Exercise-related alterations in MCT1 and GLUT4 expressions in the liver and pancreas of rats with STZ-induced diabetes.

Background: The liver and pancreas tissues play a central role in controlling glucose homeostasis. In patients with type I diabetes mellitus (T1DM), the function of these tissues is impaired. The positive effects of exercise have been shown in diabetic patients. To demonstrate the positive effects of exercise in T1DM, we examined the effects of moderate-intensity endurance training (MIET) on the liver enzymes and expression of MCT1 and GLUT4 genes. Methods: Male Wistar rats were allocated into 4 groups of control (C), training (T), diabetic control (DC), and diabetes + training (DT). The serum levels of liver enzymes such as alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were determined by ELIZA. MCT1 and GLUT4 mRNA expressions in the liver and pancreas tissues were evaluated through real-time qPCR after 10 weeks of training. Results: The mRNA levels of MCT1 and GLUT4 decreased in DC group and increased in DT group. T1DM led to weight loss, but the weight loss was less in the DT group. T1DM caused an increase in liver enzymes such as ALT, AST and ALP, whereas endurance training preserved enzymatic levels. Conclusion: These results suggested that MIET increases levels of MCT1 and GLUT4 liver and pancreas in the diabetic rats and improves liver function tests. Upregulation of MCT1 and GLUT4 can probably improve the function of liver and pancreas tissues and promote glucose homeostasis in T1DM.

Comparative Study of Extremely Low-Frequency Electromagnetic Field, Radiation, and Temozolomide Administration in Spheroid and Monolayer Forms of the Glioblastoma Cell Line (T98).

BACKGROUND: Glioblastoma is the most common primary malignant tumor of the central nervous system. The patient's median survival rate is 13.5 months, so it is necessary to explore new therapeutic approaches. OBJECTIVE: Extremely low-frequency electromagnetic field (EMF) has been explored as a noninvasive cancer treatment. This study applied the EMF with previous conventional chemoradiotherapy for glioblastoma. METHODS: In this study, we evaluated the cytotoxic effects of EMF (50 Hz, 100 G), temozolomide (TMZ), and radiation (Rad) on gene expression of T98 glioma cell lines in monolayer and spheroid cell cultures. RESULTS: Treatment with Rad and EMF significantly increased apoptosis-related gene expression compared to the control group in monolayers and spheroids (p<0.001). The expression of apoptotic-related genes in monolayers was higher than the similar spheroid groups (p<0.001). We found that treatment with TMZ and EMF could increase the gene expression of the autophagy cascade markers compared to the control group (p<0.001). Autophagy-related gene expression in spheroids was higher than in the similar monolayer group (p<0.001). We demonstrated that coadministration of EMF, TMZ, and Rad significantly reduced cell cycle and drug resistance gene expression in monolayers and spheroids (p<0.001) compared to the control group. CONCLUSION: The combinational use of TMZ, Rad and, EMF showed the highest antitumor activity by inducing apoptosis and autophagy signaling pathways and inhibiting cell cycle and drug resistance gene expression. Furthermore, EMF increased TMZ or radiation efficiency.

The Prevalence and 5-Year Incidence Rate of Cigarette Smoking and Water-Pipe Tobacco Smoking and Their Associated Factors among 15 to 80 Years Old Urban Population in Southeast Iran: Results from KERCADR Study.

Background: Cigarette and tobacco smoking are closely associated with chronic cardiovascular disease and lung cancer. We aimed to assess the prevalence and 5-year incidence rate (IR) of these two risk factors for cardiovascular diseases in Kerman, southeastern of Iran. Methods: 10015 individuals aged 15-80 were recruited to the study between 2014 and 2018 (Kerman coronary artery disease (CAD) risk factors study, KERCADRS) of which 2820 had also participated in the first phase (5 years earlier). We took fasting blood samples and collected demographic information and data on cigarette and water-pipe tobacco smoking (WPTS) through interviews. Findings: The overall prevalence of cigarette smoking increased from 8.1% in phase1 to 8.8% in phase 2. During the same period, the prevalence of WPTS increased from 10% to 14%, especially in the age groups of 15-45 years. The prevalence of opium dependance was higher among cigarette smokers compared to WPT users. The overall 5-year IR of cigarette and WPTS was 3.6 and 4.65 per 1000 person-years respectively. The highest IRs of cigarette smoking and WPTS were reported in the age group of 15-39 years, and IR of WPTS was higher among women. Obesity, diabetes, and hypertension associated with a reduced IRs of cigarette and WPTS. Conclusion: Over the past five years, the prevalence of cigarette smoking has increased slightly, but WPTS has increased more rapidly, especially among women. The highest prevalence of cigarette and WPT smoking was in the age groups of 15-39 years. Smoking is shifting from cigarette smoking to WPTS. Age- and gender-oriented interventions would help correct the unhealthy life style in the community and prevent further smoking-related morbidities and mortalities.

