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Saleh, D. O., A. R. Bayoumi, W. I. El-Eraky, and A. S. El-Khatib, "Streptocin-induced vascular and biochemical changes in rats: Effects of rosiglitazone vs. metformin", Bulletin of Faculty of Pharmacy, Cairo University, vol. 51, pp. 131-138, 2013.
Saleh, D. O., S. A. El-Awdan, S. M. Nofel, W. I. El-Eraky, A. S. el-Khatib, and S. A. Kenawy, "ESTROGENS IMPROVE THE CARDIOVASCULAR ALTERATIONS IN FRUCTOSE-INDUCED INSULIN RESISTANT OVARIECTOMIZED RATS", Int. J. Pharm. Pharm. Sci, vol. 7, issue 7, pp. 241-247, 2015.
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Rasheed, N. A. O., N. S. El Sayed, and A. S. El-Khatib, "Targeting central $\beta$2 receptors ameliorates streptozotocin-induced neuroinflammation via inhibition of glycogen synthase kinase3 pathway in mice", Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 86: Elsevier, pp. 65–75, 2018. Abstract
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Raafat, S. N., R. M. Amin, M. M. Elmazar, M. M. Kattab, and A. El-Khatib, "The sole and combined effect of simvastatin and platelet rich fibrin as a filling material in induced bone defect in tibia of albino rats", Bone, vol. 711: Elsevier, pp. 12–34, 2018. Abstract
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Mansour, M. A., O. T. Ginawi, T. El-Hadiyah, A. S. el-Khatib, O. A. Al-Shabanah, and H. A. Al-Sawaf, "Effects of volatile oil constituents of Nigella sativa on carbon tetrachloride-induced hepatotoxicity in mice: evidence for antioxidant effects of thymoquinone.", Research communications in molecular pathology and pharmacology, vol. 110, issue 3-4, pp. 239-51, 2001. Abstract

Effects of the volatile oil constituents of Nigella sativa, namely, thymoquinone (TQ), p-cymene and alpha-pinene, on carbon tetrachloride (CCl4-indued acute liver injury were investigated in mice. A single dose of CCl4 (15 microl/Kg i.p.) induced hepatotoxicity 24 h after administration manifested biochemically as significant elevation of the enzymes activities of serum alanine transaminase (ALT, EC:2.6.1.2), asparate transaminase (AST, EC:2.6.1.1) and lactate dehydrogenase (LDH, EC: 1.1.1.27). The toxicity was further evidenced by a significant decrease of non-protein sulfhydryl(-SH) concentration, and a significant increase of lipid peroxidation measued as malondialdhyde (MDA) in the liver tissues. Administration of different doses of the TQ (4, 8, 12.5, 25 and 50 mg/Kg i.p.) did not alter the chosen biochemical parameters measured, while higher doses of TQ were lethal. The LD50 was 90.3 mg/Kg (77.9-104.7, 95% CL). Pretreatment of mice with different doses of TQ 1 h before CCl4 injection showed that the only dose of TQ that ameliorated hepatotoxicity of CCl4 was 12.5 mg/Kg i.p. as evidenced by the significant reduction of the elevated levels of serum enzymes as well as hepatic MDA content and significant increase of the hepatic nonprotein sulfhydryl(-SH) concentration. Treatment of mice with the other volatile oil constituents, p-cymene or alpha-pinene did not induce any changes in the serum ALT measured. In addition, i.p. administration of these compounds 1 h before CCl4 injection, did not protect mice against CC4-induced hepatotoxicity. The results of the present study indicate that TQ (12.5 mg/Kg, i.p.) may play an important role as antioxidant and may efficiently act as a protective agent against chemically-induced hepatic damage. In contrast, higher doses of TQ were found to induce oxidative stress leading to hepatic injury.

