Khalid M Alkharfy

King Saud University, Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia

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Publications (150)340.22 Total impact

  • Khalid M Alkharfy · Mukhtar Ahmed · Sobhy M Yakout · Nasser M Al-Daghri ·
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    ABSTRACT: Thisaim of the studyisto investigate the effects of calcitriol (vitamin D) on mouse kidneys under obese conditions. Male C57BL/6J mice were maintained on either low fat diet (LFD) or high fat diet (HFD) with/without calcitriol treatment (150 IU/kg/day) for 16 consecutive weeks. Results of HFD fed mice demonstrated more weight gain and showed numerous structural abnormalities in the corticomedullary region compared to those under control and LFD conditions. Near nephropathy condition in HFD mice were characterized by damage in renal tubules, including dilatation of interstitial cells and blood vessels. Furthermore, exfoliation and shedding of proximal tubular cells takes place. The conditions further worsen by thickening the basement membrane and interstitial inflammation, as evidenced by abundant interstitial debris. Additionally, a large number of degenerated mitochondria, fat droplets, lysosomal bodies' mesangial expansion, and cellular debris were found throughout the kidney. Sustained cell hypertrophy was also evident by transmission electron microscope confirming a marked increase in degeneration of cells within renal areas. No significant variances were detected in the glomerulus' area and diameter in both low and high fat diets with/without calcitriol treatment as well as inner and outer diameters of both distal and proximal tubule in all groups. Evidently, calcitriolcould act as a protective agent to normalize kidney structure in obese condition. This study suggests that calcitriol could normalize the function of kidney and protect its structural integrity in obesity.
    International Journal of Clinical and Experimental Medicine 11/2015; 8(8):12390-6. · 1.28 Impact Factor
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    Farooq Anwar · Naveed Ahmad · Khalid M. Alkharfy · Anwar-ul-Hassan Gilani ·

    Essential Oils in Food Preservation, Flavor and Safety, First edited by Preedy, V.R., 11/2015: chapter Mugwort (Artemisia vulgaris) Oils: pages 573-579; Elsevier Inc., ISBN: 9780124166417
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    ABSTRACT: Glibenclamide and thymoquinone plasma concentrations were analysed using a sensitive RP-HPLC method, and non-compartmental model pharmacokinetic parameters were calculated. The maximum reduction in blood glucose level was observed 3 hours following glibenclamide administration, which reached 47.4% of baseline, whereas it was reduced by 53.0% to 56.2% when co-administrated with thymoquinone. Plasma concentration of glibenclamide was increased by 13.4% and 21.8% by the co-administration of thymoquinone as single and multiple doses, respectively (P<0.05). The AUC and TI/2 of glibenclamide were also increased respectively by 32.0% and 17.4% with a thymoquinone single dose, and by 52.5% and 92.8% after chronic treatment. Furthermore, diabetic rats treated with thymoquinone demonstrated a marked decrease in hepatic protein expressions of CYP3A2 and CYP2C 11 enzymes that are responsible for the metabolism of glibenclamide. The current data suggest that thymoquinone exhibits a synergistic effect with glibenclamide on glucose level, which could be explained by reducing CYP450 activity at the protein level.
    Natural product communications 10/2015; 10(8):1395-8. · 0.91 Impact Factor
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    ABSTRACT: The present study investigated the effect of fenugreek seeds powder and its alcoholic extract on metabolic activity of drug-metabolizing enzymes CYP2D6 and CYP3A4. Dextromethorphan (DEX) was used as a probe for measuring metabolic activity, based on its CYP2D6- and CYP3A4-mediated metabolism to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. For the in vitro investigations, DEX (25µM) was incubated with human liver microsomes and NADPH and tested with and without the fenugreek extract. For the in vivo study, phase I, 6 subjects received a single dose of DEX (30 mg); in phase II, after washout period, the fenugreek seeds powder was administered for 1 week and DEX was administered with its last dose. In vitro, fenugreek extract inhibits CYP2D6-mediated O-demethylation of DEX. Higher concentrations (50 and 100µg/ml) of extract inhibit CYP2D6 and CYP3A4 activity. In vivo results indicated that fenugreek does not significantly inhibit CYP2D6 and CYP3A4 metabolic activity. There was no significant change in the levels of DEX metabolites (DOR 12% and 3-MM 9%) excreted in urine and their urine metabolic ratios (P values: 0.257 and 0.333 DEX/DOR and DEX/3-MM, respectively). In vitro and in vivo observations suggested that fenugreek may not have substantial effect on the metabolic activity of CYP2D6 and CYP3A4. © 2015 S. Karger GmbH, Freiburg.
