Khalid M Alkharfy

Elsevier B.V., Philadelphia, Pennsylvania, United States

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Publications (130)298.62 Total impact

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    ABSTRACT: Endoglin, a 180 kDa disulfide-linked homodimeric, transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a coreceptor of T�RII that binds Transforming Growth Factor-� (TGF-�) and is important for vascular development, and consequently has become a compelling target for antiangiogenic therapies. A few recent studies in Gastrointestinal Stromal Tumor (GIST), breast cancer and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond anti-angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the anti-proliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable anti-proliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the anti-tumor effect of both RNAi based and competitive inhibitor based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells.
    Molecular Cancer Therapeutics 08/2014; In Press. · 5.60 Impact Factor
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    ABSTRACT: Aim: Combined use of herbs and drugs may result in clinically important herb-drug interactions. The majorities of these interactions are thought to be metabolism-based and involve induction or inhibition of cytochrome P450 (CYP). The current study was designed to investigate the effect of some commonly used herbs on rat CYP2C11 gene expression and metabolic activity. Methods: Wistar rats were treated for 7 days with increasing doses of 3 herbs; Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida. Thereafter, CYP2C11 mRNA and protein levels were determined by real-time polymerase chain reaction (RT-PCR) and western blot analyses, respectively. In vitro metabolic activity of CYP2C11 was performed on rat hepatic microsomes using tolbutamide as specific substrate. Results: Our results showed that all the 3 herbs significantly inhibited the mRNA and protein expression levels of CYP2C11 in a dose-dependent manner. Furthermore, the in vitro enzyme metabolic activity study showed a significant decrease in the formation of 4-hyroxy-tolbutamide, a tolbutamide metabolite, at the higher doses. The inhibitory effects of the investigated herbs on rat CYP2C11 was in the order: Nigella Sativa > Trigonella foenum-graecum > Ferula asafoetida. Conclusions: The 3 herbs are strong inhibitor of CYP2C11 expression, which can lead to an undesirable pharmacological effect of clinically used CYP2C11 substrate drugs with a low therapeutic index.
    Drug research. 08/2014;
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    ABSTRACT: Linking gender-specific differences to the molecular etiology of obesity has been largely based on genomic and transcriptomic evidence lacking endophenotypic insight and is not applicable to the extracellular fluid compartments, or the milieu intérieur, of the human body. To address this need, this study profiled the whole serum proteomes of age-matched nondiabetic overweight and obese females (n = 28) and males (n = 31) using a multiplex design with pooled biological and technical replicates. To bypass basic limitations of immunodepletion-based strategies, subproteome enrichment by size-exclusion chromatography (SuPrE-SEC) followed by iTRAQ 2D-LC-nESI-FTMS analysis was used. The study resulted in the reproducible analysis of 2472 proteins (peptide FDR < 5%, q < 0.05). A total of 248 proteins exhibited significant modulation between men and women (p < 0.05) that mapped to pathways associated with β-estradiol, lipid and prostanoid metabolism, vitamin D function, immunity/inflammation, and the complement and coagulation cascades. This novel endophenotypic signature of gender-specific differences in whole serum confirmed and expanded the results of previous physiologic and pharmacologic studies exploring sexual dimorphism at the genomic and transcriptomic level in tissues and cells. Conclusively, the multifactorial and pleiotropic nature of human obesity exhibits sexual dimorphism in the circulating proteome of importance to clinical study design.
