Metformin enhances anti-cancer properties of resveratrol in MCF-7 breast cancer cells via induction of apoptosis, autophagy and alteration in cell cycle distribution.

Breast cancer is the fifth leading cause of death, worldwide affecting both genders. Accumulating evidence suggests that metformin, an oral hypoglycemic agent used in the management of type 2 diabetes, exerts anti-tumor effects in many cancers, including the breast cancer. Resveratrol, a natural product found abundantly in many fruits, exhibits marked cytotoxic and pro-oxidant effects. This study was designed to investigate the effect of metformin in combination with resveratrol and cisplatin in MCF-7 cells. Study groups were as follows: untreated control group, single treatment groups (metformin, resveratrol, and cisplatin), double treatment groups (metformin + resveratrol, metformin + cisplatin, and cisplatin + resveratrol) and triple treatment groups (metformin + resveratrol + cisplatin). Our results indicated that metformin inhibits proliferation of MCF-7 cells, an effect that was associated with ROS production and G0/G1 cell cycle arrest, but not apoptosis. Moreover, resveratrol suppressed the proliferation of MCF-7 cells by induction of apoptosis as well as cell cycle arrest. Notably, a significant inhibitory effect in the co-treatment of metformin, resveratrol, and cisplatin was observed which was attributed to induction of autophagy-mediated cell death and apoptosis along cell cycle arrest. In conclusion, our results advocate the anti-cancer properties of metformin and resveratrol on MCF-7 cell s via induction of cell cycle arrest. Additionally, synergistic anti-cancer effects of metformin in a triple combination with cisplatin and resveratrol was attributed to induction of autophagy-mediated cell death and apoptosis along cell cycle arrest. Based on our findings it is proposed that patients may benefit from addition of a drug with a safe profile to conventional anticancer therapies.

The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies.

The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.

Impact of vitamin D receptor gene polymorphisms (TaqI and BsmI) on the incidence and severity of coronary artery disease: a report from southern Iran.

BACKGROUND: The association of vitamin D level and vitamin D receptor (VDR) gene polymorphisms with the prevalence of coronary artery disease (CAD) has been evaluated in various studies; however, the reported results were inconsistent. Hence, we aimed to investigate the impact of two VDR gene polymorphisms, TaqI (rs731236) and BsmI (rs1544410), on the incidence and severity of CAD in Iranian population. METHODS: Blood samples were collected from 118 CAD patients underwent elective percutaneous coronary intervention (PCI) and 52 control subjects. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed for genotyping. SYTNAX score (SS) was calculated as a grading tool for complexity of CAD by an interventional cardiologist. RESULTS: TaqI polymorphism of VDR was not associated with the incidence of CAD. A significant difference was observed between CAD patients and controls regarding BsmI polymorphism of VDR (p < 0.001). GA and AA genotypes was significantly associated with a decreased risk of CAD (p = 0.01, p-adjusted = 0.01 and p < 0.001, p-adjusted = 0.001 respectively). A allele of BsmI polymorphism was shown to have a protective effect against CAD (p < 0.001, p-adjusted = 0.002). No association was found between TaqI and BsmI polymorphisms of VDR and SS as a measure of CAD severity. CONCLUSION: Association of BsmI genotypes with the incidence of CAD revealed that the genetic variation of VDR might play a role in the pathogenesis of CAD.

SNPs of ACE1 (rs4343) and ACE2 (rs2285666) genes are linked to SARS-CoV-2 infection but not with the severity of disease.

