Interaction of estradiol and renin-angiotensin system with microRNAs-21 and -29 in renal fibrosis: focus on TGF-ß/smad signaling pathway.

Kidney fibrosis is one of the complications of chronic kidney disease (CKD (and contributes to end-stage renal disease which requires dialysis and kidney transplantation. Several signaling pathways such as renin-angiotensin system (RAS), microRNAs (miRNAs) and transforming growth factor-ß1 (TGF-ß1)/Smad have a prominent role in pathophysiology and progression of renal fibrosis. Activation of classical RAS, the elevation of angiotensin II (Ang II) production and overexpression of AT1R, develop renal fibrosis via TGF-ß/Smad pathway. While the non-classical RAS arm, Ang 1-7/AT2R, MasR reveals an anti-fibrotic effect via antagonizing Ang II. This review focused on studies illustrating the interaction of RAS with sexual female hormone estradiol and miRNAs in the progression of renal fibrosis with more emphasis on the TGF-ß signaling pathway. MiRNAs, especially miRNA-21 and miRNA-29 showed regulatory effects in renal fibrosis. Also, 17ß-estradiol (E2) is a renoprotective hormone that improved renal fibrosis. Beneficial effects of ACE inhibitors and ARBs are reported in the prevention of renal fibrosis in patients. Future studies are also merited to delineate the new therapy strategies such as miRNAs targeting, combination therapy of E2 or HRT, ACEis, and ARBs with miRNAs mimics and antagomirs in CKD to provide a new therapeutic approach for kidney patients.

Prevalence and trend of multiple coronary artery disease risk factors and their 5-year incidence rate among adult population of Kerman: results from KERCADR study.

BACKGROUND: Coronary artery diseases (CADs) are the most important non­communicable diseases (NCDs), which cause the highest number of deaths around the world. Hypertension (HTN), dyslipidemia (DL), diabetes mellitus (DM), obesity (OB), low physical activity (LPA), smoking, opium consumption (OC) and anxiety are the most important CAD risk factors, which are more dangerously present in combination in some patients. METHODS: A total of 5835 people aged 15 to 75 years were enrolled in the phase 1 (2012) and followed up to the phase 2 (2017) of the population-based Kerman coronary artery diseases risk factors study (KERCADRS). The prevalence and pattern of different combinations of CAD risk factors (double to quintuple) and their 5-year incidence rates were assessed. RESULTS: The prevalence of single CAD risk factors (RFs) in phase 2 was 50.2% (DL), 47.1% (LPA), 28.1% (abdominal obesity), 21.2% (OB), 16.5% (HTN), 9.2% (smoking), 9.1% (OC), and 8.4% (DM). The most frequent combination of risk factors was LPA plus DL (23.9%), metabolic syndrome (19.6%), and DL plus OB (17.8%). The 5-year incidence rates of multiple comorbidities (in persons per 100 person-years) was DL plus LPA (2.80%), HTN plus DL (1.53%), and abdominal obesity (AOB) plus DL (1.47%). The most participants (84.4%) suffered from at least one RF, while 54.9% had at least two and 29.9% had at least three RFs. CONCLUSION: The results showed that a large portion of the study population suffers from multiple CAD RFs. The findings underscore the importance of identifying multiple CAD risk factors to reduce the overall burden of these NCDs.

High-intensity intermittent training ameliorates methotrexate-induced acute lung injury.

