Publications by authors named "Asser Ghoneim"

18 Publications

  • Page 1 of 1

Protective effects of melatonin and L-carnitine against methotrexate-induced toxicity in isolated rat hepatocytes.

Naunyn Schmiedebergs Arch Pharmacol 2021 Nov 25. Epub 2021 Nov 25.

Pharmacology & Toxicology Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.

The present study was designed to evaluate the possible protective effects of melatonin (MEL) and/or L-carnitine (L-CAR) against methotrexate (MTX)-induced toxicity in isolated rat hepatocytes. Hepatocytes were prepared using collagenase techniques of perfusion and digestion of rat liver. Trypan blue uptake, as well as, glutathione (GSH), lipid peroxidation (LPO), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α) levels were measured. Caspase-3 activity was also assessed. Pre-incubation of hepatocytes with MEL (1 mM) and/or L-CAR (10 mM) 30 min prior to intoxication with MTX, significantly protected hepatocytes against toxicity. In addition, LPO, NO, TNF-α levels, and caspase-3 activity were decreased in comparison to the MTX-intoxicated group. Furthermore, the two drugs increased the MTX-depleted GSH level. MEL and L-CAR prevented MTX-induced hepatocytotoxicity, at least partly, by their antioxidative, antiinflammatory, and antiapoptotic effects. Further studies are recommended on the clinical pharmacologic and toxicologic effects of MEL and L-CAR in patients receiving MTX.
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http://dx.doi.org/10.1007/s00210-021-02176-1DOI Listing
November 2021

Community pharmacists' needs, education, and readiness in facing COVID-19: Actions & recommendations in Egypt.

Int J Clin Pract 2021 Nov 20;75(11):e14762. Epub 2021 Sep 20.

Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt.

Introduction: Coronavirus disease 2019 (COVID-19) outbreak is considered one of the most important public health crises all over the world and in Egypt. Community pharmacists represent the third largest health care professional group after physicians and nurses. Community pharmacists are expected to be fully prepared at the frontline of defending their community needs by limiting the spread of COVID-19 via different pharmaceutical care services.

Aim: This study aimed to evaluate the sources of knowledge and readiness of community pharmacists in facing COVID-19 early outbreak in Egypt.

Methods: A descriptive cross-sectional study was performed via a self-administered online google form questionnaire during the early period from 14 April to 3 June 2020. The questionnaire focused on; evaluating education level, sources of information, and readiness of Egyptian community pharmacists in the COVID-19 pandemic crisis.

Results: A total of 318 community pharmacists from Egypt participated in this questionnaire. About half of the surveyed pharmacists reported that they were frequently consulted and that their patients were seeking consultation regarding COVID-19 management more than 10 times per day. More than half of the pharmacists reported using social media as a source of information and knew the right social distancing recommendations. Regarding protective measures, only a quarter of pharmacists disclosed the availability of personal protective equipment (PPE). Nevertheless, the majority of pharmacists significantly reported some initial lack of support either inform of recommendations or PPE supply.

Conclusion: The study revealed the dependence of community pharmacists on social media as the main source of information and the lack of early awareness of evidence-based practice resources. Community pharmacists were in need of more initial support to achieve better satisfaction, patient counselling and infection control. Corrective measures were promptly undertaken to support and satisfy the Egyptian community pharmacists' initial awareness and readiness facing COVID-19.
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http://dx.doi.org/10.1111/ijcp.14762DOI Listing
November 2021

Combinatorial antitumor effects of amino acids and epigenetic modulations in hepatocellular carcinoma cell lines.

Naunyn Schmiedebergs Arch Pharmacol 2021 11 20;394(11):2245-2257. Epub 2021 Aug 20.

Pharmacology & Toxicology Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.