COVID-19 and the renin-angiotensin system (RAS) are linked by angiotensin-converting enzyme 2 (ACE2), a key enzyme in RAS that has been validated as a SARS-CoV-2 receptor. Functional ACE1/ACE2 gene polymorphisms may lead to the imbalance between ACE/ACE2 ratio and thus generating RAS imbalance that is associated with higher degrees of lung damage in ARDS that may contribute to the COVID-19 infection outcome. Herein, we investigated the role of RAS gene polymorphisms, ACE1 (A2350G) and ACE2 (G8790A) as risk predictors for susceptibility and severity of COVID-19 infection. A total of 129 included: negative controls without a history of COVID-19 infection (n = 50), positive controls with a history of COVID-19 infection who were not hospitalized (n = 35), and patients with severe COVID-19 infection who were hospitalized in the intensive care unit (n = 44). rs4343 of ACE and rs2285666 of ACE2 were genotyped using PCR-RFLP method. Our results indicated that susceptibility to COVID-19 infection was associated with age, GG genotype of A2350G (Pa = 0.01; OR 4.7; 95% CI 1.4-15.1 and Pc = 0.040; OR 2.5; 95% CI 1.05-6.3) and GG genotype of G8790A (Pa = 0.044; OR 6.17; 95% CI 1.05-35.71 and Pc = 0.0001; OR 5.5; 95% CI 2.4-12.4). The G allele of A2350G (Pa = 0.21; OR 1.74; 95% CI 0.73-4.17 and Pc = 0.007; OR 2.1; 95% CI 1.2-3.5) and G allele of G8790A (Pa = 0.002; OR 4.26; 95% CI 1.7-10.65 and Pc = 0.0001; OR 4.7; 95% CI 2.4-9.2) were more frequent in ICU-admitted patients and positive control group. Also lung involvement due to COVID-19 infection was associated with age and the comorbidities such as diabetes. In conclusion, our findings support the association between the wild genotype (GG) of ACE2 and homozygote genotype (GG) of ACE1 and sensitivity to COVID-19 infection, but not its severity. However, confirmation of this hypothesis requires further studies with more participants.

Anticancer properties of vincristine is modulated by microRNAs in acute lymphoblastic leukemia Nalm6 cell line.

Precursor B-cell acute lymphoblastic leukemia (B-ALL), a highly diverse disease, is the most widespread pediatric malignancy characterized by cytogenetic and molecular abnormalities such as altered microRNA (miR) expression signatures. MiRs are a class of short noncoding RNAs. Dysregulation in the expression of miRs plays a crucial role in different types of cancers. Vincristine is an antineoplastic drug with a broad spectrum of activity against different hematologic malignancies and is the first-line treatment for B-ALL. Previous studies have proposed miR-17 and miR-181/b as oncomirs and miR-34/a as a tumor suppressor in Nalm6 cells, thus in the current study, we investigated the effects of vincristine treatment on the expression of miR-17, miR-34/a and miR-181/b expression levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was conducted to estimate the optimal concentration of vincristine in the Nalm-6 cell line. Expression of miRs was calculated using real-time PCR. Our results showed significant downregulation of miR-17 (FC = 0.226; P < 0.0004) in Nalm6 cells after vincristine treatment. Conversely, miR-34/a (FC = 4.823; P < 0.0001) was significantly upregulated. Also, the expression of miR-181/b (FC = 0.156; P < 0.3465) was not significantly different between the vincristine treated group and the control group. In conclusion, it is proposed that one of the mechanisms by which vincristine improves B-ALL is by modulating the expression of specific miRs. These specific miRs will serve as good diagnostic and prognostic biomarkers.

ncRNAs and polyphenols: new therapeutic strategies for hypertension.