    Forschende Komplementärmedizin / Research in Complementary Medicine 09/2015; 22(3):180-4. DOI:10.1159/000432412 · 1.65 Impact Factor
  • Khalid M Alkharfy · Ajaz Ahmad · Mohammad Raish · Paul M Vanhoutte ·
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    ABSTRACT: The present investigation was designed to evaluate the effect of thymoquinone in a septic animal model and to explore the role of nitric oxide (NO) in the process. To achieve this, mice (n=12 per group) were treated in parallel with thymoquinone (0.75 mg/kg/day) and/or NG-nitro-L-arginine methyl ester (L-NAME; 400 μg/g/day) prior to sepsis induction with live Escherichia coli. Thymoquinone significantly improved renal and hepatic functions alone and in combination with L-NAME. This was associated with less NO production and lower oxidative stress in treated animals. Tumor necrosis factor-α concentration with thymoquinone and L-NAME were 36.27 ±3.41 pg/ml and 56.55 ±5.85 pg/ml, respectively, as opposed to 141.11 ±6.46 pg/ml in septic controls. Similarly, Interleukin-1α, 2, 6 and 10 levels decreased significantly upon treatment with thymoquinone and L-NAME as compared with untreated septic animals. NF-κB and NF-κB-DNA binding activity in nuclear proteins were also significantly down-regulated. Vascular responsiveness studies in isolated mouse aortae demonstrated a reduced relaxation to acetylcholine exposure in septic mice treated with thymoquinone. These findings suggest that thymoquinone prevents sequels of the multiple organ failure syndrome of sepsis by modulating the production of NO and its inflammatory sequela, and adjusting vascular responsiveness. Copyright © 2015. Published by Elsevier Inc.
    Life sciences 08/2015; 143. DOI:10.1016/j.lfs.2015.08.007 · 2.70 Impact Factor
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    Farooq Anwar · Shamsa Kanwal · Ghulam Shabir · Khalid M. Alkharfy · Anwar H. Gilani ·
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    ABSTRACT: The current study appraises the antioxidant and antimicrobial activities of the leave extracts from four different species of Mulberry (Morus nigra L., Morus alba L., Morus macroura Miq. and Morus laevigata W.). In addition to estimation of total phenolic and total flavonoids contents, the antioxidant activity of the extracts was evaluated by measuring the reducing power, inhibition of linoleic acid peroxidation and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity. The yield of the extractable components from leaves ranged from 4.41-14.53 g/100 g Dry Weight (DW). The tested leave extracts exhibited widely variable amounts of total phenolics (3.14 to 11.38 g GAE/100g DW) and total flavonoids (0.53-5.83 g CE/100g DW). Reducing power of extracts at concentration 2.5 to 12.5 mg mLG−1 ranged from 0.40-1.52. The leave extracts considerably inhibited linoleic acid peroxidation up to the level of 60.23-88.51% and also showed remarkable DPPH radical scavenging activity with contribution 43.83-77.51%. The antioxidant and antimicrobial potential of the tested leave extracts varied considerably in relation to the species and extraction solvents employed. Overall, the aqueous-methanolic extract of Morus nigra exhibited the superior antioxidant and antimicrobial activities among others. The present results advocate that mulberry leaves are a potential candidate for isolation of antioxidant and antimicrobial agents for potential nutraceutical and pharmaceutical applications.
