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Abstract Primary cilia are microtubule‐based organelles that function as cellular antennae to address multiple metabolic and extracellular cues. The past decade has seen significant advances in understanding the pro‐tumorigenic role of N6‐methyladenosine (m6A) modification in tumorigenesis. Nevertheless, whether m6A modification modulates the cilia dynamics during cancer progression remains unclear. Here, the results show that m6A methyltransferase METTL3 regulates cilia length in cancer cells via HDAC6‐dependent deacetylation of axonemal α‐tubulin, thereby controlling cancer development. Mechanically, METTL3 positively regulates the translation of HDAC6 in an m6A‐dependent manner, while m6A methylation of A3678 in the coding sequence (CDS) of HDAC6 ameliorates its translation efficiency via facilitating the binding with YTHDF3. The upregulation of HDAC6 induced by METTL3 over‐expression is capable of inhibiting cilia elongation and acetylation of α‐tubulin, thereby shortening cilia length and accelerating the progression of cervical cancer both in vitro and in vivo. Collectively, depletion of METTL3‐mediated m6A modification leads to abnormally elongated cilia via suppressing HDAC6‐dependent deacetylation of axonemal α‐tubulin, ultimately attenuating cell growth and cervical cancer development.

Background: Some recommendations and health protocols were presented to control COVID-19 after the outbreak, such as the use of face masks, observing social distancing, closure of schools, etc. Despite these protocols, we witnessed different peaks and variants of COVID-19 for more than two years. This study investigated some risky behaviors, such as not wearing face masks, violating social distancing, and attendance at crowded places. Methods: We used a checklist containing some demographic, caring behaviors, and survey questions. Data were collected from four universities in Iran. Patients with positive PCR results for COVID-19 were included in the study. The minimum sample size required for this study was estimated to be 407, which were selected from the universities by proportional allocation. Results: The use of face mask proportion was different between the upper and lower age groups of 50 years (P=0.005). Also, this proportion was different in the subgroups of educational level, job status, income, and living area. Conclusion: The space of most crowded places was confined and many patients did not use face masks and did not observe social distancing in these places. Hence, social distancing and face mask use can be considered the most important caring behaviors to deal with COVID-19.

Background: Human chorionic gonadotropin (hCG) is a polypeptide hormone synthesized during pregnancy and is also upregulated in some pathologic conditions such as certain tumors. Its measurement is essential for diagnosing pregnancy and malignancies. Despite numerous attempts to introduce an accurate method capable of detecting hCG levels, several limitations are found in previous techniques. This study aimed to address the limitations of current hCG assay methods by designing an electrochemical biosensor based on voltammetry for the rapid, selective, inexpensive, and sensitive measurement of hCG levels. Methods: A carbon paste electrode was prepared and functionalized by para-aminobenzoic acid. The primary anti-β-hCG monoclonal antibody was immobilized on the electrode surface by activating the carboxyl groups with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide solutions. The study also involved optimizing parameters such as the time for primary antibody fixation, the time for hCG attachment, and the pH of the hydrogen peroxide solution to maximize the biosensor response. Different concentrations of hCG hormone were prepared and loaded on the electrode surface, the secondary antibody labeled with HRP enzyme was applied, thionine in phosphate-buffered saline solution was placed on the electrode surface, and the differential pulse electrical signal was recorded. Results: The linear range ranged from 5 to 100 mIU/ml, and the limit of detection was calculated as 0.11 mIU. The relative standard deviation was 3% and 2% for five repeated measurements of commercial standard samples with concentrations of 2 and 20 mIU/mL, respectively. The percent recovery was obtained from 98.3% to 101.5%. Conclusion: The sensor represents a promising advancement in hCG level measurement, offering a potential solution to overcome the existing limitations in current diagnostic strategies. Simple and inexpensive design, detecting hCG in its important clinical range during early pregnancy, and successful measurement of hCG in real serum samples are the advantages of this sensor.

Abstract Introduction In the current study, we investigate whether oral administration of agmatine (AGM) could effectively reduce motor and cognitive deficits induced by bile duct ligation (BDL) in an animal model of hepatic encephalopathy (HE) through neuroprotective mechanisms. Methods The Wistar rats were divided into four groups: sham, BDL, BDL+ 40 mg/kg AGM, and BDL+ 80 mg/kg AGM. The BDL rats were treated with AGM from 2 weeks after the surgery for 4 consecutive weeks. The open field, rotarod, and wire grip tests were used to assess motor function and muscle strength. The novel object recognition test (NOR) was performed to evaluate learning and memory. Finally, blood samples were collected for the analysis of the liver markers, the animals were sacrificed, and brain tissues were removed; the CA1 regions of the hippocampus and cerebellum were processed to identify apoptosis and neuronal damage rate using caspase‐3 immunocytochemistry and Nissl staining. Results The serological assay results showed that BDL severely impaired the function of the liver. Based on histochemical findings, BDL increased the neuronal damage in CA1 and Purkinje cells, whereas apoptosis was significantly observed only in the cerebellum. AGM treatment prevented the increase of serum liver enzymes, balance deficits, and neuronal damage in the brain areas. Apoptosis partially decreased by AGM, and there were no differences in the performance of animals in different groups in the NOR. Conclusions The study suggests AGM as a potential treatment candidate for HE because of its neuroprotective properties and/or its direct effects on liver function.

PurposeCancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients.MethodsOCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis.ResultsFurther TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, P=0.001) and P16 (OR=5.65, P

Introduction:It has been reported that inflammation may be a potential risk factor for the progression of epistaxis. Due to the major roles played by Th17 in the induction of inflammation, the present study aimed to assess the serum levels of Interleukin 17A (IL-17A) and IL-23, as the most important cytokines in the Th17 pathway, as well as IFN-g, IL-4, and IL-10 serum levels, as regulatory cytokines for Th17 cells in patients with idiopathic epistaxis. Materials and Methods:The serum levels of IL-4, IL-10, IL-17A, IL-23, and IFN-g were evaluated in 90 patients with idiopathic epistaxis and 90 healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. Results:The obtained results pointed out that the serum levels of IL-17A and IL-10, but not IL-4 and IL-23, were significantly up-regulated, and IFN-g serum levels were significantly down-regulated in patients with idiopathic epistaxis. Furthermore, female patients with epistaxis had higher IL-10 serum levels. Conclusions:As evidenced by the results of the present study, IL-17A is the main cytokine which participates in the pathogenesis of idiopathic epistaxis; moreover, in association with IL-10, it can be regarded as the suppressor of IFN-g in patients.

Abstract Pesticides are classified into several groups based on their structure, including fungicides, insecticides, herbicides, bactericides, and rodenticides. Pesticides are toxic to both humans and pests. For pest control, a very small amount of pesticides reach their target pests. Therefore, nearly all pesticides move through the environment and exert adverse effects on beneficial biota and public health. These chemicals pollute the water, soil, and atmosphere of the ecosystem. Agricultural workers in greenhouses and open fields, exterminators of house pests, and workers in the pesticide industry are occupationally exposed to pesticides. Pesticide exposure in the general population primarily happens through the consumption of food and water contaminated with pesticide residues; however, substantial exposure can also occur outside or inside the house. Currently, intelligent, responsive, biodegradable, and biocompatible materials have attracted considerable interest for the formulation of green, safe, and efficient pesticides. It was indicated that utilizing nanotechnology to design and prepare targeted pesticides with an environmentally responsive controlled release via chemical modifications and compounds offers great potential for creating new formulations. Furthermore, biopesticides include microbial pesticides, which are naturally happening biochemical pesticides. In addition, pesticidal substances generated by plants with added genetic materials, i.e., plant-incorporated protectants (PIPs), have emerged. Based on the foregoing evidence, various types of pesticides are summarized in this review for the first time. Here, new pesticides including nano-pesticides and biopesticides are discussed while focusing on the most recent findings on targeted and safe nano-formulated biopesticides and nano-pesticides. Graphical Abstract

Background: Type2 Diabetes (T2D) remains one of the most important causes of cardiovascular diseases (CVD). Menopause leads to an increase in CVD and metabolic syndrome, which indicates the role of sex steroids as a protective factor. In the present study, we surveyed the effects of 17β-estradiol (E2) alone and in combination with progesterone (P4) on cardiovascular dysfunction in T2D. Methods: Female ovariectomized (OVX) diabetic rats were divided into eight groups: Sham-Control, Diabetes (Dia), OVX + Dia, OVX + Dia + Vehicle, OVX + Dia + E2, OVX + Dia + P4, OVX + Dia + E2+P4, and OVX + Dia + E2+Vehicle. T2D was induced by a high-fat diet and streptozotocin. E2 and P4 were administrated every four days for four weeks. The heart cytokines and angiotensin II, lipid profile, insulin, water, and food intake and cardiovascular indices were measured. Results: Results showed that single treatment with E2 decreased fasting blood glucose, water, and food intake, atherogenic and cardiac risk indices, and blood pressure. Also, P4 led to a decrease in atherogenic and cardiac risk indices. TNFα and IL-6 levels were increased and IL-10 was decreased in the Dia group, while E2 alone was able to inhibit these changes. The combined use of E2 and P4 eliminated the beneficial effects of E2 on these indices. Although diabetes results in an increment of cholesterol, LDL and triglyceride, hormone therapy with E2 was associated with improved dyslipidemia. Conclusion: The use of E2 alone, and not the individual use of P4, and its combination with E2 improved cardiovascular function in OVX diabetic animals, possibly by reducing the amount of inflammatory cytokines and improving metabolic parameters.

Objective(s): Along with increased intracranial pressure (ICP) and brain damage, brain edema is the most common cause of death in patients with hepatic encephalopathy. Curcumin can pass the blood-brain barrier and possesses anti-inflammatory and antioxidant properties. This study focuses on the curcumin protective effect on intrahepatic and extrahepatic damage in the brain. Materials and Methods: One hundred and forty-four male Albino N-Mary rats were randomly divided into 2 main groups: intrahepatic injury group and extrahepatic cholestasis group. In intra-hepatic injury group intrahepatic damage was induced by intraperitoneal (IP) injection of acetaminophen (500 mg/kg) [19] and included four subgroups: 1. Sham, 2. Acetaminophen (APAP), 3. Normal saline (Veh) which was used as curcumin solvent, and 4. Curcumin (CMN). In extrahepatic cholestasis group intrahepatic damage was caused by common bile duct litigation (BDL) and included four subgroups: 1. Sham, 2. BDL, 3. Vehicle (Veh), and 4. Curcumin (CMN). In both groups, 72 hr after induction of cholestasis, brain water content, blood-brain barrier permeability, serum ammonia, and histopathological indicators were examined and ICP was measured every 24 hr for three days.Results: The results showed that curcumin reduced brain edema, ICP, serum ammonia, and blood-brain barrier permeability after extrahepatic and intrahepatic damage. The maximum effect of curcumin on ICP was observed 72 hr after the injection.Conclusion: According to our findings, it seems that curcumin is an effective therapeutic intervention for treating encephalopathy caused by extrahepatic and intrahepatic damage.