Polyphenols have gained significant attention in protecting several chronic diseases, such as cardiovascular diseases (CVDs). Accumulating evidence indicates that polyphenols have potential protective roles for various CVDs. Hypertension (HTN) is among the hazardous CVDs accounting for nearly 8.5 million deaths worldwide. HTN is a complex and multifactorial disease and a combination of genetic susceptibility and environmental factors play major roles in its development. However, the underlying regulatory mechanisms are still elusive. Polyphenols have shown to cause favourable and beneficial effects in the management of HTN. Noncoding RNAs (ncRNAs) as influential mediators in modulating the biological properties of polyphenols, have shown significant footprints in CVDs. ncRNAs control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct link with blood pressure (BP) regulation is highly probable. Recent evidence suggests that a number of ncRNAs, including main small ncRNAs, microRNAs (miRNAs) and long ncRNAs (lncRNAs), play crucial roles with respect to the antihypertensive effects of polyphenols. Indeed, targeting lncRNAs by polyphenols will be a novel and promising strategy in the management of HTN. Herein, we reviewed the effects of polyphenols in HTN. Additionally, we emphasized on the potential effects of polyphenols on regulations of main ncRNAs, which imply the role of polyphenols in regulating ncRNAs in order to exert protective effects and thus proposing them as new targets for HTN treatment.Abbreviations : CVD: cardiovascular disease; BP: blood pressure; HTN: hypertension, lncRNAs: long noncoding RNAs; p38-MAPK: p38-mitogenactivated protein kinase; OPCs: oligomeric procyanidins; GTP: guanosine triphosphate; ROS: reactive oxygen species; cGMP: cyclic guanosine monophosphate; SGC: soluble guanylate cyclase; PI3K: phosphatidylinositol 3-kinase; cGMP: Cyclic GMP; eNOS: endothelial NO synthase; ERK ½: extracellular signal-regulated kinase ½; L-Arg: L-Arginine; MAPK: mitogen-activated protein kinases; NO: Nitric oxide; P: Phosphorus; PDK1: Phosphoinositide-dependent kinase 1; PI3-K: Phosphatidylinositol 3-kinase; PIP2: Phosphatidylinositol diphosphate; ncRNAs: non-protein-coding RNA; miRNAs: microRNAs; OPCs: oligomeric procyanidins; RES: resveratrol; GE: grape extract; T2DM: type 2 diabetes mellitus; IL: interleukin; TNF-α: tumour necrosis factor-alpha; NF-κB: nuclear factor NF-kappa-B; ALP: alkaline phosphatase; PARP1: poly [ADP-ribose] polymerase 1; HIF1a: Hypoxia-inducible-factor 1A; NFATc2: nuclear factor of activated T cells 2; PAD: peripheral artery disease; SHR: spontaneously hypertensive rat; RAAS: renin-angiotensin-aldosterone system; AT1R: angiotensin type-1 receptor; Nox: NADPH oxidase; HO-1: haem oxygenase-1; JAK/STAT: Janus kinase/signal transducers/activators of the transcription; PNS: panax notoginseng saponin; snoRNA: small nucleolar RNA; hnRNA: heterogeneous nuclear RNA; VSMCs: vascular smooth muscle cells; irf7: interferon regulatory factor 7; limo2: LIM only domain 2; GWAS: genome-wide association study; GAS5: Growth arrest-specific 5; Asb3, Ankyrin repeat and SPCS box containing 3; Chac2: cation transport regulator homolog 2; Pex11b: peroxisomal membrane 11B; Sp5: Sp5 transcription factor; EGCG: epigallocatechin gallate; ApoE: Apo lipoprotein E; ERK-MAP kinase: extracellular signal-regulated kinases-mitogen-activated protein kinase; PAH: pulmonary artery hypertension; PAP: pulmonary arterial pressure; HIF1a: hypoxia-inducible-factor 1A; NFATc2: nuclear factor of activated T cells 2; HMEC-1: Human microvascular endothelial cells; stat2: signal transducers and activators of transcription 2; JNK: c-Jun N-terminal kinase; iNOS: inducible NO synthase. SNP: single nucleotide polymorphism; CAD: coronary artery disease.

Impact of ACE2 genetic variant on antidepressant efficacy of SSRIs.

Identification of a new axis of angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7)/Mas receptor, in the renin-angiotensin system (RAS), has opened a new insight regarding the role of RAS and angiotensin in higher brain functions. ACE2 catabolizes angiotensin II and produces angiotensin (1-7), an agonist of Mas receptor. Mice lacking the Mas receptor (angiotensin 1-7 receptor) exhibit anxiety-like behaviours. The present study was conducted to test the hypothesis of the involvement of ACE2 genetic variant (G8790A) on response to selective serotonin reuptake inhibitors (SSRIs). In a randomised control trial, 200 newly diagnosed Iranian patients with major depressive disorder completed 6 weeks of fluoxetine or sertraline treatment. Patients with a reduction of 50% or more in the Hamilton Rating Scale for Depression score were considered responsive to treatment. G8790A polymorphism was determined in extracted DNAs using restriction fragment length polymerase chain reaction method. Our results show that the A allele and AA and GA genotypes were significantly associated with better response to SSRIs (p = 0.008; OR = 3.4; 95% CI = 1.4-8.5 and p = 0.027; OR = 3.3, 95% CI = 1.2-9.2, respectively). Moreover, patients with GA and AA genotypes responded significantly better to sertraline (p = 0.0002; OR = 9.1; 95% CI = 2.4-33.7). The A allele was significantly associated with better response to sertraline (p = 0.0001; OR = 7.6; 95% CI = 2.5-23.3). In conclusion, our results confirm the role of G8790A in response to some SSRIs.