  • Anwarul-Hassan Gilani · Najeeb-Ur Rehman · Aslam Khan · Khalid M Alkharfy ·
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    ABSTRACT: The aqueous methanolic extract of the aerial parts of Salvia officinalis (So.Cr) was studied to provide possible underlying mechanism(s) for its medicinal use in asthma using the in vivo bronchodilatory assay and isolated tracheal preparations. S. officinalis (1-10 mg/kg) dose-dependently inhibited carbachol (CCh)-induced bronchospasm in anesthetized rats with three-fold greater potency than the positive control, aminophylline. In tracheal preparations, So.Cr inhibited the low K(+) (25 mM)-induced contractions. Pretreatment of the tissues with 4-aminopyridine reversed the inhibitory effect of the plant extract against low K(+) , whereas glibenclamide did not show any effect, thus showing the involvement of voltage-sensitive K(+) channels. When tested against the CCh-induced pre-contractions for the involvement of any additional mechanism, interestingly, the extract showed a dose-dependent (0.03-0.1 mg/mL) inhibitory effect and shifted the inhibitory concentration response curves of isoprenaline to the left, thus showing phosphodiesterase enzyme inhibitory-like action, similar to that of papaverine. These results indicate that the crude extract of S. officinalis possesses bronchodilatory activity mediated predominantly via activation of voltage-dependent K(+) channels and inhibition of phosphodiesterase enzyme; thus, this study provides sound pharmacological basis for its medicinal use in hyperactive airways disorders such as asthma and cough. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Phytotherapy Research 06/2015; 29(9). DOI:10.1002/ptr.5384 · 2.66 Impact Factor
  • W.M. Al-Shaqha · K.M. Alkharfy · N.M. Al-Daghri · A.K. Mohammed ·
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    ABSTRACT: Background and Objectives: There have been inconsistent reports on N-acetyltransferase (NAT) gene polymorphism in type 2 diabetes mellitus (T2DM), and data is particularly limited in the Arab population. Therefore, the main objective of this study was to identify whether the genetic polymorphisms of NAT1 and NAT2 play a role in susceptibility to T2DM in the Saudi population. Design and setting: A population-based, prospective genetic association case-control study on a Saudi population. Patients and Methods: Whole blood, anthropometric measurements and biochemistry data were collected from 369 Saudi individuals (186 T2DM patients and 183 healthy controls). DNA was isolated from the blood. Polymorphism of NAT1 and NAT2 SNPs [NAT2∗7B, rs1041983(C>T); NAT2∗7, rs1799931(G>A); NAT2∗6A, rs1799930(G>A); NAT2∗5A, rs1799929(C>T); and NAT1∗11A, rs4986988(C>T)] were evaluated by allelic discrimination using real-time PCR. Results: Subjects with T2DM had a significantly increased body mass index (BMI), waist circumference, systolic and diastolic blood pressure, glucose, triglycerides, and LDL-cholesterol compared with healthy controls (P<.05). The rs1799931(G>A) genotype was detected in the control population but not in the T2DM population (P<.001). The wild type (G) allele frequency was higher in T2DM than controls (P=.038). The mutant allele (A) in rs1799931(G>A) had a protective effect for T2DM (OR 0.32, 95% CI 0.16-0.62; P=.001). Regression analysis showed that BMI, systolic BP and triglycerides are potential risk factors for T2DM. Conclusion: The genotypes as well as the individual alleles of rs1799931(G>A) differed significantly between the case and control populations. The variation in the data reported so far suggest that polymorphism of the NAT gene may vary among different geographical areas. Environmental or dietary factors may also contribute to disease manifestation.
    Annals of Saudi medicine 05/2015; 35(3):214-221. DOI:10.5144/0256-4947.2015.214 · 0.49 Impact Factor
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    ABSTRACT: Commiphora myrrha (Burseraceae), a shrub resembling a small tree, has been used for several centuries for the treatment of various diseases. This study investigates the hepatoprotective activity of C. myrrha ethanol extract against d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced acute hepatic injury in an animal model. Rats were pretreated with ethanolic extract C. myrrha (250 and 500 mg/kg; p.o.) for 7 d prior to the induction of an acute phase response by d-GalN/LPS. Animals were sacrificed 24 h after d-GalN/LPS (800 mg/kg and 50 µg/kg i.p.) administration for the biochemical and histological analyses. The administration of d-GalN/LPS increased plasma aminotransferases (174.47 ± 4.5761 and 260.96 ± 1.9839 µkat/l) and total bilirubin levels (1.012 ± 0.0288 mg/dl), which were attenuated by C. myrrha treatment. Hepatic lipid peroxidation activity and nitric oxide content also increased, while the antioxidant activity measured by GSH (0.76 nmol/g protein), SOD (81.91 U/mg protein), and CAT (15.78 U/mg protein) was reduced. Commiphora myrrha provided significant restoration of GSH (0.815 nmol/gm protein), SOD (140.57 U/mg protein), and CAT (27.02 U/mg protein) levels. Furthermore, the acute phase response elicited by d-GalN/LPS administration enhanced mRNA expressions of TNF-α, IL-6, IL-10, iNOS-2, and HO-1, which were ameliorated by C. myrrha treatment. These findings indicate that C. myrrha considerably reduces the oxidative stress of d-GalN/LPS-induced hepatic injury via multiple pathways including adown regulation of inflammatory mediators and cytokines. Such a property might be sufficient to combat cellular damage caused by various conditions that resemble fulminant hepatitis and could be of a potential clinical application.