Inflammation and oxidative stress are recognized as two primary causes of lung damage induced by methotrexate, a drug used in the treatment of cancer and immunological diseases. This drug triggers the generation of oxidants, leading to lung injury. Given the antioxidant and anti-inflammatory effects of high-intensity intermittent training (HIIT), our aim was to evaluate the therapeutic potential of HIIT in mitigating methotrexate-induced lung damage in rats. Seventy male Wistar rats were randomly divided into five groups: CTL (Control), HIIT (High-intensity intermittent training), ALI (Acute Lung Injury), HIIT+ALI (pretreated with HIIT), and ALI + HIIT (treated with HIIT).HIIT sessions were conducted for 8 weeks. At the end of the study, assessments were made on malondialdehyde, total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (Gpx), myeloperoxidase (MPO), interleukin 10 (IL-10), tumor necrosis factor-alpha (TNF-α), gene expression of T-bet, GATA3, FOXP3, lung wet/dry weight ratio, pulmonary capillary permeability, apoptosis (Caspase-3), and histopathological indices.Methotrexate administration resulted in increased levels of TNF-α, MPO, GATA3, caspase-3, and pulmonary edema indices, while reducing the levels of TAC, SOD, Gpx, IL-10, T-bet, and FOXP3. Pretreatment and treatment with HIIT reduced the levels of oxidant and inflammatory factors, pulmonary edema, and other histopathological indicators. Concurrently, HIIT increased the levels of antioxidant and anti-inflammatory factors.

Inhalation of Spray-Dried Extract of Salvia rosmarinus Spenn Alleviates Lung Inflammatory, Oxidative, and Remodeling Changes in Asthmatic Rats.

INTRODUCTION: For centuries, Salvia rosmarinus Spenn has been applied as folk medicine to cure different diseases due to its anti-inflammatory, antibacterial, antioxidant, antifungal, and antitumor effects. To find bioactive medicinal herbs exerting a protective effect on airway inflammation and remodeling, we assessed the anti-oxidative and anti-inflammatory effects of an aqueous spray-dried extract of Salvia rosmarinus Spenn. (rosemary) in an ovalbumin-induced asthmatic rat model. METHODS: Rats were randomly divided into normal control (control), asthma, asthma+rosemary extract (RE) (13 mg/kg), asthma+RE (50 mg/kg), and asthma+budesonide groups. After 50 days, animals were anesthetized, and then blood, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for subsequent serological and pathological studies. Histopathology of lung tissues was evaluated by H&E staining. The oxidative stress parameters and airway inflammation factors in BALF and lung tissue were explored. RESULTS: Using thin layer chromatography, the presence of rosmarinic acid was confirmed in aqueous extract of rosemary. Furthermore, RE markedly decreased immunoglobulin E levels (50 mg/kg; p < 0.001 vs. asthma group) and inflammatory cytokines (50 mg/kg; p < 0.001 vs. asthma group) and increased antioxidant enzymes (50 mg/kg, p < 0.001 vs. asthma group). Furthermore, RE at a concentration of 50 mg/kg obviously reduced the number of inflammatory cells, goblet cells, and pathological changes compared to the asthma group. CONCLUSION: The results showed that RE administration might prevent or alleviate allergic asthma-related pathological change, probably via antioxidant and anti-inflammatory mechanisms.

Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients.

BACKGROUND: Coronary artery disease (CAD) is a devastating illness and a leading cause of death worldwide, primarily caused by atherosclerosis resulting from a genetic-environmental interaction. This study aimed to investigate the relationship between the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) polymorphisms, lipid profile parameters, and CAD risk in a southeast Iranian population. METHODS: A total of 400 subjects (200 CAD patients with hyperlipidemia and 200 healthy controls) were enrolled in this case-control study. Five selected polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: For all single nucleotide polymorphisms (SNPs), the population under study was in the Hardy-Weinberg equilibrium. The T-risk allele frequency of rs2228570 was associated with an increased risk of CAD. The TT and CT genotypes of rs2228570 had also been associated with the risk of CAD. Additionally, the TT genotype was associated with higher serum low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels. The GG genotype of the rs3736234 was associated with higher body mass index (BMI) and triglyceride (TG) levels, and the AA genotype of the rs708272 was associated with higher HDL-c levels. Based on these findings, we propose that the VDR (rs2228570) polymorphism was associated with serum HDL-c and LDL-c levels and may serve as potential risk factors for CAD within the Iranian population. Moreover, rs3736234 and rs708272 influence the concentrations of TG and HDL-c, respectively. CONCLUSION: These findings provided insights into the complex interplay between genetic variations, cardiovascular risk, and lipid metabolism.