Background: Hempseed oil is a suitable source of alpha-linolenic acid, an omega-3 polyunsaturated fatty acid. In this study, we aimed to evaluate the effects of hempseed oil on the plasma levels of inflammation markers interleukin-6 and tumor necrosis factor-α in maintenance hemodialysis patients.Methods: This 8-week single-blind randomized study was conducted on 97 hemodialysis patients. Patients were randomly assigned to the hempseed oil (receiving 20 ml of hempseed oil per day) or control (receiving no intervention) group. The plasma concentrations of interleukin-6 and tumor necrosis factor-α were measured at baseline and at the end of the study.Results: The plasma concentrations of interleukin-6 and tumor necrosis factor- α changed significantly in neither of the group. Furthermore, the comparison of changes in the concentrations of IL-6 and TNF-α throughout the study showed no significant difference between the hempseed oil and control groups.Conclusion: Hempseed oil consumption did not decrease inflammation in the maintenance hemodialysis patients.

Background: Coronary artery ectasia (CAE) is a rare cardiovascular disorder with unknown mechanisms and related risk factors. The roles played by homocysteine in induction of cardiovascular diseases (CVDs) have also been documented previously. This project was designed to assess the relationship between opium and CAE and coronary artery disease (CAD). Methods: This cross-sectional study was performed on 46 patients with CAE, 30 patients with CAD, and 42 cases without CAE and CAD (controls). Demographic data and information regarding opium consuming and also smoking were collected using a standard checklist. Serum levels of homocysteine, creatinine (Cr), urea, fasting blood glucose (FBG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and cholesterol were determined. Findings: Statistical analysis revealed that opium consumers were significantly higher in patients with CAD and CAE when compared to healthy controls. Opium increased serum levels of Cr in the normal controls, and decreased HDL in the patients with CAD. Homocysteine serum levels were not significantly different between the groups. Conclusion: The results of study showed that opium addiction was associated with increased risk of CAE and CAD, independent of homocysteine serum levels.

Background: Alterations in the methylation levels of tumor suppressor genes are considered as one of the essential aspects of malignancies. The present study explored the association of O6-methylguanineDNA methyltransferase (MGMT) gene promoter methylation, as a tumor suppressor, with some organochlorine pesticides (OCPs) in primary brain tumor (PBT) patients. Methods: The present study was conducted on a total of 73 PBT patients. The patients’ serum was analyzed using gas chromatography for seven OCP derivatives. The methylation-specific PCR (MSP) method was also used to determine the methylation status of the MGMT promoter. Results: The current findings demonstrated that the methylation of MGMT promoter occurred in 22 out of 34 glioma cases (64%), but in only one out of 35 meningioma cases. No MGMT promoter methylation was observed in other PBT, hemangioma, and anaplastic medulloblastoma stages. Besides, there were significant associations between MGMT methylation and γ-HCH (odds ratio [OR]: 1.50; 95% CI: 1.03- 2.40, P = 0.04), 4,4DDE (OR: 1.44; 95% CI: 1.01- 2.05, P = 0.02), 2,4 DDT (OR: 1.23; CI: 1.04- 1.45, P = 0.03), and 4,4DDT (OR: 1.46; CI: 1.23- 2.15, P = 0.02) in glioma patients. Conclusion: The results of the study suggested that the hypermethylation of the MGMT promoter in glioma patients is associated with increased OCPs in their serum, especially γ- HCH, 4,4DDE, 2,4DDT, and 4,4DDT. Moreover, it may lead to the hypermethylation of the MGMT promoter gene. Hence, it can be concluded that exposure to OCPs may potentially induce glioma.

BackgroundThe present systematic review and meta-analysis aimed to ascertain if the circulating levels of apelin, as an important regulator of the cardiovascular homeostasis, differ in patients with cardiovascular diseases (CVDs) and controls.MethodsA comprehensive search was performed in electronic databases including PubMed, Scopus, EMBASE, and Web of Science to identify the studies addressing apelin in CVD up to April 5, 2021. Due to the presence of different units to measure the circulating levels of apelin across the included studies, they expressed the standardized mean difference (SMD) and their 95% confidence interval (CI) as summary effect size. A random-effects model comprising DerSimonian and Laird method was used to pool SMDs.ResultsTwenty-four articles (30 studies) comprised of 1793 cases and 1416 controls were included. Pooled results obtained through random-effects model indicated that apelin concentrations in the cases' blood samples were significantly lower than those of the control groups (SMD = -0.72, 95% CI: -1.25, -0.18, P = 0.009; I2 = 97.3%, PConclusionThe association of apelin with CVDs is different based on the region and disease subtypes. These findings account for the possible usefulness of apelin as an additional biomarker in the diagnosis of CVD in diabetic patients and in the diagnosis of patients with CAD. Moreover, apelin/HDL-c, apelin/LDL-c, and apelin/TC ratios could be offered as diagnostic markers for CVD.

