Meta-analysis of association between the Pro12Ala polymorphism of the peroxisome proliferator–activated receptor-γ2 gene and diabetic retinopathy in Caucasians and Asians

PubMed Central

Ma, Jinlan; Li, Yan; Zhou, Fang; Xu, Xiaoyi; Guo, Gang

2012-01-01

Purpose The Pro12Ala polymorphism of the peroxisome proliferator–activated receptor-γ2 (PPARγ2) gene is reported to be associated with diabetes. However, the gene’s association with diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) has been investigated in numerous epidemiologic studies with controversial results. This meta-analysis aimed to collectively assess the association of the Pro12Ala polymorphism with DR in T2DM. Methods An electronic literature search was conducted on PubMed, ISI Web of Knowledge, EMBASE, and the China National Knowledge Internet. A dominant model [(Pro/Ala +Ala/Ala) versus Pro/Pro] was used to ensure adequate statistical power. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed effect model. Potential sources of heterogeneity and bias were explored. Results This meta-analysis included genotype data from 2,720 cases with DR and 2,450 controls free of DR from eight eligible publications. The results showed the Ala allele had a protective effect on DR in T2DM (OR=0.81; 95% CI: 0.68–0.98, p=0.03). There was no significant evidence against homogeneity (I2=46%, Pheterogeneity=0.07). The sensitivity analysis showed a robust association of the Pro12Ala polymorphism with DR in T2DM after a study involving Caucasians that presented a big effect on heterogeneity (OR=0.75; 95% CI: 0.62–0.91, p=0.003) was excluded. Possible ethnic differences in the association of the Pro12Ala single nucleotide polymorphism and DR were demonstrated; a significant association was illustrated in the Caucasian subgroup (OR=0.74; 95% CI: 0.59–0.94, p=0.01) but was not found in the Asian subgroup (OR=0.77; 95% CI: 0.55–1.07, p=0.12). No publication bias was observed. Conclusions This meta-analysis suggested a significant association exists between the Pro12Ala polymorphism and DR in T2DM with ethnic differences. The Ala allele had a significant protective effect against DR in T2DM. PMID:22993484

Impact of the Pro12Ala polymorphism of the PPARγ2 gene on diabetes and obesity in a highly consanguineous population

PubMed Central

Bener, Abdulbari; Zirie, M; Al-Hamaq, AOAA; Nawaz, Z; Samson, N; Mohammad, R

2015-01-01

Background: The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors. It has been reported that they play important roles in obesity and the development of type 2 diabetes mellitus (T2DM). Materials and Methods: This case-control study was carried out among 764 Qatari patients with diabetes and 764 healthy subjects above 20 years of age at Primary Healthcare Clinics (PHCs) from January 2011 to December 2012. Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI) and other clinical parameters. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler using two specific probes. Univariate and multivariate statistical analysis were performed. Results: The study revealed that in the diabetes group, Pro/(10.2% vs 9.4%; P = 0.606) and Ala/Ala (1.4% vs 0.9%; P = 0.343) were higher than in controls, whereas Pro/Pro (88.4% vs 89.7%;P = 0.413) was lower in diabetes patients, but no significant difference was observed among the genotype groups. In obese patients with diabetes, Pro/Pro (89% vs 89.9%;P = 0.792) and Pro/Ala (8.9% vs 10.1%;P = 0.671) were lower than in obese healthy subjects. No homozygous Ala/Ala was found in obese healthy subjects, whereas 6 Ala/Ala homozygotes were in obese diabetes group. But in diabetes group, obese patients had higher homozygous of Pro/Pro (89.3% vs 87.8%;P = 0.523) and Ala/Ala (1.8% vs 1.2%;P = 0.771) compared to non-obese patients. Conclusion: The current study did not reveal an association between the Pro12Ala polymorphism of the PPAR γ2 gene and type 2 diabetes (T2D) in Qatari's population. PMID:25593831

PPARγ Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet

PubMed Central

Garaulet, Marta; Smith, Caren E; Hernández-González, Teresa; Lee, Yu-Chi; Ordovás, Jose M.

2014-01-01

Scope The goal of this study was to examine whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ (PPARγ) is associated with insulin resistance, obesity and weight loss and to analyze potential interactions between fat intake and PPARγ polymorphism in a Spanish overweight/obese population. Materials and methods We recruited 1465 subjects enrolled in a behavioural treatment program for obesity based on a Mediterranean diet, which included the following: dietary treatment, physical activity, nutritional education and behavioral techniques. A significant association was found between PPARγ2 Pro12Ala genotype and plasma insulin concentration and homeostasis model assessment insulin resistance. Subjects with the Ala12 genotype had lower insulin levels than those with the Pro12Pro genotype. We detected a gene–diet interaction between the PPARγ Pro12Ala polymorphism and MUFA for BMI and body fat. Furthermore, we detected an interaction between the PPARγ Pro12Ala polymorphism and fat intake for total weight loss (p<0.001). When total fat intake was high, Ala12-carriers exhibited a significantly lower percentage of total weight loss than major-allele-carriers (p=0.037). Conclusion Data are consistent with previous results showing a protective role for the Ala12 allele against insulin resistance, and replicate an earlier study that detected an interaction between dietary MUFA and PPARγ2 for BMI. Our detection of a gene–diet interaction between PPARγ Pro12Ala and fat intake for weight loss may explain previous discrepancies among different studies. PMID:22102511

Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children

PubMed Central

Stryjecki, Carolina; Peralta-Romero, Jesus; Alyass, Akram; Karam-Araujo, Roberto; Suarez, Fernando; Gomez-Zamudio, Jaime; Burguete-Garcia, Ana; Cruz, Miguel; Meyre, David

2016-01-01

The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10−4  ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia. PMID:27075119

Association between the Peroxisome proliferator-activated receptor-gamma Pro12Ala Variant and Haplotype and Pancreatic Cancer in a High-Risk Cohort of Smokers: A Pilot Study

PubMed Central

Fesinmeyer, Megan Dann; Stanford, Janet L.; Brentnall, Teresa A.; Mandelson, Margaret T.; Farin, Federico M.; Srinouanprachanh, Sengkeo; Afsharinejad, Zahra; Goodman, Gary E.; Barnett, Matt J.; Austin, Melissa A.

2010-01-01

Objectives The Pro12Ala variant in the proliferator-activated receptor-gamma (PPARG) gene has been associated with diabetes and several cancers. This pilot study tested for the association between Pro12Ala and pancreatic cancer risk in a high-risk sample of smokers. Methods A nested case-control study was conducted in 83 incident cases of pancreatic cancer and 166 matched controls originally recruited into a cohort chemoprevention study of lung cancer. Associations between Pro12Ala and pancreatic cancer risk were measured using conditional logistic regression. Results Carriers of the G allele (Ala) of the Pro12Ala variant had a borderline increased relative risk of pancreatic cancer compared to homozygous carriers of the C allele (Pro), with an odds ratio (OR) of 1.79 (95% confidence interval (CI): 0.96–3.33, p-value: 0.06). Among subjects randomized to high-dose vitamin A, the OR was 2.80 (95: CI: 1.16–6.74, p-value 0.02) versus 1.20 (95% CI: 0.45–3.23, p-value 0.71) in the placebo group. A haplotype including Pro12Ala was also significantly associated with pancreatic cancer risk in all subjects and in subjects randomized to vitamin A. Conclusions This analysis presents the first evidence that PPARG may be associated with pancreatic cancer risk, and this candidate gene should be investigated in future, larger studies. PMID:19436234

Effect of the PPARG2 Pro12Ala Polymorphism on Associations of Physical Activity and Sedentary Time with Markers of Insulin Sensitivity in Those with an Elevated Risk of Type 2 Diabetes.