Comparison of preventive and therapeutic effects of continuous exercise on acute lung injury induced with methotrexate.

Methotrexate (Mtx) is used to treat various diseases, including cancer, arthritis and other rheumatic diseases. However, it induces oxidative stress and pulmonary inflammation by stimulating production of reactive oxygen species and cytokines. Considering the positive effects of physical activity, our goal was to investigate the preventive and therapeutic role of continuous training (CT) on Mtx-induced lung injury in rats. The rats were divided into five groups of 14 animals: a control group (C); a continuous exercise training group (CT; healthy rats that experienced CT); an acute lung injury with Mtx group (ALI); a pretreatment group with CT (the rats experienced CT before ALI induction), and a post-treatment group with CT (the rats experienced CT after ALI induction). One dose of 20 mg/kg Mtx intraperitoneal was administered in the Mtx and training groups. Forty-eight hours after the last exercise session all rats were sacrificed. According to our results, the levels of tumour necrosis factor-α (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), GATA binding protein 3 (GATA3) and caspase-3 in the ALI group significantly increased compared to the control group, and the levels of superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC), interleukin-10 (IL-10), forkhead box protein 3 (FOXP3), and T-bet decreased. In contrast, compared to the acute lung injury group, pretreatment and treatment with CT reduced TNF-α, MDA, MPO, GATA3 and caspase-3 and increased SOD, GPX, TAC, IL-10, FOXP3 and T-bet levels. The effects of CT pretreatment were more significant than the effects of CT post-treatment. Continuous exercise training effectively reduced oxidative stress and inflammatory cytokines and ameliorated Mtx-induced injury, and the effects of CT pretreatment were more significant than the effects of CT post-treatment. NEW FINDINGS: What is the central question of this study? Considering the high prevalence of lung injury in society, does exercise as a non-pharmacological intervention have ameliorating effects on lung injury? What is the main finding and its importance? Exercise can have healing effects on the lung after pulmonary injury through reducing inflammation, oxidative stress and apoptosis. Considering the lower side effects of exercise compared to drug treatments, the results of this study may be useful in the future.

Evaluation of the novel three lipid indices for predicting five- and ten-year incidence of cardiovascular disease: findings from Kerman coronary artery disease risk factors study (KERCADRS).

BACKGROUND: Data are limited on the relationship between cardiovascular disease (CVD) and the combinational indices of lipid accumulation product (LAP), triglyceride-glucose index (TyG), and visceral adiposity index (VAI). The association of these novel indices with the 5- and 10-year incidence of CVD was assessed. METHOD: A total of 1888 and 1450 healthy adults aged between 15 and 75 years (out of the 5895 participants of the KERCADR study, 2012) were followed for five and ten years, respectively. Baseline LAP, TyG, and VAI were calculated and logistic regression models were used to assess their relationship with the incidence of CVD in the two follow-up periods. Also, the predictive performance of these three indices was analyzed using the area under ROC curve (AUC) for the development of CVD compared with traditional single indices. RESULTS: In the 5- and 10-year follow-ups, 399 and 476 CVD cases (21.1% and 32.8%) were documented, respectively. For the 5-year CVD risk, the adjusted odds ratio (AOR, 95% CI) was LAP (2.24 [1.44, 3.50]), VAI (1.58 [1.08, 2.33]), and TyG (1.57 [1.02, 2.42]). For the 10-year CVD risk, the AOR was LAP (1.61 [1.04, 2.49]), TyG (1.57 [1.02, 2.41]), and VAI (1.41 [0.96, 2.09]). In both periods and sexes, LAP had the best performance with the highest AUCs (0.644 and 0.651) compared to the other two indices and compared to the traditional single indices (e.g., BMI, LDL, etc.). CONCLUSION: Overall LAP, TyG, and VAI were better CVD risk predictors compared to the traditional single risk factors, with LAP showing the strongest predictive power for the incidence of CVD.

