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1.  PhiC31/PiggyBac modified stromal stem cells: effect of interferon γ and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma 
Molecular Cancer  2014;13(1):255.
TRAIL and IFNγ are promising anti-cancer cytokines and it has been shown that IFNγ may sensitize cancer cells to TRAIL. Adipose derived mesenchymal stem cells (ADSCs) are attractive vehicles for delivering anti-cancer agents. In this study, we evaluated the therapeutic potential of PhiC31 (φC31) recombinase and/or piggyBac transposase (pBt) modified ADSCs expressing either TRAIL, IFNγ, or co-expressing TRAIL/IFNγ in mouse models of melanoma.
The expression and bioactivity of mouse IFNγ and TRAIL in φC31 and pBt modified cells were confirmed. We examined the effects of modified ADSCs on signal intensity of red fluorescence protein expressed by melanoma cells in subcutaneous tumors or established lung metastases and on survival (6 mice per group). We also conducted a flow cytometric analysis of systemic CD4+CD25+FOXP3+ T regulatory cells (Tregs) and histological analysis of melanoma tumors. Data were analyzed by Student t test, ANOVA, and log-rank tests. All statistical tests were two-sided.
We demonstrated non-viral DNA-integrating vectors can be used for stable transgene expression. IFNγ inhibited melanoma cell growth in vitro probably via IFNγ-induced JAK/STAT1 signaling pathway activation. Murine TRAIL induced apoptosis in the human cell lines CAOV-4 and Ej-138, while MCF7 and B16F10 cells appeared to be insensitive to TRAIL. Treatment of melanoma cells with IFNγ did not influence their response to TRAIL. In contrast, results from in vivo studies showed that IFNγ-expressing ADSCs, engrafted into tumor stroma, inhibited tumor growth and angiogenesis, prevented systemic increase of Tregs, increased PD-L1 expression and CD8+ infiltration (but not interleukin-2+ cells), and prolonged the survival of mice (68 days, 95% confidence interval [CI] =52 to 86 days compared to 36 days, 95% CI =29 to 39 days for control, P < .001).
For the first time, we employed DNA integrating vectors for safe and stable modification of MSCs. Our data indicate potential of non-virally modified IFNγ-expressing ADSCs for treatment of melanoma through direct effects of IFNγ. This study may have a significant role in the management of cancer in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-255) contains supplementary material, which is available to authorized users.
PMCID: PMC4258801  PMID: 25428727
PhiC31 integrase; PiggyBac transposase; Adipose derived mesenchymal stem cell; Interferon γ; TRAIL; Murine melanoma
2.  Genetic Diversity of Echinococcus granulosus in Center of Iran 
Hydatid cyst caused by Echinococcus granulosus is one of the most important parasitic diseases around the world and many countries in Asia, including Iran, are involved with this infection. This disease can cause high mortality in humans as well as economic losses in livestock. To date, several molecular methods have been used to determine the genetic diversity of E. granulosus. So far, identification of E. granulosus using real-time PCR fluorescence-based quantitative assays has not been studied worldwide, also in Iran. Therefore, the aim of this study was to investigate the genetic diversity of E. granulosus from center of Iran using real-time PCR method. A total of 71 hydatid cysts were collected from infected sheep, goat, and cattle slaughtered in Isfahan, Iran during 2013. DNA was extracted from protoscolices and/or germinal layers from each individual cyst and used as template to amplify the mitochondrial cytochrome c oxidase subunit 1 gene (cox1) (420 bp). Five cattle isolates out of 71 isolates were sterile and excluded from further investigation. Overall, of 66 isolates, partial sequences of the cox1 gene of E. granulosus indicated the presence of genotypes G1 in 49 isolates (74.2%), G3 in 15 isolates (22.7%), and G6 in 2 isolates (3.0%) in infected intermediate hosts. Sixteen sequences of G1 genotype had microgenetic variants, and they were compared to the original sequence of cox1. However, isolates identified as G3 and G6 genotypes were completely consistent with original sequences. G1 genotype in livestock was the dominant genotype in Isfahan region, Iran.
PMCID: PMC4170037  PMID: 25246720
Echinococcus granulosus; cox1 gene; genotyping
3.  Insulin and leptin levels in overweight and normal-weight Iranian adolescents: The CASPIAN-III study 
In this study, we aim to compare insulin and leptin levels in adolescents with or without excess weight and in those with or without abdominal obesity.
Materials and Methods:
This case-control study was conducted among 486 samples. We randomly selected 243 overweight and an equal number of normal-weight adolescents from among participants of the third survey of a national surveillance program entitled Childhood and Adolescence Surveillance and PreventIon of Adult Non-communicable diseases study. Serum insulin and leptin were compared between two groups and their correlation was determined with other variables.