How metformin affects various malignancies by means of microRNAs: a brief review.

Metformin known as the first-line orally prescribed drug for lowering blood glucose in type II diabetes (T2DM) has recently found various therapeutic applications including in cancer. Metformin has been studied for its influences in prevention and treatment of cancer through multiple mechanisms such as microRNA (miR) regulation. Alteration in the expression of miRs by metformin may play an important role in the treatment of various cancers. MiRs are single-stranded RNAs that are involved in gene regulation. By binding to the 3'UTR of target mRNAs, miRs influence protein levels. Irregularities in the expression of miRs that control the expression of oncogenes and tumor suppressor genes are associated with the onset and progression of cancer. Metformin may possess an effect on tumor prevention and progression by modifying miR expression and downstream pathways. Here, we summarize the effect of metformin on different types of cancer by regulating the expression of various miRs and the associated downstream molecules.

Association of human platelet alloantigens encoding gene polymorphisms with the risk of Coronary artery disease in Iranian patients.

BACKGROUND: Coronary artery disease (CAD) is characterized by narrowing/ blockade of coronary arteries that is mainly caused by atherosclerotic plaques. Considering the involvement of platelet abnormalities, such as defective aggregation and adhesion, in the cardiovascular-related disorders, genetic variations in human platelet alloantigens (HPA) have been implicated in the CAD susceptibility. Herein, we intended to determine the association of HPA-1 to -6, -9, and -15 biallelic polymorphisms with CAD in an Iranian population. METHODS: In this retrospective case-control study, 200 CAD subjects and 100 matched healthy individuals were enrolled. DNA samples were isolated from peripheral blood samples and genotyping of HPA polymorphisms was accomplished using polymerase chain reaction-sequence-specific primers. RESULTS: The alleles and genotypes of studied HPA polymorphisms were equally distributed among cases and controls and therefore no statistically significant differences were detected. Univariate analysis identified no association of combined haplotypes with CAD risk. However, multivariate analysis showed a positive association of the| HPA1b/2a/3b haplotype with CAD after adjustment for some covariates (including BMI, TG, LDL, FBS and blood pressure) that conferred a CAD susceptibility haplotype (P = 0.015; OR = 2.792; 95% CI 1.45-8.59). CONCLUSIONS: Although alleles, genotypes, and haplotypes of HPA polymorphisms were not associated with CAD risk, HPA1b/2a/3b haplotype was found to be a dependent disease risk haplotype in Iranian population after correcting for confounding factors.

Effect of escitalopram on an acetic acid-induced ulcerative colitis model.

Ulcerative colitis (UC) is a chronic and recurrent gastrointestinal (GI) disorder with an unknown aetiology and pathogenesis. Regarding the effectiveness of antidepressants on UC in animal models of depression and the known anti-inflammatory effects of escitalopram this study was conducted to evaluate the beneficial effects of escitalopram on an acetic acid-induced UC model without depression. UC model was induced by intra rectal (i.r.) administration of 4% acetic acid in rats after 24 hours of fasting. Animals were treated with three doses of escitalopram (5, 10 and 20 mg/kg). Prednisolone (4 mg/kg) was used as a reference drug in UC. Histological and oxidative stress markers were measured in all groups. Results showed significant increase in superoxide dismutase (SOD) activity and glutathione (GSH) levels, as well as significant decrease in myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, macroscopic factors (ulcer surface area, ulcer severity and weight-to-colon ratio) and microscopic and histological parameters (severity and extent of inflammation, cryptic destruction and severity of tissue involvement) in escitalopram treated rats (10, 20 mg/kg) compared to the UC group. In conclusion, the results of our study are in support of beneficial anti-inflammatory and antioxidant effects of escitalopram in UC.

Pharmacogenetic-based management of depression: Role of traditional Persian medicine.