Promotion of aging heart function and its redox balance following hind-limb blood flow restriction plus endurance exercise training in rats: klotho and PGC1-α as involving candidate molecules.

Mild to moderate-intensity endurance exercise training combined with hind-limb blood flow restriction (BFR) induces elderly heart rejuvenation and improves cardiac inotropy and resistance to ischemia. However, the mediators of these beneficial effects are still not well known. The present study investigated the possible role of some important molecules in the mediatory of this model of exercise training in the promotion of heart health in aged rats. Male old Wistar rats randomly were divided into control-sham (CTL), hind limbs blood flow restriction (BFR), sham-operated plus 10 weeks' treadmill exercise training (Ex), and BFR plus exercise (BFR + Ex) groups. Left ventricular end-diastolic pressure (LVEDP), contractility, and Tau indices were measured. ELISA and western blot tests were used for measuring determined cardiac biochemical factors. BFR + Ex displayed significantly lower LVEDP (P < 0.05 and P < 0.01 vs. Ex, and other groups, respectively), improved heart cardiac contractility (P < 0.01), and significantly reduced Tau index in comparison with other groups. BFR + Ex significantly reduced both BAX and BAX to BCL2 ratio (P < 0.05) and as well MDA to TAC ratio (P < 0.05, compared to the CTL group). Also, BFR + Ex significantly increased the level of klotho (P < 0.05) and PGC1-α (P < 0.001) proteins compared to the CTL group but had no significant effect on P-STAT3 expression. Exercise training alone increased Apelin protein (P < 0.05). Our findings suggest that mild to moderate BFR endurance training improves heart performance in the aging rat partly through ameliorating apoptosis, recovering redox balance, improving the longevity factor klotho, and increasing the key energy metabolism regulator PGC1-α.

Associations between serum vitamin D3, atherogenic indices of plasma and cardiometabolic biomarkers among patients with diabetes in the KERCADR study.

BACKGROUND: We sought the association between serum 25-hydroxyvitamin D3 (25(OH) D3) levels and atherogenic indices of plasma as novel predictive biomarkers of cardiometabolic disease risk in patients with type 2 diabetes mellitus (T2DM). METHODS: The present study was a nested case-control study conducted on 252 participants with T2DM and controls from the second phase of the KERCADR cohort study. The participants with a mean (±SD) age of 49.79 ± 5.85 years were randomly selected and allocated into case and control groups. Independent t-test, Hierarchical Linear Regression, Univariate ANOVA, and partial correlation were used for analysis the data. Atherogenic indices of plasma include Castelli Risk Index I (CRI I), Castelli Risk Index II (CRI II), and the novel Atherogenic Index of Plasma (AIP), and Atherogenic Coefficient (AC). RESULTS: There was a significant difference among case and control groups for AIP in males and females (P < 0.001 and P = 0.007, respectively). The levels of AIP, CRI I, and AC significantly decreased (P = 0.017, P = 0.029, and P = 0.029, respectively) with improved serum vitamin D status only in control male participants. The main effect of BMI and vitamin D status on AIP, CRI I, and AC, and the main effect of BMI on CRI I, CRI II, and AC were significant in control males and females, respectively. CONCLUSION: We conclude that there is a reverse significant association between AIP and serum vitamin D among healthy males. Low serum level of vitamin D is associated with atherogenic dyslipidemia. Therefore, improving vitamin D status as an important indicator may alleviate AIP as a surrogate marker for predicting the risk of CVD events in healthy men and women with normal BMI.

Beneficial effects of PEGylated graphene quantum dot on arrhythmias induced by myocardial infarction.

