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1.  Metformin Eased Cognitive Impairment Induced by Chronic L-methionine Administration: Potential Role of Oxidative Stress 
Current Neuropharmacology  2014;12(2):186-192.
Chronic administration of L-methionine leads to memory impairment, which is attributed to increase in the level of oxidative stress in the brain. On the other hand, metformin is a commonly used antidiabetic drug with strong antioxidant properties. In the current study, we tested if chronic metformin administration prevents memory impairment induced by administration of L-methionine. In addition, a number of molecules related to the action of metformin on cognitive functions were examined. Both metformin and L-methionine were administered to animals by oral gavage. Testing of spatial learning and memory was carried out using radial arm water maze (RAWM). Additionally, hippocampal levels or activities of catalase, thiobarbituric acid reactive substances (TBARs), glutathione peroxidase (GPx), glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio were determined. Results showed that chronic L-methionine administration resulted in both short- and long- term memory impairment, whereas metformin treatment prevented such effect. Additionally, L-methionine treatment induced significant elevation in GSSG and TBARs, along with reduction in GSH/GSSG ratio and activities of catalase, and GPx. These effects were shown to be restored by metformin treatment. In conclusion, L-methionine induced memory impairment, and treatment with metformin prevented this impairment probably by normalizing oxidative stress in the hippocampus.
PMCID: PMC3964748  PMID: 24669211
Memory; learning; hippocampus; maze; oxidative stress; L-methionine; metformin.
2.  5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9-dependent and mediated by activation of protein kinase C-δ 
Oncology Letters  2014;8(2):699-704.
Elucidation of the molecular mechanisms by which 5-fluorouracil (5-FU) induces apoptosis is required in order to understand the resistance of colorectal cancer (CRC) cells to 5-FU. In the current study, 5-FU-induced apoptosis was assessed using the propidium iodide method. Involvement of protein kinase C (PKC) was assessed by evaluating the extent of their activation in CRC, following treatment with 5-FU, using biochemical inhibitors and western blot analysis. The results revealed that 5-FU induces varying degrees of apoptosis in CRC cells; HCT116 cells were identified to be the most sensitive cells and SW480 were the least sensitive. In addition, 5-FU-induced apoptosis was caspase-dependent as it appeared to be initiated by caspase-9. Furthermore, PKCɛ was marginally expressed in CRC cells and no changes were observed in the levels of cleavage or phosphorylation following treatment with 5-FU. The treatment of HCT116 cells with 5-FU increased the expression, phosphorylation and cleavage of PKCδ. The inhibition of PKCδ was found to significantly inhibit 5-FU-induced apoptosis. These results indicated that 5-FU induces apoptosis in CRC by the activation of PKCδ and caspase-9. In addition, the levels of PKCδ activation may determine the sensitivity of CRC to 5-FU.
PMCID: PMC4081407  PMID: 25013487
protein kinase C; colorectal cancer; 5-fluorouracil; apoptosis
3.  Novel N-substituted aminobenzamide scaffold derivatives targeting the dipeptidyl peptidase-IV enzyme 
The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion of meals enhance insulin release to the blood, and DPP-IV inactivates these incretins within a short period and stops their action. Inhibition of this enzyme escalates the action of incretins and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition of this enzyme will lead to better control of blood sugar levels.
In this study, computer-aided drug design was used to help establish a novel N-substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the DPP-IV enzyme. The designed compounds were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The synthesized compounds were characterized using proton and carbon nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and determination of melting point.
Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against DPP-IV than the reference compounds, with the most active compounds scoring 38% activity at 100 μM concentration.
The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds possessing the same scaffold.
PMCID: PMC3896277  PMID: 24470754
diabetes mellitus; dipeptidyl peptidase-IV; aminobenzamide derivatives; hypoglycemic activity; CDOCKER software
4.  Comparison of Coconut Water and Jordanian Propolis on Survival of Bench-dried Periodontal Ligament Cells: An in vitro Cell Culture Study 
Aim: The aim of this study is to assess and compare the efficacy of Jordanian propolis and full concentration mature coconut water in their ability to preserve periodontal ligament (PDL) cell viability after exposure of PDL cells to up to 120 minutes dry storage.
Materials and methods: PDL cells were obtained from sound permanent first molars which were cultured in Dulbecco's Modified Eagles Medium (DMEM). Cultures were subjected to 0, 30, 45, 60, 90 and 120 minutes dry storage times then incubated with 100% mature coconut water, Jordanian propolis and DMEM for 45 minutes at room temperature (18-26°C). Untreated cells served as controls at each dry storage time tested. PDL cell viability was assessed by MTT assay. Statistical analysis of data was accomplished by using one-way analysis of variance complemented by Tukey test and the level of significance was 5% ( p < 0.05).