PubMed

Yates, Thomas; Davies, Melanie J; Henson, Joseph; Edwardson, Charlotte; Webb, David; Bodicoat, Danielle H; Webb, M'Balu; Howard, Philip; Cooper, Jackie A; Humphries, Steve E; Khunti, Kamlesh; Talmud, Philippa

2015-01-01

Peroxisome proliferator-activated receptor gamma (PPARγ) is an important regulator of metabolic health and a common polymorphism in the PPAR-γ2 gene (PPARG2) may modify associations between lifestyle behaviour and health. To investigate whether the PPARG2 Pro12Ala genotype modifies the associations of sedentary behaviour and moderate-to-vigorous intensity physical activity (MVPA) with common measures of insulin sensitivity. Participants with a high risk of impaired glucose regulation were recruited, United Kingdom, 2010-2011. Sedentary and MVPA time were objectively measured using accelerometers. Fasting and 2-hour post-challenge insulin and glucose were assessed; insulin sensitivity was calculated using Matsuda-ISI and HOMA-IS. DNA was extracted from whole blood. Linear regression examined associations of sedentary time and MVPA with insulin sensitivity and examined interactions by PPARG2 Pro12Ala genotype. 541 subjects were included (average age = 65 years, female = 33%); 18% carried the Ala12 allele. Both sedentary time and MVPA were strongly associated with HOMA-IS and Matsuda-ISI after adjustment for age, sex, ethnicity, medication, smoking status and accelerometer wear time. After further adjustment for each other and BMI, only associations with Matsuda-ISI were maintained. Every 30 minute difference in sedentary time was inversely associated with a 4% (0, 8%; p = 0.043) difference in Matsuda-ISI, whereas every 30 minutes in MVPA was positively associated with a 13% (0, 26%; p = 0.048) difference. The association of MVPA with Matsuda-ISI was modified by genotype (p = 0.005) and only maintained in Ala12 allele carriers. Conversely, sedentary time was not modified by genotype and remained inversely associated with insulin sensitivity in Pro12 allele homozygotes. The association of MVPA with Matsuda-ISI was modified by PPARG2 Pro12Ala genotype with significant associations only observed in the 18% of the population who carried the Ala12 allele, whereas

Genetic polymorphisms of PPAR gamma, arsenic methylation capacity and breast cancer risk in Mexican women.

PubMed

Pineda-Belmontes, Cristina P; Hernández-Ramírez, Raúl U; Hernández-Alcaraz, César; Cebrián, Mariano E; López-Carrillo, Lizbeth

2016-04-01

To evaluate whether the presence of polymorphisms of peroxisome proliferator-activated receptor gamma PPARγ (Pro 1 2Ala) and PPARGC1B (Ala203Pro) modifies the association between the inorganic arsenic (iAs) methylation capacity and breast cancer (BC). Mexican women were interviewed, and blood and urine samples were collected from them (cases/controls= 197/220). The concentration of urinary arsenic species and the polymorphisms of interest were determined by high-performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and polymerase chain reaction (PCR), respectively. In women with a high %MMA (urinary monomethyl arsenic) and high primary methylation ratio (PM = MMA/iAs), the risk of BC was increased (odds ratio [OR]%MMA T3 vs.T1= 3.60: 95% confidence interval [CI] 2.02-6.41, ORPMI T3 vs.T1= 3.47: 95%CI 1.95-6.17), which was maintained after adjusting for polymorphisms. No significant interactions were observed between the polymorphisms and the arsenic variables on the risk of BC. Pro 12Ala and Ala203Pro polymorphisms did not modify the association between the iAs methylation capacity and BC.

Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant: results from the HERITAGE Family Study.

PubMed

Ruchat, S-M; Rankinen, T; Weisnagel, S J; Rice, T; Rao, D C; Bergman, R N; Bouchard, C; Pérusse, L

2010-04-01

Exercise training improves glucose homeostasis, but large inter-individual differences are reported, suggesting a role of genetic factors. We investigated whether variants either confirmed or newly identified as diabetes susceptibility variants through genome-wide association studies (GWAS) modulate changes in phenotypes derived from an IVGTT in response to an endurance training programme. We analysed eight polymorphisms in seven type 2 diabetes genes (CDKAL1 rs7756992; CDKN2A and CDKN2B rs10811661 and rs564398; HHEX rs7923837; IGF2BP2 rs4402960; KCNJ11 rs5215; PPARG rs1801282; and TCF7L2 rs7903146) in a maximum of 481 sedentary, non-diabetic white individuals, who participated in a 20-week endurance training programme. Associations were tested between the variants and changes in IVGTT-derived phenotypes. The only evidence of association with training response was found with PPARG rs1801282 (Pro12Ala). We observed that Ala carriers experienced greater increase in overall glucose tolerance (Deltaglucose disappearance index Ala/Ala 0.22 +/- 0.22, Pro/Ala 0.14 +/- 0.06, Pro/Pro 0.004 +/- 0.03; p = 0.0008), glucose effectiveness (Ala/Ala 0.28 +/- 0.41, Pro/Ala 0.44 +/- 0.14, Pro/Pro 0.09 +/- 0.06; p = 0.004), acute insulin response to glucose (Ala/Ala 64.21 +/- 37.73, Pro/Ala -11.92 +/- 40.30, Pro/Pro -46.30 +/- 14.70; p = 0.03) and disposition index (Ala/Ala 551.8 +/- 448.5, Pro/Ala 534.6 +/- 218.3, Pro/Pro -7.44 +/- 88.18; p = 0.003). Compared with Pro/Pro individuals, PPARG Ala carriers experienced greater improvements in glucose and insulin metabolism in response to regular endurance training. However, we did not find evidence of association between type 2 diabetes susceptibility variants recently identified through GWAS and glucose homeostasis response to exercise. Our results extend those of previous studies showing that Ala carriers appear to be more responsive to beneficial health effects of lifestyle interventions.

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

PubMed Central

Al-Jarallah, Khaled F.; Shehab, Diaa K.; Haider, Mohammad Z.

