Osama M. Ashour

Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity

Doxorubicin (Dox) is a potent anticancer agent; its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study investigated the possible protective effect of telmisartan, an angiotensin AT(1)-receptor blocker versus captopril, an angiotensin-converting enzyme inhibitor, on Dox-induced cardiotoxicity and nephrotoxicity in rats. Rats were allocated into four groups. Control group, Dox group, Dox+telmisartan group, and Dox+captopril group. Cardiotoxicity and nephrotoxicity were assessed biochemically and histopathologically. Frozen heart and kidney specimens were used for estimation of lipid peroxides product (MDA), reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO). Expression of induced nitric oxide synthase (iNOS) was detected by immunohistochemistry. Coadministration of either telmisartan or captopril with Dox equally decreased the biochemical markers of both cardiotoxicity (LDH and CK-MP) and nephrotoxicity (urea and creatinine). Both telmisartan and captopril attenuated the effects of Dox on oxidative stress parameters and NO. Histopathologically, coadministration of either drug with Dox was able to attenuate Dox-induced myocardial fibrosis and renal tubular damage. Immunohistochemistry, expression of iNOS was increased in both cardiac and renal tissues. Both telmisartan and captopril significantly and equally attenuated the effect of Dox on all measured parameters. These results suggested that telmisartan has protective effects equal to that of captopril against Dox-induced cardiotoxicity and nephrotoxicity; implying that angiotensin II pathway plays a role in Dox-induced cardiac and renal damage. The protective effect of either drug relies, at least in part, on their antioxidant effects and decreased the expression of iNOS.

Anti-inflammatory and antiproliferative activities of date palm pollen (Phoenix dactylifera) on experimentally-induced atypical prostatic hyperplasia in rats

BackgroundAtypical prostatic hyperplasia (APH) is a pseudoneoplastic lesion that can mimic prostate adenocarcinoma because of its cytologic and architectural features. Suspension of date palm pollen (DPP) is an herbal mixture that is widely used in folk medicine for male infertility. The aim of the present study was to evaluate the effect of DPP suspension and extract on APH-induced rats.MethodsAPH was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100mg/kg), DPP suspension (250, 500 and 1000 mg/kg), and lyophilized DPP extract (150,300 and 600 mg/kg) were given orally daily for 30 days. All medications were started 7 days after castration and along with testosterone and citral.ResultsThe histopathological feature in APH-induced prostate rats showed evidence of hyperplasia and inflammation. Immunohistochemical examination revealed that the expressions of IL-6, IL-8, TNF-α, IGF-1 and clusterin were increased, while the expression of TGF-β1 was decreased that correlates with presence of inflammation. Moreover, histopathological examination revealed increased cellular proliferation and reduced apoptosis in ventral prostate. Both saw palmetto and DPP treatment has ameliorated these histopathological and immunohistochemical changes in APH-induced rats. These improvements were not associated with reduction in the prostatic weight that may be attributed to the persistence of edema.ConclusionDPP may have a potential protective effect in APH-induced Wistar rats through modulation of cytokine expression and/or upregulation of their autocrine/paracrine receptors.

Mechanisms of the antihyperglycemic activity of Retama raetam in streptozotocin-induced diabetic rats.

Retama raetam (RR) fruits are used in Saudi traditional medicine for the treatment of diabetes. Current study aimed at evaluating the potential and mechanisms of the antidiabetic activity of the RR methanolic extract in streptozotocin-induced diabetic rats. Oral LD(50) of the extract was found to be 1995 mg/kg. The extract was administered once orally to STZ-diabetic rats at three dose levels; 100, 250 or 500 mg/kg/day for 4 consecutive weeks. RR extract at 250 or 500 mg/kg significantly lowered blood glucose levels at the 3rd and 1st week of treatment, respectively. Meanwhile, oral glucose tolerance test indicated that the same two doses significantly lowered glucose levels at 30 and 60 min after glucose challenge. Administration of RR extract at 500 mg/kg/day for 4 consecutive weeks significantly increased serum insulin level. In vitro studies indicated that the extract significantly inhibits glucose absorption by rat isolated intestine. The extract neither altered glucose uptake by rat isolated psoas muscle nor the activity of hepatic microsomal glucose-6-phosphatase. In conclusion, the methanolic extract of RR improves STZ-induced diabetes in rats. This can be attributed, at least partly, to stimulating pancreatic insulin release and reducing intestinal glucose absorption.

