Genetic polymorphisms in promoter and intronic regions of CYP1A2 gene in Roma and Hungarian population samples

The purpose of this study was to determine the interethnic differences of four CYP1A2 drug metabolizing enzyme variants. A total of 404 Roma and 396 Hungarian healthy subjects were genotyped for −163C>A, −729C>T, −2467delT and −3860G>A variants of CYP1A2 by RT-PCR and PCR-RFLP technique. The −3860A and −729T allele were not detectable in Roma samples, while in Hungarian samples were present with 2.02% and 0.25% prevalence, respectively. There was a 1.5-fold difference in presence of homozygous −163AA genotype between Hungarian and Roma samples (49.5% vs. 31.9%, p < 0.001). The −163A allele frequency was 68.6% in Hungarians and 56.9% in Romas (p = 0.025). The −2467delT allele frequency was 6.81% in Roma group and 5.81% in Hungarians. The most frequent allelic constellation was −3860G/−2467T/−729C/−163A in both populations. In conclusion, Hungarians have markedly elevated chance for rapid metabolism of CYP1A2 substrates, intensified procarcinogen activation and increased risk for cancers.     

Vitamin D Binding Protein rs7041 polymorphism and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

BackgroundVitamin D deficiency represents a major health problem in general population, especially for its association with cardiovascular disorders and thrombotic risk, even in patients on dual antiplatelet therapy (DAPT). Vitamin D Binding Protein (VDBP) is the main transporter of vitamin D in the bloodstream and genetic polymorphisms of this protein have been shown to account for a significant variability of vitamin D levels and its systemic effects. Contrasting data have linked the rs7041 T → G substitution with cardiovascular disease. However, no study has so far addressed the role of rs7041 polymorphism on platelet reactivity in patients on DAPT, that was the aim of the present study.MethodsPatients treated with DAPT (ASA and clopidogrel or ticagrelor) for an ACS or elective PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by Multiplate® (Roche Diagnostics AG), and VDBP genetic status by polymerase chain reaction and restriction fragment length polymorphism technique. Fasting samples were obtained for main chemistry parameters and vitamin D levels assessment.ResultsWe included 400 patients, 187 (46.8%) receiving clopidogrel and 213 (53.2%) ticagrelor. The genetic polymorphism rs7041 (T → G) was observed in 318 patients, (79.5%), in 38.7% of them in homozygosis. Main clinical and chemistry features did not significantly differ according to genetic status, but for a higher rate of ACE-inhibitors and beta-blockers use among the carriers of the G allele (p = 0.04 and p = 0.01, respectively).VDBP genetic status did not affect the rate of HRPR with ADP-antagonists (25.6% vs 24.6% vs 28.5%, p = 0.59; adjusted OR[95%CI] = 0.94[0.52–1.7], p = 0.83 for T/G patients; adjusted OR[95%CI] = 1.14[0.6–2.2], p = 0.67 for G homozygotes).However, the rate of HRPR with ADP-antagonists was influenced by severe hypovitaminosis D (< 10 ng/ml) only in patients carrying the G allele, especially in homozygosis (T/T: 25.9% vs 26.1%, p = 0.99; G carriers: 22.1% vs 35.3%, p = 0.02, p_interaction = 0.019; adjusted OR[95%CI] = 1.93[1.11–3.34], p = 0.02 for G carriers).ConclusionThe present study shows that rs7041 polymorphism of Vitamin D Binding Protein does not affect platelet reactivity or the rate of HRPR among patients receiving DAPT. However the carriage of the G allele could condition the impact of hypovitaminosis D on the response to antiplatelet agents, increasing the occurrence of HRPR especially in homozygotes, thus suggesting a more significant role of vitamin D deficiency among these patients.     

Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients

Objective We investigated the association between mycophenolic acid (MPA) pharmacokinetics and organic anion-transporting polypeptide (OATP/SLCO)1B1, 1B3, 2B1 and multidrug resistance-association protein 2 (MRP2/ABCC2) genetic polymorphisms and diarrhea. Methods Eighty-seven renal allograft recipients were given repeated doses of mycophenolate mofetil every 12 h at a designated time (09:00 and 21:00). The pharmacokinetics of MPA were analyzed on day 28 posttransplantation. Results The dose-adjusted area under the cuve (AUC)_6–12 of MPA, an estimate of enterohepatic recirculation, was greater in SLCO1B3 T334G GG (or G699A AA) carriers than in TT carriers (or G699A GG) (40 vs. 25 ng·h/mL per milligram, respectively, P = 0.0497). None of the polymorphism of SLCO1B1, SLCO2B1, or ABCC2 C-24T were associated with MPA pharmacokinetics or diarrhea. However, the oral clearance of MPA in recipients having both the SLCO1B3 T334G GG genotype and the ABCC2 C-24T T allele was significantly lower than in patients having both the SLCO1B3 T334G TT and ABCC2 C-24T CC genotypes (0.15 vs. 0.18 L/h per kilogram, respectively, P = 0.0010). Conclusions MPA excretion into bile in patients with SLCO1B3 T334G GG (or G699A AA) was higher than in those with T334G TT (or G699A GG), probably resulting in a higher AUC_6–12 value of MPA. MPA uptake into hepatocytes and excretion into bile at first pass may be greater in SLCO1B3 T334G GG carriers than in TT carriers. In addition, the ABCC2 C-24T polymorphism also seems to be associated with enhanced enterohepatic circulation of MPA. The SLCO1B3 and ABCC2 transporters rather than uridine diphosphate-glucuronosyltransferase (UGT) may partly affect interindividual variety in plasma MPA concentration.     

Polymorphisms of endothelin 1 (G5665T and T-1370G) and endothelin receptor type A (C+70G and G-231A) in Graves' disease

PurposeEndothelin 1 (EDN1) is a strong angiogenic and mitogenic factor, playing a key role in hypervascularization, thyroid follicle cell hyperplasia, and lymphocyte infiltration in the thyroid gland of patients with Graves’ disease (GD). EDN1 induces angiogenesis and mitogenesis via endothelin receptor type A (EDNRA). This study examined the possible association of EDN1 (G5665T and T-1370G) and EDNRA (C + 70G and G-231A) single nucleotide polymorphisms (SNPs) with the occurrence of GD, and evaluates the relationship between genotypes and clinical/laboratory manifestations of GD.Materials and methodsWe analyzed genotype and allele distributions of EDN1 and EDNRA polymorphisms in 165 patients with GD and 181 healthy controls by real-time PCR combined with melting curve analysis.ResultsNo significant associations between GD and variant alleles of the studied polymorphisms were observed. However, the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) levels in EDN1 G5665T GG genotype were higher than those in T allele carriers (GT + TT) (p = 0.001 and p = 0.026, respectively). In addition, anti-TPO levels in EDN1 T-1370G wild-type homozygous patients were found to be higher than in mutant gene carrying patients (GT + GG) (p = 0.006). The presence of EDNRA + 70G allele was associated with 3.37-fold increased risk for development of ophthalmopathy in GD patients (p = 0.009).ConclusionAlthough there were no associations between EDN1 (G5665T and T-1370G) and EDNRA (C + 70G and G-231A) SNPs and susceptibility to GD, EDN1 G5665T and T-1370G polymorphisms were related to alterations of autoantibody production and EDNRA C + 70G polymorphism is related with increased risk for ophthalmopathy in GD patients.     

An assessment of an HIV prevention intervention among People Who Inject Drugs in the states of Manipur and Nagaland,India

BackgroundThe present study describes an assessment of a large-scale intervention, “Avahan”, using an evaluation framework that assesses the program coverage, changes in injection patterns, condom use, and STI and HIV prevalence among People Who Inject Drugs (PWID) in two states of India – Manipur and Nagaland.MethodsProgram monitoring data and results from two rounds of a cross sectional biological and behavioural surveys in 2006 (Round 1) and 2009 (Round 2) were used. The sample included 839 and 860 PWIDs from Manipur and 821 and 829 PWIDs from Nagaland in Round 1 and Round 2 respectively for current analysis. Bivariate and multivariate analyses were done to measure the changes in behavioural and biological outcomes between the two rounds and to examine the association between programme exposure and behavioural outcomes.ResultsIn Manipur, about 77% of the PWIDs were contacted by the peer educators/outreach workers every month and about 18% of the PWIDs visited the clinic every month by March 2010. In Nagaland, however, the proportion of PWIDs visiting the clinic monthly remained low (11% in March 2010). PWIDs in both states were more likely to report ‘consistent safe injection practice in the last six months’ in Round 2 compared to Round 1 (Manipur: adjusted odds ratio (aOR): 1.88, 95% confidence intervals (CI): 1.46–2.43; Nagaland: aOR: 2.35, 95% CI: 1.86–2.80) PWIDs were also more likely to report consistent condom use with regular partners in Round 2. The prevalence of Hepatitis B virus (HBV) increased in Round 2 in Manipur (11% vs 6%, p < 0.001) and Nagaland (8% vs 6%, p = 0.05). The prevalence of Hepatitis C virus (HCV) was high and did not change, either in Manipur (67.3% vs 69.9%, p = 0.42) and Nagaland (14.7% vs 15.1%, p = 0.82). Similarly, the prevalence of HIV did not change significantly between the two Rounds either in Manipur (27.8% in Round 1 vs 29.2% in Round 2, p = 0.59) or in Nagaland (1.2% in Round 1 and 1.6% in Round 2 of the IBBA, p = 0.82).ConclusionImprovements in safe injection practices and consistent condom use with regular partners suggest effectiveness of prevention efforts. However, increase in HBV prevalence and non-decline in HCV and HIV prevalence in both the states also underscore the need to continue and intensify targeted interventions (such as Hepatitis B vaccination, needle exchange programmes, condom distribution) for long term risk reduction among PWID population.     