Mansour, S. M., A. K. Bahgat, A. S. El-Khatib, and M. T. Khayyal, "Ginkgo biloba extract (EGb 761) normalizes hypertension in 2K, 1C hypertensive rats: role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction.", Phytomedicine : international journal of phytotherapy and phytopharmacology, vol. 18, issue 8-9, pp. 641-7, 2011 Jun 15. Abstract

The 2 kidney, 1-clip (2K, 1C) model of hypertension was used to investigate the potential antihypertensive effect of a standardized leaf extract of Ginkgo biloba (EGb 761). Clipping of the renal artery resulted in gradual elevation of the systolic blood pressure (SBP) reaching a plateau after 4 weeks of surgery. Treatment of hypertensive rats with EGb 761 (60, 90, 180 mg/kg/day orally) was therefore started 4 weeks after surgery and continued for 3 weeks. This led to a dose-dependent reduction in SBP with no significant change in heart rate. Control hypertensive rats showed a significant elevation of total protein thiols (Pr-SHs level) in both clipped and non-clipped kidneys as well as in the serum. However, glutathione peroxidase (GSH-Px) activity was decreased in the clipped kidneys but elevated in the non-clipped ones and in the blood. The malondialdehyde (MDA) level was raised in clipped kidneys but not in non-clipped ones nor in the serum. Nitric oxide (NO level) and angiotensin converting enzyme (ACE) activity were increased in both clipped and non-clipped kidneys but not in the serum. Endothelium-dependent and -independent relaxation of aortic rings towards acetylcholine (Ach) and sodium nitroprusside (SNP) were impaired. Treatment with EGb 761 (180 mg/kg/day for 3 weeks) was associated with recovery of GSH-Px activity in clipped kidneys, inhibition of ACE activity in both kidneys and a reduction in the elevated NO level of the non-clipped kidneys, decreased responsiveness to the vasoconstrictor NE and improvement of endothelial function as evidenced by restoration of endothelium-dependent vasorelaxation induced by Ach. The observed beneficial effects of the EGb 761 may be attributed to different factors, including ACE inhibition and maintenance of cellular antioxidant capacity as well as preserving vascular reactivity towards endothelium-dependent and -independent vasodilators while inhibiting responses to vasoconstrictors.

Mansour, M., A. S. el-Khatib, and O. El-Ahmady, "INHIBITED GENERATION OF LEUKOTRIENES FROM STIMULATED HUMAN LEUKOCYTES BY THE AQUEOUS EXTRACT OF PROPOLIS", Bull. Fac. Pharm. Cairo Uni, vol. 33, issue 2, pp. 75-79, 1995.
Mansour, M. A., M. N. Nagi, A. S. El-Khatib, and A. M. Al-Bekairi, "Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action.", Cell biochemistry and function, vol. 20, issue 2, pp. 143-51, 2002 Jun. Abstract

The present investigation focused, firstly, on the effects of oral administration of thymoquinone (TQ) on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase activity in hepatic, cardiac and kidney tissues of normal mice. Superoxide dismutase (SOD; E.C:1.15.1.1), catalase (CAT; E.C:1.11.1.6), glutathione peroxidase (GSH-Px; E.C:1.11.1.9), glutathione-S-transferase (GST; E.C:2.5.1.18), and DT-diaphorase (E.C:1.6.99.2) enzyme activities in each tissue type were determined. Treatment of mice with the different doses of TQ (25, 50 and 100 mg kg(-1) day(-1) orally) for 5 successive days, produced significant reductions in hepatic SOD, CAT and GSH-Px activities. In addition cardiac SOD activity was markedly inhibited with the higher doses of TQ, (namely 50 and 100 mg kg(-1)). Moreover, TQ (100 mg kg(-1)) significantly reduced hepatic and cardiac lipid peroxidation as compared with the respective control group. Conversely, TQ (50,100 mg kg(-1)) and TQ (100 mg kg(-1)) enhanced cardiac and renal DT-diaphorase activity respectively. However, the selected doses of TQ neither produced any change in GST activity nor influenced reduced glutathione content in all tissues studied. TQ was tested, secondly, as a substrate for hepatic, cardiac and renal DT-diaphorase of normal mice in the presence of NADPH. Kinetic parameters for the reduction of TQ to dihydrothymoquinone (DHTQ) indicated that DT-diaphorase of different tissues can efficiently reduce TQ to DHTQ. K(m) and V(max) values revealed that hepatic DT-diaphorase exhibited the higher values, while the lower values were associated with renal DT-diaphorase. TQ and DHTQ were tested, thirdly, as specific scavengers for superoxide anion (generated biochemically) or as general scavengers for free radicals (generated photochemically). The results revealed that TQ and DHTQ acted not only as superoxide anion scavengers but also as general free radical scavengers. The IC(50) for TQ and DHTQ in biochemical and photochemical assays were in the nanomolar and micromolar range respectively. Our data may explain at least partly the reported beneficial in vivo protective effects of TQ through the combined antioxidant properties of TQ and its metabolite DHTQ.