Hepatocellular carcinoma (HCC) is a highly fatal form of liver cancer. Recently, the interest in using amino acids as therapeutic agents has noticeably grown. The present work aimed to evaluate the possible antiproliferative effects of selected amino acids supplementation or deprivation in human HCC cell lines and to investigate their effects on critical signaling molecules in HCC pathogenesis and the outcomes of their combination with the histone deacetylase inhibitor vorinostat. HepG2 and Huh7 cells were treated with different concentrations of L-leucine, L-glutamine, or L-methionine and cell viability was determined using MTT assay. Insulin-like growth factor 1 (IGF1), phosphorylated ribosomal protein S6 kinase (p70 S6K), p53, and cyclin D1 (CD1) protein levels were assayed using ELISA. Caspase-3 activity was assessed colorimetrically. L-leucine supplementation (0.8-102.4 mM) and L-glutamine supplementation (4-128 mM) showed dose-dependent antiproliferative effects in both cell lines but L-methionine supplementation (0.2-25.6 mM) only affected the viability of HepG2 cells. Glutamine or methionine deprivation suppressed the proliferation of HepG2 cells whereas leucine deprivation had no effect on cell viability in both cell lines. The combination between the effective antiproliferative changes in L-leucine, L-glutamine, and L-methionine concentrations greatly suppressed cell viability and increased the sensitivity to vorinostat in both cell lines. The growth inhibitory effects were paralleled with significant decreases in IGF-1, phospho p70 S6k, and CD1 levels and significant elevations in p53 and caspase-3 activity. Changes in amino acids concentrations could profoundly affect growth in HCC cell lines and their response to epigenetic therapy.
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http://dx.doi.org/10.1007/s00210-021-02140-zDOI Listing
November 2021

Transforming iodoquinol into broad spectrum anti-tumor leads: Repurposing to modulate redox homeostasis.

Bioorg Chem 2021 08 31;113:105035. Epub 2021 May 31.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address:

We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their ICs, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments.
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http://dx.doi.org/10.1016/j.bioorg.2021.105035DOI Listing
August 2021

Systemic bee venom exerts anti-arthritic and anti-inflammatory properties in a rat model of arthritis.

Biomed Rep 2020 Oct 9;13(4):20. Epub 2020 Jul 9.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Beheira 22516, Egypt.

Bee venom (BV) is widely used as a traditional China medicine to treat various conditions, including rheumatoid arthritis (RA). The aim of the present study was to evaluate the effects of systemic BV (60 mg/kg) as an anti-arthritic natural product, compare it with Methotrexate and determine the possible underlying mechanisms of BV action using complete Freund's adjuvant-induced arthritic rats. The development of signs of RA signs (knee joint circumference and arthritis scoring index) was evaluated. Erythrocyte sedimentation rate, serum tumor necrosis factor-α (TNF-α) and serum interleukin-1β (IL-1β) levels were measured at the end of the study. Histopathological examination followed by immunostaining of NF-κB (P65) was performed on the affected knee joints. Additionally, cyclooxygenase (COX) inhibition activity, carrageenan paw edema test and acetic acid writhing tests were performed to evaluate the anti-inflammatory and analgesic effects of the assessed dose and compared with diclofenac. An acute toxicity test was performed to establish the safety of BV at high doses. The results of the present study highlighted the potential of systemic BV on preventing the development of signs of RA. BV also significantly reduced serum levels of TNF-α, IL-1β and NF-κB in the affected joints. In addition to its potent analgesic activity, BV exhibited favorable inhibitory activity of the COX pathway in both and models. Therefore, high dose administration of systemic BV displayed safe and promising anti-arthritic, anti-inflammatory and analgesic properties through regulation of different mechanisms associated with the pathogenesis of RA.
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http://dx.doi.org/10.3892/br.2020.1327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403832PMC
October 2020

The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-κB axis.

Mol Biol Rep 2020 Mar 22;47(3):2217-2230. Epub 2020 Feb 22.

Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.