    Pharmaceutical Biology 04/2015; 53(12):1-9. DOI:10.3109/13880209.2015.1005754 · 1.24 Impact Factor
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    Ashraf · R. A. Sarfraz · F. Anwar · Shaukat Ali Shahid · K. M. Alkharfy ·
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    ABSTRACT: Ziziphus mauritiana L., is a fruit tree well known for its nutritional and medicinal benefits. The aim of the current study was to investigate the chemical composition as well as biological (antioxidant, antimicrobial, antitumor and anticancer) attributes of different solvent extracts from the leaves of Ziziphus mauritiana. It was established by colorimetric method that chloroform extract had greater amount of total phenolics (84.69 ± 0.92 μg GAE/mg of extract), while methanol extract contained higher content of total flavonoids (46.94±1.55 μg QE/mg of extract). Meanwhile, methanol extract exhibited higher DPPH free radical scavenging potential (IC50 = 0.11 mg/mL) and antimicrobial (antibacterial and antifungal) activity among others. Overall, E. coli was noted to be the most resistant microbial strain against all the tested extracts. Chloroform extract showed strongest antitumor (IC50 = 70.74μg/mL) and anticancer activity (IC50 values of 27.78 and 18.32 μg/mL against human cancer cell lines U937 and HCT-116, respectively) and significantly inhibited the viability of these cell lines.According to GC-MS analysis methyl stearate (15.59%), plamitic acid (38.55%) and α-linolenic acid (26.45%) were identified as the major components of methanol, chloroform and hexane extracts, respectively in addition to presence of several other bioactives. The results of this study conclude that Z. mauritiana leaves extract with efficient biological activities can be explored for potential uses as antioxidant, antitumor and anticancer agents for pharmaceutical industry.
    Pakistan Journal of Botany 02/2015; 47(1):367-376. · 0.82 Impact Factor
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    A. Ahmad · R.M.A. Khan · K.M. Alkharfy ·
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    ABSTRACT: A rapid, accurate, and sensitive reverse phase high-performance liquid chromatographic method was developed and validated for the simultaneous determination and quantification of glibenclamide and thymoquinone in rat plasma in the presence of internal standard (thymol). Chromatograms were developed with methanol, acetonitrile, and buffer (50:20:30, v/v/v) solvent system on a Symmetry® C18 (5 Im, 3.9 à 150 mm) column, and pH was adjusted to 4.5 with orthophosphoric acid. Mobile phase was pumped at a flow rate of 1.5 mL mina 1 with 254 nm ultraviolet (UV) detection. Validation of the method was performed in order to demonstrate its selectivity, linearity, precision, accuracy, limits of detection, and quantification (LOD and LOQ). Standard curves were linear (r2 = 0.996 and 0.999 for glibenclamide and thymoquinone) over the concentration range 0.5â€"50 Ig mLa 1. The coefficient of variation (CV) of < 6% and accurate recovery of 87.54â€"105.19% for glibenclamide and CV of <5% and accurate recovery of 86.08â€"103.19% for thymoquinone were found to be in the selected concentration range of 0.5â€"50 Ig mLa 1. The lower limits of detection and quantitation of the method were 0.109 and 0.332 Ig mLa 1 for glibenclamide and 0.119 and 0.361 Ig mLa 1 for thymoquinone, respectively. The within and between-day coefficients of variation were less than 7%. The validated method has been successfully applied to measure the plasma concentrations in a drug interaction study of glibenclamide with thymoquinone in an animal model to illustrate the scope and application of the method.