The mean age and body mass index (BMI) of participants were 14.10 ± 2.82 years and 22.12 ± 6.49 kg/m2, respectively. Leptin and insulin levels were higher in overweight than in normal-weight adolescents (P < 0.05). Leptin level was higher in children with abdominal obesity than in their other counterparts (P < 0.001). Leptin level was correlated with age, fasting blood glucose, BMI, and insulin level.
Insulin and leptin levels were higher among overweight and obese children, which may reflect insulin and leptin-resistance. Given the complications of excess weight from early life, prevention and controlling childhood obesity should be considered as a health priority.
PMCID: PMC4116567  PMID: 25097618
Children; insulin; leptin; obesity; overweight
4.  Prognostic value of the high-mobility group box-1 in young patients with chest pain 
ARYA Atherosclerosis  2014;10(3):154-158.
Atherosclerosis is accepted as an inflammatory disease. Evidence suggests that inflammation evoked by injury plays a pathogenic role in all stages of atherosclerosis. This study aimed to investigate whether the high-mobility group box-1 (HMGB1) a proinflammatory cytokine/nuclear protein, which is derived from both injured endothelium and activated macrophages/monocytes, could contribute to the progression of atherosclerosis and other cardiovascular diseases.
This study was designed as case-control. A total of 135 patients who referred to the hospital due to angina pectoris had the diagnosis of unstable angina and were candidates of angiography were recruited in this study. Forty patients who had coronary artery disease confirmed by angiography were considered as case group and control group consists of 40 persons who had no plaque, and 55 persons were excluded according to the exclusion criteria. At first, a questionnaire was filled for each patient including demographic factors and their medical history. Then a blood sample was taken to assess the level of HMGB1. Data were analyzed using SPSS, Student’s independent t-test, and chi-square tests.
The mean plasma level of HMGB1 in the case group was 27.1 ± 2.9 ng/ml, while it was 19.6 ± 1.9 ng/ml in control groups (P = 0.03). The odds ratio for coronary artery plaque associated with high (> 15.03 ng/ml) levels of HMGB1 was 2.50 (95% confidence interval, 1.02-6.17, P = 0.03).
Increased plasma HMGB1 concentration may be associated with an increased risk of coronary atherosclerosis.
PMCID: PMC4144380  PMID: 25161686
High-Mobility Group Box-1; Coronary Artery Diseases; Inflammation; Biomarkers
5.  EphB4 Tyrosine Kinase Stimulation Inhibits Growth of MDA-MB-231 Breast Cancer Cells in a Dose and Time Dependent Manner 
Disease Markers  2013;35(6):933-938.
Background. EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc. Methods. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence. Results. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel. Conclusion. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.
PMCID: PMC3884623  PMID: 24427781
6.  Relationship between Vitamin D Receptor Gene Polymorphisms and Migraine without Aura in an Iranian Population 
BioMed Research International  2013;2013:351942.
Background. Inflammation has a key role in migraine pathophysiology. Vitamin D is an effective anti-inflammatory agent. The aim of this study was to investigate the association between migraine and two vitamin D receptor (VDR) polymorphisms (TaqI and FokI) and also the relationship between VDR polymorphisms and headache severity. Methods. In this case-control study we assessed 103 patients with newly diagnosed migraine without aura and 100 healthy subjects. Patients filled headache impact test-6 (HIT-6) as a tool to assess headache severity. Results. Genotype frequencies of VDR were significantly different between control and migraine patients. Heterozygote genotypes (Ff and Tt) were statistically more frequent in the migraine patients than the control subjects both for TaqI gene (P = 0.018; OR = 1.81, 95% CI = 1.03–3.18) and FokI gene polymorphisms (P = 0.001; OR = 2.91, 95% CI = 1.47–5.77). Also f and t alleles were more frequent in the migraine patients. Total HIT-6 score was significantly different between FokI heterozygote and homozygote patients (60.32 ± 1.87 versus 49.87 ± 2.69, resp., P = 0.004). Conclusions. In conclusion our results showed that TaqI and FokI gene polymorphisms are associated with migraine without aura in Iranians patients. Also headache severity in FokI heterozygote patients was significantly greater than in the homozygote patients.