Arrhythmias are one of the leading causes of early death following myocardial infarction (MI) and heart failure. Graphene derivatives have emerged as an therapeutic target that have electrical conductivity. The study aimed to evaluate the impacts of polyethylene glycol-graphene quantum dots (GQDs-PEG) on arrhythmias created by MI in the rat. Animals were randomly assigned to five groups of sham, MI, and MI + GQDs-PEG at doses of 5, 10, and 20 mg/kg. MI was induced by the closure of the left anterior descending artery. The day after MI, animals were administered vehicle (phosphate buffered saline) or GQDs-PEG at different doses every other day for 2 weeks. On day 15, electrocardiogram (ECG), mean arterial pressure (MAP), and heart contractility indices were recorded by the PowerLab data acquisition system. GQDs-PEG 20 mg/kg increased contractility and improved the reduction of MAP in the MI group. The prolonged QT and QTc intervals, inverted T wave, and deviated ST segment were modified by GQDs-PEG 10 and 20 mg/kg in rats with MI. The amplitude of the Q wave was also decreased in a dose-dependent manner in the GQDs-PEG-treated rats. The results demonstrated that 2 weeks of treatment with GQDs-PEG normalized ECG abnormalities and improved left ventricular dysfunction in rats with MI.

A Cluster-wise Linear Regression Model to Investigate the Effect of Demographical and Clinical Variables on the Average Depression Score.

Background: Depression is a prevalent illness in the world. Given the importance of mental disorders, many researchers have investigated the effects of different variables on average depression scores. In this study, we decided to investigate the effect of some explanatory variables on the average depression score. Methods: The data were provided from the second phase of the Kerman Coronary Artery Diseases Risk Factors study (KERCADRS), which took place between 2014 and 2018. To obtain more precise connections between depression ratings and predictor variables, we employed a cluster-wise linear regression model. Results: The total number of the participants in this study was 9811, out of whom 2144 were allocated to cluster 1, 4540 to cluster 2, and 3127 to cluster 3. The average depression score was 13.76 ± 7.6 in cluster 1, 4.39 ± 4.7 in cluster 2, and 10.83 ± 6.7 in cluster 3. However, the average depression score for all the data was 8.5 ± 7.2. In all the clusters, the average depression score of females was significantly greater than that of men (P < 0.001). In cluster 1, the age category of 35-54 years, in cluster 2, the age category of 55-80 years, and in cluster 3, the age category of 15-34 years had a maximum average depression score. Conclusion: We may classify the 3 clusters as having a low (cluster 2), moderate (cluster 3), or high (cluster 1) depression score, according to the age group with the highest artery diseases risk. The patients were 55-80 years, 15-34 years, and 35-54 years in cluster 2 (low), cluster 3 (moderate), and cluster 1 (high), respectively.

Improvement of Cardiac Function in Rats With Myocardial Infarction by Low-Intensity to Moderate-Intensity Endurance Exercise Is Associated With Normalization of Klotho and SIRT1.

ABSTRACT: Exercise training (Ex) has beneficial effects on cardiovascular diseases by increasing Klotho and SIRT1. This study aimed to investigate whether the beneficial impact of Ex on myocardial infarction (MI) is mediated through Klotho and SIRT1. Fifty-six Wistar rats were divided into 4 main groups of Sham, MI, Ex, and MI + Ex. MI was induced by the closure of the left anterior descending. Animals were trained by endurance exercise for 4 weeks. In the end, hemodynamic and heart contractility indices were assessed. The levels of Klotho and SIRT1 in the serum and heart were measured by enzyme-linked immunosorbent assay and Western blot, respectively. The ADAM17 level in the heart and kidneys was assessed by enzyme-linked immunosorbent assay. The infarct size and fibrosis area were assessed by triphenyltetrazolium chloride and Masson trichrome staining, respectively. Ex recovered the reduction of dp/dt max and dp/dt min and decreased myocardial infarct size and fibrotic area in the MI group. Ex normalized the increase in heart rate, systolic blood pressure, left ventricular systolic pressure, and left ventricular end diastolic pressure in the MI group. Ex also normalized the reduction of the levels of Klotho and SIRT1 in serum and heart in the MI group. The changes of Klotho and SIRT1 in serum were positively correlated. Ex also restored ADAM17 levels in the MI group. Ex improved cardiac function in the MI group and is associated with reduction of the infarct size and normalization of Klotho and SIRT1 levels. Regarding unidirectional changes in Klotho and SIRT1, these proteins may play a role in beneficial effects of Ex on MI recovery.