One of the most lethal malignancies worldwide is colorectal cancer (CRC). Alterations in various signalling pathways, including PI3K-mTOR and NF-κB, have been reported in CRC with subsequent dysregulation of proliferation, apoptosis, angiogenesis and, questionably, autophagy processes. BEZ-235 (dactolisib) is a dual PI3K-mTOR inhibitor with potent anti-tumour activity. However, the observed toxicity of BEZ-235 necessitated the termination of its clinical trials. Hence, we aimed to evaluate the potential long-lasting anti-carcinogenic effects of adding diosmin (DIO, a natural NF-κB inhibitor) to BEZ-235 in HCT-116 CRC cells. The median inhibitory concentrations (IC50s) of BEZ-235 and/or DIO were evaluated in the HCT-116 CRC cell line. Caspase-3 activity was assessed colorimetrically, and p-Akt, NF-κB, CD1, VEGF and LC3B levels were assessed by ELISA. Additionally, LC3-II and P62 gene expression were assessed using qRT-PCR. The observed CIs (combination indices) and DRIs (dose reduction indices) confirmed the synergistic effect of DIO and BEZ-235. Co-administration of both drugs either in combination-1 (1 μM for BEZ-235, 250 μM for DIO) or in combination-2 (0.51 μM for BEZ-235 + 101.99 μM for DIO) inhibited the PI3K/Akt/mTOR/NF-κB axis, leading to the induction of apoptosis (via active caspase-3), and the inhibition of proliferation marker (CD1), angiogenesis marker (VEGF), autophagy protein (LC3B) and altered effects on LC3-IIandP62 gene expression. Our results reveal the synergistic chemotherapeutic effects of DIO combined with BEZ-235 in the HCT-116 CRC cell line and encourage future preclinical and clinical studies of this combination with reduced BEZ-235 concentrations to avoid its reported toxicity.
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http://dx.doi.org/10.1007/s11033-020-05327-4DOI Listing
March 2020

Synergistic antiproliferative effects of curcumin and celecoxib in hepatocellular carcinoma HepG2 cells.

Naunyn Schmiedebergs Arch Pharmacol 2018 12 28;391(12):1399-1410. Epub 2018 Aug 28.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.

Hepatocellular carcinoma (HCC) is still a leading cancer killer in the community. Molecular targeted therapy with celecoxib (CXB) has shown promising antitumor effects; however, its use may be limited due to serious side effects. Curcumin (CUR) has also shown beneficial effects against HCC. Then, it was aimed to investigate the effects of adding CUR to CXB on HCC HepG2 cells. HepG2 cells were treated with CXB and/or CUR at increasing concentrations to investigate synergistic drug interactions, as calculated combination index (CI). Combination treatment effects on cell viability and caspase-3 activation were assessed. The levels of Akt, nuclear factor-kappa B (NF-κB), prostaglandin E (PGE), malondialdehyde (MDA), cyclin D1 (CD1), and vascular endothelial growth factor (VEGF) were also evaluated. CXB (3.13-100 μM) and/or CUR (1.25-40 μM) reduced HepG2 cell viability dose-dependently. Nevertheless, lower combined concentrations showed higher synergism (CI < 1) and higher CXB dose reduction index (DRI > 1). Also, the addition of CUR to CXB resulted in increased cytotoxicity and caspase-3 activation, as compared to CXB alone. In addition, the selected combination significantly reduced the levels of Akt, NF-κB, PGE, MDA, CD1, and VEGF, as compared to either agent alone. In conclusion, CUR augmented the CXB-mediated antitumor effects in HepG2 cells through, at least in part, antiproliferative, antioxidant, and pro-apoptotic mechanisms. This may allow the further use of CXB at lower concentrations, combined with CUR, as a promising safer targeted strategy for HCC management.
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http://dx.doi.org/10.1007/s00210-018-1557-6DOI Listing
December 2018

Evaluation of anti-inflammatory, analgesic activities, and side effects of some pyrazole derivatives.

Inflammopharmacology 2016 Aug 24;24(4):163-72. Epub 2016 Jun 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.

Background And Purpose: Non-steroidal anti-inflammatory drugs are associated with several side effects, such as gastrointestinal mucosal damage, renal toxicity, and cardiovascular side effects. Aiming to find a novel analgesic/anti-inflammatory drug with minimal side effects, the present study was designed to screen and evaluate some newly synthesized pyrazole derivatives.

Method: Anti-inflammatory activity using carrageenan-induced rat paw edema and cotton-pellet-induced granuloma, COX-1/COX-2 selectivity using thin layer chromatography, and analgesic using hot plate and tail flick tests as well as ulcerogenic and renal side effects of the ten compounds were assessed.