2011-01-01

BACKGROUND AND OBJECTIVES: Peroxisome proliferator–activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association. DESIGN AND SETTING: A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one-year period. PATIENTS AND METHODS: The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading. RESULTS The Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne’s functional index, and radiological grading using Kellgren-Lawrence (K-L) grading. CONCLUSIONS This study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA. PMID:21245597

Impact of GNB3-C825T, ADRB3-Trp64Arg, UCP2-3′UTR 45 bp del/ins, and PPARγ-Pro12Ala Polymorphisms on Bofutsushosan Response in Obese Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Park, Junghyun; Bose, Shambhunath; Hong, Sun-Woo; Lee, Dong-Ki; Yoo, Jae-Wook; Lim, Chi-Yeon; Lee, Myeongjong

2014-01-01

Abstract Obesity is known to be influenced by a number of genes, including the β3 subunit of G protein (GNB3), β3-adrenergic receptor (ADRB3), uncoupling protein 2 (UCP2), and peroxisome proliferator activated receptor gamma (PPARγ). The single nucleotide polymorphisms (SNPs) of the above genes, such as GNB3-C825T, ADRB3-Trp64Arg, UCP2-3′UTR 45 bp del/ins, and PPARγ-Pro12Ala, are associated with obesity and body mass index. The present study evaluates the impact of Bofutsushosan, a traditional Eastern Asian herbal medicine with known anti-obesity properties, on obese subjects according to the presence of the above-mentioned SNPs. Upon randomization, the volunteers were allocated to receive Bofutsushosan (n=55) or placebo (n=56) treatments for 8 weeks. Following the treatment schedule, significant reductions in total cholesterol and significant improvement in the Korean version of obesity-related quality of life scale were seen in the Bofutsushosan-treated group, but not in placebo. Bofutsushosan exerted significant anti-obesity effects on a number of parameters in the carriers of the GNB3-825T allele, but only on waist circumference in the GNB3-C/C homozygote. Significant anti-obesity impact of Bofutsushosan was also seen on a number of obesity-indices in both ADRB3-Arg64 carriers and ADRB3-Trp64 homozygotes, as well as in UCP2-D/D carriers, but not in UCP2-D/I+I/I variants. The effect of Bofutsushosan was more pronounced in PPARγ-Pro/Pro genotype compared to PPARγ-Pro/Ala variants. Thus, the results revealed differential responses of the subjects to the anti-obesity effects of Bofutsushosan treatment according to the polymorphism of the vital obesity-related genes. Our study provides new insight into individualized clinical applications of Bofutsushosan for obesity. PMID:24827746

The association between the Pro12Ala variant in the PPARγ2 gene and type 2 diabetes mellitus and obesity in a Chinese population.

PubMed

Wang, Xia; Liu, Jun; Ouyang, Yingying; Fang, Min; Gao, Hui; Liu, Liegang

2013-01-01

Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity. A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49-0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42-0.96; P = 0.030). Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population.

Vibrational and chiroptical spectroscopic characterization of gamma-turn model cyclic tetrapeptides containing two beta-Ala residues.

PubMed

Vass, Elemér; Majer, Zsuzsa; Kohalmy, Krisztina; Hollósi, Miklós

2010-08-01

The optical spectroscopic characterization of gamma-turns in solution is uncertain and their distinction from beta-turns is often difficult. This work reports systematic ECD and vibrational circular dichroism (VCD) spectroscopic studies on gamma-turn model cyclic tetrapeptides cyclo(Ala-beta-Ala-Pro-beta-Ala) (1), cyclo(Pro-beta-Ala-Pro-beta-Ala) (2) and cyclo(Ala-beta-Ala-Ala-beta-Ala) (3). Conformational analysis performed at the 6-31G(d)/B3LYP level of theory using an adequate PCM solvent model predicted one predominant conformer for 1-3, featuring two inverse gamma-turns. The ECD spectra in ACN of 1 and 2 are characterized by a negative n-->pi* band near 230 nm and a positive pi-->pi* band below 200 nm with a long wavelength shoulder. The ECD spectra in TFE of 1-3 show similar spectra with blue-shifted bands. The VCD spectra in ACN-d(3) of 1 and 2 show a +/-/+/- amide I sign pattern resulting from four uncoupled vibrations in the case of 1 and a sequence of two positive couplets in the case of 2. A -/+/+/- amide I VCD pattern was measured for 3 in TFE-d(2). All three peptides give a positive couplet or couplet-like feature (+/-) in the amide II region. VCD spectroscopy, in agreement with theoretical calculations revealed that low frequency amide I vibrations (at approximately 1630 cm(-1) or below) are indicative of a C(7) H-bonded inverse gamma-turns with Pro in position 2, while gamma-turns encompassing Ala absorb at higher frequency (above 1645 cm(-1)). Copyright 2010 Wiley-Liss, Inc.

The 482Ser of PPARGC1A and 12Pro of PPARG2 Alleles Are Associated with Reduction of Metabolic Risk Factors Even Obesity in a Mexican-Mestizo Population.

PubMed

Vázquez-Del Mercado, Mónica; Guzmán-Ornelas, Milton-Omar; Corona Meraz, Fernanda-Isadora; Ríos-Ibarra, Clara-Patricia; Reyes-Serratos, Eduardo-Alejandro; Castro-Albarran, Jorge; Ruíz-Quezada, Sandra-Luz; Navarro-Hernández, Rosa-Elena

2015-01-01

The aim of this study was to investigate the relationship between functional polymorphisms Gly482Ser in PPARGC1A and Pro12Ala in PPARG2 with the presence of obesity and metabolic risk factors. We included 375 individuals characterized as Mexican-Mestizos and classified by the body mass index (BMI). Body dimensions and distribution of body fat were measured. The HOMA-IR and adiposity indexes were calculated. Adipokines and metabolic profile quantification were performed by ELISA and routine methods. Genetic polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism analysis. A difference between obese and nonobese subjects in polymorphism PPARGC1A distribution was observed. Among obese individuals, carriers of genotype 482Gly/Gly were observed to have decreased body fat, BMI, and body fat ratio versus 482Ser/Ser carriers and increased resistin and leptin levels in carriers Gly+ phenotype versus Gly- phenotype. Subjects with PPARG2 Ala- phenotype (genotype 12Pro/Pro) showed a decreased HOMA-IR index versus individuals with Ala+ phenotype (genotypes 12Pro/Ala plus 12Ala/Ala). We propose that, in obese Mexican-Mestizos, the combination of alleles 482Ser in PPARGC1A and 12Pro in PPARG2 represents a reduced metabolic risk profile, even when the adiposity indexes are increased.

The 482Ser of PPARGC1A and 12Pro of PPARG2 Alleles Are Associated with Reduction of Metabolic Risk Factors Even Obesity in a Mexican-Mestizo Population

PubMed Central

Vázquez-Del Mercado, Mónica; Guzmán-Ornelas, Milton-Omar; Corona Meraz, Fernanda-Isadora; Ríos-Ibarra, Clara-Patricia; Reyes-Serratos, Eduardo-Alejandro; Castro-Albarran, Jorge; Ruíz-Quezada, Sandra-Luz; Navarro-Hernández, Rosa-Elena

