Nifuroxazide modulates hepatic expression of LXRs/SR-BI/CES1/CYP7A1 and LDL-R and attenuates experimentally-induced hypercholesterolemia and the associated cardiovascular complications.

Hyperlipidemia is a serious disorders affecting the metabolism of fats in the human body, and it is usually associated with some serious cardiovascular complications increasing the risk for sudden death. Nifuroxazide (NFR) is an oral nitrofuran antibiotic that has long been used for management of diarrhea and recently various recent out merging valuable therapeutic impacts were reported. The current study sought the concept of repositioning nifuroxazide in management of hyperlipidemia. Hyperlipidemia was induced in male rabbits using cholesterol enriched diet for 9 weeks and starting from the beginning of 5th week; NFR (100 and 300 mg/kg) were administered once daily for the further 5 weeks; till the end of the 9th week of the experiment. NFR significantly recovered balanced lipid profile as serum cholesterol, total glycerides, LDL significantly declined with significant elevation in serum HDL. Meanwhile, serum LDH, CK, ALT and AST activities were significantly corrected. These biochemical changes were correlated with significant improvement in the histopathological examination of hepatic, cardiac and aortic specimen with decreased expression of CD68 and Ki67 in the myocardium and the aorta implying retraction in macrophages' infiltration and tissue regeneration. Myocardial specimen confirmed significant recovery with preservation of cardiac muscle fibers. Aortic specimen confirmed retraction in the aortic thickness and fewer deposition of fat globules. In conclusion, NFR attenuated experimentally-induced hyperlipidemia with significant recovery of serum profile and tissue necrotic changes. The histopathological examination of hepatic, myocardial and aortic specimen confirmed the onset of tissues' recovery alongside biochemical improvement.

Tranilast attenuates methotrexate-induced renal and hepatic toxicities: Role of apoptosis-induced tissue proliferation.

Drug-induced organ toxicity is a frequently encountered obstacle in the field of medical practice that limits the use of numerous pharmacologically valuable drugs. Methotrexate (MTX)-induced organ toxicity is unfortunately the rate-limiting factor for its clinical application. In the current study, MTX injection induced significant renal and hepatic toxicities manifested on functional, biochemical, and histopathological scales. This was associated with a significant elevation in both renal and hepatic contents of TNF-related apoptosis-inducing ligand (TRAIL) and caspase-8, biomarkers of tissue apoptosis. Inline, immunohistochemical analysis confirmed that tissue increased expression of Ki67 as a biomarker of tissue regeneration in both organs. Tranilast (TRAN) is a small molecular weight anti-inflammatory and antiallergic agent. TRAN's coadministration with MTX in the current study induced a significant tissue recovery via modulation of TRAIL/caspase-8 signaling and modulation of apoptosis-induced tissue proliferation confirmed by quantification of Ki67 expression. In conclusion, TRAN can be proposed as an effective drug to attenuate MTX-induced organ toxicity via modulation of apoptosis-induced tissue proliferation pathway.

Carvedilol attenuates experimentally induced silicosis in rats via modulation of P-AKT/mTOR/TGFß1 signaling.

Silicosis is a well acknowledged occupational lung disorder with considerable negative impact on the patients' quality of life. Various signaling pathways have been reported to interplay in the pathogenesis of pulmonary fibro-proliferative disorders; of which, P-AKT/mTOR signaling pathway. The current study highlights the potential pulmonary protective effect of carvedilol; a non-selective α/ß blocker against experimental silicosis-induced in rats by the intranasal installation of silica (50 mg/rat, 1 ml 0.9% NaCl). Carvedilol (20 mg/kg, orally) was administered for 8 weeks post intranasal silica installation. Carvedilol significantly attenuated silica-induced pulmonary damage on all the investigated scales. Inflammatory, oxidative/anti-oxidative and fibrotic incidences significantly improved with a significant histopathological restoration of lung architecture and attenuation of inflammatory and fibrotic biomarkers expression. Carvedilol significantly reduced lung contents of P-AKT and mTOR which, appears to be the main mechanism underlying the pulmonary protective effect of carvedilol. In conclusion; carvedilol attenuated silica-induced pulmonary fibrosis by modulating P-AKT/mTOR/TGFß1 signaling and underlying inflammatory and fibrotic sequel.

Nephroprotective effect of saxagliptin against gentamicin-induced nephrotoxicity, emphasis on anti-oxidant, anti-inflammatory and anti-apoptic effects.

Nephrotoxicity is a serious adverse effect frequently encountered with aminoglycosides administration. Given the value of aminoglycosides in management of serious infections, nephro-protection is highly recommended. The current study investigated the nephro-protective effect of saxagliptin (SAXA) (12.5 mg/kg, I.P.) against gentamicin (GEN)-induced nephrotoxicity in rats. SAXA administration for 14 days conferred significant nephro-protection against GEN-induced nephrotoxicity manifested in decreased kidney/somatic index, enhanced cytoprotection and significant decrease in serum LDH activity together with functional renal improvement; significant increase in creatinine clearance with significant reduction in serum creatinine, BUN, proteinuria and albuminuria. Oxidant/antioxidants hemostasis was significantly improved with SAXA treatment with significant reduction in kidney MDA content and enhancement of GSH concentration and catalase activity. Moreover, kidney content of NO significantly declined with significant decline in kidney tumor necrosis factorα (TNFα), vascular adhesion molecule-1 (VCAM-1) and caspase-3 content. Ultimately, SAXA administration was associated with significant attenuation of GEN-induced necrotic and inflammatory changes. In conclusion; the modulatory effect of SAXA on inflammatory cytokines, its anti-apoptic properties, ameliorative impact on oxidative load and positive impact on host antioxidant defenses accounts for the observed nephro-protective impact.