Samir Ahmed El-Shazly

AhR and PPARa: antagonistic effects on CYP2B and CYP3A, and additive inhibitory effects on CYP2C11

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. The peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor super-family of ligand-activated transcription factors and it functions as an obligate heterodimer with retinoid X-receptor alpha RXRα. The aim was to investigate whether the negative cross-talk recently proposed by the present authors between AhR and PPARα on CYP4A and CYP1A has any impact on other cytochrome P450 enzymes. Treatment of male Wistar rats with a PPARα ligand clofibric acid (CA) induced CYP2B1/2 and CYP3A proteins, activities, and the mRNA expression of CYP2B1, CYP2B2, CYP3A1 and CYP3A2, and suppressed CYP2C11 protein, activities and mRNA expression. AhR ligand Sudan III (S.III) treatment decreased basal and CA-induced CYP2B, CYP3A and CYP2C11 protein, activities and mRNA expression. To the best of the authors’ knowledge, this is the first study showing the presence of mutual effects of AhR and PPARα on CYP2B and CYP3A and an additive inhibitory effect on CYP2C11 in the livers of male rats.

Identification of a new anti-diabetic agent by combining VOSO4 and vitamin E in a single molecule: studies on its spectral, thermal and pharmacological properties.

Vanadium(IV) complex of vitamin E (Vit E) ligand was reported. In this complex, binuclear ligand acts as a monodentate via oxygen of phenolic group. The vanadyl(II) ion is surrounded by two molecules of Vit E and two water molecules. The [VO(Vit E)(2)(H(2)O)(2)]2H(2)O complex was isolated by the reaction between VOSO(4) and vitamin E in ethanol/water solvent (50/50 w/w) at pH=8. The solid vanadyl(II) complex has been characterized by elemental analyses (CHN), photometric titrations, infrared spectra, molar conductivity, electronic spectra, TGA/DSC, SEM and XRD studies. Electronic and magnetic measurements are confirmed that the speculated geometry of vanadyl(II) complex is square pyramidal geometry. The microbial test was performed for the vanadyl complex against some kinds of bacteria and fungi. The [VO(Vit E)(2)(H(2)O)(2)]2H(2)O complex was proved effective in addressing diabetic of type I in case of experimental animal than other compounds were prepared in the literature.

l-Carnitine protects against testicular dysfunction caused by gamma irradiation in mice

This study was conducted on mice to evaluate the radioprotective role of L-carnitine against γ-ray irradiation-induced testicular damage. Adult male mice were exposed to whole body irradiation at a total dose of 1 Gy. Radiation exposure was continued 24 h a day (0.1 Gy/day) throughout the 10 days exposure period either in the absence and/or presence of L-carnitine at an i.p. dose of 10 mg/kg body weight/day. Results revealed that γ-rays irradiation suppressed the expression of ABP and CYP450SCC mRNA, whereas treatment with L-carnitine prior and throughout γ-rays irradiation exposure inhibited this suppression. Treatment with γ-ray irradiation or L-carnitine down-regulated expression of aromatase mRNA. With combined treatment, L-carnitine significantly normalized aromatase expression. γ-Ray irradiation up-regulated expression of FasL and Cyclin D2 mRNA, while L-carnitine inhibited these up-regulations. Results also showed that γ-ray-irradiation up-regulated TNF-α, IL1-β and IFN-γ mRNA expressions compared to either controls or the L-carnitine treated group. Moreover, γ-irradiation greatly reduced serum testosterone levels, while L-carnitine, either alone or in combination with irradiation, significantly increased serum testosterone levels compared to controls. In addition, γ-irradiation induced high levels of sperm abnormalities (43%) which were decreased to 12% in the presence of L-carnitine. In parallel with these findings, histological examination showed that γ-irradiation induced severe tubular degenerative changes, which were reduced by L-carnitine pre-treatment. These results clarified the immunostimulatory effects of L-carnitine and its radioprotective role against testicular injury.

Impact of aspartame and saccharin on the rat liver: Biochemical, molecular, and histological approach.

