Dose-dependent ameliorating effect of lipoxin A4 on gentamicin-induced nephrotoxicity in rats: The role of TNFα, TGF-ß, ICAM-1, and JNK signaling.

Gentamicin (GEN) possesses a broad range of antimicrobial effects. However, it belongs to the aminoglycosides, and has the greatest potential for nephrotoxic effect above all other antibiotics from this group. This study aims to evaluate the possible protective effect of lipoxin A4 (LXA4) against GEN-induced nephrotoxicity in rats. Nephrotoxicity was induced in male Wistar rats by injection of GEN (80 mg/kg/day, i.p.) for 6 days starting from day 7 of the experiment. Rats were treated with either LXA4 (10 µg/kg/day, i.p.) or LXA4 (50 µg/kg/day, i.p.) for 14 days starting from day 1 of the experiment, along with GEN as the previous schedule. GEN resulted in a significantly elevated renal function in the form of higher serum creatinine and urea levels. Further, GEN induced abnormal renal histopathology including degenerated glomeruli and tubules, with perivascular inflammation and hemorrhage. All of these findings were significantly decreased by the LXA4 administration. Additionally, LXA4 remarkably reduced the increased serum lipid biomarkers. Moreover, LXA4 significantly inhibited the GEN-induced oxidative stress in the kidneys by decreasing the elevated levels of renal malondialdehyde (MDA) and total nitrite while raising the suppressed levels of renal superoxide dismutase (SOD) and serum total antioxidant capacity (TAC). LXA4 inhibited the up-regulated inflammatory mediators ICAM-1, TGFß 1 protein levels, and TNF-α protein expression. Finally, LXA4 suppressed the elevated apoptotic mediators; p-JNK and cleaved caspase-3 expression. Our results proved for the first time that LXA4 ameliorated GEN-induced nephrotoxicity through its antioxidant, anti-inflammatory and anti-apoptotic properties.

Diacerein protects rats with liver ischemia/reperfusion damage: Down-regulation of TLR4/ NFκ-B signaling pathway.

PURPOSE: Liver ischemia-reperfusion (I/R) injury is an inescapable problem. Diacerein, a chondro-protective drug, has antioxidant and anti-inflammatory effects. Its effect on liver I/R injury has not yet been fully clarified. Therefore, the current study aimed to detect its hepatic protective effect with the explanation of possible underlying mechanisms. METHODS: Adult male albino rats were assigned to 4 groups: sham group, diacerein pretreated sham group, I/R non-treated group, and I/R diacerein pretreated group. Serum liver enzymes, hepatic tissue oxidative stress parameters, inflammatory biomarkers mainly Toll-like receptors-4 (TLR4), and liver fatty acid binding protein (L-FABP) levels were determined. Histopathological examination of liver tissues and immunohistochemical studies of heat shock protein 70, nuclear factor-kappa B, and Cluster of Differentiation 68 were also done. RESULTS: Diacerein pretreatment has the ability to restore the hepatic I/R damaging effect, proved by the reduction of serum liver enzymes, the decrease of the oxidative stress and hepatic inflammation via down-regulation of TLR4/ NFκ-B signaling pathway together with the restoration of L-FABP level and improvement of the histopathological and immunohistochemical study findings in the hepatic tissue. CONCLUSION: These results suggested the hepatoprotective effect of diacerein relies on its antioxidant and anti-inflammatory effects reducing TLR4/ NFκ-B signaling pathway.

Allopurinol potentiates the hepatoprotective effect of metformin and vitamin E in fructose-induced fatty liver in rats.

AIM OF THE STUDY: Non-alcoholic fatty liver disease (NAFLD) is a challenging health problem. Hyperuricemia is a key player in the pathogenesis of NAFLD. This study investigated the effect of allopurinol (uric acid synthesis inhibitor) in combination with metformin and vitamin E in prevention of fructose induced-fatty liver in rats. MATERIAL AND METHODS: Rats were divided into 7 groups: control group, fructose group (model group of NAFLD), allopurinol-treated group, metformin-treated group, vitamin E-treated group, metformin plus vitamin E-treated group and a combination group (received allopurinol plus metformin plus vitamin E). Development of NAFLD was assessed biochemically by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as by histopathological examination. Oxidative stress parameters [reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA)], and the inflammatory mediators tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) were assessed, along with serum levels of uric acid and triglyceride (TG). RESULTS: Combination of allopurinol plus metformin plus vitamin E significantly attenuated fatty changes compared to their respective monotherapy. Interestingly, though all treated groups showed significant attenuation in the oxidative stress markers, TNF-α level and iNOS immunostaining in hepatic tissue, along with a significant decrease in the levels of uric acid and TG, the combination group showed a further significant decrease in the serum level of uric acid and iNOS immunostaining compared to other treated regimens. CONCLUSIONS: Allopurinol synergistically increases the protective effect of metformin and vitamin E in treatment of NAFLD, namely via reduction of uric acid synthesis and iNOS expression.

Sitagliptin prevents isoproterenol-induced myocardial infarction in rats by modulating nitric oxide synthase enzymes.

Ischemic heart disease is a common cause of mortality worldwide. Sitagliptin is a new anti-diabetic drug acting as dipeptidyl peptidase-4 (DPP-4) inhibitor. The study investigated the ability of sitagliptin to prevent pathological changes of isoproterenol- (ISO-) induced myocardial injury in rats. The role of nitric oxide (NO) was also reported. Rats were assorted into six groups (n = 7) and treated for 12 days. Group 1: normal control, received normal saline. Group 2, sitagliptin control, received sitagliptin (10 mg/kg, orally). Group 3, ISO group, received isoproterenol (ISO) (100 mg/kg, i.p.). Group 4, sitagliptin + ISO, co-treated with sitagliptin plus ISO. Group 5, L-NNA + ISO, co-treated with L-NG-nitro arginine (L-NNA) (25 mg/kg, orally) plus ISO. Group 6, sitagliptin + L-NNA + ISO, co-treated with sitagliptin plus ISO plus L-NNA. Blood glucose, serum creatine kinase-MB (CK-MB, and cardiac tissue parameters of oxidative stress parameters and NO, along with histopathological examination, and immunohistochemical study of inducible NO synthase (iNOS) expression were done. The results showed that sitagliptin caused a significant reduction in CK-MB, and attenuated histopathological damage-induced by ISO. Its effect was associated with a significant decrease in oxidative stress parameters, NO contents as well as by a significant decrease in the expression of iNOS in cardiac tissue. The protective effect of sitagliptin was abrogated by coadministartion of L-NNA, a selective inhibitor of both endothelial NOS (eNOS) and neuronal NOS (nNOS). In conclusion, sitagliptin ameliorates ISO-induced myocardial injury via antioxidant effects and modulation of NOS enzymes.

Nonalcoholic fatty liver disease: current and potential therapies.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury worldwide. It covers a wide spectrum of hepatic disorders ranging from simple steatosis, through steatohepatitis (steatosis with inflammation), to cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD are not clear. Several evidences suggest that multiple mechanisms including insulin resistance, oxidative stress, inflammation, and genetic factors interact to initiate the development of NAFLD. Despite that there is currently no approved drug therapy for NAFLD, many approaches appear to be beneficial. Insulin sensitizers, antioxidants and antiinflammatory agents showed promising effects. This review highlights the current as well as the potential therapies of NAFLD.