Mahran, L. G., A. S. el-Khatib, A. M. Agha, and M. T. Khayyal, "The protective effect of aqueous propolis extract on isolated rat hepatocytes against carbon tetrachloride toxicity.", Drugs under experimental and clinical research, vol. 22, issue 6, pp. 309-16, 1996. Abstract

The protective effect of honeybee aqueous propolis extract (APE) against the hepatotoxicity of carbon tetrachloride was investigated using isolated liver-cell suspensions as the experimental model. Various concentrations of the extract were preincubated with the hepatocyte suspensions for 30 min before being subjected to the hepatotoxin for a further 30 min. The hepatocyte toxicity was assessed using three parameters, namely, the release of lactate dehydrogenase, the formation of lipid peroxides and the depletion of intracellular reduced glutathione. It was found that a dose-related protection against the induced cell injury was conferred by APE as evidenced by its inhibitory influence on the changes induced by CCl4 on the measured parameters. The hepatocyte protective effect of APE is probably a result of its antioxidant and free-radical-scavenging properties which in turn help to maintain the intracellular level of reduced glutathione.

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Khayyal, M. T., M. A. El-Ghazaly, and A. S. el-Khatib, "Mechanisms involved in the antiinflammatory effect of propolis extract.", Drugs under experimental and clinical research, vol. 19, issue 5, pp. 197-203, 1993. Abstract

Propolis is a natural product produced by the honey bee. The extract contains amino acids, flavanoids, terpenes and cinnamic acid derivatives. In various in vitro models propolis extract was shown to inhibit platelet aggregation and to inhibit eicosanoid synthesis, suggesting that it might have potent antiinflammatory properties. A 13% aqueous extract was tested orally in three dose levels (1, 5 and 10 ml/kg) on the carrageenan rat paw oedema model and on adjuvant-induced arthritis in rats. In both models, the extract showed potent dose-related antiinflammatory activity, which compared well with that of diclofenac (as a reference standard). The extract was then tested on an isolated sensitized guinea pig lung preparation to study its effect on the release of prostaglandins, leukotrienes and histamine. It is concluded that propolis extract has potent antiinflammatory properties in vivo. Its activity can be well correlated with its effects on the release of various mediators of inflammation.

Khayyal, M. T., M. A. El-Ghazaly, A. S. el-Khatib, A. M. Hatem, P. J. F. de Vries, S. el-Shafei, and M. M. Khattab, "A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients.", Fundamental & clinical pharmacology, vol. 17, issue 1, pp. 93-102, 2003 Feb. Abstract