    Journal of Proteome Research 07/2014; · 5.06 Impact Factor
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    ABSTRACT: Thymoquinone (THQ), the active constituent of Nigella sativa seeds, has demonstrated some potential pharmacological activities. The present study was designed to investigate the pharmacokinetic behavior of THQ following intravenous (IV) and oral (PO) administration using an animal model. THQ was given vascularly (5 mg/kg IV) and extravascularly (20 mg/kg PO) to Vole rabbits, and blood samples were collected at predetermined time points. The concentrations of THQ in plasma were measured by a high-performance liquid chromatography, and the pharmacokinetic parameters were determined using both compartmental and non-compartmental analyses. The calculated clearance (CL) following IV administration was 7.19 ± 0.83 ml/kg/min, and the estimated volume of distribution at steady state (V ss) was 700.90 ± 55.01 ml/kg. Whereas with PO dosing, apparent CL/F value was 12.30 ± 0.30 ml/min/kg and V ss/F was 5,109.46 ± 196.08 ml/kg. These parameters were associated with an elimination half-life (T 1/2) of 63.43 ± 10.69 and 274.61 ± 8.48 min with IV and PO dosing, respectively. The calculated absorption T 1/2 was about 217 min. Compartmental analysis revealed T 1/2α of ~8.9 min and T 1/2β of ~86.6 min. The calculated absolute bioavailability of THQ was ~58 % with a lag time of ~23 min. The estimated THQ protein binding was >99 %. Therefore, THQ represents a compound with rapid elimination and relatively slower absorption following PO administration.
    European journal of drug metabolism and pharmacokinetics. 06/2014;
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    ABSTRACT: In this observational study, we aimed to see whether transition in Saudi students entering university life could be a breeding stage for cardiometabolic risk factor emergence and clustering. A total of 1878 apparently healthy Saudi students of the Preparatory Year, King Saud University, Riyadh, KSA (1112 men and 766 women) spanning 2 academic years were included. They were divided into 2 groups based on the validated perceived stress test (PST). Anthropometrics were obtained and fasting blood samples were collected for measurement of fasting blood glucose and a lipid profile. PST score (>27) considered indicative of stress was noted in 44.4% of students. The prevalence of this score was higher in women than in men (49.7% versus 40.7%). The prevalence of obesity, hypertension and dyslipidemia was significantly higher in men than women (p < 0.01), and this was even more apparent among stressed men, who had a significantly higher prevalence of all the above cardiometabolic factors than the non-stressed ones (p < 0.01). Perceived stress is alarmingly high among Saudi students entering universities. This study sheds light on the social responsibility of universities in promoting a healthy lifestyle, particularly in this age group, when exposure to different kinds of stressors may result in body weight and metabolic changes.
    BMC Public Health 04/2014; 14(1):391. · 2.08 Impact Factor
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    ABSTRACT: To determine the gender-dependent association of socio-economic status variables with the prevalence of metabolic syndrome (MetS) in the adult Saudi population. A total of 9164 adult Saudis (aged 18-70 years) were included in this cross-sectional study. Marital status, income, education, and occupation were used as socio-economic indicators while behavioral factor like physical exercise was also taken into account. MetS was defined using the criteria based from the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III). In males, the odds ratio (OR) of harboring MetS was higher in married [OR1.6 (Confidence Interval (CI) 1.1, 2.4); p < 0.03], and high income class [OR 2.3(CI 1.5, 3.5); p < 0.001] and lowest in retired and unemployed individuals [1.4(1.0, 1.9); p < 0.04, 0.61(0.45, 0.82); p < 0.001] respectively. In females, MetS was inversely related to high income [OR 0.70 (CI 0.46, 1.1); p < 0.09] and education level [OR 0.38 (CI 0.26, 0.56); p < 0.001], and was significantly higher in the unemployed class [OR 1.6 (CI 1.2, 2.2); p < 0.004]. The prevalence of MetS is significantly high among retired, married and high-earning Saudi males while in females, high earners and high education seem to confer a protective effect against MetS.