Perillyl alcohol suppresses monocrotaline-induced pulmonary arterial hypertension in rats via anti-remodeling, anti-oxidant, and anti-inflammatory effects.

Background: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of perillyl alcohol (PA), a natural monoterpene, on the experimental PAH in male Wistar rats. Methods: Rats divided into eight groups of control, Monocrotaline (MCT), MCT+vehicle, and MCT+PA with doses of 20, 30, 40, 50, and 60 mg/kg. PAH was induced by a single injection of monocrotaline (60 mg/kg) on day 0. The animals in the groups of MCT+vehicle and MCT+PA received the vehicle or PA from day 22 to 42 once a day. On day 43, under general anesthesia, right ventricular systolic pressure (RVSP), as an index of pulmonary artery systolic pressure, and the ratio of the right ventricle to the left ventricle plus septum weight, as the right ventricular hypertrophy index (RVHI), were measured. Also, some histological and biochemical indices were assessed in the lung tissue. Results: MCT significantly (p < .001) enhanced the RVSP and RVHI compared to the control group (89.4 ± 8.2 vs 23 ± 3.3 mmHg & 0.63 ± 0.08 vs 0.26 ± 0.04 respectively). It also increased oxidative stress and inflammatory cytokines and reduced Bax/Bcl2 ratio. Treatment with PA significantly recovered RVSP and hypertrophy index and suppressed vascular cell proliferation, oxidant production, and inflammatory processes. Conclusion: PA exerted noticeable protective and curative effects against MCT-induced PAH and pulmonary vascular remodeling through inhibiting cellular proliferation, oxidative stress, and inflammation. Therefore, PA can be considered as a new therapeutic goal for the treatment of PAH.

Perillyle alcohol and Quercetin ameliorate monocrotaline-induced pulmonary artery hypertension in rats through PARP1-mediated miR-204 down-regulation and its downstream pathway.

BACKGROUND: Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the pathophysiology of PAH. Perillyle alcohol (PA) and Quercetin (QS) are plant derivatives with antioxidant and anti-proliferative properties. We investigated the effect of PA and QS on PAP, expression of PARP1, miR-204, and their targets, HIF1α and NFATc2, in experimental PAH. METHODS: Thirty rats were divided into control, MCT, MCT + Veh, MCT + PA and MCT + QS groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered for 3 weeks after inducing PAH. PAP, lung pathology, expression of miRNA and mRNA, and target proteins were evaluated through right ventricle cannulation, H&E staining, real-time qPCR, and western blotting, respectively. RESULTS: Inflammation and lung arteriole thickness in the MCT group increased compared to control group. PA and QS ameliorated inflammation and reduced arteriole thickness significantly. miR-204 expression decreased in PAH rats (p < 0.001). PA (p < 0.001) and QS (p < 0.01) significantly increased miR-204 expression. Expression of PARP1, HIF1α, NFATc2, and α-SMA mRNA increased significantly in MCT + veh rats (all p < 0.001), and these were reduced after treatment with PA and QS (both p < 0.01). PA and QS also decreased the expression of PARP1, HIF1α, and NFATc2 proteins that had increased in MCT + Veh group. CONCLUSION: PA and QS improved PAH possibly by affecting the expression of PARP1 and miR-204 and their downstream targets, HIF1a and NFATc2. PA and QS may be therapeutic goals in the treatment of PAH.