Results And Discussion: The results of the carrageenan-induced rat paw edema showed that the carboxyphenylhydrazone derivative (N9) was more potent than the chlorophenyl counterpart (N8) with a relative activity compared to celecoxib of 1.08 and -0.13, respectively, after 1 h. Even though this is true, N9 caused significant increase in the ulcer index, creatinine, and Blood Urea Nitrogen levels. The cotton granuloma test showed that the carboxyphenylhydrazone derivative (N7) was also more potent than its chlorophenyl counterpart (N6) with a relative activity compared to celecoxib of 1.13 and 0.86, respectively. Moreover, adding an acetyl not only increased the anti-inflammatory activity from a relative activity compared to celecoxib of 0.57-1.17 for the compounds X4 and N5, respectively, in the granuloma test, but also increased the selectivity toward COX-2 from 0.197 to 47.979.

Conclusion: As a conclusion, from the ten compounds analyzed, N5 and N7 showed promising results as anti-inflammatory/analgesic agents with low ulcerogenicity and nephrotoxicity and thus should be further analyzed to determine the ED50 and other side effects.
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http://dx.doi.org/10.1007/s10787-016-0270-7DOI Listing
August 2016

Anti-Inflammatory and Antioxidant Activities of Salvia fruticosa: An HPLC Determination of Phenolic Contents.

Evid Based Complement Alternat Med 2016 3;2016:7178105. Epub 2016 Jan 3.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Beirut Arab University, Beirut 115020, Lebanon.

Objectives. Salvia fruticosa Mill. (S. fruticosa) is widely used in folk medicine. Accordingly, the present study was designed to evaluate the antioxidant and anti-inflammatory activities of S. fruticosa, and to determine the phenolic constituents of its extracts. Methods. The antioxidant activity was determined using 2,2-diphenylpicrylhydrazyl assay. Total phenolic contents were estimated using Folin-Ciocalteu reagent, and high-performance liquid chromatography was performed to identify phenolic constituents. To evaluate the anti-inflammatory activity, carrageenan-induced mouse paw edema was determined plethysmographically. Key Findings. Different plant extracts demonstrated strong radical scavenging activity, where the ethyl acetate extract had the highest value in the roots and the lowest in the aerial parts. This antioxidant activity was correlated to the total phenolic content of different extracts, where rutin and luteolin were the most abundant constituents. Interestingly, both the roots and aerial parts revealed a significant anti-inflammatory activity comparable to diclofenac. Conclusions. This study is the first to demonstrate pharmacologic evidence of the potential anti-inflammatory activity of S. fruticosa. This activity may partly be due to the radical scavenging effects of its polyphenolic contents. These findings warrant the popular use of the East Mediterranean sage and highlight the potential of its active constituents in the development of new anti-inflammatory drugs.
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http://dx.doi.org/10.1155/2016/7178105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735903PMC
February 2016

Synthesis of some new amide-linked bipyrazoles and their evaluation as anti-inflammatory and analgesic agents.

J Enzyme Inhib Med Chem 2016 Dec 20;31(6):1079-94. Epub 2015 Oct 20.

d Department of Pharmaceutical Chemistry , Faculty of Pharmacy, Alexandria University , Alexandria , Egypt .

Four series of new bipyrazoles comprising the N-phenylpyrazole scaffold linked to polysubstituted pyrazoles or to antipyrine moiety through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory and analgesic activities. In vitro COX-1/COX-2 inhibition study revealed that compound 16b possessed the lowest IC50 value against both COX-1 and COX-2. Moreover, the effect of the most promising compounds on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) protein expression in lipopolysaccharide (LPS)-activated rat monocytes was also investigated. The results revealed that some of the synthesized compounds showed anti-inflammatory and/or analgesic activity with less ulcerogenic potential than the reference drug diclofenac sodium and are well tolerated by experimental animals. Moreover, they significantly inhibited iNOS and COX-2 protein expression induced by LPS stimulation. Compounds 16b and 18 were proved to display anti-inflammatory activity superior to diclofenac sodium and analgesic activity equivalent to it with minimal ulcerogenic potential.
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http://dx.doi.org/10.3109/14756366.2015.1094469DOI Listing
December 2016

Novel microstructured sildenafil dosage forms as wound healing promoters.