    BMC Cardiovascular Disorders 04/2014; 14(1):51. · 1.46 Impact Factor
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    ABSTRACT: The present study was conducted to investigate the effects of some commonly used herbs namely Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetics of sildenafil in beagle dogs. The study design involved four treatments in a non-balanced crossover design. Sildenafil was given one tablet 100 mg orally to each dog and blood samples were obtained. After a suitable washout period, animals were commenced on a specific herb treatment for 1 week. Blood samples were withdrawn at different time intervals and sildenafil was analyzed by HPLC method. Oral administration of Nigella sativa resulted in reduction of AUC0-∞, C max and t 1/2 as compared to the control. Treatment of Lepidium sativum resulted in a significant reduction in the C max and AUC. There were no significant differences between the rests of the pharmacokinetic parameters relative to those of the control. For Trigonella foenum-graecum, the effects were similar to those obtained in case of Lepidium sativum. It was concluded that concurrent use of investigated herbs alters the pharmacokinetics of sildenafil. Co-administration of investigated herbs should be cautious since their concomitant use might result in decrease in sildenafil bioavailability.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2014; · 1.31 Impact Factor
  • The FASEB Journal 04/2014; 28(1):575.4. · 5.70 Impact Factor
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    ABSTRACT: The prevalence of metabolic syndrome (MetS) is rising alarmingly in the Saudi Arabian population. This study was conducted to assess the association between vitamin D receptor (VDR) polymorphisms and genetic susceptibility to components of the metabolic syndrome, type 2 diabetes mellitus (T2DM), and vitamin D deficiency in the Saudi Arabian population. Five-hundred-seventy Saudi individuals (285 MetS and 285 controls) were enrolled in this cross-sectional study. TaqI, BsmI, ApaI and FokI single nucleotide polymorphisms (SNPs) of the VDR gene were genotyped. The CT genotype and allele T of BsmI were associated with lower HDL-C levels [OR 0.60 (0.37, 0.96), p=0.03] and obesity [OR 1.4 (1.0, 1.90), p=0.04], respectively. The CT genotype and the dominant model CT+TT of BsmI were associated with increased risk of diabetes [OR 1.7 (1.2, 2.4), p=0.007], and [OR 1.5 (1.1, 2.2), p=0.01], respectively. On the contrary, the CT and CT+CC genotypes of FokI exhibited an association with a reduced risk of diabetes [OR 0.70 (0.49, 0.99), p=0.05] and [OR 0.67 (0.48, 0.94), p=0.02], respectively. The allele C of FokI was associated with lower risk of developing T2DM [OR 0.73 (0.56, 0.95), p=0.02]. The prevalence of vitamin D deficiency was lower in subjects with the AC genotype of ApaI [OR, 0.34 (0.14, 0.80), p=0.01]. Components of the MetS such as obesity, low HDL and T2DM were associated with the VDR gene. FokI and BsmI have protective and facilitative effects on the risk for T2DM, while the ApaI genotype was associated with reduced vitamin D deficiency.
    Gene 03/2014; · 2.20 Impact Factor
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    ABSTRACT: Vitamin D deficiency is an increasingly recognized comorbidity in patients with type 1 diabetes mellitus (DMT1), suggesting that vitamin D deficiency might play a role in DMT1. We aimed to determine and compare the vitamin D status of Saudi adults with and without DMT1. A total of 60 Saudi adults with DMT1 from the Diabetes Clinics and 60 non-DM, healthy controls were included in the study. The mean age for those with DMT1 was 25.9 +/- 16.1 years versus 36.7 +/- 3.6 years among the controls. We measured serum 25-hydroxy vitamin D (25OHD), calcium, cholesterol, blood glucose, HDL, and triglycerides and compared the results between the DMT1 group and control subjects. Both the DMT1 and healthy groups had vitamin D deficiency. The mean levels of 25OHD were significantly lower in the DMT1 adults than in the controls (28.1 +/- 1.4 nmol/L versus 33.4 +/- 1.6 nmol/L). In the DMT1 adults, 66.7% were mildly, 31.7% moderately, and 3.3% severely vitamin D deficient as compared with 41.7% (mildly), 31.7% (moderately), and 5% (severely) in the control group. Overall, 100% of the DMT1 adults and 78% of the healthy children were vitamin D deficient. The prevalence of vitamin D deficiency among DMT1 adults was relatively high. Therefore, screening for vitamin D deficiency and supplementation for this population should be warranted.