The effect of losartan treatment on the response of diabetic cardiomyocytes to ATP depletion

The present work aimed to investigate the effect of losartan treatment of healthy and diabetic rats on cardiomyocyte response to ATP depletion.Cells were isolated from normoglycemic (N) and streptozotocin-injected (55 mg/kg) rats (D) treated or not treated with losartan (20 mg/kg/day in the drinking water; NL and DL, respectively) for 3 weeks. In each group of cells, enzyme activities such as glucose-6-phosphate (G6PDH) and glycerol-3-phosphate dehydrogenases (G3PDH), lactate/pyruvate, glycogen levels and citrate synthase were measured as an index of glycolytic dysregulation and mitochondrial mass, respectively.Cells were then challenged with NaCN (2 mM) in glucose-free Tyrode solution (metabolic intoxication, MI), a protocol to study ischemia at cell level. Under these conditions, the time to contractile failure up to rigor-type hyper-contracture in field-stimulated cells and K_ATP current activation by patch-clamp recordings were measured.In comparison with N and NL, D cells presented higher G6PDH and cytoplasmic G3PDH activities, lactate/pyruvate, glycogen content but similar levels of citrate synthase, and decay time of contraction. When subjected to MI, D cells showed delayed activation of the K_ATP current (25.7 ± 7.1 min; p < 0.001 vs. N and NL), increased time to contractile failure and rigor-type hyper-contracture (p < 0.001 vs. N and NL). In cells from DL rats both functional (time to rigor and to K_ATP current activation) and metabolic parameters, approached values similar to those measured in N and NL cells.These results demonstrate that diabetic cardiomyocytes from rats treated with losartan, maintain the capacity to respond promptly to ATP depletion reaching contractile failure, rigor-type hypercontracture and K_ATP opening with a similar timing of N cells.     

Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice

The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively. Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0.001), body weight (p < 0.01), circulating insulin and LDL-cholesterol (p < 0.001) and improved insulin sensitivity (p < 0.001) as well as oral and intraperitoneal (p < 0.001) glucose tolerance. Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls. In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle. Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0.001) elevated pancreatic glucagon content. Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0.001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1. Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0.05), body weight (p < 0.05 to p < 0.01), circulating glucose (p < 0.05 to p < 0.01) and insulin (p < 0.05 to p < 0.001) and improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Notably, these beneficial effects were still evident 18 days following cessation of treatment. These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes.     