The aqueous extract of propolis has been formulated as a nutritional food product and administered, as an adjuvant to therapy, to patients with mild to moderate asthma daily for 2 months in the framework of a comparative clinical study in parallel with a placebo preparation. The diagnosis of asthma was made according to the criteria of patient classification of the National Institutes of Health and Global Initiative for Asthma Management. At inclusion, the pulmonary forced expiratory volume in the first second (FEV1) as a percentage of the forced vital capacity (FVC) was more than 80% in mild persistent cases, and between 60 and 80% in moderate persistent cases, showing an increase in the degree of reversibility of > 15% in FEV1. All patients were on oral theophylline as controller therapy, none was receiving oral or inhaled corticosteroids, none had other comorbidities necessitating medical treatment, and all were from a middle-class community and had suffered from asthma for the last 2-5 years. Twenty-four patients received the placebo, with one drop-out during the study, while 22 received the propolis extract, with no drop-outs. The age range of the patients was 19-52 years; 36 were male and 10 female. The number of nocturnal attacks was recorded on a weekly basis, while pulmonary function tests were performed on all patients at the beginning of the trial, 1 month later and at the termination of the trial. Immunological parameters, including various cytokines and eicosanoids known to play a role in asthma, were measured in all patients at the beginning of the trial and 2 months later. Analysis of the results at the end of the clinical study revealed that patients receiving propolis showed a marked reduction in the incidence and severity of nocturnal attacks and improvement of ventilatory functions. The number of nocturnal attacks dropped from an average of 2.5 attacks per week to only 1. The improvement in pulmonary functions was manifested as a nearly 19% increase in FVC, a 29.5% increase in FEV1, a 30% increase in peak expiratory flow rate (PEFR), and a 41% increase in the forced expiratory flow rate between 25 and 75% of the vital capacity (FEF25-75). The clinical improvement was associated with decreases by 52, 65, 44 and 30%, respectively, of initial values for the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, ICAM-1, interleukin (IL)-6 and IL-8, and a 3-fold increase in the 'protective' cytokine IL-10. The levels of prostaglandins E2 and F2alpha and leukotriene D4 were decreased significantly to 36, 39, and 28%, respectively, of initial values. Patients on the placebo preparation showed no significant improvement in ventilatory functions or in the levels of mediators. The findings suggest that the aqueous propolis extract tested is potentially effective as an adjuvant to therapy in asthmatic patients. The benefits may be related to the presence in the extract of caffeic acid derivatives and other active constituents.

Khayyal, M. T., M. El-Ghazaly, A. S. el-Khatib, and A. Hatem, "Tolerability of mofebutazone in asthmatic patients.", International journal of clinical pharmacology research, vol. 15, issue 4, pp. 145-51, 1995. Abstract

Twenty-seven human volunteer asthmatic patients were each given one tablet of mofebutazone (300 mg) twice daily for 15 days. Pulmonary ventilatory function test (forced expiratory volume test) as well as bronchoalveolar lavage (BAL) were performed one day before initiation of treatment and one day after completion of the course; in the BAL, prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha) and leukotrienes (LTs) were also estimated. It was found that there was no increase in the incidence or severity of the asthmatic attacks during the course of mofebutazone treatment. The drug tended to improve the tested pulmonary ventilatory functions or at least to leave them unchanged. All the mofebutazone-treated individuals showed a dramatic reduction in the concentrations of PGE2, PGF2alpha and LTs in their BAL, but there was no consistent correlation between the extent of reduction and the degree of benefit or worsening sustained by any individual patient. It is evident from the present study that mofebutazone has shown good tolerability which was associated with an improvement in the pulmonary ventilatory functions, a fact that would seem to advocate the use of this non-steroidal antiinflammatory drug (NSAID) in asthmatic patients whenever a need for such therapy becomes necessary.

Khayyal, M. T., A. S. el-Khatib, M. El-Ghazaly, and A. Hatem, "Inhibition of leukotriene release by mofebutazone: a possible clinical advantage.", International journal of clinical pharmacology research, vol. 13, issue 5, pp. 255-61, 1993. Abstract

The isolated perfused lung preparation from actively sensitized guinea-pigs was used; after it was challenged with antigen, mediators such as histamine, prostaglandins and leukotrienes were released into the lung effluent. It was found that treatment of the perfused lungs before and during challenge with mofebutazone (10 micrograms/ml) inhibited the immunological release of prostaglandins as well as leukotrienes. Phenylbutazone, on the other hand, at the same dose level inhibited the release of prostaglandins, whereas the release of leukotrienes was much less affected by the drug. Histamine release was not altered by either drug. When clinically mofebutazone tablets (300 mg) were given as an analgesic twice daily for 15 days to a number of asthmatic volunteers including 3 aspirin-sensitive individuals, there was no increase in the incidence or intensity of the asthmatic attacks, even in the aspirin-sensitive patients. Pulmonary ventilatory functions which showed a certain obstructive pattern were not worsened by the treatment and even tended to be somewhat improved.

