Samira Saleh

Protective effects of the angiotensin II receptor blocker losartan on cisplatin-induced kidney injury.

Background: In the present study, we investigated the possible modulatory effect of losartan, an angiotensin receptor blocker, on oxidative stress induced by cisplatin (CDDP) as well as on CDDP uptake by the kidney. Methods: Rats were injected with a single dose of CDDP (7 mg/kg) and/or losartan (in either a single dose of 60 mg/kg or divided doses (10 mg/kg daily for 6 days), starting 1 h before CDDP injection. In addition, rat renal cortical slices were incubated with CDDP (2 mM) and/or losartan (2 mM) for 4 h. Nephrotoxicity was evaluated by measuring serum creatinine and blood urea nitrogen (BUN) in vivo and lactate dehydrogenase (LDH) leakage in vitro; histopathological examination of kidney tissue was also done. Oxidative stress markers including reduced glutathione (GSH) and lipid peroxides were also assessed. Furthermore, CDDP uptake by renal cortical slices was determined. Results: Losartan has protective effects against CDDP-induced nephrotoxicity as evidenced by restoration of normal serum levels of creatinine and BUN, and LDH leakage. Histopathological examination of the kidney confirmed these results. Also, losartan significantly counteracted CDDP-induced lipid peroxidation and GSH depletion. However, losartan did not affect CDDP uptake by the kidney. Conclusion: Our results indicate that losartan has proved to be a promising drug for clinical use as a nephroprotectant against CDDP-induced nephrotoxicity.

Modulation of Diabetes and Dyslipidemia in Diabetic Insulin-Resistant Rats by Mangiferin: Role of Adiponectin and TNF-α

Mangiferin, present in Mangifera indica bark, was reported to produce hypoglycemic and antidiabetic activity in an animal model of genetic type 2 diabetes and in streptozotocin diabetic rats. Its effect on diabetic insulin-resistant animals has not been investigated. The current work aimed to explore the effect of mangiferin on diabetic insulin-resistant rat model. Diabetes was induced by high-fat/high fructose diet for eight weeks followed by a subdiabetogenic dose of streptozotocin (HFD-Fr-STZ). Rats were treated with mangiferin (20 mg/kg i.p.) for 28 days starting one week after STZ and its effects were compared to the standard insulin sensitizer, rosiglitazone. HFD-Fr-STZ, induced obesity, hyperglycemia and insulin resistance accompanied by depletion in liver glycogen and dyslipidemia. Moreover, there was an elevation in serum TNF-α and a reduction in adiponectin. Mangiferin ameliorated the consequences of HFD-Fr-STZ and its actions were comparable to the effects of the standard insulin sensitizer, rosiglitazone. The results obtained in this study provide evidence that mangiferin is a possible beneficial natural compound for type 2 diabetes and metabolic disorders associated with the metabolic syndrome. This effect is mediated through improving insulin sensitivity, modulating lipid profile and reverting adipokine levels to normal.

Effect of exposure to radiation on the inflammatory process and its influence by diclofenac.

1 The effect of radiation exposure on the inflammatory process was studied in rats using the carrageenan‐induced paw oedema and adjuvant‐induced arthritis tests. 2 Irradiation (0.5,1 and 2 Grays) resulted in a significant augmentation of the tissue response to carrageenan and the early phase of adjuvant‐induced arthritis, but suppressed the late phase. 3 Diclofenac (1–5 mg kg−1) effectively reduced the exaggerated inflammatory response in irradiated animals in both the carrageenan paw oedema and adjuvant‐induced arthritis tests. The drug also had a prophylactic value in guarding against the induction of radiation damage. 4 The inflammatory responses produced by irradiation and the benefits obtained by drug treatment may be related to changes in tissue prostaglandin levels and/or changes in the immune system.

Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression

AIM To evaluate the effect of resveratrol, alone and in combination with fenofibrate, on fructose-induced metabolic genes abnormalities in rats. METHODS Giving a fructose-enriched diet (FED) to rats for 12 wk was used as a model for inducing hepatic dyslipidemia and insulin resistance. Adult male albino rats (150-200 g) were divided into a control group and a FED group which was subdivided into 4 groups, a control FED, fenofibrate (FENO) (100 mg/kg), resveratrol (RES) (70 mg/kg) and combined treatment (FENO + RES) (half the doses). All treatments were given orally from the 9(th) week till the end of experimental period. Body weight, oral glucose tolerance test (OGTT), liver index, glucose, insulin, insulin resistance (HOMA), serum and liver triglycerides (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST, ALT, AST/ALT ratio and tumor necrosis factor-α (TNF-α) were measured. Additionally, hepatic gene expression of suppressor of cytokine signaling-3 (SOCS-3), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), malonyl CoA decarboxylase (MCD), transforming growth factor-β1 (TGF-β1) and adipose tissue genes expression of leptin and adiponectin were investigated. Liver sections were taken for histopathological examination and steatosis area were determined. RESULTS Rats fed FED showed damaged liver, impairment of glucose tolerance, insulin resistance, oxidative stress and dyslipidemia. As for gene expression, there was a change in favor of dyslipidemia and nonalcoholic steatohepatitis (NASH) development. All treatment regimens showed some benefit in reversing the described deviations. Fructose caused deterioration in hepatic gene expression of SOCS-3, SREBP-1c, FAS, MDA and TGF-β1 and in adipose tissue gene expression of leptin and adiponectin. Fructose showed also an increase in body weight, insulin resistance (OGTT, HOMA), serum and liver TGs, hepatic MDA, serum AST, AST/ALT ratio and TNF-α compared to control. All treatments improved SOCS-3, FAS, MCD, TGF-β1 and leptin genes expression while only RES and FENO + RES groups showed an improvement in SREBP-1c expression. Adiponectin gene expression was improved only by RES. A decrease in body weight, HOMA, liver TGs, AST/ALT ratio and TNF-α were observed in all treatment groups. Liver index was increased in FENO and FENO + RES groups. Serum TGs was improved only by FENO treatment. Liver MDA was improved by RES and FENO + RES treatments. FENO + RES group showed an increase in liver GSH content. CONCLUSION When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate.

Imipramine and amitriptyline ameliorate the rotenone model of Parkinson's disease in rats.

Amitriptyline (AMI), a commonly prescribed tricyclic antidepressant (TCA) to parkinsonian patients, specifically showed a significant delay in dopaminergic therapy initiation and improvement in motor disability in parkinsonian patients. Moreover, it was recently shown that AMI has neuroprotective properties; however, the mechanisms underlying this effect in Parkinsons disease (PD) are not fully understood. The current study aimed to investigate the possible neuroprotective mechanisms afforded by AMI in the rotenone model of PD and to assess whether another TCA member, imipramine (IMI), shows a corresponding effect. Rats were allocated into seven groups. Four groups were given either saline, dimethyl sulfoxide, AMI or IMI. Three rotenone groups were either untreated or treated with AMI or IMI. Rats receiving rotenone exhibited motor impairment in open field and rotarod tests. Additionally, immunohistochemical examination revealed dopaminergic neuronal damage in substantia nigra. Besides, striatal monoamines and brain derived neurotrophic factor levels were declined. Furthermore, oxidative stress, microglial activation and inflammation were evident in the striata. Pretreatment of rotenone groups with AMI or IMI prevented rotenone-induced neuronal degeneration and increased striatal dopamine level with motor recovery. These effects were accompanied by restoring striatal monoamines and brain-derived neurotrophic factor levels, as well as reducing oxidative damage, microglial activation and expression of proinflammatory cytokines and inducible nitric oxide synthase. The present results suggest that modulation of noradrenaline and serotonin levels, up-regulation of neurotrophin, inhibition of glial activation, anti-oxidant and anti-inflammatory activities could serve as important mechanisms underlying the neuroprotective effects of the used drugs in the rotenone model of PD.