2015-01-01

The aim of this study was to investigate the relationship between functional polymorphisms Gly482Ser in PPARGC1A and Pro12Ala in PPARG2 with the presence of obesity and metabolic risk factors. We included 375 individuals characterized as Mexican-Mestizos and classified by the body mass index (BMI). Body dimensions and distribution of body fat were measured. The HOMA-IR and adiposity indexes were calculated. Adipokines and metabolic profile quantification were performed by ELISA and routine methods. Genetic polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism analysis. A difference between obese and nonobese subjects in polymorphism PPARGC1A distribution was observed. Among obese individuals, carriers of genotype 482Gly/Gly were observed to have decreased body fat, BMI, and body fat ratio versus 482Ser/Ser carriers and increased resistin and leptin levels in carriers Gly+ phenotype versus Gly− phenotype. Subjects with PPARG2 Ala− phenotype (genotype 12Pro/Pro) showed a decreased HOMA-IR index versus individuals with Ala+ phenotype (genotypes 12Pro/Ala plus 12Ala/Ala). We propose that, in obese Mexican-Mestizos, the combination of alleles 482Ser in PPARGC1A and 12Pro in PPARG2 represents a reduced metabolic risk profile, even when the adiposity indexes are increased. PMID:26185753

Characterization of the Ala62Pro polymorphic variant of human cytochrome P450 1A1 using recombinant protein expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Seung Heon; Kang, Sukmo; Dong, Mi Sook

2015-06-15

Cytochrome P450 (CYP) 1A1 is a heme-containing enzyme involved in detoxification of hydrophobic pollutants. Its Ala62Pro variant has been identified previously. Ala62 is located in α-helix A of CYP1A1. Residues such as Pro and Gly are α-helix breakers. In this study, the Ala62Pro variant was characterized using heterologous expression. E. coli expressing the Ala62Pro variant, and the purified variant protein, had lower CYP (i.e. holoenzyme) contents than their wild-type (WT) equivalents. The CYP variant from E. coli and mammalian cells exhibited lower 7-ethoxyresorufin O-dealkylation (EROD) and benzo[a]pyrene hydroxylation activities than the WT. Enhanced supplementation of a heme precursor during E.more » coli culture did not increase CYP content in E. coli expressing the variant, but did for the WT. As for Ala62Pro, E. coli expressing an Ala62Gly variant had a lower CYP content than the WT counterpart, but substitution of Ala62 with α-helix-compatible residues such as Ser and Val partially recovered the level of CYP produced. Microsomes from mammalian cells expressing Ala62Pro and Ala62Gly variants exhibited lower EROD activities than those expressing the WT or Ala62Val variant. A region harboring α-helix A has interactions with another region containing heme-interacting residues. Site-directed mutagenesis analyses suggest the importance of interactions between the two regions on holoenzyme expression. Together, these findings suggest that the Ala62Pro substitution leads to changes in protein characteristics and function of CYP1A1 via structural disturbance of the region where the residue is located. - Highlights: • Ala62 is located in α-helix A of the carcinogen-metabolizing enzyme CYP1A1. • Pro acts as an α-helix breaker. • A variant protein of CYP1A1, Ala62Pro, had lower heme content than the wild-type. • The variant of CYP1A1 had lower enzyme activities than the wild-type.« less

Interactions of the PPARγ2 polymorphism with fat intake affecting energy metabolism and nutritional outcomes in obese women.

PubMed

Rosado, Eliane L; Bressan, Josefina; Martínez, J Alfredo; Marques-Lopes, Iva

2010-01-01

To determine the influence of the Pro12Ala polymorphism of the PPARγ2 gene and the dietary lipid intake on energy metabolism and nutritional outcomes in obese women after an acute fat load or following a low-calorie diet for 10 weeks. Sixty obese women (aged 30-46 years) participated in the study and were assigned to 2 groups depending on the genotype: Pro12Pro and Pro12Ala/Ala12Ala carriers. At baseline and after 2 nutritional (short- or long-term) interventions, measurement of anthropometrical and body composition (bioelectrical impedance) variables, dietary assessments, energy metabolism (indirect calorimetry) measurements as well as biochemical and molecular (PPARγ2 genotype) analyses were performed. All women received a high-fat test meal to determine the postprandial metabolism (short term) and an energy-restricted diet for 10 weeks (long term). The frequencies of the Pro12Pro and Pro12Ala/Ala12Ala genotypes were 83.33 and 16.67%, respectively, and reached Hardy-Weinberg equilibrium. Interestingly, the postprandial energy expenditure after the fat load was higher in subjects carrying the Ala allele. At baseline, the habitual monounsaturated fatty acid (MUFA) intake inversely correlated with fat oxidation and body mass index in the obese Pro12Ala/Ala12Ala carriers, while a lower PUFA intake (%) in the long-term trial was associated with an increase in the respiratory quotient only in Ala carriers but not in the Pro12Pro genotyped group. The Pro12Ala polymorphism in the PPARγ2 gene influenced energy metabolism in the assayed short- and long-term situations since the response to both nutritional interventions differed according to the genotype. The results suggest that fat oxidation and energy expenditure may be lower in Pro12Pro carriers compared to Pro12Ala/Ala12Ala genotypes, while in obese women with Pro12Ala/Ala12Ala polymorphisms in the PPARγ2 gene fat oxidation was negatively correlated with the MUFA and PUFA (%) intake. Copyright © 2010 S. Karger AG

Towards Understanding the Tandem Mass Spectra of Protonated Oligopeptides. 2: The Proline Effect in Collision-Induced Dissociation of Protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp)

NASA Astrophysics Data System (ADS)

Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G.; Paizs, Béla

2011-06-01

The product ion spectra of proline-containing peptides are commonly dominated by y n ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y 2 ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y 2 / b 3 abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y 2 / b 3 abundance ratio decreases.

Towards understanding the tandem mass spectra of protonated oligopeptides. 2: The proline effect in collision-induced dissociation of protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp).

PubMed

Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G; Paizs, Béla

2011-06-01

The product ion spectra of proline-containing peptides are commonly dominated by y(n) ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y(2) ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y(2)/b(3) abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y(2)/b(3) abundance ratio decreases.

Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nitz, Inke; Ewert, Agnes; Klapper, Maja

2007-02-09

Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha}more » and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.« less

PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men.

PubMed

Kahara, Toshio; Takamura, Toshinari; Hayakawa, Tetsuo; Nagai, Yukihiro; Yamaguchi, Hiromi; Katsuki, Tatsuo; Katsuki, Ken-Ichi; Katsuki, Michio; Kobayashi, Ken-Ichi

2003-02-01

Exercise training improves insulin sensitivity, but individual responses vary greatly. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a regulator of adipose cell differentiation and plays an important role in systemic insulin action. We investigated whether PPARgamma gene polymorphism affects insulin resistance in response to exercise in Japanese healthy men. The exercise program at an individual intensity of 50% of the maximal heart rate was performed for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical activity of 700 kcal/wk. The program was conducted for 3 months without any dietary intervention, and the clinical and metabolic characteristics were examined before and after the exercise program. Body mass index (BMI) did not change significantly after the exercise program, whereas percentage of body fat (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased significantly. Pro12Ala polymorphism in PPARgamma gene was performed on genomic DNA isolated from human leukocytes and examined with polymerase chain reaction (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the Ala allele did not correlate with fasting immunoreactive insulin (IRI) and homeostasis model assessment-insulin resistance index (HOMA-R) at baseline, but did so with the changes in IRI and HOMA-R after exercise (DeltaIRI, Pro/Pro 0.55 +/- 3.49 microU/mL v Pro/Ala -2.83 +/- 1.47 microU/mL, P <.05; DeltaHOMA-R, Pro/Pro 0.09 +/- 0.86 v Pro/Ala -0.61 +/- 0.32, P <.05). This result suggests that the Ala allele is associated with improvement in insulin resistance after exercise. We conclude that PPARgamma gene polymorphism may be a reliable indicator of whether exercise will have a beneficial effect as part of the treatment of insulin resistance syndrome. Copyright 2003, Elsevier Science (USA). All rights reserved.