The current work was undertaken to settle the debate about the toxicity of artificial sweeteners (AS), particularly aspartame and saccharin. Twenty-five, 7-week-old male Wistar albino rats with an average body weight of 101 ± 4.8 g were divided into a control group and four experimental groups (n = 5 rats). The first and second experimental groups received daily doses equivalent to the acceptable daily intake (ADI) of aspartame (250 mg/Kg BW) and four-fold ADI of aspartame (1000 mg/Kg BW). The third and fourth experimental groups received daily doses equivalent to ADI of saccharin (25 mg/Kg BW) and four-fold ADI of saccharin (100 mg/Kg BW). The experimental groups received the corresponding sweetener dissolved in water by oral route for 8 weeks. The activities of enzymes relevant to liver functions and antioxidants were measured in the blood plasma. Histological studies were used for the evaluation of the changes in the hepatic tissues. The gene expression levels of the key oncogene (h-Ras) and the tumor suppressor gene (P27) were also evaluated. In addition to a significant reduction in the body weight, the AS-treated groups displayed elevated enzymes activities, lowered antioxidants values, and histological changes reflecting the hepatotoxic effect of aspartame and saccharin. Moreover, the overexpression of the key oncogene (h-Ras) and the downregulation of the tumor suppressor gene (P27) in all treated rat groups may indicate a potential risk of liver carcinogenesis, particularly on long-term exposure.

Genetic polymorphism in β-lactoglobulin gene of some sheep breeds in the Kingdom of Saudi Arabia (KSA) and its influence on milk composition

β-Lactoglobulin (β-Lg) is one of the most important proteins in mammals’ milk. It plays a crucial role in milk quality. The polymorphism of β-Lg gene can be used as a marker system . To analyze the genotype distribution of β-Lg gene in some sheep breeds reared in Taif region of Saudi Arabia and its influence on milk composition, sixty (60) animals belonging to four sheep breeds named Noami, Sawakni, Harry and Nagdi, were utilized. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) test was performed and genetic polymorphism was detected by the digestion of a 452 bp PCR fragment of exon II of β-Lg gene with the endonuclease Rsa I. The results revealed that Noami and Sawakni breeds belong to β-Lg -A genotype while Harry and Nagdi belong to genotype β-Lg -B. Sequence analysis of a 340 bp fragment in the promoter region of β-Lg showed polymorphism among the examined breeds. Analysis of milk composition in the different breeds indicated that the total protein content of milk was the highest in Noami breed followed by Sawakni, Nagdi and Harry. Concerning milk total fat and total solids contents, Harry breed was the highest, while no significant difference was evident among different breeds in lactose or non-fat solid contents. These results indicate the feasibility of PCR-RFLP test for differentiating sheep breeds and the existence of a significant relationship between β-Lg -A genotype and total milk protein content while no clear association between β-Lg genotypes and other milk content was proved.

Synthesis, characterization, and efficacy evaluation of a new anti-diabetic vanadyl(II) thiamine hydrochloride complex in streptozotocin-induced diabetic rats:

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to abnormalities in either insulin secretion or action. A range of vanadium complexes have been synthesized and demonstrated to be effective in lowering hyperglycemia. Thiamine administration was also reported to prevent deterioration in fasting glucose and insulin levels, and to improve glucose tolerance in hyperglycemic patients. This study has been conducted to evaluate the ionic vanadyl(II) thiamine hydrochloride complex (VC) as a new anti-diabetic candidate. The new complex was characterized by infrared spectroscopy (FT-IR), electronic spectra, magnetic susceptibility, electron spin resonance (ESR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The anti-diabetic effect of VC was investigated in comparison to vanadium sulfate in streptozotocin (STZ)-induced diabetic rats. Treatment of diabetic rats with VC versus vanadyl sulfate showed a more potent effect on reducing serum glucose and cholesterol close to normal levels. VC suppressed the diabetes-induced upregulation of hepatic glucose transporter (GLUT)-2, Phosphoenol pyruvate carboxykinase (PEPCK), and hormone-sensitive lipase (HSL) more significantly than vanadyl sulfate. Either vanadyl sulfate or VC restored hepatic sterol regulatory element-binding protein transcription factor-1c (SREBP-1c) and muscle hexokinase (HK) mRNA expression that was downregulated in diabetic group. Pyruvate kinase (PK) mRNA expression was restored more significantly in VC-treated than vanadyl sulfate-treated diabetic rats. These results indicate that the newly synthesized VC could be an effective anti-diabetic candidate as the anti-diabetic activity of the ionic vanadium was enhanced after being modified with the organic ligand, thiamin. The results also suggest that VC achieves its effect most likely through modulating the transcription of energy metabolizing enzymes.

Ethanolic extract of sharah, Plectranthus aegyptiacus, enhances healing of skin wound in rats.