Inhibition of endotoxin-induced vascular hyporeactivity by 4-amino-tetrahydrobiopterin

The 4‐amino analogue of tetrahydrobiopterin (4‐ABH4) is a potent pterin‐site inhibitor of nitric oxide synthases (NOS). Although 4‐ABH4 does not exhibit selectivity between purified NOS isoforms, a pronounced selectivity of the drug towards inducible NOS (iNOS) is apparent in intact cells. This work was carried out to investigate the potential iNOS selectivity of 4‐ABH4 in isolated pig pulmonary and coronary arteries. Endothelium‐dependent relaxations of pig pulmonary and coronary artery strips to bradykinin or calcium ionophore A23187 were inhibited by 4‐ABH4 in a concentration‐dependent manner. Half‐maximal inhibition was observed at 60–65 μM (pulmonary artery) and 200–250 μM 4‐ABH4 (coronary artery). Pig coronary artery strips precontracted with 0.1 μM 9, 11‐dideoxy‐9, 11‐methanoepoxy‐prosta‐glandin F2α (U46619) showed a time‐dependent relaxation (monitored for up to 18 h) upon incubation with 1 μg ml−1 lipopolysaccharide (LPS). Addition of 10 μM 4‐ABH4 1 h after LPS led to a pronounced inhibition of the LPS‐triggered relaxation, whereas the pterin antagonist had no effect when given4 h after LPS. Incubation of pulmonary and coronary artery strips with 1 μg ml−1 LPS attenuated contractile responses to norepinephrine (1 μM) and U46619 (0.1 μM). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4‐ABH4 in a concentration‐dependent manner [IC50=17.5±5.9 μM (pulmonary artery) and 20.7±3 μM (coronary artery)]. The effect of 0.1 mM 4‐ABH4 was antagonized by coincubation with 0.1 mM sepiapterin, which is known to supply intracellular BH4 via a salvage pathway. These results demonstrate that 4‐ABH4 is a fairly selective inhibitor of iNOS in an in vitro model of endotoxaemia, suggesting that this drug and/or related pterin‐site NOS inhibitors may be useful to increase blood pressure in severe infections associated with a loss of vascular responsiveness to constrictor agents caused by endotoxin‐triggered iNOS induction in the vasculature.

Effect of acetylsalicylic acid and phenylbutazone on glucose absorption in vitro

Abstract The effect of acetylsalicylic acid and phenylbutazone on the intestinal absorption of glucose in vitro has been studied. Incubation of the rat everted intestine in a modified Krebs bicarbonate solution containing either acetylsalicylic acid or phenylbutazone resulted in an inhibition of active glucose transport, as well as an increase in the utilization and/or storage of the sugar. On a molar basis, phenylbutazone was shown to have a greater effect on glucose absorption than acetylsalicylic acid. The results are discussed with an attempt to explain some of the systemic effects of these drugs.

Photothermal therapy mediated by gum Arabic-conjugated gold nanoparticles suppresses liver preneoplastic lesions in mice

This study validates the utility of Gum Arabic-conjugated gold nanoparticles (GA-AuNPs) and laser to induce photothermal inhibition of hepatocarcinogenesis, via employing a diethylnitrosamine (DEN)-mediated hepatocellular carcinoma model. This work included both of in vitro and in vivo studies; to investigate the GA-AuNPs cytotoxicity and phototoxicity in hepatic cell line; to delineate the GA-AuNPs therapeutic efficiency in DEN-induced preneoplastic lesions (PNLs) in the liver of Balb-C mice. The therapeutic effects of GA-AuNPs on the mediators of apoptosis, inflammation, and tumor initiation, as well as the histopathological changes in preneoplastic liver have been investigated. Our results infer that GA-AuNPs in combination with laser irradiation led to a significant reduction in the cell viability and in histone deacetylase activity in hepatocarcinoma HepG2 cells. In chemically-induced PNLs mice model our results have demonstrated that GA-AuNPs, with or without laser irradiation, induced cancer cell apoptosis through the activation of death receptors DR5 and caspase-3 and inhibited both of the PNLs incidence and the initiation marker (placental glutathione S-transferase; GST-P). The laser-stimulated GA-AuNPs significantly reduced the tumor necrosis factor-α levels. In summary, GA-AuNPs with laser treatment inhibited liver PNLs via the induction of the extrinsic apoptosis pathway and the inhibition of inflammation.