Khattab, M. M., A. M. Moustafa, O. A. Al-Shabanah, and A. S. el-Khatib, "INVOLVEMENT OF NITRIC OXIDE IN CARBON TETRACHLORIDE-INDUCED ACUTE HEPATOTOXICITY IN MICE", Res. Commun. Pharmacol. Toxicol, vol. 7, issue 1-2, pp. 53-64, 2002.
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Hammam, O. A., N. Elkhafif, Y. M. Attia, M. T. Mansour, M. M. Elmazar, R. M. Abdelsalam, S. A. Kenawy, and A. S. El-Khatib, "Wharton's jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis.", Scientific reports, vol. 6, pp. 21005, 2016. Abstract

Liver fibrosis is one of the most serious consequences of S. mansoni infection. The aim of the present study was to investigate the potential anti-fibrotic effect of human Wharton's jelly-derived mesenchymal stem cells (WJMSCs) combined with praziquantel (PZQ) in S. mansoni-infected mice. S. mansoni-infected mice received early (8(th) week post infection) and late (16(th) week post infection) treatment with WJMSCs, alone and combined with oral PZQ. At the 10(th) month post infection, livers were collected for subsequent flow cytometric, histopathological, morphometric, immunohistochemical, gene expression, and gelatin zymographic studies. After transplantation, WJMSCs differentiated into functioning liver-like cells as evidenced by their ability to express human hepatocyte-specific markers. Regression of S. mansoni-induced liver fibrosis was also observed in transplanted groups, as evidenced by histopathological, morphometric, and gelatin zymographic results besides decreased expression of three essential contributors to liver fibrosis in this particular model; alpha smooth muscle actin, collagen-I, and interleukin-13. PZQ additionally enhanced the beneficial effects observed in WJMSCs-treated groups. Our results suggest that combining WJMSCs to PZQ caused better enhancement in S. mansoni-induced liver fibrosis, compared to using each alone.

Hammam, O. A., N. Elkhafif, Y. M. Attia, T. Mansour, M. M. Elmazar, R. M. Abdelsalam, S. A. Kenawy, and A. S. el-Khatib, "EFFICACY OF WHARTON'S JELLY-DERIVED MESENCHYMAL STEM CELLS COMBINED WITH PRAZIQUANTEL IN SCHISTOSOMA MANSONI-INDUCED LIVER FIBROSIS IN MICE", J. Hepatol, vol. 62, issue S3000, 2015.
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El-Sheikh, M. M., R. M. El-Hazek, A. S. El-Khatib, and M. A. El-Ghazaly, "Anti-apoptotic effect of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, against multiple organ damage induced by gamma irradiation in rats", International journal of radiation biology, vol. 94, no. 1: Taylor & Francis, pp. 45–53, 2018. Abstract
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El-Mezayen, N. S., W. F. El-Hadidy, W. M. El-Refaie, T. I. Shalaby, M. M. Khattab, and A. S. El-Khatib, "Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence.", Journal of controlled release : official journal of the Controlled Release Society, vol. 283, pp. 32-44, 2018 Aug 10. Abstract

So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (V) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to V and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled V-coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, V-coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity.

El-Mezayen, N. S., W. F. El-Hadidy, W. M. El-Refaie, T. I. Shalaby, M. M. Khattab, and A. S. El-Khatib, "Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.", Journal of controlled release : official journal of the Controlled Release Society, vol. 266, pp. 226-237, 2017 Nov 28. Abstract

Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (V) storage cells, they can be actively targeted by coupling liposomes to V. In this study, novel V-coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding V-coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected V-coupled liposomes loaded with Nile Red (LCNR) to rats with CCl-induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional imatinib. It can represent a promising novel approach for liver fibrosis treatment.