Quercetin, Perillyl Alcohol, and Berberine Ameliorate Right Ventricular Disorders in Experimental Pulmonary Arterial Hypertension: Effects on miR-204, miR-27a, Fibrotic, Apoptotic, and Inflammatory Factors.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease causing right ventricular (RV) hypertrophy, failure, and death. Some miRNAs are involved in the pathophysiology of PAH. As the current treatments cannot prevent the progression of the disease, we investigated whether 3 plant derivatives, namely perillyl alcohol (PA), quercetin (QS), and berberine (BBR), can improve RV function and affect the expression of miR-204, miR-27a, and biochemical factors in monocrotaline-induced PAH (MCT-PAH). Thirty-six rats were divided into control (CTL), MCT, MCT+Veh (vehicle), MCT+PA, MCT+QS, and MCT + BBR groups (n = 6 each). After inducing PAH using MCT (60 mg/kg), PA (50 mg/kg), QS (30 mg/kg), and BBR (30 mg/kg) were administrated daily for 3 weeks. miR-204 expression, total antioxidant capacity, and antiapoptotic protein Bcl-2 significantly declined in the RV of PAH rats, and PA, QS, and BBR treatment significantly compensated for these decreases. Proapoptotic protein Bax and p21 cell cycle inhibitor increased in the RV. All 3 herbal derivatives compensated for Bax increase, and BBR caused a decrease in p21. TNFα, IL-6, and malondialdehyde increased in the RV, and PA, QS, and BBR significantly counterbalanced these increases. miR-27a expression was not affected by MCT and plant derivatives. Overall, PA, QS, and BBR improved ventricular disorders in rats with PAH by decreasing inflammation, apoptosis, and fibrosis and increasing the antioxidant-to-oxidant ratio. Therefore, these herbal derivatives may be considered as target therapeutic goals for this disease either alone or in combination with current medications.

Prevalence and risk factors of urinary incontinence among Iranian women.

BACKGROUND: Urinary incontinence is a common condition among women. Although it is not a life-threatening condition, it dramatically influences the quality of life. This study aimed to estimate the prevalence of urinary incontinence and its risk factors among Iranian women in Kerman, Iran. METHODS: This cross-sectional, population-based study was conducted on 3100 Iranian women aged 15-80 years in 2017 in Kerman, Iran. The participants were selected via cluster sampling and were invited to complete the questionnaires. Their demographic information and medical history were assessed, the urinary incontinence questionnaire was completed, and the associated risk factors were also recorded. Quantitative variables are reported as mean ± SD, while qualitative and ranked variables are expressed in percentage. All analyses were conducted in Stata version 12 (Stata Corp.). RESULTS: The mean age of the participants was 46 years, and the overall prevalence of urinary incontinence was estimated to be 63%. The highest and lowest prevalence rates of urinary incontinence were reported in the elderly and the youth, respectively (79% and 41%, respectively). Age, increase of body mass index (BMI), pregnancy, diabetes, anxiety, and depression were the associated risk factors. CONCLUSION: We found that the prevalence of urinary incontinence is high in Iran. Therefore, to control this condition and improve women's quality of life, effective plans are needed.

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.

SIRT1 and Klotho expression in the heart and kidneys of rats with acute and chronic renovascular hypertension.