Protective effect of N-acetylcysteine against carmustine-induced myelotoxicity in rats.

Carmustine (BCNU) is used to treat a variety of tumors, in particular gliomas. However, the success of such treatment is limited by severe myelosuppression. The role of N-acetylcysteine (NAC) in protection against BCNU-induced myelotoxicity is still needed to be explored. The aim of this work is to study the possible protective role of NAC against BCNU-induced myelotoxicity through evaluation of apoptosis, lipid peroxidation, antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase(CAT)) as well as glutathione (GSH) content in bone marrow cells of rats. Administration of BCNU in a single dose (30 mg/kg, i.p.) significantly decreased RBCs, WBCs and platelets counts as well as hemoglobin level. In addition, BCNU produced a significant apoptotic effect as well as a significant lipid peroxidation in bone marrow cells. Pretreatment of animals with NAC (150 mg/kg, i.p.) daily for 5 days significantly ameliorated the changes in oxidant and antioxidant parameters as well as apoptosis induced by BCNU. In addition the pattern of blood parameters was shifted markedly to normal values in animals pretreated with NAC when compared to BCNU-treated group. Conclusively, NAC could have a potential protective effect against BCNU-induced myelotoxicity; an effect that is mainly attributed to the antioxidant property.

Metabolic profile and hepatoprotective activity of the anthocyanin-rich extract of Hibiscus sabdariffa calyces.

Abstract Context: Hibiscus sabdariffa L. (Malvaceae) is a common traditional tea that has many biological activities. Objectives: To evaluate the hepatoprotective effect and study the metabolic profile of the anthocyanin-rich extract of H. sabdariffa calyces (HSARE). Materials and methods: The hepatoprotective activity of HSARE was assessed (100 mg/kg/d for 4 weeks) by examining the hepatic, inflammatory, oxidative stress markers and performing a histopathological examination in rats with thioacetamide (TAA)-induced hepatotoxicity. HSARE was analyzed using ultra-performance liquid chromatography-quadrupole-time-of-flight-photodiode array-mass spectrometry (UPLC-qTOF-PDA-MS). Results: The UPLC-qTOF-PDA-MS analysis of HSARE enabled the identification of 25 compounds represented by delphinidin and its derivatives, cyanidin, kaempferol, quercetin, myricetin aglycones and glycosides, together with hibiscus lactone, hibiscus acid and caffeoylquinic acids. Compared to the TAA-intoxicated group, HSARE significantly reduced the serum levels of alanine aminotransferase, aspartate aminotransferase and hepatic malondialdehyde by 37.96, 42.74 and 45.31%, respectively. It also decreased hepatic inflammatory markers, including tumour necrosis factor alpha, interleukin-6 and interferon gamma (INF-γ), by 85.39, 14.96 and 70.87%, respectively. Moreover, it decreased the immunopositivity of nuclear factor kappa-B and CYP2E1 in liver tissue, with an increase in the effector apoptotic marker (caspase-3 positive cells), restoration of the altered hepatic architecture and increases in the activities of superoxide dismutase (SOD) and glutathione by 150.08 and 89.23%, respectively. Discussion and conclusion: HSARE revealed pronounced antioxidant and anti-inflammatory potential where SOD and INF-γ were significantly improved. HSARE possesses the added value of being more water-soluble and of natural origin with fewer side effects expected compared to silymarin.