El-Marasy, S. A., S. M. El-Shenawy, A. S. el-Khatib, O. A. El-Shabrawy, and S. A. Kenawy, "EFFECT OF NIGELLA SATIVA AND WHEAT GERM OILS ON SCOPOLAMINE-INDUCED MEMORY IMPAIRMENT IN RATS", Bull. Fac. Pharm. Cairo Uni, vol. 50, pp. 81-88, 2012.
El-Marasy, S. A., H. M. I. Abdallah, S. M. El-Shenawy, A. S. El-Khatib, O. A. El-Shabrawy, and S. A. Kenawy, "Anti-depressant effect of hesperidin in diabetic rats.", Canadian journal of physiology and pharmacology, vol. 92, issue 11, pp. 945-52, 2014 Nov. Abstract

This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.

El-Khatib, A. S., A. M. Agha, L. G. Mahran, and M. T. Khayyal, "Prophylactic effect of aqueous propolis extract against acute experimental hepatotoxicity in vivo.", Zeitschrift für Naturforschung. C, Journal of biosciences, vol. 57, issue 3-4, pp. 379-85, 2002 Mar-Apr. Abstract

Propolis has been extensively used in folk medicine for the management of a wide spectrum of disorders. In a previous study, we demonstrated the protective effect of the aqueous propolis extract (APE) against the injurious effects of carbon tetrachloride (CCl4) on hepatocytes in vitro. The present investigation was carried out to show whether the hepatoprotective effect of the extract could also be manifested in vivo. Rats were given APE orally for 14 consecutive days, before being subjected to a single intraperitoneal injection of CCl4. One day after the CCl4 injection, the animals were sacrificed, hepatocytes were isolated and liver homogenates were prepared for the assessment of liver injury. In isolated hepatocytes, APE afforded protection against CCl4-induced injury as manifested by a decrease in the leakage of the cytosolic enzyme lactate dehydrogenase (LDH), decreased generation of lipid peroxide and maintenance of cellular reduced glutathione (GSH) content. In principle, similar findings were observed in liver homogenates. The present findings show that APE has in vivo hepatoprotective potential which could be attributed at least in part to the maintenance of cellular GSH content. The latter effect seems to play an important role in conserving the integrity of biomembranes as it was associated with a decrease in lipid peroxidation and reduced leakage of cytosolic LDH.

El-Khatib, A. S., "Possible modulatory role of nitric oxide in lung toxicity induced in rats by chronic administration of bleomycin.", Chemotherapy, vol. 48, issue 5, pp. 244-51, 2002 Dec. Abstract

BACKGROUND: The present study was undertaken to evaluate whether stimulation or inhibition of nitric oxide (NO) synthesis could affect lung toxicity induced by chronic administration of bleomycin (BLM). L-arginine (ARG) and N(G)-nitro-L-arginine methyl ester (L-NAME) were employed as NO precursor and NO synthesis inhibitor, respectively.

METHODS: BLM was administered intraperitoneally to male Wistar rats at a dose of 15 mg/kg, 3 times a week, for a total period of 4 weeks. ARG (500 mg/kg/day) and L-NAME (100 mg/kg/day) were given in drinking water, the treatments commenced with BLM and continued up to the end of the experiment. Appropriate controls were performed.

RESULTS: BLM treatment resulted in a pronounced fall in the average body weight of animals, together with a rise in the lung weight/body weight ratio. In the lung tissue, elevated levels of hydroxyproline (HP) and lipid peroxides (LP) as well as decreased activity of angiotensin converting enzyme (ACE) further evidenced the toxicity. Pulmonary level of NO end products, nitrite and nitrate, tended to rise but did not reach a significant level. Glutathione (GSH) content and GSH-peroxidase activity measured in the lung remained unaltered. In animals given concurrent treatment of BLM and ARG, a remarkable rise in the pulmonary level of nitrite and nitrate was observed. Average body weight was still decreased when compared with the untreated control group, but the decrease was significantly less than that observed in the BLM group. In addition, ARG decreased the extent of BLM-induced elevations of lung HP and LP levels. Meanwhile, ARG failed to significantly affect the BLM-evoked decrease in pulmonary ACE activity and increase in lung weight/body weight ratio. In animals given simultaneous treatment of BLM and L-NAME, noticeable reductions in the pulmonary levels of nitrite/nitrate and GSH were detected. BLM-induced decrease in body weight and increase in lung weight/body weight ratio were accentuated by L-NAME co-treatment. Furthermore, administration of L-NAME led to more profound elevations in lung HP and LP levels, without affecting the decrease in pulmonary ACE activity elicited by BLM.