Abstract Background CD36 is associated with regulation of lipid metabolism, atherosclerosis, and blood pressure. Moreover, its variation may be involved in the development of hypertension and/or coronary artery disease (CAD). The present study was conducted to investigate the possible association of CD36 rs1761667 (G > A) polymorphism with hypertension and/or CAD in the southeastern of Iran. Methods The present observational study was composed of 238 subjects who were admitted for coronary angiography, and divided into four groups: 1) hypertensive without CAD (H-Tens, n = 52); 2) hypertensive with CAD (CAD + H-Tens, n = 57); 3) CAD without hypertension (CAD, n = 65); and 4) non-hypertensive without CAD as the control group (Ctrl, n = 64). The CD36 rs1761667 polymorphism was genotyped with PCR-RFLP method. Association between CD36 rs1761667 genotypes and the risk of CAD and hypertension was assessed using multinomial regression by adjusting for age, sex, creatinine, fasting blood sugar (FBS), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Results In the present study, minor allele (A) frequency was 0.36. The genotype, but not allele frequency of the CD36 rs1761667 was significantly different between the four study groups (p = 0.003). Furthermore, using a recessive inheritance model CD36 rs1761667 polymorphism was significantly associated with an increased risk of CAD with hypertension (OR = 5.677; 95% CI = 1.053–30.601; p = 0.043). However, using the dominant model of CD36 rs1761667 had a protective effect on H-Tens and CAD patients. Conclusion The present findings revealed an association between CD36 rs1761667 polymorphism and susceptibility to hypertension and/or CAD in a southeastern Iranian population.

Protective effects of estrogen (E2) on traumatic brain injury (TBI) have been determined. In this study, the hepatoprotective effects of E2 after TBI through its receptors and oxidative stress regulation have been evaluated. Diffuse TBI induced by the Marmarou method in male rats. G15, PHTPP, MPP, and ICI182–780 as selective antagonists of E2 were injected before TBI. The results indicated that TBI induces a significant increase in liver enzymes [Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutamyl transferase (GGT)], and oxidants levels [Malondialdehyde (MDA), Nitric oxide (NO)] and decreases in antioxidant biomarkers [Glutathione peroxidase (GPx) and Superoxide dismutase (SOD)] in the brain and liver, and plasma. We also found that E2 significantly preserved levels of these biomarkers and enzymatic activity. All antagonists inhibited the effects of E2 on increasing SOD and GPx. Also, the effects of E2 on brain MDA levels were inhibited by all antagonists, but in the liver, only ICI + G15 + E2 + TBI group was affected. The impacts of E2 on brain and liver and plasma NO levels were inhibited by all antagonists. The current findings demonstrated that E2 probably improved liver injury after TBI by modulating oxidative stress. Also, both classic (ERβ, ERα) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are affected in the protective effects of E2.

Background: The aim of this study was to assess the relationship between hypertension and aldosterone-renin ratio (ARR) with the severity of coronary artery disease (CAD). Methods: This cross-sectional study was performed on non-diabetic patients who were candidate for coronary angiography in Shafa hospital in Kerman in 2017. The levels of active renin and aldosterone were measured by the radioimmunoassay (RIA) method before angiography. All patients underwent coronary angiography to determine the severity of CAD. The CAD severity was described by the Gensini score. Results: Of the 306 patients, 174 (55.1%) were hypertensive. The overall prevalence of CAD in hypertensive and normotensive groups was not statistically different (39.7% versus 38.9%, p = 0.898). In groups with and without hypertension, normal coronary arteries were found in 60.3% and 60.8%, single-vessel disease in 15.5% and 17.7%, two-vessel disease in 14.4% and 11.5%, and three-vessel disease in 9.8% and 10.0%, respectively. The differences were not significant (p = 0.880). The average Gensini scores in hypertensive and normotensive groups were 29.27 ± 28.42 and 33.74 ± 33.05, respectively with no significant differences (p = 0.370). The mean ARR in those with normal coronaries, one, two, and three-vessel diseases was 3.17 ± 7.63, 2.51 ± 4.21, 1.93 ±1.57, and 1.20 ± 0.68, respectively with no significant difference (p = 0.696). We did not observe any association between the Gensini score and ARR (r = -0.126, p = 0.263). In multivariable linear regression model (Table 3), ARR could not predict the severity of CAD assessed by determining the Gensini score (Beta = -0.463, p = 0.636). Conclusion: There was no significant relation between hypertension and ARR to the severity of CAD.

Background: Diabetes is a global health problem that its prevalence is increasing rapidly. Rosa damascena extract has shown to have an intensive non-competitive inhibitory effect on α-glucosidase in an animal study. The aim of this study was to assess the safety and efficacy of Rosa damascena (RD) Mill in diabetic patients and healthy subjects. Methods: In a triple-blind, placebo and Acarbose-controlled randomized trial in Kerman in the south-east of Iran, we randomly allocated diabetic patients (n=32) and healthy volunteers (n=28) to 100mg Acarbose, 200 mg RD-methanolic extract, 400mg RD-methanolic extract and placebo groups. Over 15 days, the participants were followed up to monitor the changes in blood biochemical parameters and apparent symptoms. Analyses were carried out by intention to treat. Results:RD extract decreased postprandial blood glucose levels comparable to the effects of Acarbose, demonstrating its α-glucosidase inhibitory activity. Besides, fasting plasma glucose levels significantly decreased in patients treated with 400 mg/day RD-methanolic extract compared to the 200 mg RD-methanolic extract (127.6±26.8vs. 165.5±27.1, p=0.041), suggesting that Rosa damascena Mill is effective in a dose dependent manner. No major or minor hypoglycemic event was observed. NO adverse event was observed in the RD treatment groups in comparison with Acarbose or placebo groups. Serum levels of biochemical parameters did not fluctuate significantly in RD treatment groups compared to Acarbose and placebo controls. Conclusion:Rosa damascena not only decreases blood glucose levels, but also is safe to be used for the purpose of controlling blood glucose levels in drug naïve patients with type II diabetes.

Cigarette smoking and opium use are risk factors for coronary artery disease (CAD). It has been known that scavenger receptors such as CD36 and CD68 play critical roles in the pathogenesis of CAD. CD9, as a member of the tetraspanin, has been shown to interact with scavenger receptors. The aim of this study was to investigate the effects of these risk factors on expression levels of CD9, CD36, and CD68 on the THP-1 cell line. The THP-1 cell line treated with cigarette smoke extract (CSE( and opium, both individually and combinatory, in 24 h incubation. The protein and mRNA levels of CD9, CD36, and CD68 were evaluated by flow cytometry and quantitative reverse transcription-Polymerase Chain Reaction (qRT-PCR) techniques, respectively. CD36 and CD68 mRNA and protein expression levels were significantly increased in the cells treated with cigarette smoke extract compared to the control (p

Abstract Background Klotho, possibly an age-regulating protein, is considered an important factor contributing to the lifespan and pathophysiology of hypertension and coronary artery disease (CAD). The present study was carried out aiming to investigate the association of Klotho-rs564481 (C1818T) gene polymorphism with hypertension and CAD. Methods A total of 286 CAD-suspicious subjects were entered into this case-control study. The polymorphism was investigated in hypertensive patients with no CAD (H-Tens, n = 60); hypertensive patients with CAD (CAD + H-Tens, n = 95); CAD patients with no hypertension (CAD, n = 61); and non-hypertensive non-CAD subjects, which were regarded as the control group (Ctrl, n = 70). Genotype and allele frequencies were assessed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results A significant difference was found in allele frequency of Klotho C1818T among the four research groups (P = 0.03). It was also found that wild-type homozygote subjects were negatively associated with hypertension as compared to heterozygote ones (OR = 0.07 [95% CI: 0.008–0.69] P = 0.02). Moreover, in the subgroups older than 57 years old, dominant genetic model demonstrated a negative association with CAD combined with hypertension (OR = 0.31 [95% CI: 0.10–0.95] P = 0.04). Conclusions In conclusion, Klotho C1818T variant may be associated with a decreased risk of hypertension. Moreover, aging enhanced positive effects of the Klotho polymorphism on CAD combined with hypertension, indicating the possibility that the KLOTHO gene might play a part in the age-related occurrence of CAD combined with hypertension.

Background and purpose: Cytokines regulate a broad range of biological and pathological processes. They play an important role in liver damage. Inflammatory and antioxidant factors are important causes of liver damage. Shilajit is known as an anti-inflammatory and antioxidant agent. Therefore, the main aim of this study was to determine the effect of Shilajit on levels of proinflammatory and anti-inflammatory cytokines in liver injury. Materials and methods: In this experimental study, 80 male Wistar rats were randomly divided into two main groups: A and B. Each group was organized into five subgroups: control, acetaminophen (A) or bile duct obstruction (BDL) (B), low dose, high dose, and vehicle. All subgroups except the controls in group A received 500 mg/ kg acetaminophen via IP injection, while BDL was performed in all subgroups in group B. Then in group A, two hours and in group B seven days after injury, the treatment subgroups with drug and vehicle received 150 mg/kg (low dose) and 250 mg/kg (high dose)shilajit and distilled water as vehicle, for one and six days, respectively. After completing treatment, liver samples were taken for laboratory analysis. Results: Low-dose Shilajit treatment reduced IL-10, IL-6, IL-1β, and TNF- α levels, which had been increased by a single dose of 500 mg/kg acetaminophen (p

Objective(s): Traumatic brain injury (TBI) is one of the most common causes of death and disability in modern societies. The role of steroids and melatonin is recognized as a neuroprotective factor in traumatic injuries. This study examined the role of melatonin receptors in the neuroprotective effects of estrogen. Materials and Methods: Seventy female ovariectomized Wistar rats were divided into five groups and two subgroups. All animals underwent brain trauma. The groups were as follow: 1) trauma, 2) melatonin receptor antagonist vehicle + estrogen, 3) MT1 melatonin receptor antagonist + estrogen, 4) MT2 melatonin receptor antagonist+ estrogen, 5) MT3 melatonin receptor antagonist+ estrogen. Brain edema (24 hr), intracranial pressure (ICP) (-1, 0, 1, 4 and 24 hr) and blood–brain barrier (BBB) permeability (5 hr) and aquaporin (AQP4) expression (24 hr) were evaluated after TBI. Results: MT1, MT2 and MT3 melatonin receptors had anti-edema effects while MT1 and MT2 have a role in protecting BBB by estrogen. Furthermore, the activity of MT3 and MT2 melatonin receptors weakened the effect of estrogen on ICP. However, melatonin receptors had no role in the effect of estrogen on AQP4 protein. Conclusion: Based on the above results, it seems that melatonin receptors appear to influence the effect of estrogen in TBI without altering AQP4 expression. The role of the receptors is different in this interaction.