    BMC Public Health 02/2014; 14(1):153. · 2.08 Impact Factor
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    ABSTRACT: Effect of Curcuma longa rhizome powder and its ethanolic extract on CYP2D6 and CYP3A4 metabolic activity was investigated in vitro using human liver microsomes and clinically in healthy human subjects. Dextromethorphan (DEX) was used as common probe for CYP2D6 and CYP3A4 enzymes. Metabolic activity of CYP2D6 and CYP3A4 was evaluated through in vitro study; where microsomes were incubated with NADPH in presence and absence of Curcuma extract. In clinical study phase-I, six healthy human subjects received a single dose (30 mg) of DEX syrup, and in phase-II DEX syrup was administered with Curcuma powder. The enzyme CYP2D6 and CYP3A4 mediated O- and N-demethylation of dextromethorphan into dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Curcuma extract significantly inhibited the formation of DOR and 3-MM, in a dose-dependent and linear fashion. The 100 μg/ml dose of curcuma extract produced highest inhibition, which was about 70 % for DOR and 80 % for 3-MM. Curcuma significantly increases the urine metabolic ratio of DEX/DOR but the change in DEX/3-MM ratio was statistically insignificant. Present findings suggested that curcuma significantly inhibits the activity of CYP2D6 in in vitro as well as in vivo; which indicates that curcuma has potential to interact with CYP2D6 substrates.
    European Journal of Drug Metabolism and Pharmacokinetics 02/2014; · 1.31 Impact Factor
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    ABSTRACT: Asthma is the most common chronic childhood disease. Imbalance of cytokines released from T helper cells and environmental factors, such as exposure to poly-aromatic hydrocarbon (PAH), play pivotal roles in the pathogenesis of asthma. The aim of this study was to compare the mRNA expression patterns of Interleukin (IL)-4, interferon(IFN)-gamma and Acyl Co A long chain 3 (ACSL3) in peripheral blood leukocytes of children with and without asthma. To correlate the obtained mRNA data with serum IL-4, IFN-gamma and PAH levels. Further, to determine the effect of in vivo exposure to PAH on mRNA expression of IL-4, IFN-gamma and ACSL3 genes in a rat model. A total of 170 children below 16 years (85 pediatric asthma patients and 85 matched healthy controls) were randomly selected from the Riyadh Cohort, Saudi Arabia. Gene expression analysis was performed using qRTPCR. Serum IL-4, IFN-gamma and PAH were measured using LINCOplex (human multiplex immunoassay kit) and HPLC respectively. IL-4 mRNA expression was significantly increased (P < 0.05) in children with asthma compared to healthy control group whereas no differences were observed for either IFN-gamma or ACSL3 mRNA. Similarly, serum IL- 4 and PAHs concentration was significantly higher as well in children with asthma in whom IFN-gamma was also significantly lower. Results obtained in rats showed that exposure to the benzopyrene prototype PAH resulted in a 2.6 fold (P < 0.001) increased IL-4 mRNA expression in blood. Peripheral blood IL-4 mRNA levels, serum concentration of this cytokine are elevated in children with asthma. Also, elevated levels of PAH were observed in children with asthma. Additionally, PAH administration in rodents resulted in an increased IL-4 mRNA which is supposed to partly mediate the inflammatory response noted in asthma.