    Acta Chromatographica 02/2015; 1(-1):1-14. DOI:10.1556/AChrom.27.2015.3.3 · 0.58 Impact Factor
  • Ajaz Ahmad · Khalid M. Alkharfy · Tanveer A. Wani · Mohammad Raish ·
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    ABSTRACT: The objective of the present work was to study the ultrasonic assisted extraction and optimization of polysaccharides from Paeonia emodi and evaluation of its anti-inflammatory response. Specifically, the optimization of polysaccharides was carried out using Box-Behnken statistical experimental design. Response surface methodology (RSM) of three factors (extraction temperature, extraction time and liquid solid ratio) was employed to optimize the percentage yield of the polysaccharides. The experimental data were fitted to quadratic response surface models using multiple regression analysis with high coefficient of determination value (R) of 0.9906. The highest polysaccharide yield (8.69%) as per the Derringer's desirability prediction tool was obtained under the optimal extraction condition (extraction temperature 47.03°C, extraction time 15.68min, and liquid solid ratio 1.29ml/g) with a desirability value of 0.98. These optimized values of tested parameters were validated under similar conditions (n=6), an average of 8.13±2.08% of polysaccharide yield was obtained in an optimized extraction conditions with 93.55% validity. The anti-inflammatory effect of polysaccharides of P. emodi were studied on carrageenan induced paw edema. In vivo results showed that the P. emodi 200mg/kg of polysaccharide extract exhibited strong potential against inflammatory response induced by 1% suspension of carrageenean in normal saline. Copyright © 2014 Elsevier B.V. All rights reserved.
    International Journal of Biological Macromolecules 01/2015; 72:990–997. DOI:10.1016/j.ijbiomac.2014.10.011 · 2.86 Impact Factor
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    ABSTRACT: GAIP interacting protein C terminus (GIPC) is known to play an important role in a variety of physiological and disease states. In the present study, we have identified a novel role for GIPC as a master regulator of autophagy and the exocytotic pathways in cancer. We show that depletion of GIPC-induced autophagy in pancreatic cancer cells, as evident from the upregulation of the autophagy marker LC3II. We further report that GIPC regulates cellular trafficking pathways by modulating the secretion, biogenesis, and molecular composition of exosomes. We also identified the involvement of GIPC on metabolic stress pathways regulating autophagy and microvesicular shedding, and observed that GIPC status determines the loading of cellular cargo in the exosome. Furthermore, we have shown the overexpression of the drug resistance gene ABCG2 in exosomes from GIPC-depleted pancreatic cancer cells. We also demonstrated that depletion of GIPC from cancer cells sensitized them to gemcitabine treatment, an avenue that can be explored as a potential therapeutic strategy to overcome drug resistance in cancer.
    PLoS ONE 12/2014; 9(12):e114409. DOI:10.1371/journal.pone.0114409 · 3.23 Impact Factor
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    ABSTRACT: The present study reports the antioxidant and antimutaganic potential of the aqueous (30 and 70%) and acidified (0.5 and 1 N) methanolic extracts from seeds and pods of green cardamom (Elettaria cardamomum). The Total Phenolic Compmmds (TPC) of extracts were determined by Follin-Ciocalteu reagent. Antioxidant activity of the extracts produced was evaluated by the measurements of 2, 2,-diphenyl-1- picrylhydrazyl (DPPH) radical scavenging activity and percentage inhibition of linoleic acid peroxidation method, whereas mutagenic and antimutagenic activities were assessed using Ames bacterial test. The TPC, scavenging of DPPH0 and inhibition of linoleic acid were fmmd to be 27.75-126.35 mg gallic acid equivalent g-1 DW, 46-91% at 5 mg L-1 of extract concentration and 34-83%, respectively. Furthermore, the extracts of seeds and pods of green cardamom showed strong antimutagenic potential against mutant strains S. typhimurium TA98 and S. typhimurium TAl 00 while none of the extract showed mutagenicity. The results of this study support that the extracts from cardamom seeds and pods can be explored as potential chemotherapeutic agents against cancer as well as for the pharmaceutical and nutraceutical applications.