Gene-gene interaction between PPAR gamma 2 and ADR beta 3 increases obesity risk in children and adolescents.

PubMed

Ochoa, M C; Marti, A; Azcona, C; Chueca, M; Oyarzábal, M; Pelach, R; Patiño, A; Moreno-Aliaga, M J; Martínez-González, M A; Martínez, J A

2004-11-01

Multiple genes are likely to be involved in obesity and these genes may interact with environmental factors to influence obesity risk. Our aim was to explore the synergistic contribution of the two polymorphisms: Pro12Ala of the PPAR gamma 2 gene and Trp64Arg of the ADR beta 3 gene to obesity risk in a Spanish children and adolescent population. We designed a sex- and age-matched case-control study. Participants were 185 obese and 185 control children (aged 5-18 y) from the Navarra region, recruited through Departments of Pediatrics (Hospital Virgen del Camino, Navarra University Clinic and several Primary Health Centers). The obesity criterion (case definition) was BMI above the 97th percentile according to Spanish BMI reference data for age and gender. Anthropometric parameters were measured by standard protocols. The genotype was assessed by PCR-RFLP after digestion with BstUI for PPAR gamma 2 mutation and BstNI for ADR beta 3 variants. Face-to-face interviews were conducted to assess the physical activity. Using a validated physical activity questionnaire, we computed an activity metabolic equivalent index (METs h/week), which represents the physical exercise during the week for each participant. Statistical analysis was performed by conditional logistic regression, taking into account the matching between cases and controls. Carriers of the polymorphism Pro12Ala of the PPAR gamma 2 gene had a significantly higher obesity risk than noncarriers (odds ratio (OR)=2.18, 95% CI=1.09-4.36) when we adjusted for sex, age and physical activity. Moreover, the risk of obesity was higher (OR=2.59, 95% CI=1.17-5.34) when family history of obesity was also taken into account in the model. The OR for obesity linked to both polymorphisms (PPAR gamma 2 and ADR beta 3) was 5.30 (95% CI=1.08-25.97) when we adjusted for sex, age and physical activity. After adjustment for family history of obesity, the OR for carriers of both polymorphisms was 19.5 (95% CI=2.43-146.8). A

Controlled self-assembling structures of ferrocene-dipeptide conjugates composed of Ala-Pro-NHCH2CH2SH chain.

PubMed

Moriuchi, Toshiyuki; Nishiyama, Taiki; Tayano, Yoshiki; Hirao, Toshikazu

2017-12-01

Bioorganometallic ferrocene-dipeptide conjugates with the Ala-Pro-cysteamine chain, Fc-L-Ala-L-Pro-NHCH 2 CH 2 SH (2) and Fc-L-Ala-D-Pro-NHCH 2 CH 2 SH (4) (Fc=ferrocenoyl), were prepared by the reduction of the ferrocene-dipeptide conjugates, Fc-L-Ala-L-Pro-cystamine-L-Pro-L-Ala-Fc (1) or Fc-L-Ala-D-Pro-cystamine-D-Pro-L-Ala-Fc (3), respectively. Control of the self-assembling structures of the ferrocene-dipeptide conjugates was demonstrated by changing the chirality of the amino acid. The molecular structure of 2 composed of the L-Ala-L-Pro-NHCH 2 CH 2 SH chain confirmed the formation of intramolecular hydrogen bond of N-H⋯N pattern between the NH of cysteamine moiety and the nitrogen of Pro moiety. Furthermore, intermolecular hydrogen bonds between NH (Ala) and CO (Pro of another molecule) and between NH (cysteamine) and CO (the ferrocenoyl moiety of another molecule) were formed, wherein each molecule is connected to four neighboring molecules by continuous intermolecular hydrogen bonds to form the hydrogen-bonded molecular assembling structure. On the contrary, the left-handed helical assembly through an intermolecular hydrogen-bonding network of 15-membered intermolecularly hydrogen-bonded ring between NH (Ala) and CO (the ferrocenoyl moiety of another molecule) and between NH (the cysteamine moiety of another molecule) and CO (Ala) was observed in the crystal packing of 4 composed of the L-Ala-D-Pro-NHCH 2 CH 2 SH chain. Copyright © 2017 Elsevier Inc. All rights reserved.

PPARγ gene polymorphism, C-reactive protein level, BMI and periodontitis in post-menopausal Japanese women.

PubMed

Wang, Yangming; Sugita, Noriko; Yoshihara, Akihiro; Iwasaki, Masanori; Miyazaki, Hideo; Nakamura, Kazutoshi; Yoshie, Hiromasa

2016-03-01

Several studies have reported inconsistent results regarding the association between the PPARγPro12Ala polymorphism and obesity. Obese individuals had higher C-reactive protein (CRP) levels compared with those of normal weight, and PPARγ activation could significantly reduce serum high-sensitive CRP level. We have previously suggested that the Pro12Ala polymorphism represents a susceptibility factor for periodontitis, which is a known risk factor for increased CRP level. The aim was to investigate associations between PPARγ gene polymorphism, serum CRP level, BMI and/or periodontitis among post-menopausal Japanese women. The final sample in this study comprised 359 post-menopausal Japanese women. Periodontal parameters, including PD, CAL and BOP, were measured per tooth. PPARγPro12Ala genotype was determined by PCR-RFLP. Hs-CRP value was measured by a latex nephelometry assay. No significant differences in age, BMI or periodontal parameters were found between the genotypes. The percentages of sites with PD ≥ 4 mm were significantly higher among the hsCRP ≥ 1 mg/l group than the hsCRP < 1 mg/l group (p = 0.003). Positive correlations were found between serum hsCRP levels and the percentages of sites with PD ≥ 4 mm (p = 0.043) in PPARγ Ala allele carriers, and BMI (p = 0.033) in non-carriers. After adjustment for model covariates, BMI was significantly associated with serum hsCRP level. The PPARγPro12Ala polymorphism was not independently associated with periodontitis, serum CRP level or BMI in post-menopausal Japanese women. However, serum hsCRP level correlated with periodontitis in Ala allele carriers, and with BMI in non-carriers. © 2014 John Wiley & Sons A/S and The Gerodontology Society. Published by John Wiley & Sons Ltd.

Gene-diet-related factors of hyperglycaemia in postmenopausal women.