    BMC Pediatrics 01/2014; 14(1):17. · 1.98 Impact Factor
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    ABSTRACT: Obesity, commonly measured as body mass index (BMI), has been on a rapid rise around the world and is an underlying cause of several chronic non-communicable diseases, including type 2 diabetes mellitus (T2DM). In addition to the environmental factors, genetic factors may also contribute to the ongoing obesity epidemic in Saudi Arabia. This study investigated the association between variants of 36 previously established T2DM SNPs and obesity phenotypes in a population of Saudi subjects. Study subjects consisted of 975 obese (BMI: ≥30), 825 overweight (25-30) and 423 lean controls (18-25) and of these 927 had a history of T2DM. Subjects were genotyped for 36 SNPs, which have been previously proved to be T2DM linked, using the KASPar method and the means of BMI and waist circumference (WC) corresponding to each of the genotypes were compared by additive, recessive and dominant genetic models. Five and seven of 36 T2DM-related SNPs were significantly associated with the BMI and WC, respectively. Variants of SNPs rs7903146, rs1552224 and rs11642841 in the control group and rs7903146 in T2DM group showed significant association with both BMI and WC. Variant of SNP rs10440833 was significantly associated with BMI in T2DM group of both males [OR = 1.8 (1.0, 3.3); P = 0.04] and females [OR = 2.0 (1.0, 3.9); P = 0.04]. Genetic risk scores explained 19 and 14 % of WC and hip size variance in this population. Variants of a number of established T2DM related SNPs were associated with obesity phenotypes and may be significant hereditary factors in the pathogenesis of T2DM.
    Molecular Biology Reports 01/2014; · 2.51 Impact Factor
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    ABSTRACT: The recently discovered myokine irisin has been implicated in several observational studies as a potential therapeutic target for obesity-related diseases. However, no information is available as to the heritability of this hormone. This study aims to fill this gap. A total of 120 families (N = 254; 121 adults and 133 children) were included in this study taken from the Riyadh Biomarkers Research Program cohort. Information gathered include anthropometrics, and glycemic, lipid and adipocytokine profiles. Irisin was measured using ELISA. Examining heritability between mother and offspring the most significant heritable traits in sons included irisin (p=1.6*10-5), systolic blood pressure (p=3.6*10-4), total cholesterol (p=3.5*10-7) and LDL-cholesterol (p=1.2*10-6). Heritable traits between mother and daughter again included irisin (p<0.002), as well as anthropometric associations such as waist (p<0.01) and hips (p<0.005) circumferences and blood pressure (p<0.002); biochemically, principal associations were noted with HDL-cholesterol (p<0.04) and (TNF-α p<0.002). HDL-cholesterol was the single most significant predictor for irisin levels in adults, explaining 17% of variance, whilst in children angiotensin II was the most significant predictor of irisin levels explaining 19% of the variance (p=0.003). Circulating irisin appears to be maternally inherited and is predicted by HDL-cholesterol in adults and angiotensin II in children, both factors influenced by energy expenditure and regulation. Taken together, these findings suggest a significant role of irisin in energy-generating processes.
    Clinical Science 01/2014; · 4.86 Impact Factor
  • The FASEB Journal 01/2014; 28(1):954.1. · 5.70 Impact Factor
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    ABSTRACT: The aim of the study was to understand whether dietary fatty acids such as saturated, polyunsaturated, and monounsaturated fatty acids act as inflammatory mediators or influence pro-coagulation in Saudi adults. The study sought to examine inflammatory factors such as C-reactive protein, tumor necrosis factor-alpha and activated plasminogen activator inhibitor 1. A total number of 232 consenting Saudi adults, aged 18-60 years were randomly selected in this cross-sectional study. Independent Student t-test was done to compare means of normally distributed data. Spearman correlation between the variables was determined. The values of different fatty acids and adipokines were transformed logarithmically/square root to normalize data before correlations were determined and statistical analyses performed. Statistical significance was set at p<0.05. The results show a significant positive correlation of dietary intake of poly and monounsaturated fatty acids, but not saturated fatty acids, with activated plasminogen activator inhibitor 1 (r=0.31, p=0.02, r=0.32 p=0.04). On the other hand, dietary intake of saturated fatty acids showed a negative correlation with serum C-reactive protein levels (p=0.001) in males. Dietary unsaturated fatty acids is possibly associated with the production of a pro-coagulation factor without enhancing the secretion of pro-inflammatory molecules, while saturated fatty acids have no effect on activated plasminogen activator inhibitor 1, but their level is negatively associated with the inflammatory factor C-reactive protein. We conclude that dietary intake may exert a gender-specific effect in inflammatory processes among adults. Further studies are warranted to confirm present findings.