Enhanced expression of Cyclin D1 and C-myc, a prognostic factor and possible mechanism for recurrence of papillary thyroid carcinoma.

A direct association has been shown between Cyclin D1 and C-myc gene expressions and the proliferation of human thyroid tumor cells. Our previous study showed that increased ß catenin led to a reduction in disease-free probability in patients with papillary thyroid cancer. This study was designed to investigate Cyclin D1 and C-myc genes as targets for ß catenin function in PTC and to determine the association between genes expression and staging, recurrence, metastasis, and disease-free survival of PTC. This study was conducted via a thorough investigation of available data from medical records as well as paraffin blocks of 77 out of 400 patients over a 10-year period. Cyclin D1 and C-myc gene expression levels were measured using real-time polymerase chain reaction (RT-PCR) and the Kaplan-Meier method was used to evaluate disease-free survival. Higher levels of Cyclin D1 and C-myc gene expressions were observed in patients with recurrence by 8.5 (P = 0.004) and 19.5 (p = 0.0001) folds, respectively. A significant positive correlation was found between Cyclin D1 expression and the cumulative dose of radioactive iodine received by patients (r = -0.2, p value = 0.03). The ten-year survival rate in the patients included in this study was 98.25% while disease-free survival was 48.1%. Higher Cyclin D1 and C-myc gene expression levels were observed in patients with recurrence/distant metastasis. Inversely, lower expression of Cyclin D1 and C-myc genes were associated with better survival of patients (SD, 0.142-0.052) (Mantel-Cox test, P = 0.002). The enhancement of Cyclin D1 and C-myc gene expression may be a potential mechanism for recurrence and aggressiveness of PTC.

The efficacy of a traditional medicine preparation on second-degree burn wounds in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lime Salve (L.S) has been well documented from the 9th to the 19th century AD by traditional Iranian medicine (TIM) as an effective remedy for burn healing. AIM OF THE STUDY: The present study was undertaken to evaluate the healing effect and related underlying mechanisms of Lime Salve in a model of deep second-degree thermal burn in male Wistar rats. MATERIALS AND METHOD: L.S was made up of a combination of refined calcium hydroxide powder, beeswax and sesame oil and its quality control was assessed. A deep second-degree burn was created by a hot plate in 48 male Wistar rats. Afterwards, they were randomly divided into four groups including normal saline (C group), L.S (T group), basement of formulation composed of beeswax and sesame oil (B group) and silver sulfadiazine (S group). On days 5, 10, 17 and 24, the wounds were digitally photographed by a camera and after sacrifice of the rats, skin samples were obtained for performing qRT-PCR, immunohistochemistry staining and histological examination. RESULTS: L.S prominently augmented the wound closure rate, neovascularization on day 10 and collagen formation on days 17 and 24 in comparison with the C group. Furthermore, the Salve-exposed specimens showed a significant higher epithelialization during the experiment with a peak on day 24. qRT-PCR also showed that on day 10, VEGF and TGF-ß1 genes were significantly higher in the T group as compared with the C group. Also, MMP-9 and MMP-2 genes had a significant peak of expression on day 17 and rapid reduction of expression on day 24. Expression levels of IL-6 and TNF-α genes peaked on day 10 in the T group, followed by a progressive reduction until the end of the examination. CONCLUSION: L.S could effectively accelerate the healing process of deep second-degree burn wounds and therefore, it may be recommended as a promising topical medication for treating burn wounds in the future clinical trials.

Association of Obesity-Related Genetic Variants (FTO and MC4R) with Breast Cancer Risk: A Population-Based Case-Control Study in Iran.