Expert Opin Drug Deliv 2014 Oct 18;11(10):1525-36. Epub 2014 Jun 18.

Alexandria University, Department of Industrial Pharmacy, Faculty of Pharmacy , Alexandria , Egypt +2 03 3630 815 ; +2 03 4873 273 ; ,

Purpose: Study the possible benefit of combining biodegradable polymers with sildenafil citrate (SC) in wound healing.

Method: Biodegradable micronized powdered formulations of SC were prepared by spray drying using chitosan (P₁) or chitosan/gum Arabic (P₂). Powders were characterized by differential scanning calorimetry, Scanning electron microscope, particle size analysis, flow and swelling behavior. The powders were also incorporated into microstructured gels and in vitro SC release from powders and gels was tested. In vivo wound healing acceleration was tested by measuring area contraction of excision wounds and histologically. Post-healing tensile strength (TS) for incision wounds in rats receiving powder formulations was tested.

Results: The powders were in the micron-size range showing no SC-polymers interaction. Powders had poor flow with angle of repose (θ) of 41 - 48°, and high moisture uptake reaching 107% for placebo powder P₁. Good excision wound healing was seen with P1 and G1 formulations showing 98.4 and 98.5% reduction in wound area, respectively, compared with 83% for the control. Incision wounds were improved with P1 showing TS value of 6.9 compared with 3.7 kg/cm² for control. Histological examinations supported.

Conclusion: Spray-dried chitosan/SC powder (P₁) and its gel form (G₁) could be promising wound healing promoters as supported by the histological examinations.
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http://dx.doi.org/10.1517/17425247.2014.929662DOI Listing
October 2014

Hepatoprotective effects of Astragalus kahiricus root extract against ethanol-induced liver apoptosis in rats.

Chin J Nat Med 2013 Jul;11(4):354-61

Pharmacology Department, Medical Division, National Research Center, Giza, Egypt.

The hepatoprotective activity of the ethanol extract of Astragalus kahiricus (Fabaceae) roots against ethanol-induced liver apoptosis was evaluated and it showed very promising hepatoprotective actions through different mechanisms. The extract counteracted the ethanol-induced liver enzymes leakage and glutathione depletion. In addition, it demonstrated anti-apoptotic effects against caspase-3 activation and DNA fragmentation that were confirmed by liver histopathological examination. Moreover, the phytochemical study of this extract led to the isolation of four cycloartane-type triterpenes identified as astrasieversianin II (1), astramembrannin II (2), astrasieversianin XIV (3), and cycloastragenol (4). The structures of these isolates were established by HRESI-MS and 1D and 2D NMR experiments. The antimicrobial, antimalarial, and cytotoxic activities of the isolates were further evaluated, but none of them showed any activity.
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http://dx.doi.org/10.1016/S1875-5364(13)60052-7DOI Listing
July 2013

Anti-apoptotic effects of tamarind leaves against ethanol-induced rat liver injury.

J Pharm Pharmacol 2012 Mar 8;64(3):430-8. Epub 2011 Dec 8.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Cairo, Egypt.

Objectives: The leaf decoctions of Tamarindus indica (TI) have long been traditionally used in liver ailments. The aim of this study was to investigate the anti-apoptotic activity of TI leaf extract against acute ethanol (EtOH)-induced liver injury. The major constituents of the extract were also examined for standardization purposes.

Methods: Rats (n = 5-7) were orally pretreated with TI leaf extract (25, 50 and 100 mg/kg) for seven days. Silymarin was used as a positive control. Liver tissue biochemical assays included key markers of apoptosis and its redox signalling. Serum enzyme levels were also determined.

Key Findings: All graded doses of TI leaf extract mitigated the EtOH-induced liver caspase-3 activation (42, 57 and 64%) as well as DNA fragmentation (32, 47 and 50%), respectively. The highest dose of the extract demonstrated membrane-stabilizing (38%) in addition to glutathione-replenishing (88%) effects. Also, the leaves improved the liver histopathological alterations. Moreover, major plant bioactive polyphenolics, that might be responsible for the extract's observed effects, were isolated and identified.