Results: Up to 60 minutes dry storage, no significant improvement on the percentage of viable cells was found from soaking in all tested media. On the other hand, soaking in mature coconut water only resulted in higher percentages of viable cells at >60 minutes dry storage. However, this improvement was not significant (p > 0.05).
Conclusion: Avulsed teeth which have been left dry for <45 minutes should be replanted immediately, whereas avulsed teeth which have been left dry for >45 minutes may benefit from soaking for 45 minutes in mature coconut water.
How to cite this article: Al-Haj Ali SN, Al-Jundi S, Mhaidat N. Comparison of Coconut Water and Jordanian Propolis on Survival of Bench-dried Periodontal Ligament Cells: An in vitro Cell Culture Study. Int J Clin Pediatr Dent 2013;6(3):161-165.
PMCID: PMC4086597  PMID: 25206215
Avulsion; Cell culture; Mature coconut water; Propolis; Dry storage
5.  Virtual Lead Identification of Farnesyltransferase Inhibitors Based on Ligand and Structure-Based Pharmacophore Techniques 
Pharmaceuticals  2013;6(6):700-715.
Farnesyltransferase enzyme (FTase) is considered an essential enzyme in the Ras signaling pathway associated with cancer. Thus, designing inhibitors for this enzyme might lead to the discovery of compounds with effective anticancer activity. In an attempt to obtain effective FTase inhibitors, pharmacophore hypotheses were generated using structure-based and ligand-based approaches built in Discovery Studio v3.1. Knowing the presence of the zinc feature is essential for inhibitor’s binding to the active site of FTase enzyme; further customization was applied to include this feature in the generated pharmacophore hypotheses. These pharmacophore hypotheses were thoroughly validated using various procedures such as ROC analysis and ligand pharmacophore mapping. The validated pharmacophore hypotheses were used to screen 3D databases to identify possible hits. Those which were both high ranked and showed sufficient ability to bind the zinc feature in active site, were further refined by applying drug-like criteria such as Lipiniski’s “rule of five” and ADMET filters. Finally, the two candidate compounds (ZINC39323901 and ZINC01034774) were allowed to dock using CDOCKER and GOLD in the active site of FTase enzyme to optimize hit selection.
PMCID: PMC3816728  PMID: 24276257
common feature pharmacophore; structure-based pharmacophore; zinc binding group; database screening; CDOCKER; GOLD
6.  Antioxidant activity of simvastatin prevents L-arginine-induced acute toxicity of pancreas 
L-arginine is a semi-essential amino acid that found naturally in food. It has been shown that administration of large doses of L-arginine can induce acute pancreatitis. In the present study, we evaluated if simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, might prevent acute pancreatitis induced by L-arginine. Thirty male Wistar rats were randomly allocated to five groups. Groups were: DMSO, saline, simvastatin, L-arginine, and simvastatin with L-arginine. Twenty four hours after the last dose, rats were sacrificed and their blood was collected from heart for biochemical analysis. Pancreatic tissues were obtained for analysis of glutathione peroxidase (GPx), glutathione s-transferase (GST), lipid peroxide levels (MDA) and histology analysis was examined for pancreas. Results indicated that treatment with simvastatin significantly enhanced levels of GPx and GST and decreased lipid peroxide levels induced by L-arginine compared to the vehicle. Moreover, histopathological analysis further confirmed that administration of simvastatin relatively prevented pancreatic acinar cell damage compared to those animals received L-arginine alone. These findings pointed out the protective role of simvastatin against acute pancreatitis induced by high doses of L-arginine.
PMCID: PMC3669738  PMID: 23750308
L-arginine; acute pancreatitis; simvastatin; lipid peroxidation; antioxidant enzymes
7.  In vitro determination of the antibiotic susceptibility of biofilm-forming Pseudomonas aeruginosa and Staphylococcus aureus: possible role of proteolytic activity and membrane lipopolysaccharide 
We carried out a comprehensive overview of inhibitory effects of selected antibiotics on planktonic and biofilm cells of Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (ATCC 27853) strains. The possible involvement of protease activity and the lipopolysaccharide (LPS) profile of P. aeruginosa were also analyzed. Biofilm cells of both strains were more resistant to antibiotics than their planktonic counterparts. Protease activity was increased in both strains in the biofilm forms. Challenge with sublethal doses of antibiotics also increased proteolytic activity of biofilm cells. Additionally, the LPS profile of P. aeruginosa showed pattern alterations of the biofilm that can contribute to biofilm resistance and survival. These observations provide evidence for the involvement of bacterial proteolytic activity and LPS profile in the resistance of biofilm bacteria to antibiotics compared to their planktonic counterparts.