Introduction: The patients with type 2 diabetes (T2D) suffer from the malfunctions of the sexual behaviors, and several mechanisms have been proposed to describe these disorders. The innate immunity may be involved in the malfunctions of T2D patients. Melanoma differentiation-associated protein 5 (MDA5) and retinoic acid (RA)-inducible gene 1 (RIG-1), as the innate immunity receptors, are the responsible molecules for the activation of some intracellular signaling pathways and the induction of inflammation. Thus, this study aimed to examine the molecules which may participate in the induction/stimulation of sexual malfunctions in the female T2D patients. Methods: Sexual functions were evaluated in 41 female T2D patients using the Female Sexual Function Index (FSFI) questionnaire. Real-time polymerase chain reaction (PCR) technique was used to quantify MDA5 and RIG-1 mRNA levels. Results: Results showed that increased RIG-1 mRNA levels were significantly associated with the bad orgasm in the female T2D patients compared to the female patients with good orgasm. Expression of RIG-1 and MDA5 levels were not associated with other sexual functions’ criteria. Conclusion: The findings of this study demonstrated that bad orgasm is associated with the increased RIG-1 expression. Consequently, the correlation between inflammation and bad orgasm in a RIG-1 dependent manner is suggested.

Background: The use of narcotics such as opium exposes addicts as susceptible targets of different diseases so that they might easily be exposed to different diseases such as fungal infections. The present study aimed to investigate the effects of addiction to opium and fungal infection on plasma levels of certain cytokines including interleukin-4 (IL-4), IL-6, IL-17, Interferon gamma (IFN-γ) and transforming growth factor-β (TGF-β).Methods: Present study included 72 individuals who were divided into 4 groups: 1) opium-addicted with fungal infection; 2) opium-addicted without fungal infection; 3) non-opium-addicted with fungal infection; and 4) normal individuals (non-opium-addicted and non-fungal infection). The fungal samples, after being detected and confirmed by a physician, were prepared based on clinical symptoms and then analyzed by direct smear and culture method. The measurement of the plasma level of cytokines was done by enzyme-linked immunosorbent assay (ELISA) method.Findings: The comparison of the mean of the plasma level of cytokines showed that addiction to opium and fungal infection had significant effect on the plasma levels of IL-17, IFN-γ, TGF-β cytokines in all studied groups. The interaction of addiction to opium and fungal infection was only significant in the case of plasma level of IL-6.Conclusion: Addiction to opium and fungal infection, either separately or simultaneously, poses significant effect on the immune system and causes disorders in the cytokine network and the immune system and also provides a suitable environment for fungal infection.

Background: The aim of the present study was to investigate the effects of opium addiction and cigarette smoking on the complete blood count (CBC).Methods: Eighty-six male subjects, including 31 opium-addicted cigarette smokers (OACS), 19 opium-addicted non-cigarette smokers (OANCS), 17 non-opium-addicted cigarette smokers (NOACS), and 19 non-opium-addicted non-cigarette smokers (NOANCS) participated in this study. The CBC test was measured in all individuals.Findings: The OACS had significantly higher white blood cell (WBC), lymphocyte, and red blood cell (RBC) count but lower in mean corpuscular volume (MCV) compared to NOANCS. The OANCS had significantly higher lymphocyte in comparison with NOACS. Our results demonstrated that the number of WBC, lymphocytes, and RBC were significantly higher, while, MCV was lower in OANCS subjects when compared to NOACS. The OACS had significantly higher level of lymphocyte in comparison with NOACS. The mean number of lymphocyte in OANCS was found significantly higher than NOACS. The smokers were shown to have significantly higher levels of WBC compared to NOANCS.Conclusion: Our results showed that opium-addiction, especially when associated with cigarette smoking, has intensive effects on hematological factors and these alteration might leads to greater risk for developing atherosclerosis, cardiovascular diseases, and imbalance in immune system.

Objective(s): Neuroprotective effects of female gonadal steroids are mediated through several pathways involving multiple peptides and receptors after traumatic brain injury (TBI). Two of these peptides are including the regulatory peptides neuromedin U (NMU) and neuromedin S (NMS), and their common receptor neuromedin U2 receptor (NMUR2). This study investigates the effects of physiological doses of estradiol and progesterone on brain edema, NMS and NMU as well as NMUR2 expression following TBI. Materials and Methods: Ovariectomized female rats were given high-and low-dose of female sex steroid hormones through implantation of capsules for a week before trauma. The brain NMUR2 expression, prepro-NMS expression, NMU content, and water content (brain edema) were evaluated 24 hr after TBI induced by Marmarou’s method. Results: Percentage of brain water content in high- and low-dose estradiol, and in high- and low- dose progesterone was less than vehicle (P

Objective(s): The aim of this study was to determine the important molecules involved in apoptosis induction by opium in Jurkat cell line. Materials and Methods: Jurkat cells were incubated 48 hrs with2.86×10-5 g/ml concentration of opium and apoptosis as well as expression levels of related molecules weremeasured. Results: Our results demonstrated that 50.3±0.2 percent of opium treated Jurkat cells were revealed apoptotic features. The levels of mRNA of several pro-apoptotic and anti-apoptotic molecules were increased and decreased, respectively, in the opium treated cells. The results also demonstrated that expression levels of BCL2, DFFA and NOL3 as anti-apoptotic molecules were increased in the opium treated cells. Conclusion: It seems that opium induces apoptosis in Jurkat cells via both intrinsic and extrinsic pathways. Although opium induces apoptosis in the cells but increased expression of some anti-apoptotic molecules may be a normal resistance of the cell for death.