BACKGROUND: Heterogeneous breast cancer is the most common cause of cancer-related mortality. Obesity defined by BMI is a known major risk factor for breast cancer. OBJECTIVES: The purpose of this study was to explore the role of obesity related-polymorphisms rs9939609 Fat Mass and Obesity-associated (FTO) and rs17782313 MC4R in breast cancer development. MATERIALS AND METHODS: Matched peripheral blood serum was obtained from 64 breast cancer patients and 83 normal controls. Height and weight were measured to calculate BMI. All were genotyped for the SNPs rs9939609 and rs17782313 using a Tetra-primer ARMS-PCR method. For statistical analysis, the chi-square test and SPSS software were used. RESULTS: In subgroup analyses defined by BMI, FTO rs9939609 genotypes (TT/AA/AT) were significantly associated with the risk of breast cancer only in non-obese subjects (p < 0.005). TT genotypes of MC4R rs17782313 in non-obese and genotypes TT/CC in the overweight group were also statistically associated with breast cancer (p < 0.005). No significant associations between any variants and breast cancer risk were seen in obese subjects. CONCLUSION: Based on the absence of an association between obesity-related SNPs and breast cancer in obese subjects, it is proposed that weight gain in Iranian women will help prevent breast cancer risk. The result help for preparing and designing a safe and versatile recombinant drug in future.

ENHANCED BETA-CATENIN EXPRESSION IS ASSOCIATED WITH RECURRENCE OF PAPILLARY THYROID CARCINOMA.

OBJECTIVE: A direct role of ß-catenin 1 (ß-cat) in the proliferation of human thyroid tumor cells has been identified. This study aimed to determine if there is an association between ß-cat gene expression and the staging, recurrence, metastasis, and disease-free survival of papillary thyroid cancer. METHODS: A retrospective cohort study was conducted using data from available information in the medical records and paraffin blocks of 81 of 400 patients referred to the endocrine clinic over a 10-year period. Real-time polymerase chain reaction was used to evaluate ß-cat gene expression. Disease-free survival was assessed using the Kaplan-Meier method. RESULTS: The 10-year survival rate in these patients was 98.25%, and disease-free survival was 48.1%. Cumulative dose of radioactive iodine that patients received was significantly and positively correlated with ß-cat gene expression ( r = -0.2; P = .03). Also, in patients with recurrence, ß-cat gene expression was higher and statistically significant (5-fold increase; P = .002). Patients in more advanced stage and those with recurrence/distant metastasis had higher ß-cat gene expression. We found that the patients had a better survival (lower recurrence) if they had a lower ß-cat gene expression (SD, 0.142 to 0.052) (Mantel-Cox test, P = .002). CONCLUSION: We conclude that ß-cat gene expression is positively correlated with recurrence, distant metastasis, and tumor-node-metastasis stage. ABBREVIATIONS: ß-cat = ß-catenin 1; CI = confidence interval; PTC = papillary thyroid carcinoma; ROC = receiver operating characteristic.

Nandrolone Plus Moderate Exercise Increases the Susceptibility to Lethal Arrhythmias.

BACKGROUND: Until now, no experimental study has directly assessed the arrhythmogenesis of chronic consumption of anabolic androgenic steroids along with moderate-intensity endurance exercise. OBJECTIVES: We evaluated the influence of integration of anabolic androgenic steroids along with moderate-intensity endurance exercise on susceptibility to lethal ventricular arrhythmias in rat. MATERIALS AND METHODS: The animal groups were as follows: control group (CTL); exercise group (EX) which were under 6 weeks of treadmill exercise; nandrolone group (Nan) which received 5 mg/kg of nandrolone decanoate twice a week; vehicle group (Arach) which received Arachis oil (solvent of nandrolone); trained vehicle group (Arach + Ex); and trained nandrolone group (Nan + Ex). One day after ending of the intervention period, arrhythmia was inducted by intravenous infusion of aconitine and ventricular arrhythmias were recorded. Then malondialdehyde (MDA) and glutathione peroxidase (GPX) of heart tissue were measured. RESULTS: Nandrolone, exercise, and their combination were associated with heart hypertrophy. Exercise could prevent the incremental effect of nandrolone on MDA/GPX ratio. Chronic administration of nandrolone with moderate-intensity endurance exercise had no significant effect on blood pressure, heart rate, and basal electrocardiographic parameters. Combination of nandrolone and exercise significantly increased the incidence of ventricular fibrillation (VF) and reduced the VF latency (P < 0.05). CONCLUSIONS: The findings suggest that chronic coadministration of nandrolone with moderate-intensity endurance exercise facilitates the VF occurrence in rat. Complementary studies are needed to elucidate the involved mechanisms of this abnormality.