    Asia Pacific Journal of Clinical Nutrition 01/2014; 23(1):55-64. · 1.06 Impact Factor
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    ABSTRACT: The prevalence of metabolic syndrome (MetS) is rising alarmingly in the Saudi Arabian population. This study was conducted to assess the association between vitamin D receptor (VDR) polymorphisms and genetic susceptibility to components of the metabolic syndrome, type 2 diabetes mellitus (T2DM), and vitamin D deficiency in the Saudi Arabian population. Five-hundred-seventy Saudi individuals (285 MetS and 285 controls) were enrolled in this cross-sectional study. TaqI, BsmI, ApaI and FokI single nucleotide polymorphisms (SNPs) of the VDR gene were genotyped. The CT genotype and allele T of BsmI were associated with lower HDL-C levels [OR 0.60 (0.37, 0.96), p = 0.03] and obesity [OR 1.4 (1.0, 1.90), p = 0.04], respectively. The CT genotype and the dominant model CT + TT of BsmI were associated with increased risk of diabetes [OR 1.7 (1.2, 2.4), p = 0.007], and [OR 1.5 (1.1, 2.2), p = 0.01], respectively. On the contrary, the CT and CT + CC genotypes of FokI exhibited an association with a reduced risk of diabetes [OR 0.70 (0.49, 0.99), p = 0.05] and [OR 0.67 (0.48, 0.94), p = 0.02], respectively. The allele C of FokI was associated with lower risk of developing T2DM [OR 0.73 (0.56, 0.95), p = 0.02]. The prevalence of vitamin D deficiency was lower in subjects with the AC genotype of ApaI [OR, 0.34 (0.14, 0.80), p = 0.01]. Components of the MetS such as obesity, low HDL and T2DM were associated with the VDR gene. FokI and BsmI have protective and facilitative effects on the risk for T2DM, while the ApaI genotype was associated with reduced vitamin D deficiency.
    Gene. 01/2014;
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    ABSTRACT: The powder and alcoholic extract of dried seeds of garden cress were investigated for their effect on metabolic activity of CYP2D6 and CYP3A4 enzymes. In vitro and clinical studies were conducted on human liver microsomes and healthy human subjects, respectively. Dextromethorphan was used as a common marker for measuring metabolic activity of CYP2D6 and CYP3A4 enzymes. In in vitro studies, microsomes were incubated with NADPH in presence and absence of different concentrations of seeds extract. Clinical investigations were performed in two phases. In phase I, six healthy female volunteers were administered a single dose of dextromethorphan and in phase II volunteers were treated with seeds powder for seven days and dextromethorphan was administered with last dose. The O-demethylated and N-demethylated metabolites of dextromethorphan were measured as dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Observations suggested that garden cress inhibits the formation of DOR and 3-MM metabolites. This inhibition of metabolite level was attributed to the inhibition of CYP2D6 and CYP3A4 activity. Garden cress decreases the level of DOR and 3-MM in urine and significantly increases the urinary metabolic ratio of DEX/DOR and DEX/3-MM. The findings suggested that garden cress seeds powder and ethanolic extract have the potential to interact with CYP2D6 and CYP3A4 substrates.
    Evidence-based Complementary and Alternative Medicine 01/2014; 2014:634592. · 1.72 Impact Factor
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    ABSTRACT: Present study investigated the potential effects of Ferula asafetida resin on metabolic activities of human drug metabolizing enzymes: CYP2D6 and CYP3A4. Dextromethorphan (DEX) was used as a marker to assess metabolic activities of these enzymes, based on its CYP2D6 and CYP3A4 mediated metabolism to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. In vitro study was conducted by incubating DEX with human liver microsomes and NADPH in presence or absence of Asafetida alcoholic extract. For clinical study, healthy human volunteers received a single dose of DEX alone (phase-I) and repeated the same dose after a washout period and four-day Asafetida treatment (phase-II). Asafetida showed a concentration dependent inhibition on DOR formation (in vitro) and a 33% increase in DEX/DOR urinary metabolic ratio in clinical study. For CYP3A4, formation of 3-MM in microsomes was increased at low Asafetida concentrations (10, 25, and 50 μg/ml) but slightly inhibited at the concentration of 100 μg/ml. On the other hand, in vivo observations revealed that Asafetida significantly increased DEX/3-MM urinary metabolic ratio. The findings of this study suggest that Asafetida may have significant effect on CYP3A4 metabolic activity. Therefore, using Ferula asafetida with CYP3A4 drug substrates should be cautioned especially those with narrow therapeutic index such as cyclosporine, tacrolimus and carbamazepine.