Depression is one of the most common mental disorders worldwide. The genetic factors are linked to depression and anti-depressant outcomes. Traditional Persian medicine (TPM) manuscripts have provided various anti-depressant remedies, which may be useful in depression management. This review has studied the bioactive compounds, underlying mechanisms, and treatment outcomes of the medicinal plants traditionally mentioned effective for depression from "The storehouse of medicament" (a famous pharmacopeia of TPM) to merge those with the novel genetics science and serve new scope in depression prevention and management. This review paper has been conducted in two sections: (1) Collecting medicinal plants and their bioactive components from "The storehouse of medicament," "Physician's Desk Reference (PDR) for Herbal Medicines," and "Google scholar" database. (2) The critical key factors and genes in depression pathophysiology, prevention, and treatment were clarified. Subsequently, the association between bioactive components' underlying mechanism and depression treatment outcomes via considering polymorphisms in related genes was derived. Taken together, α-Mangostin, ß-carotene, ß-pinene, apigenin, caffeic acid, catechin, chlorogenic acid, citral, ellagic acid, esculetin, ferulic acid, gallic acid, gentiopicroside, hyperoside, kaempferol, limonene, linalool, lycopene, naringin, protocatechuic acid, quercetin, resveratrol, rosmarinic acid, and umbelliferone are suitable for future pharmacogenetics-based studies in the management of depression.

A longitudinal item response model for Aberrant Behavior Checklist (ABC) data from children with autism.

This manuscript aims to present the first item response theory (IRT) model within a pharmacometric framework to characterize the longitudinal changes of Aberrant Behavior Checklist (ABC) data in children with autism. Data were obtained from 120 patients, which included 20,880 observations of the 58 items for up to three months. Observed scores for each ABC item were modeled as a function of the subject's disability. Longitudinal IRT models with five latent disability variables based on ABC subscales were used to describe the irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech over time. The IRT pharmacometric models could accurately describe the longitudinal changes of the patient's disability while estimating different time-course of disability for the subscales. For all subscales, model-estimated disability was reduced following initiation of therapy, most markedly for hyperactivity. The developed framework provides a description of ABC longitudinal data that can be a suitable alternative to traditional ABC data collected in autism clinical trials. IRT is a powerful tool with the ability to capture the heterogeneous nature of ABC, which results in more accurate analysis in comparison to traditional approaches.

Response to sertraline is influenced by GNß3 gene G-350A variant in patients with major depressive disorder.

PURPOSE: Heterotrimeric guanine nucleotide-binding proteins (G proteins) are a major group of human genome membrane protein receptors. Genetic variation in the ß3 subunit (GNß3) associated with gene splicing and increased activity is associated with major depressive disorder (MDD). However, the effect of G-350A GNß3 genetic polymorphism and therapeutic outcome of selective serotonin reuptake inhibitors (SSRIs) in MDD has not yet been studied. METHOD: One hundred newly diagnosed MDD patients were treated with sertraline for 6 weeks. The severity of depressive symptoms was weekly assessed by Hamilton Rating Scale for Depression (HRSD). A 50% decrease in HRSD was defined as response to treatment. GNß3 polymorphisms (G-350A, A657T) were determined in each individual using a PCR-RFLP technique. RESULTS: Our results suggested that subjects with GG genotype of G-350A responded 5.9-folds more to sertraline compared to carriers of other variants (P = 0.004, OR = 5.9; 95% CI = 1.66-21.99). In addition, carriers of the G allele responded 1.9-folds more to sertraline than carriers of the A allele (P = 0.032, OR = 1.92; 95% CI = 1.05-3.65). However, no association was observed between A657T variants and response to sertraline (P = 0.920, OR = 0.9; 95% CI = 0.31-2.69). CONCLUSION: The results suggest that G-350A variant of GNß3 plays a foremost part as a predictor of response to antidepressant treatment.

Glucocorticoid Receptor Genetic Variants and Response to Fluoxetine in Major Depressive Disorder.

Hyperactivity of the hypothalamic pituitary adrenocortical (HPA) axis is one of the main clinical findings in depression. The HPA axis is interrelated with glucocorticoid signaling via glucocorticoid receptors (GCRs). Thus, functional genetic variants on GCRs might influence therapeutic outcomes in depression. The aim of the present study was to investigate the association between three functional polymorphisms (rs41423247, rs6195, and rs6189/rs6190) on GCR and response to fluoxetine in a group of depressed patients. One hundred newly diagnosed patients completed 6 weeks of fluoxetine treatment. Response to treatment was defined as a 50% decrease in the Hamilton Depression Rating Scale score. Variants of rs41423247, rs6195, and rs6189/rs6190 polymorphisms were determined in extracted DNAs using PCR-RFLP method. Regarding rs41423247 polymorphism, carriers of the CG and GG genotype responded significantly better to fluoxetine compared with CC carriers (p=0.008, OR=3.3, 95% CI=1.35-8.07). Moreover, the G allele of rs41423247 polymorphism was strongly associated with response to fluoxetine (p=0.032, OR=2.2, 95% CI=1.09-4.44). There was no significant association between different genotypes and alleles of rs6195, rs6189/rs6190 variants, and response to fluoxetine (p=0.213 and 0.99, respectively). In conclusion, rs41423247 polymorphism might be a predictor for better response to fluoxetine. These findings support the idea that some variants of the GCR might contribute to interindividual variability of response to antidepressants.