Background: Opiates affect blood factors as well as pain and inflammation in a gender-dependent manner. The aim of the present study was to evaluate the effects of morphine on serum glucose, cholesterol, triglycerides, and urea in gonadectomized and inflammation conditions. Methods: Animals were divided as follows: control group, carrageenan and chronic morphine recipients, acute morphine recipients, chronic morphine recipients, carrageenan recipients, acute morphine and carrageenan recipients, gonadectomized group, gonadectomized recipients of carrageenan, gonadectomized recipients of morphine, gonadectomized recipients of chronic morphine, gonadectomized recipients of carrageenan and chronic morphine, gonadectomized recipients of acute morphine and carrageenan. Findings: Our results have shown that acute and chronic morphine elevates blood glucose level in the acute and chronic morphine group. Cholesterol level has shown to be increasing in the morphine and carrageenan recipient group compared with a group which merely received morphine. Triglyceride has shown to be decreasing in acute and chronic morphine recipient group compared with control group. A significant increase in serum urea was observed in acute and chronic morphine recipients compared with the carrageenan recipient group. Conclusion: Morphine alters the serum glucose, cholesterol, triglyceride, and urea in the normal and inflammatory conditions differently, hence, this finding should be considered in the patients who use morphine as a relief of pain, especially in an inflammatory condition.

Niosomes are used in studies for drug delivery or gene transfer. However, their physical properties and features relative to liposomes are not well documented. To characterize and more rationally optimize niosome formulations, the properties of these vesicle systems are compared to those of liposomes composed of phosphatidylcholine and phosphatidylethanolamine lipids plus cholesterol. Niosomes are highly stable and only slightly more leaky than liposomes as assayed by calcein leakage; the permeability for ions (KCl) is higher than that of liposomes. Contrary to liposomes, the size of niosomes decreases substantially upon freezing in liquid nitrogen and subsequent thawing, as shown by cryo-EM and dynamic light scattering. The packing of niosomal membranes was determined by laurdan fluorescence and is slightly lower than that of liposomes. We did not succeed in the functional reconstitution of the L-arginine/L-ornithine antiporter ArcD2 in niosomes, which we attribute to the non-ionic nature of the surfactants. The antimicrobial peptides alamethicin and melittin act similarly on niosomes and liposomes composed of unsaturated components, whereas both niosomes and liposomes are unaffected when saturated amphiphiles are used. In conclusion, in terms of stability and permeability for drug-size molecules niosomes are comparable to liposomes and they may offer an excellent, inexpensive alternative for delivery purposes.

Background: The risk of infectious, autoimmune and immunodeficiency diseases and cancers rise in opioid addicts due to changes in innate and acquired immune responses. Three types of opioid receptors (К،δ،μ) are expressed on the surface of lymphocytes and mononuclear phagocytes. The present study was designed to examine the effects of different concentrations of opium on the secretion of some cytokines produced by lymphocyte cells. Methods: Jurkat cells were exposed to different concentrations of opium for periods of 6, 24 and 72 h in cell culture medium. The amount of interleukin-6 (IL-6), interferon-γ (IFN-γ) and transforming growth factor-b (TGF-β) were then measured using enzyme-linked immunosorbent assay (ELISA) method. Findings: The results showed that opium increases the secretion of IL-6 in different concentration of opium in 6 h. The amount of IFN-γ decreased in 6 h and increased in 24 h significantly compared with control. On the other hand, opium had an inhibitory effect on the TGF-β secretion in 6, 24 and 72 h. Conclusion: Overall, the study showed that opium stimulates pro-inflammatory and suppressed anti-inflammatory cytokine secretion in Jurkat cells. This may account for the negative effect of opium on the immune system leading to chronic inflammation and a base for many disorders in opium addicts.

Background: Mycotoxins are natural toxins, produced by several fungal species and are associated with morbidity or even mortality in animals, plants, and humans. In this study, 120 samples of herbs and spices in both bulk and packaged forms were prepared in order to measure aflatoxin level in different regions of Iran Methods: The aflatoxin was extracted during Mar to May 2015, using 80% methanol and then purified via immunoaffinity column. Measurements were performed, using high-performance liquid chromatography, equipped with a fluorescence detection system at excitation and emission wavelengths of 365 and 435 nm, respectively. Results: The highest prevalence of aflatoxin contamination in food products was attributed to aflatoxin B1 (30.8%). In addition, the highest prevalence of aflatoxin contamination was reported in red pepper (100%). Examination of effective factors indicated the substantial impact of moisture on aflatoxin level (P=0.046). Conclusion: Even at low levels of aflatoxin, contamination could be a serious threat, given the prevalent use of spices (either raw or not) as ingredients in food preparation. Therefore, regular monitoring of spices, especially chili pepper, is highly recommended.