Objective: remission of depression in primary care: The Oreon Study

ObjectiveTreatment of depression should result in the absence of symptoms, i.e. remission, in order to restore the functional status of the patient and reduce the risk for relapse. The study assessed the current remission rates in primary care and determined the influencing factors.Methods10 consecutive depressive patients treated by antidepressants for at least 3 months and not more than 12 months were screened by each investigator. Remission rates were defined using the Hamilton-Depression scale 7 items (score of 3 or less) as well as the Carroll self rating scale (score of 7 or less). In addition, patients completed the Sheehan Disability Scale (SDS). Initial severity of depression, type of treatment and socio-economic factors were collected.Results292 general practitioners screened a total of 2630 patients. Results indicated low remission rates: 28.3% according to the clinician and 17.1% according to the patient. Absence of remission was associated with higher impairment in work, social and family life. The most frequently reported residual symptoms in nonremitters were general somatic symptoms (92%), depressed mood (92%), psychic anxiety (91%) and impaired work and activities (89%). No differences were observed in remission rates between men and women. Remission rates were significantly lower in patients living alone as compared to those living in couple or family (25.1% vs 30.2%, p = 0.03), in patients with lower education (21.3% vs 32.3%, p < 0.001), in patients speaking French as compared to Dutch (24.0% vs 34.0% p < 0.001), and unemployed patients compared to patients having an occupation (17.1% vs 39.0%, p < 0.001). Higher initial severity and number of previous episodes decreased remission rates (p < 0.001).ConclusionThis study shows low remission rates in depressed patients treated in general practice. The absence of remission is associated with impairment in work, social and family life. Special attention should be given to identify patients who do not reach remission.     

Regulation of arginase/nitric oxide synthesis axis via cytokine balance contributes to the healing action of malabaricone B against indomethacin-induced gastric ulceration in mice

The role of the arginine-metabolism in the healing action of the Myristica malabarica phenol malabaricone B (mal B) and omeprazole against indomethacin-induced stomach ulceration in mouse was investigated. Indomethacin (18 mg kg^− 1) was found to induce maximum stomach ulceration in Swiss albino mice on the 3rd day of its administration, which was associated with reduced arginase activity (30.8%, P < 0.01), eNOS expression, along with increased iNOS expression, total NOS activity (5.55 folds, P < 0.001), NO generation (2.19 folds, P < 0.001), and ratio of pro-/anti-inflammatory cytokines. Besides providing comparable healing as omeprazole (3 mg kg^− 1 × 3 days), mal B (10 mg kg^− 1 × 3 days, p. o.) shifted the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity (51.6%, P < 0.001), eNOS expression, and reduced iNOS expression, total NOS activity (~ 75%, P < 0.001), and NO level (50.6%, P < 0.01). These could be attributed to a favourable anti/pro inflammatory cytokines ratio, generated by mal B. The healing by omeprazole was however, not significantly associated with those parameters.     

Impact of the Spanish smoking laws on tobacco consumption and secondhand smoke exposure: A longitudinal population study

BackgroundIn Spain, two smoke-free laws have been passed after the approval of the WHO-FCTC. This study assesses the impact of these Spanish smoking legislations on the active and passive smoking through a population cohort in Barcelona (Spain).MethodsThis is a longitudinal study before and after the implementation of two national smoking bans in Spain in a representative sample (n = 1245) of adults (≥ 16 years old) from Barcelona (Spain) surveyed in 2004–2005 and followed-up in 2013–2014. The final sample analyzed was 736 individuals. Both questionnaires (before and after the two laws) included the same variables about active and passive smoking. We calculated the prevalence and the prevalence ratio (PR, with their 95% confidence intervals, 95% CI) of smoking cigarettes and hand-rolled tobacco and also the prevalence of exposure to secondhand smoke (SHS) at home, work, public transport, leisure time and at any setting after vs. before Spanish legislations.ResultsAfter the implementation of the two Spanish smoke-free bans, a significant decrease was observed in the smoking prevalence (from 34.5% to 26.1%, PR = 0.76, p < 0.001), in the average cigarettes per day (median from 15.2 to 10.0, p < 0.001), and in the percentage of conventional tobacco consumption (from 92.6% to 74.4%, PR = 0.80, p < 0.001). Furthermore, a significant increase in the use of hand-rolled tobacco (from 6.1% to 30.9%, PR = 5.07, p < 0.001) and other tobacco products (from 17.1% to 32.8%, PR = 1.92, p < 0.001) was observed. In addition, a significant decrease in the self-reported SHS exposure was observed in all the assessed settings (home, work, transport, and leisure time).ConclusionsThe implementation of the two smoke-free legislations in Spain is related to a reduction in smoking prevalence and SHS exposure. However, the smoking of other tobacco products, particularly hand-rolled tobacco, has increased among young population.     