AIM: To evaluate Klotho and SIRT1 expression in the heart and kidneys of rats with acute and chronic renovascular hypertension. METHODS: Four and sixteen weeks after the induction of renovascular hypertension by clipping the left renal artery, systemic blood pressure, serum angiotensin II level, and the expression of Klotho and SIRT1 proteins and oxidative stress indices in the heart and kidneys were assessed. RESULTS: SIRT1 level was significantly reduced in the ischemic (left) kidney in acute and chronic phases of hypertension. In the heart, it decreased in the acute phase, but increased in the chronic phase. Klotho levels in the heart and kidneys did not change significantly in either hypertension phase. Superoxide dismutase (SOD) activity in the heart significantly decreased, and SOD, total antioxidant capacity, and malondialdehyde in the ischemic kidney significantly increased during the development of hypertension. Serum angiotensin II level significantly increased in the acute phase of hypertension. CONCLUSION: Development of renovascular hypertension was associated with a reduction of SIRT1 expression in the heart and ischemic kidney. As angiotensin II and SIRT1 counteract each other's expression, a SIRT1 reduction in the heart and kidney, along with the influence of systemic/local angiotensin II, seems to be partly responsible for hypertension development. A combination of SIRT1 agonists and angiotensin II antagonists may be considered for use in the treatment of renovascular hypertension.

Prevalence and 5-year incidence rate of dyslipidemia and its association with other coronary artery disease risk factors in Iran: Results of the Kerman coronary artery disease risk factors study (Phase 2).

BACKGROUND: Dyslipidemia (DL) is an important risk factor of coronary artery disease (CAD). We evaluated DL prevalence and its 5-year incidence rate in southeastern Iran, to assess the severity and growth rate of this CAD risk factor in the region. MATERIALS AND METHODS: This study was a part of the Kerman CAD Risk Factors Study Phase 2 (2014-2018) among 9996 individuals aged 15-80 years, from whom 2820 individuals had also participated in Phase 1 (2009-2011). In mg/dl, cholesterol ≥240 and/or low-density lipoprotein cholesterol ≥160 and/or high-density lipoprotein cholesterol <40 for men and <50 for women and/or triglyceride >200 were defined as DL. RESULTS: The lipid profile of 9911 persons was analyzed. Overall 19.6% had borderline cholesterol and 6.4% suffered from hypercholesterolemia. 56.6% of the population (62.5% of females vs. 48.5% of males) suffer from DL, from whom 73.4% were undiagnosed. Female gender, advanced age, obesity, hypertension, diabetes, anxiety, and depression predicted DL in the study population. The prevalence of DL was significantly lower in Phase 2 (56.6%) compared to Phase 1 (81.4%). The prevalence of undiagnosed DL (UDL) and diagnosed DL (DDL) was 40.7% and 16.2%, respectively. The 5-year incidence rate of DL was 2.58 persons/100 person-years (3.24 in females vs. 2.20 in males). CONCLUSION: Although there were promising signs of a reduction in DL and increase in DDL in the last 5 years, a high percentage of the population have DL yet, from whom mostly are undiagnosed. DL was significantly associated with other CAD risk factors. Therefore, the health-care management system should improve its strategies to reduce the health burden of DL.

Chronic treatment with apelin, losartan and their combination reduces myocardial infarct size and improves cardiac mechanical function.

The renin-angiotensin system (RAS) has a deleterious and apelin/APJ system has protective effect on the ischaemic heart. The collaboration between these systems in the pathophysiology of myocardial infarction is not clear. We determined the effect of chronic pretreatment with apelin, losartan and their combination on ischaemia-reperfusion (IR) injury in the isolated perfused rat heart and on the expression of apelin-13 receptor (APJ) and angiotensin type 1 receptor (AT1R) in the myocardium. During 5 days before the induction of IR, saline (vehicle), apelin-13 (Apl), F13A (apelin antagonist), losartan (Los, AT1R antagonist) and the combination of Apl and Los were administered intraperitoneally in rats. Ischaemia was induced by left anterior descending (LAD) artery occlusion for 30 minutes followed by reperfusion for 55 minutes in the Langendorff isolated heart perfusion system. Pretreatment with Apl, Los and the combination of Apl + Los significantly reduced infarct size by about 30, 33 and 48 percent respectively; and significantly improved the left ventricular function indices such as left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP) and rate pressure product (RPP). IR increased AT1R protein level but it did not change APJ significantly. AT1R expression was reduced in groups treated with Apl, Los and Apl + Los. Findings showed that chronic pretreatment with apelin along with AT1R antagonist had more protective effects against IR injury. Combination therapy may diminish the risk of IR-induced heart damage, by reducing AT1R expression, in the heart of patients with coronary artery disease that are at the risk of MI and reperfusion injury.