PubMed

Grygiel-Górniak, Bogna; Kaczmarek, Elżbieta; Mosor, Maria; Przysławski, Juliusz; Nowak, Jerzy

2018-05-01

As ageing and increased body fat are the signs of insulin resistance, we have studied whether the presence of Pro12Ala and C1431T of peroxisome proliferator-activated receptor gamma 2 gene and Trp64Arg of beta 3-adrenergic receptor gene may predispose to the hyperglycaemia development in postmenopausal women, who have never undergone hypoglycaemic treatment. The distributions of selected allele and genotype frequencies were determined by the PCR-RFLP method in normo- and hyperglycaemic, who have never been diagnosed and treated for diabetes mellitus were measured. The amount of body fat and lean body mass (LBM) were assessed by the bioimpedance method and nutritional habits by 7-day dietary recall. There were no differences between the distribution of genotypes and the allele frequencies of the Pro12Ala, C1431T and Trp64Arg polymorphisms in normo- and hyperglycaemic women. Hyperglycaemic women were characterized by visceral obesity, hypertension, higher serum insulin and triglycerides, higher intake of fat and lower consumption of complex carbohydrates and B vitamins. Normoglycaemic women with Pro12Pro polymorphism acquired higher energy from dietary fat (p < 0.0276) and lower energy from carbohydrates (p < 0.0480) than normoglycaemic Ala12 carriers. Subjects with Pro12Pro polymorphism and LBM > 58% of total body mass or with Trp64Trp and normal triglycerides have higher chance of normoglycaemia. Genotyping for Pro12Ala and Trp64Arg polymorphism in postmenopausal women may have the clinical benefit of predicting hyperglycaemia, thereby contributing to the prevention of diabetes mellitus development in the future. However, not only the genetic background but also the dietary habits (intake of fat, carbohydrates and B vitamins) determine the risk of hyperglycaemia.

Analysis of Manganese Superoxide Dismutase and Glutathione Peroxidase 1 Gene Polymorphisms in Vitiligo.

PubMed

Seçkin, Havva Yıldız; Kalkan, Göknur; Bütün, İlknur; Akbaş, Ali; Baş, Yalçın; Karakuş, Nevin; Benli, İsmail

2016-08-01

Vitiligo is a hereditary/acquired progressive pigmentation disorder characterized by discoloration of skin as a result of melanocyte dysfunction. Recent studies have proposed that oxidant/antioxidant status plays an important role in vitiligo pathogenesis because of the toxic effects on melanocytes. In this study, we aimed to investigate possible associations of MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms with vitiligo with in Turkish population. The study group consists of 57 patients with vitiligo and 69 healthy controls. Genotyping is performed to identify MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms. The method used for genotyping was based on the PCR amplification and detection of polymorphisms by hybridization probes labeled with fluorescent dyes. Both the genotype and allele frequencies of MnSOD Ala-9Val (p = 0.817 and p = 0.553, respectively) and GPx1 Pro198Leu polymorphisms (p = 0.422 and p = 0.673, respectively) were not significantly different between vitiligo patients and the control group. Although no significant difference was found, this is the first report investigating the possible associations between the MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms in Turkish population. Further studies with large populations will be able to clarify the association better.

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

PubMed Central

Millikan, Robert C; Player, Jon; de Cotret, Allan René; Moorman, Patricia; Pittman, Gary; Vannappagari, Vani; Tse, Chiu-Kit J; Keku, Temitope

2004-01-01

Introduction A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. Methods We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). Results The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. Conclusions The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer. PMID:15217492

Spontaneous abortion and functional polymorphism (Val16Ala) in the manganese SOD gene.

PubMed

Eskafi Sabet, E; Salehi, Z; Khodayari, S; Sabouhi Zarafshan, S; Zahiri, Z

2015-02-01

Spontaneous abortion is the most common complication of early pregnancy. Genetic factors have been hypothesised to play a role in spontaneous abortion. Since it is possible that the balance of oxidants and antioxidants can be affected by different genetic variants, gene polymorphisms have been proposed as a susceptibility factor that increases the chance of miscarriage. Manganese superoxide dismutase is an important antioxidant enzyme encoded by manganese superoxide dismutase (MnSOD) gene. The aim of this experiment was to assess whether Val16Ala polymorphism of MnSOD gene is associated with miscarriage in northern Iran. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Statistical analyses were conducted using the χ(2)-test. The genetic distributions did not differ significantly between cases and controls, however slightly more Val/Val genotypes were found among the patients compared with control subjects (p = 0.059). No correlation was observed between susceptibility to abortion and MnSOD Val16Ala polymorphism. Larger population-based studies are needed for clarifying the relationship between abortion and MnSOD genotypes.

[Peptide Ala-Glu-Asp-Gly and interferon gamma: their role in immune response during aging].

PubMed

Lin'kova, N S; Kuznik, B I; Khavinson, V Kh

2012-01-01

The decrease of lymphocyte interferon gamma expression during aging is one of the main mechanisms leading to the immunodeficiency state in the elderly. Cell penetrating geroprotective peptide Ala-Glu-Asp-Gly has the capability to activate the proliferation of lymphocytes in thymus during its aging. The nucleotide sequence which is complementary contacted with peptide Ala-Glu-Asp-Gly was found in promoter region of interferon gamma gene. Thus, the immune protection of this peptide can be explained by its activation of the interferon gamma production in T-cells.

Intestinal fatty acid binding protein Ala54Thr polymorphism is associated with peripheral atherosclerosis combined with type 2 diabetes mellitus.

PubMed

Khattab, Salma A; Abo-Elmatty, Dina M; Ghattas, Maivel H; Mesbah, Noha M; Mehanna, Eman T

2017-09-01

Intestinal fatty acid-binding protein 2 (FABP2) is expressed in enterocytes and binds saturated and unsaturated long-chain fatty acids. The FABP2 Ala54Thr polymorphism has been reported to effect lipid metabolism. The aim of the present study was to assess the relationship between this polymorphism and peripheral atherosclerosis combined with type 2 diabetes mellitus (T2DM) in an Egyptian population. The study was performed on 100 T2DM patients with peripheral atherosclerosis and 100 control subjects. The Ala54Thr polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism, whereas serum FABP2 levels were determined using ELISA. Fasting blood glucose, fasting serum insulin concentrations, HbA1c, lipid profile, body mass index (BMI) and systolic and diastolic blood pressure (SBP and DBP, respectively) were determined. There was a higher frequency of the Thr54 allele among the patient group (P = 0.002). In Ala54/Thr54 heterozygotes and carriers of the rare Thr54/Thr54 genotype, there were significant increases in BMI and FABP2. Those with the Thr54/Thr54 genotype had significantly decreased high-density lipoprotein cholesterol (HDL-C) concentrations; in addition, those with the Thr54/Thr54 genotype had significantly higher SBP and DBP than subjects with the Ala54/Ala54 and Ala54/Thr54 genotypes. There was a positive correlation between FABP2 levels and BMI, SBP and DBP, and a negative correlation with HDL-C. The Thr54 allele of the FABP2 Ala54Thr polymorphism was associated with an increased incidence of peripheral atherosclerosis combined with T2DM in the population studied. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia.