    International Journal of Pharmacology 11/2014; 10(8):461-469. DOI:10.3923/ijp.2014.461.469 · 0.71 Impact Factor
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    ABSTRACT: The aim of current study was to investigate the effect of some commonly used medicinal herbs on the regulation of rat CYP2D gene expression and its metabolic activity. Wistar albino rats were treated for seven consecutive days with selected doses of five commonly used herbs (Trigonella foenum-graecum, Ferula asafoetida, Nigella sativa, Commiphora myrrha and Lepidium sativum). Thereafter, rat livers were harvested and CYP2D mRNA levels were determined by RT-PCR. The metabolic activity of CYP2D was performed on rat hepatic microsomes using dextromethorphan as specific substrate. All investigated herbs produced inhibition of CYP2D mRNA expression and metabolic activity. The inhibitory potential of investigated herbs on rat CYP2D mRNA was in the following order: Commiphora myrrha > Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Ferula asafoetida. Whereas, the inhibitory potential of investigated herbs on CYP2D mediated enzyme metabolic activity was found in following order: Nigella sativa ≥ Lepidium sativum > Trigonella foenum-graecum > Commiphora myrrha > Ferula asafoetida. The current study shows that only used herbs reduce CYP2D activity in rat liver microsomes at the transcriptional levels. Such effects could lead to undesirable pharmacological effects of clinically used low therapeutic index CYP2D substrate drugs.
    Pharmazie 11/2014; 69(11). DOI:10.1691/ph.2014.4651 · 1.05 Impact Factor
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    ABSTRACT: Context: Herb–drug interactions are a serious problem especially for drugs with a narrow therapeutic index, taking into consideration that herbal medicines are commonly used in various parts of the world. Objective: The present study investigates the effect of fenugreek, garden cress, and black seed on the pharmacokinetics of theophylline in beagle dogs. Materials and methods: Beagle dogs received theophylline (200 mg) orally and blood samples were withdrawn at different time intervals (0.33, 0.66, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24, and 30 h). After a suitable washout period, each herb was given orally at doses of 25, 7.5, and 2.5 g, twice daily for 7 d. On the eighth day, theophylline was re-administrated orally and blood samples were collected. Plasma concentrations of theophylline were determined using HPLC and pharmacokinetic parameters were calculated using a non-compartmental analysis. Results: Treatment with fenugreek (25 g, orally) lead to a decrease in Cmax and AUC0–t of theophylline of about 28% (p < 0.05) and 22% (p < 0.05), respectively, with no significant changes in T1/2λ compared with the baseline values. Garden cress caused a decrease in Cmax to a lesser extent and delayed Tmax of theophylline (2.10 ± 0.24 h versus 3.40 ± 0.74 h), while AUC0–∞ increased by 37.44%. No significant effect was observed for the black seed treatment on theophylline disposition as measured by Cmax, Tmax, AUC0–∞, and CL/F. Discussion and conclusion: The concurrent use of fenugreek or garden cress alters theophylline pharmacokinetic behavior in an animal model. This could represent a modulation in cytochrome P450 activity, which is responsible for theophylline metabolism in beagle dogs. Further confirmation of these results in humans will warrant changes in theophylline dosing before the co-administration of such herbs.
    Pharmaceutical Biology 09/2014; 53(2). DOI:10.3109/13880209.2014.916312 · 1.24 Impact Factor
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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(10). DOI:10.1158/1535-7163.MCT-14-0291 · 5.68 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.
    08/2014; 65(7). DOI:10.1055/s-0034-1384604
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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; 13(11). DOI:10.1021/pr5003406 · 4.25 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 07/2014; 9(7):e102141. DOI:10.1371/journal.pone.0102141 · 3.23 Impact Factor

Publication Stats

1k Citations
340.22 Total Impact Points


  • 2006-2015
    • King Saud University
      • • College of Science
      • • Department of Biochemistry
      • • Department of Clinical Pharmacy
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2013
    • University of Southampton
      • Centre for Biological Sciences
      Southampton, England, United Kingdom
    • The University of Warwick
      • Division of Metabolic and Vascular Health
      Coventry, England, United Kingdom
  • 2000-2002
    • University of Pittsburgh
      • Pharmaceutical Sciences
      Pittsburgh, Pennsylvania, United States