Protective effect of bilberry ( Vaccinium myrtillus ) against doxorubicin-induced oxidative cardiotoxicity in rats

Summary Background Doxorubicin (DOX) is a commonly used chemotherapeutic agent. It is associated with serious dose-limiting cardiotoxicity, which is at least partly caused by generation of reactive oxygen species (ROS). Supplementations with bilberries were effective in reducing oxidative stress in many tissue injuries due their high content of antioxidants. The present study investigated the potential protective effect of bilberry extract against DOX-induced cardiotoxicity in rats. Material/Methods Rats were treated orally with a methanolic extract of bilberry for 10 days. DOX was injected intraperitoneally on day 7. Twenty-four hours after the last bilberry administration, rats were subjected to ECG study. Blood was then withdrawn and cardiac tissues were dissected for assessment of oxidative stress and cardiac tissue injury. Cardiac tissues were also subjected to histopathological examination. Results Bilberry extract significantly inhibited DOX-provoked reduced glutathione depletion and accumulation of oxidized glutathione, malondialdehyde and protein carbonyls in cardiac tissues. This was accompanied by significant amelioration of reduced cardiac catalase, superoxide dismutase, and glutathione peroxidase activities; and increased cardiac myeloperoxidase activity in response to DOX challenge. Pretreatment with bilberry significantly guarded against DOX-induced increase in serum activities of lactate dehydrogenase, creatine phosphokinase and creatine kinase-MB, as well as the level of troponin I. Bilberry alleviated ECG changes in rats treated with DOX and attenuated its pathological changes. Conclusions Bilberry protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to its antioxidant activity.

Gastroprotective effects of the insulin sensitizers rosiglitazone and metformin against indomethacin‐induced gastric ulcers in Type 2 diabetic rats

1. Gastric ulcers are common in Type 2 diabetic patients. Of all drugs used in the treatment of Type 2 diabetes, the insulin sensitizers thiazolidinediones (e.g. rosiglitazone) and metformin exhibit additional effects in ameliorating oxidative stress and inflammation, rendering them attractive candidates for the prevention of gastric ulcer in Type 2 diabetes. Thus, the aim of the present study was to evaluate the gastroprotective effects of rosiglitazone and metformin against indomethacin‐induced gastric ulcer in Type 2 diabetic and non‐diabetic rats.

Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - A review.

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Modulation of plasma uridine concentration by 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy.

Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plasma uridine concentration as well as its ability to improve the bioavailability of oral uridine. PSAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. Methods: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma uridine (2.6 ± 0.7 μM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with uridine elevated the concentration of plasma uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1421 to 787 μmol/h · l and 273 μmol/h · l, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1320 mg/kg uridine was used. Conclusion: The effectiveness of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.

Changes in nitric oxide and free radical levels in rat gastrocnemius muscle during contraction and fatigue

1. The ratio of nitric oxide (NO) to free radicals is critical during skeletal muscle contraction. Changes in this ratio have been suggested to play a role in muscle fatigue.

Ameliorative effect of lycopene against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced rat liver microsomal toxicity An in vitro study

The objective of the current study was to investigate the potential oxidative damage of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hepatic microsomal fractions in vitro and to further elucidate the potential modulatory effect of lycopene. Rat liver microsomes were divided into four groups. Group I served as a control and is incubated with vehicle (toluene). Groups II and IV were incubated with 20 µM lycopene for 1 h before further incubating; groups III and IV with 15 nM of TCDD for further 1 h. Hydrogen peroxide (H2O2) production, lipid peroxidation (LPO), protein carbonyl content and activities of uridine 5′-diphospho-glucuronyltransferase (UDPGT) and P450 were significantly increased. Moreover, the activity of antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalse, glutathione-S-transferase and glutathione reductase as well as the microsomal thiol content were significantly decreased. Incubation with lycopene (group IV) maintained near normal activities of the enzymes, normalized thiol and carbonyl content and significantly reduced LPO and H2O2 production. In conclusion, the findings of the study indicate that TCDD induces a significant oxidative stress in liver microsomes as manifested by increased LPO, H2O2 production, protein carbonyl content and activities of UDPGT and P450 and decreased antioxidant enzymes activities and thiol content. By the reversal of biochemical and oxidative markers toward normalcy, the protective role of lycopene is illuminated in rat liver microsomal toxicity.

Evaluation of the potential cardioprotective activity of some Saudi plants against doxorubicin toxicity.

Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L’ Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect