Polymorphisms in Phase I (CYP450) Genes CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP19A1 (rs749292) and CYP2C8 (rs1058930) and Their Relation to Risk of Breast Cancer: A Case-Control Study in Mazandaran Province in North of Iran

BACKGROUND: The second leading cause of cancer-related death in women is breast cancer. Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. In the metabolism of xenobiotic, cytochrome P450s or monooxygenases perform an important function by catalysing the hydroxylation reaction. In this study, the susceptibility and genetic polymorphisms of CYP450 isoenzymes was investigated that may have an etiological role in breast cancer. AIM: The main purpose of this study was to evaluate the association of CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP2C8 (rs1058930), and CYP19A1 (rs749292) polymorphisms with the risk of breast cancer in Mazandaran province. MATERIAL AND METHODS: This cross-sectional case-control study were recruited 72 patients and 51 healthy individuals and was performed between March 2018 to May 2018 in the Oncology Department at Imam Hospital in Sari city, Iran. Peripheral blood samples were collected in EDTA tube, and DNA extraction was performed using the salting-out method and WizPrep extraction kits. Breast cancer patients with known clinicopathological characters and healthy women as control group were genotyped for genes polymorphisms by PCR-RFLP technique, using restriction enzymes. Chi-square, Fisher exact test and Logistic regression model, were applied for statistical analysis. RESULTS: The results of the experiments showed that there was a significant relationship between two groups and the age of the patients is significantly higher than the control group (p = 0.044). According to the chi-square and Fisher exact test, education, pregnancy, menopause status and oppose were significant between the two groups. Based on using a logistic regression model in two normalized and age-adjusted models to finding relationship between the genotypes of each gene and breast cancer risk, it was determined that in the CYP2C8 genotype, those who have the CG allele have a 7.74 degree increased risk of breast cancer (CI = 95% 0.95-62.5) and in the CYP19A1 gene, individuals with GA genotype, increased risk of breast cancer (CI = %95 1.52-27.21), about the CYP1B1 gene, people with two genotypes of CG + GG had higher risk of breast cancer (CI = %95 1.19-5.71) and allele G has decreased risk of breast cancer in this gene (P = 0.0271), also allele G in CYP2C8 gene had the protective effect (P = 0.02). In the age-adjusted model, for the CYP2C8 gene, GG genotype increased risk of breast cancer (CI = %95 1.11-75.84) as well as, the CG + GG genotype in CYP1B1 gene (CI = %95 1.31-6.57). CONCLUSION: Our results confirm the association between CYP2C8 (rs1058930), CYP19A1 (rs749292) and CYP1B1 (rs1056836) gene polymorphisms and increased risk of breast cancer in women in Mazandaran province

Effect of fruit essential oil on ephedrine induced manic like behavior: evidence from a new protocol

Introduction: Estimating ephedrine’s effect on animal’s locomotor activity and evaluation of cumin fruit essential oil (FEO) effect and mechanism of ephedrine-induced hyper-locomotion.Methods: A new protocol developed for evaluation of manic behavior induced by ephedrine in a dose and time dependent manner. Following the suppressive effects of cumin FEO on acquisition and expression of ephedrine induced manic behavior was examined. Furthermore, the effect of L-NAME on expression of manic behavior and effect of bicuculline on suppressive effects of cumin FEO was evaluated.Results: Ephedrine at the dose of 100 mg/kg (i.p.) in a five days protocol significantly increased the locomotor activity in mice. In addition, cumin FEO at the specific dose of 2% significantly suppressed the acquisition and expression of hyperactivity induced by ephedrine. L-NAME at doses of 30 (p<0.01) and 40 mg/kg (p<0.05) showed similar effects as cumin FEO at the dose of 2%. Bicuculline (as a GABAA antagonist) at the specific dose of 2 mg/kg (p<0.01) could significantly reverse the suppressive effects of cumin at the dose of 2%.Conclusion: It could be concluded that cumin can suppress the manic behavior induced by ephedrine through the both previously suggested mechanisms of nitric oxide syntheses pathway and GABAergic system.Declaration of Interest:None.Keywords: Cuminum cyminum fruit, Ephedrine, Manic disorder

Ameliorative Effect of Melatonin Against Reproductive Toxicity of Tramadol in Rats via the Regulation of Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis-related Gene Expression Signaling Pathway

Background: The aim of the present study was to investigate the protective properties of melatonin (MT)against oxidative stress, mitochondrial dysfunction, and apoptosis induced by tramadol-reproductive toxicityin male rats.Methods: The rats were divided into the 7 groups of control, melatonin (1.5 mg/kg), tramadol (50 mg/kg), andmelatonin (1, 1.5 and 2.5 mg/kg) administered 30 minutes before tramadol and vitamin C group (100 mg/kg).All injections were performed intraperitoneally. After administration for 3 consecutive weeks, the animals werekilled and testis tissues were used for assessment of oxidative stress markers including lipid peroxidation(LPO), glutathione (GSH) content and protein carbonyl (PrC), and sperm analysis. Mitochondria were isolatedfrom rat’s testis using differential centrifugation technique and were studied in terms of mitochondrialviability, mitochondrial membrane potential (MMP), and mitochondrial swelling. The other part of the tissuesample was placed in RNA protector solution for assessment of Bax and Bcl-2 gene expression through realtime polymerase chain reaction (real-time PCR) assay.Findings: Tramadol caused a significant decline in epidermal sperm count, motility, and morphology, as wellas a significant decrease in GSH level and mitochondrial function, and a significant evaluation of LPO, PrC,MMP, and mitochondrial swelling. In addition, tramadol induced a significant decrease in Bcl-2 geneexpression, and increase in Bax gene expression. However, pretreatment of rats with MT improved spermanalysis, and testicular antioxidative status, and mitochondrial function. Furthermore, MT pretreatmentregulated testicular Bcl-2 and Bax expressions.Conclusion: Considering the protective effects of MT against reproductive toxicity induced by tramadol, thiscompound can be used as a possible agent for the prevention and treatment of tramadol-induced reproductivetoxicity

Evaluation of the glycemic effect of methotrexate in psoriatic arthritis patients with metabolic syndrome: A pilot study

Methotrexate (MTX) is a systemic immunosuppressant drug used for the treatment of psoriasis and psoriatic arthritis. Previous studies demonstrated a potential association between psoriasis and diabetes mellitus, obesity, atherosclerosis, hypertension, eventuating into metabolic syndrome. This study aimed at exploring the glycemic effects of MTX in psoriatic arthritis (PsA) patients. In this prospective cross-sectional study, 27 patients with PsA were evaluated. The status of PsA and presence of accompanying metabolic syndrome was determined by standard criteria and indices. Blood indicators including HbA1c, erythrocyte sedimentation rate, fasting blood sugar, total cholesterol, high-density lipoprotein, triglycerides, and C-reactive protein were examined before and 12 weeks after MTX therapy. There were no significant changes between HbA1c levels before and after MTX therapy in both genders (men: P=0.131, women: P=0.803). In addition, HbA1c levels in PsA patients with metabolic syndrome were not different before and after treatment (P=0.250). Finally, HbA1c levels did not change in PsA patients without metabolic syndrome before and after therapy (P=0.506). MTX in PsA patients does not appear to have hyperglycaemic effects in the short-term and can be safely used in patients with metabolic syndrome and diabetes

Evaluation of G2677T/A polymorphism of MDR1 gene by polymerase chain reaction in Mazandaran province, Iran

The human MDR1 gene encodes for a P-glycoprotein (PGP), which acts as an efflux pump that transports a large variety of substrates from the inside of cells to the outside until protection against xenobiotics. The G2677T/A polymorphism in exon 21 is associated with PGP expression and function in humans. The present study was aimed to determine the frequencies of this polymorphism in a healthy population from Mazandaran province of Iran. A total of 120 unrelated healthy subjects from Mazandaran province, residing in Sari, coming for blood donating at Sari Blood Transfusion Center were enrolled. Genomic DNA was extracted from the peripheral blood lymphocytes of each subject. All subjects were genotyped for G2677T/A polymorphism by polymerase chain reaction-restriction fragment length polymorphism method. The genotype frequencies were G2677G (65%), G2677T (20.83%), G2677A (14.17%) and TT, AA, TA genotypes were not observed. Moreover, frequency of G allele (82.5%) was significantly (p ˂ 0.05) higher than the T (10.42%) and A (7.08%). This is the first study to investigate the G2677T/A polymorphism of MDR1 gene in population from Mazandaran province of Iran. These data may be relevant for dose recommendation of PGP substrate drugs and can help for individualizing drug therapy of organ transplantation and important diseases such as cancer and AIDS, congestive heart failure and etc