DRD3 Ser9Gly Polymorphism and Its Influence on Risperidone Response in Autistic Children.

PURPOSE: Autism, a neuropsychiatric illness, is a complex ailment of mainly indefinite cause. Although precise pathophysiological mechanism is unclear but the role of genetics is undeniable therefore pharmacogenetics may assist to a better management of symptoms. Risperidone is widely used in autism. Considering the significance of dopaminergic system in psychological and neurological diseases and its association with autism, the hypothesis that genetic variant of dopamine receptor (DRD3), Ser9Gly (rs6280), may influence treatment of autism may be assumed. METHOD: In the present study, 56 autistic Persian children within the age range of 2.5 to 14 years were included. Diagnosis of autism was based on DSM-V criteria and the severity degree was measured by ABC-C checklists at base line and after 8 weeks of treatment with risperidone. Based on their scores patients were categorized as responsive and non-responsive groups. DRD3 Ser9Gly (rs6280) was determined by PCR-RFLP. RESULTS: Carriers of Gly allele as well as carriers of Gly/Gly and Ser/Gly genotypes showed significantly better response to risperidone compared with carriers of Ser allele and Ser/Ser genotype (P=0.027; OR= 4.18; 95%CI=1.16-15.03 and P=0.014; OR=6.825; 95%CI=1.36-34.13). CONCLUSION: Our results advocate the possible influence of genetic variation of DRD3 in clinical response to antipsychotics like risperidone in autistic individuals. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Beta Adrenoceptor Polymorphism and Clinical Response to Sertraline in Major Depressive Patients.

PURPOSE: The adrenoceptor family, as one of the main contributors in regulating the noradrenergic system, has been studied in involvement of depression and its treatment. A functional polymorphism of G1165C on beta adrenoceptor (ßAR) enhances post receptor signalling and is assumed to be involved in pharmacotherapy of depression. The aim of the present study was to discern the influence of G1165C polymorphism in the ß1AR gene on individual differences in response to sertraline. METHODS: One hundred newly diagnosed patients completed 6 weeks of sertraline treatment. Response to treatment was defined as a 50% decrease in Hamilton Rating Scale for depression (HRSD). RESULTS: The patients who carried CC genotype responded five times more to sertraline comparing with other variants (P=0.005; OR=5.7; 95%CI=1.4-23.9). Moreover, carriers of C allele responded three times more to sertraline than patients with the G allele (P=0.001; OR= 3.3; 95%CI= 1.72-6.50). CONCLUSION: In conclusion, our results support the hypothesis that genetic variation of ß1AR might influence clinical response to sertraline. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Association of renin-angiotensin-aldosterone system gene polymorphisms with left ventricular hypertrophy in patients with heart failure with preserved ejection fraction: A case-control study.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has close ties with hypertension, though risk factors to the development of HFpEF in hypertensive patients are not fully understood. Left ventricular hypertrophy (LVH) signifies the susceptibility toward diastolic heart dysfunction, and genetic determinants of LVH as a result may serve as risk predictors for HFpEF in hypertension. We investigated the role of three renin-angiotensin-aldosterone system (RAAS) gene polymorphisms in the development of LVH in hypertensive patients with a diagnosis of HFpEF. METHODS: A total of 176 hypertensive patients with a diagnosis of HFpEF were divided to cases with LVH and controls without. rs4343 and rs4291 of angiotensin-converting enzyme (ACE) and rs5186 of angiotensin receptor type 1 were genotyped using PCR-RFLP method. RESULTS: Genotypes and allele frequencies were significantly different between the case and control groups for rs4343 and rs4291, whereas no difference was observed for rs5186. CONCLUSION: Increased ACE activity explains the significant association of rs4343 and rs4291 polymorphisms with LVH in the carriers. Furthermore, findings support the pathophysiologic links between RAAS and increased LV mass in hypertension and suggest a genetic susceptibility to HFpEF. Such polymorphisms may serve as risk predictors of HFpEF in hypertensive patients.