Sharah, Plectranthus aegyptiacus (Forssk.) C. Chr. is a common native plant in the Taif region of Saudi Arabia. An ethanolic extract of freeze dried sharah leaves was added as 10% (w/w) to an ointment base of beeswax and sesame oil. The resultant ointment was examined as a potential enhancer of wound healing. Excision wounds in the nape region of the skin were induced in sixty albino Wistar rats. Animals were allocated in 4 groups (n=15) and kept individually in clean cages. The first group served as negative untreated controls without medication; the second group was treated with ointment base (vehicle); the third group represented the positive control and was treated with a reference ointment and the fourth one served as the experimental group and received the test plant extract (as ointment). Animal groups received the respective medications for 14 successive days. Wounds were measured and photographed every 3 days till the end of the experiment (day 21) in order to determine the wound closure rate (WCR). Specimens from wounds and surrounding skin were collected from sacrificed animals for histological and molecular studies. Both morphometric (based on WCR) and histological findings showed that the healing in animals treated with the sharah plant extract was better than those in control group or vehicle-treated group and was similar to that in the group that received the reference ointment. Moreover, the molecular findings concerning the expression levels of hepatocyte growth factor (HGF) and its receptor (c-Met) displayed a reasonable healing enhancing effect of the plant extract with the expression levels of both being higher in the extract-treated group than in the control group.

Synthesis of some quinolinyl chalcone analogues and investigation of their anticancer and synergistic anticancer effect with doxorubicin

Two derivatives of 2-(4-acetylanilino)quinolines (IIIa, b) were synthesized as scaffolds for synthesis of open chalcone analogues (Va-f) through Claisen-Schmidt condensation with a set of aromatic aldehydes (IVa-d). Derivatives (Va, b) were further manipulated into cyclic α,β-unsaturated ketones by Michael-addition of acetylacetone and ethylacetoacetate affording derivatives (VI–VII). Deethoxycarboxylation of derivatives (VIIa, b) afforded cyclohexenons (VIIIa, b) allowing formation of a mini library of α,β-unsaturated ketones for screening their anticancer and synergistic anticancer effect with doxorubicin using colon cancer cell line (Caco-2). Two open enones, (Vb) and (Ve), showed significant anticancer activity with IC50 of 5.0 and 2.5 μM respectively. Only one cyclic enone, (VIa) showed synergistic anticancer activity with doxorubicin at 10 μM.

Physiological and molecular study on the anti-obesity effects of pineapple (Ananas comosus) juice in male Wistar rat

The present study was performed to assess anti-obesity effects of raw pineapple juice in high fat diet (HFD)-induced fatness. Based on food type, rats were divided into normal diet and HFD groups. When animals of HFD group become obese, they were given pineapple juice along with either HFD or normal diet. Blood biochemistry, liver and muscle gene expressions were analyzed. HFD induced significant elevations in body weight, body mass index (BMI), body fat accumulation, liver fat deposition and blood lipids while juice restored these parameters near to their normal values. Juice significantly decreased serum insulin and leptin while adiponectin was increased. Juice administration downregulated the increment of FAS and SERBP-1c mRNA expression in liver and upregulated HSL and GLUT-2 expressions. The muscular lipolytic CPT-1 expression was upregulted by juice treatment. Pineapple juice, therefore, may possibly be used as anti-obesity candidate where it decreased lipogenesis and increased lipolysis.

Protective potential of royal jelly against cadmium-induced infertility in male rats

This study aimed to investigate the protective potential of Royal jelly (RJ) against cadmium (Cd)‐induced testicular dysfunction in rats. Thirty‐five adult male Wistar rats were assigned into five groups. G I; (control) injected intraperitoneally with saline, G II injected intraperitoneally with a single dose of CdCl2 (1 mg/kg BW), G III received RJ (100 mg/kg BW/day) orally, G IV was pre‐treated with RJ for 1 week then, treated with CdCl2, and G V was co‐treated with RJ and CdCl2. After day 56, serum and tissue samples were collected and analysed. The results showed decreased serum testosterone, luteinising hormone (LH), follicle‐stimulating hormone (FSH), superoxide dismutase, glutathione reductase, sperm motility and count while increased malondialdehyde, nitric oxide, tumour necrosis factor‐α (TNF‐α) and sperm abnormalities, along with a severely damaged seminiferous tubules epithelium with cytoplasmic and nuclear disruptions following Cd toxicity. Additionally, Cd stimulated testicular mRNA expression of TNF‐α while inhibited those of steroidogenic acute regulatory protein, cytochrome P450 cholesterol side chain cleavage enzyme androgen binding protein, FSH‐receptor, LH‐receptor, androgen receptor, 3β‐hydroxysteroid dehydrogenase (HSD), 17β‐HSD, and cytochrome P450 17A1. These negative alterations of cadmium were greatly reduced by RJ treatment. This study concluded that RJ protects against Cd‐induced testicular toxicity.