Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury.

BACKGROUND AND PURPOSE: The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats. EXPERIMENTAL APPROACH: Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks. FINDINGS/RESULTS: DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity via alleviation of all the above-mentioned parameters when compared to DXR-control rats. CONCLUSION AND IMPLICATIONS: The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1ß, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.

Hepatoprotective effect of kaempferol glycosides isolated from Cedrela odorata L. leaves in albino mice: involvement of Raf/MAPK pathway.

BACKGROUND AND PURPOSE: Paracetamol is the most implicated xenobiotic in inducing hepatotoxicity. Our study aimed to determine the impact of some kaempferol glycosides isolated from the leaves of Cedrela odorata L. on paracetamol hepatotoxicity. EXPERIMENTAL APPROACH: The methanolic extract of dried leaves of C. odorata L. was subjected to the combination of spectroscopic methods (1H and 13CNMR). Six kaempferol glycosides were isolated: kaempferol-3-O-ß-D-glycopyranoside (astragalin), kaempferol-3-O-ß-L-rhamnopyranoside, kaempferol-3-O-ß-D-rutinoside, kaempferide-3-O-ß-D-rutinoside, kaempferide-3-O-ß-Drutinosyl-7-O-ß-D-rhamnopyranoside, and kaempferol-3-O-ß-D- rutinosyl-7-O-a-D-arabinopyranoside. Fifty-four female Swiss Albino mice were divided randomly into 9 groups including (1) control negative (1 mL/kg saline; IP), (2) control positive (paracetamol 300 mg/kg; IP), (3) silymarin 50 mg/kg (IP). Animals of groups 4-9 were injected with 6 different samples of isolated compounds at 100 mg/kg (IP). One h later, groups 3-9 were injected with paracetamol (300 mg/kg IP). Two h later, tissue samples were taken from all animals to assess nitrotyrosine, c-Jun N-terminal protein kinase (c-JNK), Raf -1kinase, and oxidative stress biomarkers viz. reduced glutathione (GSH) and malondialdehyde (MDA). FINDINGS/RESULTS: Isolated glycosides had a prominent anti-apoptotic effect via inhibition of c-JNK and Raf-1 kinase. They also exerted a powerful antioxidant effect by modulating the oxidative stress induced by paracetamol via increasing GSH, reducing MDA and nitrotyrosine concentrations compared to positive control. The glycoside (1) showed a better effect than silymarin (standard) in ameliorating the formation of nitrotyrosine, Raf-1 kinase, c-JNK, and GSH. CONCLUSION AND IMPLICATION: Kaempferol glycosides isolated for the first time from C. odorata L. leaves exerted antioxidant and antiapoptotic effects via amelioration of oxidative stress and inhibition of Raf/MAPK pathway.

Pharmacological study of the effect of licorice alone and in combination with diclofenac sodium on hepatotoxicity-induced experimentally in rats.

The protective effect of licorice and diclofenac sodium in doses of 50 mg/kg bwt. and 5 mg/kg bwt. respectively against liver toxicity induced by CCl4 (1ml/kg bwt.) in olive oil [1:1 (v/v)] every other day for 8 weeks and by hepatic ischemia/reperfusion in adult male albino rats was studied. Different antioxidant and liver function parameters were reported to find the protective effect of both licorice and diclofenac sodium against hepatotoxicity. Results showed that licorice protected against CCl4-induced hepatotoxicity as well as ischemia/reperfusion-induced liver injury. On the other hand, diclofenac sodium caused deleterious effects, especially in presence of CCl4, where a high mortality rate was observed.

Immunological studies on Amaranth, Sunset Yellow and Curcumin as food colouring agents in albino rats.

The use of food dyes is at least controversial because they are only of essential role. Moreover many of them have been related to health problems mainly in children that are considered a very vulnerable group. This study was carried out to investigate the effect of oral administration of Amaranth, Sunset Yellow and Curcumin for 4 weeks at doses of 47, 315 and 157.5 mg/kg b. wt. and after 2 weeks all animals were immunostimulated by intra peritoneal injection of sheep RBCs 10% (1 ml/rat). Body weight, relative body weight, total and differential leukocytes count, mononuclear cell count, delayed hypersensitivity, total protein and serum fractions were determined. Results revealed that oral administration of Amaranth, Sunset Yellow and Curcumin did not affect the body weight gain or the spleen weight. On the other hand Sunset Yellow and Curcumin significantly decreased the weight of thymus gland of the rats. Total leukocyte count were not affected while Amaranth and Curcumin-treated rats revealed a significant decrease in neutrophiles and monocytes and a compensatory increase in lymphocytes. Moreover, oral administration of Sunset Yellow revealed a significant decrease in monocyte percent. Amaranth, Sunset Yellow and Curcumin significantly decreased the delayed hyper sensitivity. Total serum protein, albumin, total globulin and albumin/globulin (A/G) ratio were not affected by administration of the colouring agents. Oral administration of Amaranth increases the density of albumin band. On the other hand oral administration of Curcumin decreases the density of the albumin band. Oral administration of any of the tested colouring agents did not change the density of globulin region as compared to control group. In conclusion we found that both synthetic (Amaranth and Sunset Yellow) and natural (Curcumin) colouring agents used at doses up to 10 times the acceptable daily intake exerted a depressing effect on the cellular but not humoral immune response.