Influence of ACE gene on differential response to sertraline versus fluoxetine in patients with major depression: a randomized controlled trial.

BACKGROUND: Extensive distribution of the different components of renin angiotensin system (RAS) in the brain, along with their roles in promoting anxiety, depression and brain inflammation, opposes RAS as a potential therapeutic target in major depression. Actions of angiotensin II, the main product of RAS, are reduced by antidepressants and this signifies the complex interplay of different mechanisms involved in response to therapy. Here, we hypothesized that genetic polymorphisms of RAS may affect the outcome of therapy in depressed patients. METHODS: The frequencies of variants of genes encoding for angiotensin-converting enzyme (ACE) insertion/deletion (I/D), rs4291 and rs4343 polymorphisms were determined in extracted DNAs of 200 newly diagnosed depressed patients. Patients were randomly divided into two groups, one treated with fluoxetine and the other treated with sertraline for 12 weeks. Responsive patients were determined by psychiatrist using Hamilton questionnaire and were compared with regard to their genetic variants. RESULTS: Carriers of the D allele and patients with DD genotype responded significantly better to sertraline than to fluoxetine (P = 0.0006, odds ratio (OR) = 3.0, 95 % confidence interval (CI) = 1.80-5.08; P = 0.006, OR = 3.7, 95 % CI = 1.66-8.29, respectively). Mutant genotypes (GG and TT) of rs4343 and rs4291 polymorphisms were also more frequent in patients responding to sertraline, though not achieving the significance level (P = 0.162 and P = 0.256, respectively). CONCLUSION: These findings suggest that special genetic variants of RAS may influence or be an indicator for better response to sertraline.

Signaling pathways and genetics of brain Renin angiotensin system in psychiatric disorders: State of the art.

Along the conventional pathways, Renin-angiotensin system (RAS) plays a key role in the physiology of the CNS and pathogenesis of psychiatric diseases. RAS is a complex regulatory pathway which is composed of several peptides and receptors and comprises two counter-regulatory axes. The classical (ACE1/AngII/AT1 receptor) axis and the contemporary (ACE2/Ang (1-7)/Mas receptor) axis. The genes coding for elements of both axes have been broadly studied. Numerous functional polymorphisms on components of RAS have been identified to serve as informative disease and treatment markers. This review summarizes the role of each peptide and receptor in the pathophysiology of psychiatric disorders (depression, bipolar disorders and schizophrenia), followed by a concise look at the role of genetic polymorphism of the RAS in the pathophysiology of these disorders.

Modulation of ACE2/Ang1-7/Mas and ACE/AngII/AT1 axes affects anticancer properties of sertraline in MCF-7 breast cancer cells.

The renin-angiotensin system (RAS) is best known for playing a major role in maintaining the physiology of the cardiovascular system. Dysregulation of the RAS pathway has been proposed as a link to some malignancies and contributes to cancer metastasis. Breast cancer is considered as one of the leading causes of cancer death in women and its prevention remains yet a challenge. Elements of RAS are expressed in both normal breast tissue and cancerous cells, signifying the essential role of RAS in breast cancer pathology. Sertraline, a widely used antidepressant, has shown anti-proliferative properties on a variety of malignancies. This study aimed to investigate the effect of sertraline and its combination with agonists and antagonists of RAS (A779, Ang 1-7 and losartan) on viability of MCF-7 cells along with their effect on apoptosis and distribution of cell cycle. Our results indicated that sertraline, losartan and Ang 1-7 significantly decreased cell viability, induced apoptosis and cell cycle arrest. A779 blunted the effect of sertraline on cell viability, ROS generation and cell cycle arrest. Combination treatment of sertraline with losartan as well as Ang 1-7 caused a remarkable decline in cell viability. In conclusion, results of the present study support the anti-cancer properties of sertraline, losartan and Ang 1-7 via induction of apoptosis and cell cycle arrest.