Conclusions: TI leaf extract demonstrated promising anti-apoptotic hepatoprotective effects in rats. The use of TI leaves in different liver diseases, having apoptosis as the underlying pathology, hence warrants further clinical investigation.
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http://dx.doi.org/10.1111/j.2042-7158.2011.01418.xDOI Listing
March 2012

Dichloroacetonitrile induces oxidative stress and developmental apoptotic imbalance in mouse fetal brain.

Environ Toxicol Pharmacol 2012 Jan 16;33(1):78-84. Epub 2011 Nov 16.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.

Dichloroacetonitrile (DCAN) is one of the disinfection by-products of chlorination of drinking water. Limited mechanistic studies exist on the developmental toxicity of haloacetonitriles (HANs). The present study was designed to investigate the potential adverse effects of maternal exposure to DCAN on mouse fetal brain. Based on initial dose-response experiment, DCAN (14 mg/kg/day) was administered orally to pregnant mice at gestation day (GD) 6, till GD 15. Maternal exposure to DCAN resulted in redox imbalance in fetal cortex and cerebellum, characterized by significant decrease in reduced glutathione (GSH), and elevation of malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. Further, DCAN induced apoptosis indicated by significant enhancement of DNA fragmentation and active caspase-3 level in fetal cortex and cerebellum. Neuronal degeneration was indicated by positive cupric silver staining. In conclusion, maternal exposure to DCAN adversely affects mouse fetal brain as evidenced by induction of oxidative stress, apoptotic imbalance and neurodegeneration.
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http://dx.doi.org/10.1016/j.etap.2011.11.004DOI Listing
January 2012

Rubus sanctus protects against carbon tetrachloride-induced toxicity in rat isolated hepatocytes: isolation and characterization of its galloylated flavonoids.

J Pharm Pharmacol 2009 Nov;61(11):1511-20

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Objectives: Rubus sanctus Schreb., known from the Bible as 'holy thorn bush', grows wild in Egypt. Rubus sanctus aqueous alcoholic extract (RE) contains a complicated phenolic mixture (ellagitanins, flavonoids and caffeic acid derivatives). In this study, the phytochemical investigation of the plant was re-evaluated. Herein, we report on the isolation and identification of three galloylated flavonoids, namely kaempferol-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside, quercetin-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside and myricetin-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside for the first time from the Rubus genus. We further aimed at evaluating the potential protective effects of RE against carbon tetrachloride (CCl(4))-induced toxicity in isolated rat hepatocytes.

Methods: Based on an initial concentration-response experiment, a concentration of 100 mug/ml was selected to investigate the hepatoprotective activity of RE.

Key Findings: Pretreatment with RE afforded protection as indicated by counteracting CCl(4)-induced cell death, and reduced glutathione depletion. In addition, RE ameliorated CCl(4)-induced enzyme leakage by 40% for lactate dehydrogenase, 30% for alanine aminotransferase and 20% for aspartate aminotransferase as compared with CCl(4)-treated cells. Moreover, RE counteracted CCl(4)-induced lipid peroxidation and inhibited spontaneous lipid peroxidation in the control group.

Conclusions: In conclusion, RE protects against CCl(4)-induced toxicity in isolated rat hepatocytes.
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http://dx.doi.org/10.1211/jpp/61.11.0011DOI Listing
November 2009

Lactoperoxidase catalyzes in vitro activation of acrylonitrile to cyanide.

Toxicol Lett 2009 Dec 13;191(2-3):347-52. Epub 2009 Oct 13.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.

