Asser I. Ghoneim

PROTECTIVE EFFECTS OF CURCUMIN AGAINST ISCHAEMIA/REPERFUSION INSULT IN RAT FOREBRAIN

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.

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

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.

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

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)‐4C1‐β‐d‐galactopyranoside, quercetin‐3‐O‐(6″‐O‐galloyl)‐4C1‐β‐d‐galactopyranoside and myricetin‐3‐O‐(6″‐O‐galloyl)‐ C1‐β‐d‐galactopyranoside for the first time from the Rubus genus. We further aimed at evaluating the potential protective effects of RE against carbon tetrachloride (CCl4)‐induced toxicity in isolated rat hepatocytes.

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

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.

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

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.

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

Abstract 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.

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

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.

Celecoxib for the Right Person at the Right Dose and Right Time: An Updated Overview

Celecoxib is the only FDA selective cyclooxygenase-2 (COX-2) inhibitor approved nowadays. Studies showed that its therapeutic efficacy and toxicity may be related to inter-individual variability in pharmacodynamics and pharmacokinetics. This review aims to give an updated overview on celecoxib pharmacodynamics and pharmacokinetics in relation to genetics. For this purpose, a Medline search was performed to collect relevant literature between 2004 and 2014. Studies showed that single nucleotide polymorphism (SNP) in PTGS2-765G>C does not control COX-2 inhibitory effect of celecoxib. PGTS1 mutations may have an impact on the selectivity of celecoxib and as such on its gastrointestinal adverse events. Moreover, CYP2C9*2 and *3 allele were identified in bleeding patients taking celecoxib versus control patients. CYP2C9*2, CYP2C*3, two PTGS1 SNPs, and other variant genotypes have shown an association with acute coronary syndromes in patients taking celecoxib. As for the metabolism of celecoxib, in vitro and ex vivo studies showed a reduced clearance of celecoxib in individuals carrier of CYP2C9*3 allele and to a lower extent with CYP2C9*2 carriers. Studies also demonstrated that CYP2C8 does not have a major role in the metabolism of celecoxib. Non-conclusive data are found on the Uridine diphosphate glucuronosyltransferases (UGTs) which catalyze the second phase of the metabolism of celecoxib. As a conclusion, celecoxib should be used with caution in patients known or suspected to be poor CYP2C9 metabolizers. As for CYP2C8, UGTs and other genotypes further studies are still needed to confirm their role in the administration of celecoxib to the right person at the right dose and right time.

Novel microstructured sildenafil dosage forms as wound healing promoters

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 Po1. 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.

Phytochemicals and Amino Acids: Inducers or Inhibitors of Cell Death?

Phytochemicals and amino acids have long been considered as important inducers of cell death. However, many of these natural compounds have been demonstrating dual action effects on cell death through inhibition as well as induction. Clinical applications may require dosage adjustment and determination of selectively vulnerable cells, either normal or cancer cells. Indeed, the opposing actions and controversial uses as cytoprotective and/or cytotoxic agents, in different tissues and diseases, need further scrutiny. The potential usefulness of these natural compounds as combined chemoprotectants for cancer chemotherapy should also be taken into consideration. Special emphasis will be placed on curcumin and Astragalus constituents as potential phytochemicals. Relevant amino acids include the excitatory and branched-chain ones, as well as glycine and cysteine.