The study of the serum level of IL-4, TGF-ß, IFN-γ, and IL-6 in overweight patients with and without diabetes mellitus and hypertension.

BACKGROUND: Obesity increases the risk of diabetes mellitus (DM) and hypertension. We aimed to analyze the serum levels of cytokines that have relevance to the pathologies including, interleukin-4 (IL-4), transforming growth factor-ß (TGF-ß), interferon-γ (IFN-γ), and IL-6 cytokines of overweight men with DM and/or hypertension. METHODS: The study collected serum from 164 men. The sample population contained, 54 overweight men without DM or hypertension (control [CTL] group), 36 men with both DM and hypertension (DH group), 20 men with DM but no hypertension (D group), and 54 had hypertension without DM (H). RESULTS: The main results showed that the concentration of IFN-γ in the DH group was significantly higher than the D, H, and CTL groups, IL-6 in DH and D groups was significantly lower than the CTL group. The serum level of TGF-ß and IL-4 cytokines did not show any significant differences across the four groups. Serum levels of IL-6 were also significantly lower in untreated patients in D group than controls and in DH when compared with H groups. CONCLUSION: In conclusion, it appears that the proinflammatory and anti-inflammatory cytokines either play a significant role in the pathogenesis of hypertension and DM or serve as markers for these pathologies. Accordingly, increased serum levels of IFN-γ may participate in the pathogenesis of hypertension in the diabetic patients and decreased IL-6 is associated with type 2 DM.

The effect of sodium valproate on differentiation of human adipose-derived stem cells into cardiomyocyte-like cells in two-dimensional culture and fibrin scaffold conditions.

Differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes is a complex phenomenon, and attempts to find an effective inducing agent are still ongoing. We studied the effect of fibrin scaffold and sodium valproate (VPA, as a histone deacetylase inhibitor) on the differentiation of human adipose-derived stem cells (hADSCs) into cardiomyocyte-like cells. The cells were cultured in culture flask (2D) and in fibrin scaffold (3D), fabricated of human plasma fibrinogen, with and without VPA (1 mM). QRT-PCR, Western blot, and immunochemistry assays were used to evaluate the expression of cardiac markers at gene and protein levels. High levels of CD44, CD90, CD73, and CD105 were expressed on the surface of hADSCs. Treated encapsulated hADSCs (3D) presented significantly higher mRNA expression of HAND1 (1.54-fold), HAND2 (1.59-fold), cTnI (1.76-fold), MLC2v (1.4-fold), Cx43 (1.38-fold), ßMHC (1.34-fold), GATA4 (1.48-fold), and NKX2.5 (1.66-fold) in comparison to 2D conditions at four weeks after induction. The protein expressions of NKX2.5 (0.78 vs 0.65), cTnI (1.04 vs 0.81), and Cx43 (1.11 vs 1.08) were observed in the differentiated cells both in 3D and 2D groups, while control cells were absolutely negative for these proteins. The frequency of cTnI and Cx43-positive cells was significantly higher in 3D (24.2 ± 15 and 12 ± 3%) than 2D conditions (19.8 ± 3 and 10 ± 2%). Overall, the results showed that VPA can increase cardiomyogenesis in hADSCs and that fibrin scaffold enhances the inductive effect of VPA. Results of this study may improve cell-based protocols for implementation of more successful cardiac repair strategies.