Effect of a Powdered Ginger Rhizome, Fenugreek Seed and Alhagi Manna Supplement in Increasing Muscle Mass and Body Composition in Male Bodybuilders

Background and purpose: In recent years, consumption of commercial protein supplements and hormones that improve body appearance endangers the health of athletes especially in bodybuilding sport. Recently, use of plant extracts to reduce the side effects of drugs and improving physical activity has gained a lot of attention. The aim of this study was to investigate the effect of a supplement (mixture powder of Fenugreek seeds, rhizomes of Ginger and Alhaji manna) on increasing muscle strength and body composition in athletes in Mashhad, Iran, 2015. Materials and Methods: A quasi-experimental study with pretest and posttest design was carried out in which 40 male athletes were selected using stratified random sampling. The participants had at least one year activity in fitness clubs. They were divided into control and experimental groups (n = 20 per group). The experimental group performed specific exercises for six weeks and had a daily intake of 5 grams of the supplement (in non-training days and one hr before the exercises). Data analysis was done in SPSS V.20 applying Mann Whitney and Wilcoxon tests. Results: The Wilcoxon test showed that taking the supplement in six weeks of bodybuilding exercises increased the factors influencing body composition and muscle strength in the experimental group (p≤0.05). Conclusion: According to this study, a mixture powder of Fenugreek seeds, rhizomes of Ginger and Alhaji manna is helpful in improving muscle strength and body composition in athletes

Polymorphisms and diazinon and malathion levels in the etiology of breastcancer: a case-controlstudy in Mazandaran Province, North of Iran

Breast cancer is the first leading cause ofcancer-related death inwomen. Xenobiotic-Metabolizing Enzymes (XMEs) contributeto the detoxification of numerous cancer therapy-inducedproducts. In the metabolism of xenobiotics, cytochromeP450s or monooxygenases and Glutathione –s transferase(GSTs) perform an important function by catalyzingthe hydroxylation reaction andconjugationofglutathione(GSH) to a wide variety of xenobiotics. Pesticides, whichare excessively used in northern Iran, are one of the mostimportantrisk factors for breast cancer incidence. Theydetoxify by phase I and II enzymes. The aim of this studywas to evaluate the association of CYP1A1(rs4646421),CYP1B1(rs1056836),CYP2C8(rs1058930),CYP19A1(rs749292) and GSTP1(rs 1695) polymorphisms and serumlevels of pesticides (Diazinon and Malathion) with therisk of breast cancer in Mazandaran province. This crosssectionalcase-control study included 72 patients and 51healthy individuals who were recruited.It wasperformedbetweenOctober 2017 to May 2018 in Oncology departmentat Imam Hospital inSari City.Breast cancer patientswith knownclinicopathological characters and healthywomen, as control, were genotyped for genes polymorphismsby PCR-RFLP and GC-MS method used for quantificationof poisons.Chisquare test, Fisher exact test,andlogistic regression model were applied for statistical analysis.The results of the experiments showed that thereweresignificant relationships between two groups andthe age of the patients wassignificantly higher than thecontrol group(p = 0.044).Regarding the relationship betweenthe genotypes of each gene and breast cancer risk,using a logistic regression model in two normalized andage-adjusted models, it was determined that in CYP2C8genotype, those havingtheCGallele, increased the risk ofbreast cancer in adjusted model (CI=95%1.11,75.84).In the CYP19A1gene of individuals with GA genotype,the risk of breast cancer increasedinnon-adjusted model(CI95%=1/52-27/21) about the CYP1B1 gene, people withtwo genotypes of CG + GGwereassociated with a higherrisk of breast in non-adjusted and adjusted model (CI71/5– 19/1 95% =)( CI=95% 1.31,6.57). In CYP2C8gene,the Gallelehada protective effect on breast cancer and decreasedthe risk of breast cancer (P = 0.02) and in GSTP1gene,theGallele increased the riskof breast cancer(P=0.0480).Moreover,in CYP1B1 gene, G alleledecreased the riskofbreast cancer (P=0.0271).Regardingthe serum levels of OPs,Diazinon in the case group hada much lower level than thecontrol groupbut(p<0.001) there was a significant relationshipbetween serum levels of Diazinon and risk of breastcancer (p<0.001). The results of the current studyconfirmedthe association between CYP2C8(rs1058930),CYP19A1(rs749292) and CYP1B1(rs1056836)gene polymorphismsand increased the risk of breast cancer.Also,there was a significantrelationship between serum levels of Diazinon andrisk of breast cancerin women in Mazandaran province