Acrylonitrile (ACN) is a widely used industrial chemical. Although it is a well reported animal carcinogen, its current designation to humans is "possibly carcinogenic". The present study aimed at investigating the ability of LPO enzyme system to oxidize ACN to cyanide (CN(-)) in vitro. Detection of CN(-) served as a marker for the possible generation of free radical intermediates implicated in ACN induced toxicity in the activation process. Optimum conditions for the oxidation of ACN to CN(-) were characterized with respect to pH, temperature and time of incubation as well as ACN, LPO and H(2)O(2) concentrations in incubation mixtures. Maximum reaction velocity (V(max)) and Michaelis-Menten constant (K(m)) were assessed. Addition of nitrite (NO(2)(-)) salts to the reaction mixtures significantly enhanced the rate of the reaction. Free radical scavengers (quercetin and trolox C), LPO enzyme inhibitor (resorcinol) and competitors for LPO binding (sodium azide and indomethacin) were found to reduce the rate of CN(-) production. Inclusion of the sulfhydryl compounds glutathione (GSH), NAC (N-acetylcysteine), D-penicillamine or L-cysteine enhanced the rate of ACN oxidation. The present results demonstrate the ability of LPO enzyme system to oxidize ACN to CN(-) and provide insight for the elucidation of ACN chronic toxicity.
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http://dx.doi.org/10.1016/j.toxlet.2009.10.005DOI Listing
December 2009

Effects of curcumin on ethanol-induced hepatocyte necrosis and apoptosis: implication of lipid peroxidation and cytochrome c.

Authors:
Asser I Ghoneim

Naunyn Schmiedebergs Arch Pharmacol 2009 Jan 21;379(1):47-60. Epub 2008 Aug 21.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.

Ethanol-induced hepatocyte necrosis and apoptosis are valid in vitro models to investigate the modulatory effects of hepatoprotective/toxic agents such as curcumin. In this study, suspension and monolayer cultures of isolated rat hepatocytes were used. Levels of trypan blue uptake, reduced glutathione, and lipid peroxidation were quantified. Chromatin condensation, caspase-3 activity, and cytochrome c extramitochondrial translocation were also evaluated. Results revealed that curcumin did not protect against either ethanol-induced necrosis or glutathione depletion. Neither did curcumin reduce caspase-3 activation nor chromatin condensation. In contrast, curcumin induced glutathione depletion, caspase-3 activation, necrosis, and apoptosis. Fortunately, all tested curcumin concentrations (1 microM-10 mM) diminished the ethanol-induced lipid peroxidation. In addition, 1 microM curcumin decreased cytochrome c translocation in hepatocyte monolayers. In conclusion, low concentrations of curcumin may protect hepatocytes by reducing lipid peroxidation and cytochrome c release. Conversely, higher concentrations provoke glutathione depletion, caspase-3 activation, and hepatocytotoxicity.
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http://dx.doi.org/10.1007/s00210-008-0335-2DOI Listing
January 2009

Protective effects of curcumin against ischaemia/reperfusion insult in rat forebrain.

Pharmacol Res 2002 Sep;46(3):273-9

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Oxidative stress is believed to be implicated in the pathogenesis of postischaemic cerebral injury. Many antioxidants were shown to be neuroprotective in experimental models of cerebral ischaemia/reperfusion (I/R). The present study was designed to investigate the potential protective effects of curcumin (CUR) against I/R insult in rat forebrain. The model adopted was that of surgically-induced forebrain ischaemia, performed by means of bilateral common carotid artery occlusion (BCCAO) for 1 h, followed by reperfusion for another 1h. The effects of a single i.p. dose of CUR (50, 100 or 200 mg kg(-1)), administered 0.5 h after the onset of ischaemia, were investigated by assessing oxidative stress-related biochemical parameters in rat forebrain. CUR, at the highest dose level (200 mg kg(-1)), decreased the I/R-induced elevated xanthine oxidase (XO) activity, superoxide anion (O(2)*(-)) production, malondialdehyde (MDA) level and glutathione peroxidase (GPx), superoxide dismutase (SOD), and lactate dehydrogenase (LDH) activities. On the other hand, CUR did not affect the declined reduced glutathione (GSH) content due to I/R insult. Worth mentioning is that the activity of catalase (CAT) did not change in response to either I/R insult or drug treatment. In conclusion, CUR was found to protect rat forebrain against I/R insult. These protective effects may be attributed to its antioxidant properties and/or its inhibitory effects on xanthine dehydrogenase/xanthine oxidase (XD/XO) conversion and resultant O(2)*(-) production.
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http://dx.doi.org/10.1016/s1043-6618(02)00123-8DOI Listing
September 2002
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