PMCID: PMC3741896  PMID: 23984350
7.  The Effect of Preoperative Melatonin on Nuclear Erythroid 2-Related Factor 2 Activation in Patients Undergoing Coronary Artery Bypass Grafting Surgery 
During and after coronary artery bypass grafting (CABG), oxidative stress occurs. Finding an effective way to improve antioxidant response is important in CABG surgery. It has been shown that patients with coronary heart disease have a low Melatonin production rate. The present study aimed to investigate the effects of Melatoninon nuclear erythroid 2-related factor 2(Nrf2) activity in patients undergoing CABG surgery. Thirty volunteers undergoing CABG were randomized to receive 10 mg oral Melatonin (Melatonin group, n = 15) or placebo (placebo group, n = 15) before sleeping for 1 month before surgery. The activated Nrf2 was measured twice by DNA-based ELISA method in the nuclear extract of peripheral blood mononuclear cells of patients before aortic clumps and 45 minutes after CABG operation. Melatonin administration was associated with a significant increase in both plasma levels of Melatonin and Nrf2 concentration in Melatonin group compared to placebo group, respectively (15.2 ± 4.6 pmol/L, 0.28 ± 0.01 versus 1.1 ± 0.59 pmol/L, 0.20 ± 0.07, P < 0.05). The findings of the present study provide preliminary data suggesting that Melatonin may play a significant role in the potentiation of the antioxidant defense and attenuate cellular damages resulting from CABG surgery via theNrf2 pathway.
PMCID: PMC3649755  PMID: 23691266
8.  Chronic Kidney Disease Stages 3-5 in Iranian Children: Need for a School-based Screening Strategy: The CASPIAN-III Study 
There is scarce epidemiological data on early and asymptomatic stages of chronic kidney disease (CKD) in children, especially from developing countries. In this study, we investigated the frequency of CKD stages 3-5 among general students of Isfahan (a large province of Iran), and compared the findings with those derived from the main pediatric nephrology referral center of province.
This study was performed among 712 Isfahani school students (377 boys) aged 7-18 years, as part of the baseline survey of a national surveillance system. Blood samples were analyzed for blood urea nitrogen, creatinine, and cystatin C. Glomerular filtration rate (GFR) was calculated based on two 2009 Schwartz equations (the “updated” and the “new” equations). CKD was defined as GFR <60 ml/min/1.73 m2. Additionally, a retrospective analysis of clinical records of children with stages 3-5 CKD referred to main referral center of province from November 2001 to December 2011 was made.
The mean age of students was 12.2 ± 2.4 years. In students’ screening, the frequency of CKD was 1.3% and 1.7% based on the updated Schwartz and the new Schwartz equation, respectively. The referral center survey revealed an annual incidence of 14.5 per million age-related population (pmarp), and a prevalence of 118.8 pmarp in our province.
The prevalence of asymptomatic and undetected low GFR in Iranian children is higher than what is reflected from the reports of referral centers. Simple screening programs like annual urinalysis among high-risk school students should be considered.
PMCID: PMC3570918  PMID: 23413177
Children; chronic kidney disease; cystatin C; epidemiology; Iran
9.  Parental perceptions of weight status of their children 
ARYA Atherosclerosis  2013;9(1):61-69.
Understanding the knowledge, attitudes, and beliefs of parents is important for planning appropriately to control their children’s weight. We aimed to study these variables in parents of normal, underweight, overweight, and obese children.
This cross-sectional study targeted the parents of normal, underweight, overweight, and obese children, who were selected using multistage random sampling method. The parents’ knowledge, attitudes, beliefs, and behaviors about the weight status of their children, weight management, obesity, diet, lifestyle, and related psychosocial factors were evaluated using a validated questionnaire. The questionnaire, which had been validated, consisted of 12 demographic, 8 knowledge, 19 attitude and beliefs, and 25 behavior questions. Mean knowledge, attitude and beliefs, and behavior scores were compared across three subgroups of parents. Student’s independent t-test, ANOVA, and Kruskal-Wallis test were used to study the correlation between different demographic and socioeconomic factors, and the studied variables.
90% of parents were aware that obesity is a disease, and 92% knew that eating too much fast food would lead to obesity in children. Only 5% assumed that obese children are healthier than non-obese children. The mean scores of the three subgroups showed no significant difference in knowledge, attitude and beliefs, and behavior. Families with fathers, whose education level was higher than high school diploma, rated their children’s weight status as overweight or obese significantly less than families with fathers, whose education level was high school diploma or lower (8.5% vs. 16.5%, respectively, P = 0.014). Only 12% of parents tried to help their children lose weight at least once, and only 6% arranged sport activities for the family members. In 57% and 41% of families, the child, respectively, decided how much time was enough to watch TV, and how much chocolates and sweets to eat. 46% of children watched TV for more than 2 hours/day, and 49% of children watched TV while eating meals. The mean total score of boys’ parents was significantly lower than that of girls’ parents (P < 0.05). Families with low income, with no medical insurance, or not owning a house thought that the cost of registration in sport activities for children was too high (P < 0.03).