CONCLUSION: In principle, the present findings indicate that the lung toxicity exerted by chronic administration of BLM is alleviated by ARG, but exacerbated by L-NAME supplementation. This could indicate a possible protective role of NO.

El-Ganainy, S. O., A. El-Mallah, D. Abdallah, M. M. Khattab, M. M. Mohy El-Din, and A. S. El-Khatib, "Rosuvastatin safety: An experimental study of myotoxic effects and mitochondrial alterations in rats.", Toxicology letters, vol. 265, pp. 23-29, 2017 Jan 04. Abstract

Myopathy is the most commonly reported adverse effect of statins. All statins are associated with myopathy, though with different rates. Rosuvastatin is a potent statin reported to induce myopathy comparable to earlier statins. However, in clinical practice most patients could tolerate rosuvastatin over other statins. This study aimed to evaluate the myopathic pattern of rosuvastatin in rats using biochemical, functional and histopathological examinations. The possible deleterious effects of rosuvastatin on muscle mitochondria were also examined. The obtained results were compared to myopathy induced by atorvastatin in equimolar dose. Results showed that rosuvastatin induced a rise in CK, a slight increase in myoglobin level together with mild muscle necrosis. Motor activity, assessed by rotarod, showed that rosuvastatin decreased rats' performance. All these manifestations were obviously mild compared to the prominent effects of atorvastatin. Parallel results were obtained in mitochondrial dysfunction parameters. Rosuvastatin only induced a slight increase in LDH and a minor decrease in ATP (∼14%) and pAkt (∼12%). On the other hand, atorvastatin induced an increase in LDH, lactate/pyruvate ratio and a pronounced decline in ATP (∼80%) and pAkt (∼65%). These findings showed that rosuvastatin was associated with mild myotoxic effects in rats, especially when compared to atorvastatin.

El-Ganainy, S. O., A. El-Mallah, D. Abdallah, M. M. Khattab, M. M. Mohy El-Din, and A. S. El-Khatib, "Elucidation of the mechanism of atorvastatin-induced myopathy in a rat model.", Toxicology, vol. 359, pp. 29-38, 2016 06 01. Abstract

Myopathy is among the well documented and the most disturbing adverse effects of statins. The underlying mechanism is still unknown. Mitochondrial dysfunction related to coenzyme Q10 decline is one of the proposed theories. The present study aimed to investigate the mechanism of atorvastatin-induced myopathy in rats. In addition, the mechanism of the coenzyme Q10 protection was investigated with special focus of mitochondrial alterations. Sprague-Dawely rats were treated orally either with atorvastatin (100mg/kg) or atorvastatin and coenzyme Q10 (100mg/kg). Myopathy was assessed by measuring serum creatine kinase (CK) and myoglobin levels together with examination of necrosis in type IIB fiber muscles. Mitochondrial dysfunction was evaluated by measuring muscle lactate/pyruvate ratio, ATP level, pAkt as well as mitochondrial ultrastructure examination. Atorvastatin treatment resulted in a rise in both CK (2X) and myoglobin (6X) level with graded degrees of muscle necrosis. Biochemical determinations showed prominent increase in lactate/pyruvate ratio and a decline in both ATP (>80%) and pAkt (>50%) levels. Ultrastructure examination showed mitochondrial swelling with disrupted organelle membrane. Co-treatment with coenzyme Q10 induced reduction in muscle necrosis as well as in CK and myoglobin levels. In addition, coenzyme Q10 improved all mitochondrial dysfunction parameters including mitochondrial swelling and disruption. These results presented a model for atorvastatin-induced myopathy in rats and proved that mitochondrial dysfunction is the main contributor in statin-myopathy pathophysiology.