[This corrects the article DOI: 10.1371/journal.pone.0168312.].

Background and Aim: Early childhood caries (ECC) is one of the most common chronic childhood diseases. Saliva as a host factor plays an essential role in maintaining the integrity of oral structures. The aim of the present study was to compare resting salivary pH, buffering capacity, and secretory immunoglobulin A (sIgA), calcium, and phosphate concentrations between children with and without ECC. Materials and Methods: In this cross-sectional study, samples of unstimulated saliva of 90 children (45 in ECC group and 45 in caries-free group) were taken with Scully method. The pH and buffering capacity were determined by pH meter. sIgA, calcium, and phosphate concentrations were quantitated with ELISA, CPC photometric, and phosphomolybdate/UV methods. Results: The mean resting salivary pH was significantly higher among children without ECC and the buffering capacity was significantly better among this group (P = 0.002). The mean sIgA concentration was significantly higher among the ECC group (P = 0.015). There were no statistically significant differences between calcium and phosphate concentrations between the two groups. Conclusion: The higher mean resting salivary pH and better buffering capacity found in children without ECC are probably the contributing factors that protect against caries development; but further studies are needed to understand the effects of saliva and its characteristics and components on ECC.

INTRODUCTION:Coronary artery disease (CAD) and hypertension are the main reasons of ischemic heart diseases (IHDs). Cytokines as the small glycoproteins are the main arm of immune system and manipulate all of the cardiovascular diseases. The aim of the current study was to examine the effects of treatment of hypertension and CAD on serum levels of IL-6, IL-8, TGF-β and TNF-α. MATERIAL AND METHODS:This interventional study was performed on the patients with hypertension without CAD (group 1), hypertension and CAD (group 2), CAD but not hypertension (group 3) and without hypertension and CAD as controls (group 4). The patients received routine treatment for hypertension and CAD. Serum levels of IL-6, IL-8, TGF-β and TNF-α were analyzed in the groups treated with various drugs, using ELISA technique. RESULTS:With regard to the medications, Atorvastatin, Losartan and Captopril were administered more in patients (groups 1, 2 and 3) than the patients without hypertension and CAD. The results revealed that serum levels of TGF-β and IL-6 were significantly increased and decreased, respectively, in the groups 1, 2 and 3 when compared to group 4. Serum levels of TGF-β were also increased in females in comparison to males in the group 4. DISCUSSION:According to the results it seems that Atorvastatin, Losartan and Captopril have reduced inflammation in in vivo conditions via downregulation of IL-6 and upregulation of TGF-β.

Objectives: The purpose of this study was to evaluate the role of female sexual hormones on the intestinal NF-κB levels following traumatic brain injury (TBI) induction. Materials and methods: Diffuse TBI was induced by Marmarou method in ovariectomized (OVX) female rats. Rats randomly assigned into 10 groups: intact, sham+OVX, TBI, TBI+OVX, vehicle, estradiol (E2), progesterone (P), E2+P, PPT and DPN (estrogen receptor alpha and beta agonists, respectively). The intestinal NF-κB p50 and p65 levels were measured by ELISA method 5 days after TBI. Results: The intestinal levels of NF-κB p65 were decreased in TBI group vs intact group (P<0.001). All treatment groups had caused a significant reduction in intestinal levels of NF-κB p65 (P<0.001) vs OVX + TBI. The trauma induction doesn't have any effect on the intestinal NF-κB p50 levels. The OVX+TBI animals treated with estrogen, progesterone and estrogen+ progesterone showed a significant reduction (P<0.05) vs OVX + TBI (P<0.001). PPT had caused a significant reduction in intestinal levels of NF-κB p50 (P <0.05) compared to OVX + TBI. PPT and DPN significantly increased the intestinal levels of NF-κB p50 vs vehicle group (P <0.05). Conclusion: The binding activity of different subunits of NF-κB (p50 and p65) varies following traumatic brain injury. Also, because the NF-κB binding activity reduced in intestinal tissue after treatment with steroids, it is possible that steroids do their performance by reducing the activity of NF-κB and thereby reduce the production of intestinal inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Cytokines, which typically regulate the immune responses, play a role in cardiovascular diseases such as coronary artery diseases (CAD) and ischemic heart diseases (IHD). The aims of this study were to evaluate serum levels of IL-6, IL-8, TGF-β and TNF-α in patients with or without CAD, as well as stable angina, and to assess the effects of drug administration on the serum levels of these cytokines. Serum levels of the cytokines were analyzed in the three groups: patients with acute coronary syndrome, stable angina and participants with normal coronary arteries as controls. Cohort study of the patients showed that Nitrocontin was the only drug used in a significantly different pattern between the groups where it was used less frequently in patients with stable angina compared to the acute coronary syndrome or control groups. Serum levels of the evaluated cytokines were not different neither between the studied groups nor between the groups with variable Gensini scores. However, IL-8 in controls that were not engaged in regular exercise was higher than the controls performing regular exercise. In the stable angina group, TNF-α in non-smokers was higher than the smokers. It was revealed that serum levels of pro-inflammatory cytokines are not associated with atherosclerosis and stable angina in patients from the South-East of Iran. However, suppressed expression of TGF-β, may increase the risk of CAD. Exercise can reduce the risk of CAD through downregulation of pro-inflammatory cytokines.