PMCID: PMC3593709  PMID: 23493936
biofilm; Pseudomonas aeruginosa; Staphylococcus aureus; proteolytic activity; lipopolysaccharide
8.  Effect of statin therapy on vaspin levels in type 2 diabetic patients 
Statins are commonly used antihyperlipidemic agents, with anti-inflammatory and immunomodulatory properties that are thought to account for a significant portion of their ability to protect against atherosclerosis and cardiovascular disease. Vaspin, a visceral adipose tissue-derived serine protease inhibitor, is an emerging adipokine with important insulin-sensitizing, cardioprotective, and antiatherosclerotic properties in patients with diabetes. In this randomized controlled clinical trial, we evaluated the effect of statin therapy on vaspin levels in patients with type 2 diabetes mellitus.
Patients were divided into two groups, ie, those receiving simvastatin (study group, n = 33), and those who did not (control group, n = 29). Patient data, blood biochemistry, and vaspin levels were recorded at the beginning of the study (baseline) and after 8 weeks (end of the study).
After 8 weeks of treatment, vaspin levels were increased in patients treated with simvastatin (504.58 ± 203.07 pg/mL at baseline versus 629.15 ± 68.39 pg/mL after 8 weeks, P < 0.01), but not in patients who were not treated with simvastatin (613.33 ± 357.53 pg/mL at baseline versus 582.37 ± 84.63 pg/mL after 8 weeks, P > 0.05). In addition, the lipid-lowering effect of simvastatin was reflected in a statistically significant reduction in total cholesterol in the study group (220.75 ± 55.66 mg/dL at baseline versus 201.90 ± 53.65 mg/dL after 8 weeks P < 0.01) but not in the control group (214.24 ± 47.2 mg/dL at baseline versus 215.72 ± 43.65 mg/dL after 8 weeks, P > 0.05) and in a statistically significant reduction in triglyceride levels in the study group (265.8 ± 210.41 mg/dL at baseline versus 223.03 ± 178.67 mg/dL after 8 weeks, P < 0.05) but not in the control group (225.44 ± 115.13 mg/dL at baseline versus 215.58 ± 110.2 mg/dL after 8 weeks, P > 0.05). Mean vaspin levels were significantly higher in the study group than in the control group.
These results indicate that statin therapy increases plasma vaspin levels in addition to having a lipid-lowering effect. This could be a mechanism underlying the pleiotropic effects seen with statins, including their cardioprotective and antiatherosclerotic effects.
PMCID: PMC3581289  PMID: 23449848
vaspin; statins; diabetes; adipokines
9.  Antibacterial activity of statins: a comparative study of Atorvastatin, Simvastatin, and Rosuvastatin 
Statins have several effects beyond their well-known antihyperlipidemic activity, which include immunomodulatory, antioxidative and anticoagulant effects. In this study, we have tested the possible antimicrobial activity of statins against a range of standard bacterial strains and bacterial clinical isolates.
Minimum inhibitory concentrations (MIC) values were evaluated and compared among three members of the statins drug (atorvastatin, simvastatin, and rosuvastatin).
It was revealed that statins are able to induce variable degrees of antibacterial activity with atorvastatin, and simvastatin being the more potent than rosuvastatin. Methicillin-sensitive staphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococcus (VRE), acinetobacter baumannii, staphylococcus epidermidis, and enterobacter aerogenes, were more sensitive to both atorvastatin, and simvastatin compared to rosuvastatin. On the other hand, escherichia coli, proteus mirabilis, and enterobacter cloacae were more sensitive to atorvastatin compared to both simvastatin and rosuvastatin. Furthermore, most clinical isolates were less sensitive to statins compared to their corresponding standard strains.
Our findings might raise the possibility of a potentially important antibacterial class effect for statins especially, atorvastatin and simvastatin.
PMCID: PMC3408379  PMID: 22564676
Antimicrobial activity; Statins; Atorvastatin; Simvastatin; Rosuvastatin
10.  Magnetic nanoparticles sensitize MCF-7 breast cancer cells to doxorubicin-induced apoptosis 
Resistance of breast cancer cells to the available chemotherapeutics is a major obstacle to successful treatment. Recent studies have shown that magnetic nanoparticles might have significant application in different medical fields including cancer treatment. The goal of this study is to verify the ability of magnetic nanoparticles to sensitize cancer cells to the clinically available chemotherapy.
The role of iron oxide nanoparticles, static magnetic field, or a combination in the enhancement of the apoptotic potential of doxorubicin against the resistant breast cancer cells, MCF-7 was evaluated using the MTT assay and the propidium iodide method.