Hypothermic activity of acetaminophen; Involvement of GABAA receptor, theoretical and experimental studies

Objective(s):The mechanism of hypothermia action of acetaminophen (APAP) remains unclear even 125 years after its synthesis. Acetaminophen produces hypothermia. The mechanism of this reduction in core body temperature is not clear but evidence shows that it is not dependent on opioid and cannabinoid receptors. Because of strong documents about the roles of GABA and benzodiazepine receptors in hypothemic activity of some drugs such as diazepam, we determined if these receptors also contributes to the hypothermic effect of APAP. Materials and Methods: Diazepam (5 mg/kg, IP) was used for induction of hypothermia. Flumazenil (10 mg/kg, IP) or picrotoxin (2 mg/kg, IP) used for reversal of this effect. Rats injected with APAP (100, 200 or 300 mg/kg, IP). Baseline temperature measurements were taken with a digital thermometer via rectum. To evaluate the structural correlation between APAP and benzodiazepine receptor ligands, numerous models are selected and studied at HF/6-31G* level of theory. Relative energies, enthalpies and Gibbs free energies were calculated for all selected drugs. Results:Diazepam induced hypothermia was reversed by flumazenil or picrotoxin. Rats injected with APAP displayed dose- and time-related hypothermia. For combined administration, the hypothermic effect of APAP (200 mg/kg) was strongly reduced by pretreatment with picrotoxin or flumazenil

How rational Aminoglycosides are being used in critically ill patients? Results from a teaching hospital in north of Iran

Background: Resistance to antimicrobial agents including aminoglycosides (AGs) is a great concern that is mainly related to inappropriate use. Since there were not adequate data regarding how rationally AGs are being prescribed in our critically ill patients, this study was conducted to determine the main issues in the area of appropriate use of this antibiotic class.   Methods: One hundred patients who were in the intensive care units (ICUs) of Imam Khomeini Teaching Hospital from February 2012 to August 2012 were included. A data gathering form was prepared based upon the recommendations provided by Up-to-date (20.1) 2012 and Medscape 2013. All demographic characteristics and other information about time of beginning and duration of dosage, interval of administration of AGs and creatinine (Cr) level were collected. In statistical analysis, SPSS Version 16 software was used. Independent samples t-test was used to compare the quantitative and chi-square for qualitative variables.  Results: Sixty six (66%) of patients received gentamicin and 38% received amikacin. In 27% of patients, serum creatinine (Cr) had been checked before and after AGs administration and 4 patients had no renal function monitoring. Monitoring of serum concentration and Cr clearance estimation was not carried out for any patients. Culture and laboratory sensitivity tests were done on 17 patients and E-coli (57%) was the most common isolated organism.  Conclusion: The results of this study revealed that majority of the hospitalized patients in the ICU and the dosage of AGs had not been adjusted to renal function

Role of rs4149056 Polymorphism of SLCO1B1 Gene in Myopathy Caused by Atorvastatin in Cardiovascular Patients in West of Mazandaran Province

Background and purpose: Statins are among the most widely used drugs in treatment of cardiovascular diseases. Reducing the side effects of these drugs is of great importance in preventing treatment failure. The aim of this study was to investigate the role of rs4149056 polymorphism in statin-induced myopathy in patients with cardiovascular diseases in West of Mazandaran province, Iran. Materials and methods: A descriptive cross-sectional study was carried out in 161 patients taking atorvastatin who attended Cardiovascular Clinic in Ramsar Imam Sajjad Hospital and Tonekabon Shahid Rajaee Hospital, 2017-2018. All patients were given atorvastatin at 40 mg daily for 8 weeks and all lipid markers and CPK enzyme levels as a measure of myopathy were measured. Then, the patients received atorvastatin at 20 mg for 4 weeks and all lipid markers were measured again. PCR-ARMS method was used to determine the distribution of rs4149056 polymorphism. Results: According to findings, reducing the dose of atorvastatin caused significant differences in total cholesterol and LDL levels (P0.05). Drug dose change caused significant differences in levels of triglycerides in patients with TC genotype and HDL in patients with CC genotype (P<0.05). Moreover, in patients with CC genotype, the percentage of those with high levels of CPK was two times higher than patients with normal CPK. Conclusion: Current study could be of help in predicting the incidence of myopathy in patients receiving statins and preventing the side effects of these drugs