    Saudi Pharmaceutical Journal 01/2014; · 0.95 Impact Factor
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    ABSTRACT: To explore the mechanisms underlying the suggested role of the vitamin D/vitamin D receptor (VDR) complex in the pathogenesis of obesity we performed genetic and immunologic analyses in obese and non-obese Saudi individuals without other concomitant chronic diseases. Genomic DNA was genotyped for gene single nucleotide polymorphisms (SNPs) of VDR by allelic discrimination in 402 obese (body mass index -BMI≥30 kg/m2) and 489 non-obese (BMI<30 kg/m2) Saudis. Q-PCR analyses were performed using an ABI Prism 7000 Sequence Detection System. The inflammosome pathway was analysed by PCR, cytokines and plasma lipopolysaccaride (LPS) concentrations with ELISA assays. Results showed that the VDR SNPs rs731236 (G) (TaqI) and rs1544410 (T) (Bsm-I) minor allele polymorphisms are significantly more frequent in obese individuals (p = 0.009, β = 0.086 and p = 0.028, β = 0.072, respectively). VDR haplotypes identified are positively (GTA) (p = 0.008, β = 1.560); or negatively (ACC) (p = 0.044, β = 0.766) associated with obesity and higher BMI scores. The GTA "risk" haplotype was characterized by an up-regulation of inflammosome components, a higher production of proinflammatory cytokines (p<0.05) and a lower VDR expression. Plasma LPS concentration was also increased in GTA obese individuals (p<0.05), suggesting an alteration of gut permeability leading to microbial translocation. Data herein indicate that polymorphisms affecting the vitamin D/VDR axis play a role in obesity that is associated with an ongoing degree of inflammation, possibly resulting from alterations of gut permeability and microbial translocation. These results could help the definition of VDR fingerprints that predict an increased risk of developing obesity and might contribute to the identification of novel therapeutic strategies for this metabolic condition.
    PLoS ONE 01/2014; 9(7):e102141. · 3.53 Impact Factor

Publication Stats

434 Citations
298.62 Total Impact Points

Institutions

  • 2014
    • Elsevier B.V.
      Philadelphia, Pennsylvania, United States
    • University of Southampton
      • Institute for Life Sciences (IfLS)
      Southampton, England, United Kingdom
  • 2005–2014
    • King Saud University
      • • Center of Excellence in Biotechnology Research
      • • Department of Clinical Pharmacy
      • • College of Pharmacy
      • • College of Science
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2013
    • King Saud medical city
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2012
    • University of Agriculture Faisalabad
      • Department of Chemistry and Biochemistry
      Faisalābād, Punjab, Pakistan
  • 2011–2012
    • University of Malaya
      • • Faculty of Medicine and Medical Center (UMMC)
      • • Department of Pharmacy
      Kuala Lumpur, Kuala Lumpur, Malaysia
    • Aga Khan University Hospital, Karachi
      • Department of Medicine
      Kurrachee, Sindh, Pakistan
    • University of Campinas
      • Faculty of Medical Sciences
      Conceição de Campinas, São Paulo, Brazil
  • 2010
    • National and Kapodistrian University of Athens
      • Division of Paediatrics I
      Athens, Attiki, Greece
  • 2000–2002
    • University of Pittsburgh
      • Pharmaceutical Sciences
      Pittsburgh, PA, United States