In the present study, results revealed that pre-incubation of MCF-7 cells with iron oxide nanoparticles before the addition of doxorubicin did not enhance doxorubicin-induced growth inhibition. Pre-incubation of MCF-7 cells with iron oxide nanoparticles followed by a static magnetic field exposure significantly (P < 0.05) increased doxorubicin-induced cytotoxicity. Sensitization with pre-exposure to the magnetic field was dose-dependent where the highest cytotoxicity was seen at 1 tesla. Further experiments revealed that the anti-proliferative effect of this treatment procedure is due to induction of apoptotic cell death.
These results might point to the importance of combining magnetic nanoparticles with a static magnetic field in treatment of doxorubicin-refractory breast cancer cells.
PMCID: PMC3407771  PMID: 22533492
Nanoparticles; MCF-7; Doxorubicin; Breast cancer
11.  Investigation of the antibacterial activity of pioglitazone 
To evaluate the antibacterial potential of pioglitazone, a member of the thiazolidinediones class of drugs, against Gram-positive (Streptococcus pneumoniae) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria.
Susceptibility testing was done using the antibiotic disk diffusion method and the minimal inhibitory concentration (MIC) of pioglitazone was measured according to the broth micro incubation standard method.
Pioglitazone induced a dose-dependent antibacterial activity in which the optimal concentration was 80 μM. Furthermore, results indicated that while E. coli was sensitive (MIC = 31.25 ± 3.87 mg/L) to pioglitazone-induced cytotoxicity, S. pneumoniae and K. pneumoniae were resistant (MIC = 62.5 ± 3.77 mg/L and MIC = 62.5 ± 4.14 mg/L, respectively). Moreover, pretreatment of bacteria with a suboptimal concentration of pioglitazone (40 μM) before adding amoxicillin, cephalexin, co-trimoxazole, or ciprofloxacin enhanced the antibacterial activity of all agents except co-trimoxazole. This enhancing effect was particularly seen against K. pneumoniae.
These results indicate the possibility of a new and potentially important pioglitazone effect and the authors’ ongoing studies aim to illustrate the mechanism(s) by which this antibacterial effect is induced.
PMCID: PMC3210070  PMID: 22087061
pioglitazone; susceptibility testing; antibiotics; diabetes
12.  Multi-drug resistance 1 genetic polymorphism and prediction of chemotherapy response in Hodgkin's Lymphoma 
The human multi-drug resistance gene (MDR1), which encodes the major trans-membrane transporter P-glycoprotein (P-gp), was found to be associated with susceptibility to cancer and response to chemotherapy. The C3435T Polymorphism of MDR1 gene was correlated with expression levels and functions of P-gp. Here, we studied the association between MDR1 C3435T polymorphism and susceptibility to Hodgkin lymphoma (HL) and patient's response to ABVD chemotherapy regimen.
a total of 130 paraffin embedded tissue samples collected from HL patients were analyzed to identify the C3435T polymorphism. As a control group, 120 healthy subjects were enrolled in the study. The C3435T Polymorphism was genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism.
these studies revealed that the frequency of T allele was significantly higher in HL patients compared to the controls (P < 0.05). In addition, the frequency of CT and TT genotypes were also significantly higher in HL patients compared to the controls (P < 0.05). No association between C3435T polymorphism and response to ABVD was detected among HL patients (P > 0.05).
these results suggest that MDR1 C3435T polymorphism might play a role in HL occurrence; however this polymorphism is not correlated with the clinical response to ABVD.
PMCID: PMC3154152  PMID: 21762523
Lymphoma; C3435T SNP; MDR-1
13.  Prevalence of migraine and tension-type headache among adults in Jordan 
The Journal of Headache and Pain  2009;10(4):265-270.
Here, we investigated the prevalence of headache among adults in Jordan. The study was conducted from January 2007 to November 2008. A sample of 4,836 participants were permitted to complete a self-conducted screening questionnaire. As much as 82.3% of participants complained from headache at least once per year. 36.1% were tension-type headache and 59% of the participants had other family members who suffered from headache. Headaches affected everyday activities in 51.6% of the participants; 82.7% of participants did not seek medical attention for their headaches. Among those who used analgesics (75.6%), acetaminophen was the most common (91.43%). In conclusion, headache and overuse of analgesics were prevalent in a significant part of the society. Thus, there is a need to educate the public to ensure safe practices and to make the use and selling of analgesics more stringent.
PMCID: PMC3451745  PMID: 19387792
Headache; Prevalence; Analgesics; Self-medication; Jordan

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