PubMed

Ghodsian, Nooshin; Ismail, Patimah; Ahmadloo, Salma; Heidari, Farzad; Haghvirdizadeh, Polin; Ataollahi Eshkoor, Sima; Etemad, Ali

2016-01-01

With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls. Close relation between Ala589Ser polymorphism and elevated systolic and diastolic blood pressure (SBP and DBP) was recognized. Sociodemographic factors including body mass index (BMI), age, the level of fasting blood sugar (FBS), low density lipoprotein (LDL), and triglyceride (TG) in the cases and healthy subjects exhibited strong differences (p < 0.05). The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences (p < 0.05) between EHT subjects with or without type 2 diabetes mellitus (T2DM) and normotensive subjects, statistically. The WNK4 gene variation influences significantly blood pressure increase. Ala589Ser probably has effects on the enzymic activity leading to enhanced predisposition to the disorder.

Effects Ala54Thr polymorphism of FABP2 on obesity index and biochemical variable in response to a aerobic exercise training

PubMed Central

Han, Tae Kyung

2013-01-01

The purpose of the current study was to investigate whether or not the FABP2 gene polymorphism modulated obesity indices, hemodynamic factor, blood lipid factor, and insulin resistance markers through 12-week aerobic exercise training in abdominal obesity group of Korean mid-life women. A total of 243 abdominally obese subjects of Korean mid-life women voluntarily participated in aerobic exercise training program for 12 weeks. Polymerase Chain Reaction with Restriction Fragment Length Polymorphism (PCR-RFLP) assay was used to assess the FABP2 genotype of the participants (117 of AA homozygotes, 100 of AT heterozygotes, 26 of TT homozygotes). Prior to the participation of the exercise training program, baseline obesity indices, hemodynamic factor, blood lipid factor, and insulin resistance markers were measured. All the measurements were replicated following the 12-week aerobic exercise training program, and then the following results were found. After 12-week aerobic exercise training program, wild type (Ala54Ala) and mutant type (Ala54Thr+Thr54Thr) significantly decreased weight (P > .001), BMI (P > .001), %bf (P > .001), waist circumference (P > .001), WHR (P > .001), muscle mass (wild type p < .022; mutant type P > .001), RHR (P > .001), viseceral adipose area (wild type p < .005; mutant type P > .001), subcutaneous area (P > .001), insulin (wild type p < .005; mutant type P > .001) and significantly increased VO2max (P > .001). And wild type significantly decresed NEFA (P > .05), glucose (P > .05), OGTT 120min glucose (P > .05) and significantly increased HDLC (p > .005). Mutant type significantly decreased SBP (P > .001), DBP (P > .01), TC (P > .01), LPL (P > .05), LDL (P > .001), HOMA index (P > .01). The result of the present study represents that regular aerobic exercise training may beneficially prevent obesity index, blood pressure, blood lipids and insulin resistance markers independent of FABP Ala54Thr wild type and mutant type. PMID:25566432

Lack of association between uncoupling protein-2 Ala55Val polymorphism and incident diabetes in the atherosclerosis risk in communities study.

PubMed

Bielinski, Suzette J; Pankow, James S; Boerwinkle, Eric; Bray, Molly S; Kao, W H Linda; Folsom, Aaron R

2008-09-01

Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion, peripheral insulin resistance, and increased hepatic glucose production. Genes that contribute to genetic susceptibility to T2DM function in numerous biochemical pathways. Uncoupling protein-2 (UCP2) functions as a negative regulator of insulin secretion. Animal studies show induction of UCP2 plays a pathogenic role in the progression of obesity-induced T2DM and some human studies have shown an association between a common UCP2 polymorphism, Ala55Val (rs660339), and T2DM, obesity, and resting metabolic rate with the Val/Val genotype conferring increased risk. We investigated the relationship between the Ala55Val variant and incidence of T2DM among 12,056 participants in the Atherosclerosis Risk in Communities (ARIC) Study aged 45-64 years at baseline. Incident T2DM (n = 1,406) cases were identified over 9 years of follow-up. The Val55 allele frequency was 44% in blacks and 41% in whites. The rate of T2DM per 1,000 person was 15.0, 15.6, and 15.6 yearsfor Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. We found no significant association between UCP2 genotypes and incident T2DM in the whole cohort, in race-gender subgroups, or in categories of body mass index (normal, overweight and obese). The Ala55Val polymorphism of UCP2 was not associated with incident T2DM in the ARIC cohort.

Dietary carotenoid-rich oil supplementation improves exercise-induced anisocytosis in runners: influences of haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms in dilutional pseudoanemia (sports anemia).

PubMed

Miranda-Vilela, Ana L; Akimoto, Arthur K; Alves, Penha C Z; Pereira, Luiz C S; Klautau-Guimarães, Maria N; Grisolia, Cesar K

2010-04-01

Physical training induces beneficial adaptation, whereas exhaustive exercises increase reactive oxygen-species generation, thereby causing oxidative damage in plasma and erythrocytes, fractions susceptible to lipid peroxidation. Pequi (Caryocar brasiliense Camb.) is a Brazilian Cerrado fruit containing a carotenoid-rich oil. The aim was to investigate the effects of pequi-oil on exercise-induced oxidative damage in plasma and erythrocytes, after running in the same environment and undergoing weekly training under the same conditions as to type, intensity and length. Evaluations were accomplished after outdoor running on flat land before and after ingestion of 400 mg pequi-oil capsules for 14 days. Blood samples were taken after running and submitted to TBARS assay and erythrogram analysis. Haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms were priorly investigated, so as to estimate genetic influence The reduction in erythrocytes, hemoglobin and hematocrit after pequi-oil treatment was notably associated with higher plasma expansion. Except for MCHC (mean corpuscular hemoglobin concentration) and RDW (red cell distribution width), the results were influenced by the polymorphisms studied. The best response to pequi-oil was presented by MnSOD Val/Val, CAT AA or AT genotypes and the GPX1 Pro allele. The significantly lower RDW and higher MHCH values were related to pequi-oil protective effects. Pequi oil, besides possessing other nutritional properties, showed protective blood effects.

The Thr92Ala 5′ Type 2 Deiodinase Gene Polymorphism Is Associated with a Delayed Triiodothyronine Secretion in Response to the Thyrotropin-Releasing Hormone–Stimulation Test: A Pharmacogenomic Study

PubMed Central

Butler, Peter W.; Smith, Sheila M.; Linderman, Joyce D.; Brychta, Robert J.; Alberobello, Anna Teresa; Dubaz, Ornella M.; Luzon, Javier A.; Skarulis, Monica C.; Cochran, Craig S.; Wesley, Robert A.; Pucino, Frank

2010-01-01

Background The common Thr92Ala D2 polymorphism has been associated with changes in pituitary–thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)–mediated TSH stimulation of the thyroid gland. Methods Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes. Results No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 ± 2.67 vs. 21.07 ± 2.86 ng/dL, p = 0.029). Thr/Ala subjects showed an intermediate response. Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 ± 6.84 vs. 69.56 ± 6.06 minutes, p = 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups. Conclusions The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSH-stimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis. PMID:21054208

[Study on association of FABP2 gene Ala54Thr polymorphism with risk of obesity, body fat mass and physical activity].

