-ß), and the anti-survival gene PMAIP-1. NAT stimulated caveolin-1 (Cav-1) which prevented expression of oxidative biomarkers, nitric oxide (NO), and myeloperoxidase (MPO) and hamper the activation of apoptotic biomarker caspase-3. In conclusion, our work postulated that NAT exhibited its neuroprotective effects in rats with ischemic stroke via attenuation of different unique oxidative, apoptotic, and inflammatory pathways.