Intersecting epidemics of HIV,HCV, and syphilis among soon-to-be released prisoners in Kyrgyzstan: Implications for prevention and treatment

BackgroundCentral Asia is afflicted with increasing HIV incidence, low antiretroviral therapy (ART) coverage and increasing AIDS mortality, driven primarily by people who inject drugs (PWID). Reliable data about HIV, other infectious diseases, and substance use disorders in prisoners in this region is lacking and could provide important insights into how to improve HIV prevention and treatment efforts in the region.MethodsA randomly sampled, nationwide biobehavioural health survey was conducted in 8 prisons in Kyrgyzstan among all soon-to-be-released prisoners; women were oversampled. Consented participants underwent computer-assisted, standardized behavioural health assessment surveys and testing for HIV, HCV, HBV, and syphilis. Prevalence and means were computed, and generalized linear modelling was conducted, with all analyses using weights to account for disproportionate sampling by strata.ResultsAmong 381 prisoners who underwent consent procedures, 368 (96.6%) were enrolled in the study. Women were significantly older than men (40.6 vs. 36.5; p = 0.004). Weighted prevalence (%), with confidence interval (CI), for each infection was high: HCV (49.7%; CI: 44.8–54.6%), syphilis (19.2%; CI: 15.1–23.5%), HIV (10.3%; CI: 6.9–13.8%), and HBV (6.2%; CI: 3.6–8.9%). Among the 31 people with HIV, 46.5% were aware of being HIV-infected. Men, compared to women, were significantly more likely to have injected drugs (38.3% vs.16.0%; p = 0.001). Pre-incarceration and within-prison drug injection, primarily of opioids, was 35.4% and 30.8%, respectively. Independent correlates of HIV infection included lifetime drug injection (adjusted odds ratio [AOR] = 38.75; p = 0.001), mean number of years injecting (AOR = 0.93; p = 0.018), mean number of days experiencing drug problems (AOR = 1.09; p = 0.025), increasing duration of imprisonment (AOR = 1.08; p = 0.02 for each year) and having syphilis (AOR = 3.51; p = 0.003), while being female (AOR = 3.06; p = 0.004) and being a recidivist offender (AOR = 2.67; p = 0.008) were independently correlated with syphilis infection.ConclusionDrug injection, syphilis co-infection, and exposure to increased risk during incarceration are likely to be important contributors to HIV transmission among prisoners in Kyrgyzstan. Compared to the community, HIV is concentrated 34-fold higher in prisoners. A high proportion of undiagnosed syphilis and HIV infections presents a significant gap in the HIV care continuum. Findings highlight the critical importance of evidence-based responses within prison, including enhanced testing for HIV and sexually transmitted infections, to stem the evolving HIV epidemic in the region.     

Influence of NADPH oxidase inhibition on oxidative stress parameters in rat hearts

BackgroundThe aim of this study was to assess whether apocynin, an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase blocker, influences lipid peroxidation TBARS, hydrogen peroxide (H₂O₂) content, protein level, heart edema, tumor necrosis factor a (TNF-α) concentration or the glutathione redox system in heart homogenates obtained from endothelin 1 (ET-1)-induced oxidative stress rats.MethodsExperiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (3 μg/kg b.w., iv); Group III: apocynin (5 mg/kg b.w., iv) administered half an hour before saline; Group IV: apocynin (5 mg/kg b.w., iv) administered half an hour before ET-1 (3 μg/kg b.w., iv).ResultsInjection of ET-1 alone showed a significant (p < 0.001) increase in thiobarbituric acid reactive substances (TBARS) and the hydrogen peroxide level (p < 0.01) vs. control, as well as a decrease (p < 0.001) in the GSH level. Apocynin significantly decreased TBARS (p < 0.001) and H₂O₂ (p < 0.05) level (vs. control) as well as improved protein level (p < 0.001) in the heart. Apocynin also prevented ET-1-induced heart edema (p < 0.05). The presence of ET-1 increased the concentration of TNF-α (p < 0.05) while apocynin decreased it (p < 0.05). Our results indicate that ET-1 may induce oxidative stress in heart tissue by reducing the GSH/GSSG ratio, stimulating lipid peroxidation and increasing TNF-α concentration. Apocynin diminished these measures of oxidative stress and TNF-α.ConclusionET-1-induced formation of ROS in the heart is at least partially regulated via NADPH oxidase.     

Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression

Experimental data suggest that the endogenous cannabinoid system is involved in mood regulation, but no study has been performed so far to investigate the role of endocannabinoid genes in the susceptibility to major depression (MD) and/or bipolar disorder (BD). We assessed the CB1 receptor gene (CNR1) single nucleotide polymorphism (SNP) rs1049353 (1359 G/A) and the fatty acid amide hydrolase (FAAH) gene rs324420 SNP (cDNA 385C to A) for their associations with MD and/or BD in 83 Caucasian patients with recurrent MD, 134 Caucasian individuals with BD, and 117 Caucasian healthy subjects. The distribution of the CNR1 1359 G/A genotypes and alleles significantly differed among the groups (χ² = 12.595; df = 4, P = 0.01 for genotypes; χ² = 13.773; df = 2, P = 0.001 for alleles) with MD patients showing a higher frequency of both AG, GG genotypes and A allele as compared to healthy controls. The distribution of the FAAH cDNA 385C to A genotypes, according to the CC dominant model (AA + AC vs. CC), significantly differed among the groups (χ² = 6.626; df = 2, P = 0.04), with both BD patients and MD patients showing a non-significant slightly higher frequency of the AC genotype. These findings, although preliminary, suggest that the CNR1 1359 G/A and the FAAH cDNA 385C to A gene variants may contribute to the susceptibility to mood disorders.     

Polymorphism of CYP1A1 gene variants rs4646903 and rs1048943 relation to the incidence of cervical cancer in Chhattisgarh

Cytochrome P450 CYP1A1 is a phase 1 xenobiotic metabolizing enzyme involved in the metabolism of toxins, endogenous hormones and pharmaceutical drugs. It is therefore possible that polymorphism of CYP1A1 gene producing functional changes in the enzyme may be susceptible factors in cervical carcinogenesis. This study was aimed to look association of CYP1A1 m1 (T > C) and m2 (A > G) gene polymorphisms in Chhattisgarh population. In this case-control study, we analyzed leukocyte DNA from a total of 200 subjects form Chhattisgarh (100 cases and 100 controls). All subjects were genotyped for CYP1A1 m1 (T > C) and m2 (A > G) using PCR-RFLP with statistical analysis by using SPSS version 16.0 and VassarStats (online). Among the two gene variants rs4646903 (T > C) and rs1048943 (A > G), individuals with AG and GG genotypes of CYP1A1 m2 polymorphism have significantly higher and increased risk of cervical cancer (OR = 2.0, 95%CI = 1.04-3.84, p = 0.035; OR = 62.9, 95%CI = 3.72-1063.83, p = 0.004 respectively) and the association of CYP1A1 m1 polymorphism did not show any significant relationship with cervical cancer patients (p = 0.23). The ‘G’ allele showed strong association with the disease (p < 0.0001). Thus, CYP1A1 m2 polymorphism showed an increased risk in the population leading to cervical cancer. Our study suggested that the presence of ‘C’ allele of rs4646903 (T > C) showed no risk and ‘G’ allele of rs1048943 (A > G) might be a leading allele to cause increased cervical cancer susceptibility due to significant association of CYP1A1 m2 gene polymorphism.     

Genetic variations in cytotoxic T-lymphocyte antigen-4 and susceptibility to cervical cancer

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule expressed predominantly on activated T cells, plays an important role in the down-regulation of T-cell activation. To evaluate the potential effects of CTLA-4 gene polymorphisms on susceptibility to cervical cancer, we genotyped polymorphisms in CTLA-4 (− 318 T/C, CT60 G/A, + 49 G/A, − 658 T/C, and − 1661 G/A) and calculated odds ratios for the genotype and allele distributions between patients and controls. We then examined the functional relevance of the polymorphisms using enzyme-linked immunosorbent assays (ELISAs), in vitro lymphocyte proliferation assay, and cytotoxic assay. The CTLA-4 − 318 CC, CT60 AA, and + 49 GG genotype frequencies were lower in patients than in controls (p < 0.05). The frequencies of CTLA-4 − 318 T allele and CT60G allele carriers were significantly higher in patients than in controls (p < 0.05). Upon stimulation, peripheral blood mononuclear cells (PBMCs) carrying the − 318TT and CT60GG genotypes exhibited significantly lower proliferation, IL-2, and IL-4 levels; fewer cytolytic activities; and higher TGF-β levels compared with PBMCs carrying the − 318 CC/CT or CT60 AA/AG genotypes. We also found that CTLA-4 − 318 T/C and CT60 G/A single nucleotide polymorphisms were associated with the severity of cervical cancer. These results indicate that CTLA-4 − 318 T/C and CT60 G/A can affect cervical cancer susceptibility by altering the immune status of an individual.     