Some parents unreasonably rated the weight status of their children as overweight/obese. It is suggested that further studies be carried out to evaluate and improve parents’ knowledge, attitudes, and behaviors regarding their children’s weight.
PMCID: PMC3653261  PMID: 23696761
Children; Obesity; Overweight; Knowledge; Attitude; Belief; Behavior
10.  Synergistic effects of genetic polymorphism and air pollution on markers of endothelial dysfunction in children 
This study aims to determine the association of some genetic polymorphisms in the relationship of air pollutants on the serum levels of thrombomodulin (TM) and tissue factor (TF) in a population-based sample of children and adolescents.
Materials and Methods:
This cross-sectional study was conducted among 110 participants (52.8% girls) with a mean age of 12.7 + 2.3 years, in Isfahan, Iran. Genotypes of TM G33-A and + 5466A > G polymorphisms were determined by the polymerase chain reaction – restriction length fragment polymorphism method (PCR-RFLP). The enzyme-linked immunosorbent assay (ELISA) was used for measurement of serum TM and TF.
The following genotypes were identified for TM: GG in 69.2%, GA in27.2%, and AA in 3.6% of the participants. Considering TF, 108 participants were homozygous for the + 5466A allele, and two subjects had + 5466AG genotype. The mean pollution standards index (PSI) value was at a moderate level; the mean particulate matter measured up to 10 μm (PM10); and ozone (O3), nitrogen dioxide, and sulfur dioxide were considerably high. The mean serum TF and TM levels were not significantly different among the participants with the aforementioned genotypes. Among participants exposed to high quartiles of O3, PM10, and PSI, the TM-33G / A polymorphism (GA + AA genotype) increased the Odds ratio (OR) of the low serum TM level. There was no statistically significant association in the areas of low pollution.
The findings of our study support the synergistic effect of the TM-33G / A polymorphism and air pollutants on factors associated with the onset of the atherosclerosis. This might be confirmatory evidence for gene-environment interaction, and related effects on atherogenesis from early life.
PMCID: PMC3687876  PMID: 23798936
Air pollution; atherosclerosis; children; genetics; prevention
11.  The Effect of Captopril on Impaired Wound Healing in Experimental Diabetes 
We aimed to investigate whether oral administration of captopril modulate wound healing, nitric oxide (NO), and vascular endothelial growth factor (VEGF) concentration in wound fluid of diabetic rats. 48 male Sprague-Dawley rats were divided in four groups (n = 12). The 36 rats were rendered diabetic by streptozotocin. The animals of the first and second groups received 25 and 50 mg/kg/day captopril, respectively, (DM-cap25 and DM-cap50). The animals of the third group were treated by distilled water (DM-control). Control rats had no intervention. The wound fluid level of NO and VEGF were measured. Wound specimens were investigated histopathologically. At the 5th day, there was significantly more NOx in wound fluid of DM-cap25 compared to other groups. At the 7th day, both captopril-treated groups had more NOx in wound fluid compared to other groups. At the 11th day, both captopril-treated groups had more NOx in wound fluid compared to DM-control group. VEGF concentration was significantly higher in both captopril-treated groups versus DM-control group (P < .05). There were significant higher wound healing scores in captopril-treated groups compared with DM-control group (P < .05). These results suggest that captopril might be useful in diabetic wound healing.
PMCID: PMC3409532  PMID: 22888345
12.  The Role of Maternal Thyroid Stimulating Hormone Receptor Blocking Antibodies in the Etiology of Congenital Hypothyroidism in Isfahan, Iran 
Considering the role of maternal thyroid stimulating hormone (TSH) receptor blocking antibody (TRAb) in the etiology of congenital hypothyroidism (CH), this study aimed to determine TRAb among patients with CH in Isfahan, Iran.
In this case–control study, patients with CH and their mothers were compared with a group of healthy neonates and their mothers. Venous blood samples were obtained for measurement of TRAb using enzyme-linked immunosorbent assay (ELISA) method among mothers and their neonates. TSH of mothers was also determined.
The case group consisted of 65 patients with CH and their mothers; controls were 148 healthy neonates and their mothers. The prevalence of positive TRAb in patients with CH and their mothers was higher than in the control group (81.5% vs. 1.3% in mothers and 80% vs. 0% in neonates, respectively, P<0.05). The relationship between the TRAb and occurrence of CH was significant (P<0.05), whereas the corresponding figure was not significant for TRAb and the level of maternal and neonatal TSH in case and control groups (P>0.05).
It seems that autoimmunity has an important role in the etiology of CH. Further studies are necessary to determine other autoantibodies in CH patients.
PMCID: PMC3278878  PMID: 22347610
Congenital hypothyroidism; etiology; thyroid stimulating hormone receptor blocking; autoimmunity

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