Influence of MRP1 G1666A and GSTP1 Ile105Val genetic variants on the urinary and blood arsenic levels of Turkish smelter workers

To understand the cellular mechanisms responsible for arsenic metabolism and transport pathways plays a fundamental role in order to prevent the arsenic-induced toxicity. The effect of MRP1 G1666A and GSTP1 Ile105Val polymorphisms on blood and urinary arsenic levels were determined in 95 Turkish smelter workers. Blood and urinary arsenic concentrations were measured by GF-AAS with Zeeman correction and gene polymorphisms were investigated by PCR-RFLP method. The mean blood and urinary arsenic levels were 21.60 ± 12.28 μg/L and 5.58 ± 4.37 μg/L, respectively. A significant association between MRP1 1666A allele and urinary arsenic levels was found (p = 0.001). GSTP1 Ile105Val polymorphism was detected not to be associated with either blood or urinary arsenic levels (p = 0.384, p = 0.440, respectively). Significant association was also detected between MRP1A^-/GSTP1Val⁻ genotypes and urinary arsenic levels (p = 0.001). This study suggested that MRP1 G1666A alone and, also, combined with GSTP1 Ile105Val were associated with inter-individual variations in urinary arsenic levels, but not with blood arsenic levels.     

Açai (Euterpe oleracea Mart.) feeding attenuates dimethylhydrazine-induced rat colon carcinogenesis

This study investigated the protective effect of spray-dried açaí powder (AP) intake on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in male Wistar rats. After 4 weeks of DMH administrations, the groups were fed with standard diet, a diet containing 2.5% or 5.0% AP or a diet containing 0.2% N-acetylcysteine (NAC) for 10 weeks, using aberrant crypt foci (ACF) as the endpoint. Additionally, two groups were fed with standard diet or a diet containing 5.0% AP for 20 weeks, using colon tumors as the endpoint. In ACF assay, a reduction in the number of aberrant crypts (ACs) and ACF (1–3 AC) were observed in the groups fed with 5.0% AP (37% AC and 47% ACF inhibition, p = 0.036) and 0.2% NAC (39% AC and 41% ACF inhibition, p = 0.042). In tumor assay, a reduction in the number of invasive tumors (p < 0.005) and tumor multiplicity (p = 0.001) was observed in the group fed with 5.0% AP. Also, a reduction in tumor Ki-67 cell proliferation (p = 0.003) and net growth index (p = 0.001) was observed in the group fed with 5.0% AP. Therefore the findings of this study indicate that AP feeding may reduce the development of chemically-induced rat colon carcinogenesis.     

Dietary fatty acid content influences the expression of genes involved in the lipid turnover and inflammation in mouse colon and spleen

BackgroundDietary interventions can improve gastrointestinal (GI) symptoms. We determined the effects of fatty acids (FAs) supplementation with medium- and long-chain saturated FAs on mouse GI motility and correlated them with the expression of genes for free FA receptors (FFAR)1-4, FA binding protein 4 (FABP4) and inflammation.MethodsForty-eight BalbC were assigned to: standard diet (STD), diet rich in medium-chain saturated FAs (COCO) and long-chain saturated FAs (HF) (7% by weight). Body weight (BW) and food intake (FI) were monitored for 8-weeks. GI motility was determined by fecal pellet output (FPO) and colon bead expulsion tests. FABP4 inhibitor, BMS309403 (1 mg/kg, ip) was injected to half of each group 2 days/week. mRNA expression of FABP4, (FFAR)1-4, and pro-inflammatory cytokines were measured in colonic and splenic tissues using real-time PCR.ResultsCOCO and HF decreased FI. COCO accelerated overall GI transit (p < 0.05). COCO increased the mRNA expression of FFAR2 (p < 0.001) and TNFα (p < 0.01); HF increased the expression of FABP4 and FFAR4 (p < 0.05), and FFAR2 (p < 0.001) in the colon, and decreased FFAR1 and FFAR4 (p < 0.001), TNFα (p < 0.01) and IL-1β (p < 0.05) in splenic tissues. BMS309403 decreased the FI and delayed colonic transit in STD+BMS and COCO+BMS vs. STD (p < 0.05). HF+BMS increased colonic expression of FFAR3 (p < 0.01), TNFα (p < 0.01), IL-6 (p < 0.01), and reduced FFAR4 (p < 0.05); COCO + BMS decreased TNFα (p < 0.01).ConclusionDiversification in the dietary lipid content affected GI motility in mice and the expression of FFARs and pro-inflammatory cytokines in vivo.