PubMed

Nasibulina, É S; Borisova, A V; Akhmetov, I I

2013-01-01

Obesity is a multifactorial disease which depends on the interaction between genome and environment. Fatty acid-binding protein 2 (FABP2) regulates lipid transport, intestinal absorption and metabolism. The aim of the study was to investigate the interrelation between the FABP2 gene Ala54Thr polymorphism, body mass index and body fat mass and to study distribution of genotypes and alleles frequencies of FABP2 gene in athletes and individuals who are not involved in sports. 315 athletes of different sport disciplines and levels and 612 controls (predominantly students) participated in the study. Genotyping for the FABP2 gene Ala54Thr polymorphism was performed by PCR. Body composition was analyzed by bioimpedance method. The study did not confirm the association of FABP2 gene Ala54Thr polymorphism with the risk of obesity and body fat mass. However, the frequency of the Thr54 allele was significantly higher in elite stayers (50.0%, p = 0.025) and combat athletes (46.2%, p = 0.013) in comparison with controls (32.2%). Thus, FABP2 gene Ala54Thr polymorphism is associated with the predisposition to endurance athletic performance.

Assay for identification of heterozygous single-nucleotide polymorphism (Ala67Thr) in human poliovirus receptor gene.

PubMed

Nandi, Shyam Sundar; Sharma, Deepa Kailash; Deshpande, Jagadish M

2016-07-01

It is important to understand the role of cell surface receptors in susceptibility to infectious diseases. CD155 a member of the immunoglobulin super family, serves as the poliovirus receptor (PVR). Heterozygous (Ala67Thr) polymorphism in CD155 has been suggested as a risk factor for paralytic outcome of poliovirus infection. The present study pertains to the development of a screening test to detect the single nucleotide (SNP) polymorphism in the CD155 gene. New primers were designed for PCR, sequencing and SNP analysis of Exon2 of CD155 gene. DNAs extracted from either whole blood (n=75) or cells from oral cavity (n=75) were used for standardization and validation of the SNP assay. DNA sequencing was used as the gold standard method. A new SNP assay for detection of heterozygous Ala67Thr genotype was developed and validated by testing 150 DNA samples. Heterozygous CD155 was detected in 27.33 per cent (41/150) of DNA samples tested by both SNP detection assay and sequencing. The SNP detection assay was successfully developed for identification of Ala67Thr polymorphism in human PVR/CD155 gene. The SNP assay will be useful for large scale screening of DNA samples.

Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

PubMed

Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

2016-12-01

Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Ala54Thr polymorphism of FABP2 on anthropometric and biochemical variables in response to a moderate-fat diet.

PubMed

Martinez-Lopez, Erika; Garcia-Garcia, Maritza R; Gonzalez-Avalos, Jorge M; Maldonado-Gonzalez, Montserrat; Ruiz-Madrigal, Bertha; Vizmanos, Barbara; Hernandez-Nazara, Zamira; Roman, Sonia; Panduro, Arturo

2013-01-01

To analyze the effect of the fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism on anthropometric and biochemical variables in response to a moderate-fat diet in overweight or obese subjects. One hundred nine subjects with a body mass index ≥ 25 kg/m(2) were studied. Participants underwent a dietary intervention that consisted of 30% fat (saturated fat <7% of total calories), 15% protein, and 55% carbohydrates. The FABP2 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Anthropometric and biochemical data were measured at baseline, 1 mo, and 2 mo of nutritional intervention. The mean age was 38.6 ± 11.3 y and the mean body mass index 32.7 ± 6.1 kg/m(2), with 20 men (18%) and 89 women (82%). Fifty-three patients (48.6%) had genotype Ala54Ala (wild-type group) and 56 patients had genotype Ala54Thr/Thr54Thr (51.4%, mutant group). At baseline, no significant difference was found between the FABP2 genotypes groups, except for the carbohydrate intake and resting metabolic rate, which were higher in the Ala54Thr/Thr54Thr group (P < 0.05). At 2 mo, participants had lost 6.8% of their initial weight. The Ala54Thr/Thr54Thr group compared with the Ala54Ala group showed significant decreases in the parameters of weight (-7.5 versus -4.2 kg), body mass index (-2.1 versus -1.2 kg/m(2)), waist circumference (-7.6 versus -5.2 cm), waist-to-hip ratio (-0.04 versus -0.02), and C-reactive protein (-1.4 versus -0.76 mg/L), respectively (P < 0.05). After the resting metabolic rate was adjusted, the decreases in waist circumference, waist-to-hip ratio, and C-reactive protein remained significant between the two groups. This study showed that the Thr54 allele carriers responded better to a moderate-fat diet. Copyright © 2013 Elsevier Inc. All rights reserved.

Lung cancer risk associated with Thr495Pro polymorphism of GHR in Chinese population.

PubMed

Cao, Guochun; Lu, Hongna; Feng, Jifeng; Shu, Jian; Zheng, Datong; Hou, Yayi

2008-04-01

The incidence of lung cancer has been increasing over recent decades. Previous studies showed that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors for lung cancer. Recent observations revealed that the growth hormone receptor (GHR) might play important roles in carcinogenesis and Rudd et al. found that the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity). To test whether this variant of GHR would modify the risk of lung cancer in Chinese population, we compared the polymorphism between 778 lung cancer patients and 781 healthy control subjects. Our results indicate that the frequency of 495Thr (2.8%) allele in cases was significantly higher than in controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele might be a risk factor for lung cancer. Further analyses revealed Thr495Pro variant was associated with lung cancer in the subpopulation with higher risk for lung cancer: male subpopulation, still-smokers subpopulation and the subpopulation with familial history of cancer. In different histological types of lung cancer, Thr495Pro SNP was significantly associated with small cell and squamous cell lung cancer, but not with adenocarcinoma, which suggested a potential interaction between this polymorphism and metabolic pathways related to smoking. The potential gene-environment interaction on lung cancer risk was evaluated using MDR software. A significant redundant interaction between Thr495Pro polymorphism and smoking dose and familial history of cancer was identified and the combination of genetic factors and smoking status or familial history of cancer barely increased the cancer risk prediction accuracy. In conclusion, our results suggested that the Thr495Pro polymorphism of GHR was associated with the risk of lung cancer in a redundant interaction with smoking and

Duplication polymorphisms in exon 4 of κ-casein gene in yak breeds/populations.

PubMed

Pingcuo, S; Gao, J; Jiang, Z R; Jin, S Y; Fu, C Y; Liu, X; Huang, L; Zheng, Y C

2015-08-28

The objective of this study was to compare 12 bp-duplication polymorphisms in exon 4 of the κ-casein gene among 3 breeds/populations of yak (Bos grunniens). Genomic DNA was extracted from yak blood or muscle samples (N = 211) and a partial sequence of exon 4 of κ-casein gene was amplified by polymerase chain reaction. A polyacrylamide gel electrophoresis assay of the products (169 bp) revealed 2 variants. These variants differed in a 12-bp duplication of the nucleotide sequence corresponding to amino acids 147-150 (Glu-Ala-Ser-Pro) or 148-151 (Ala-Ser-Pro-Glu). The genotype frequency and gene frequency of the 2 κ-casein variants differed among the 3 yak breeds/populations. The long form of the κ-casein gene was the predominant allele, and the Jiulong yak showed the highest frequency of the short form variant of the κ-casein gene. In addition, 2 nucleotide differences resulting in amino acid substitutions were also identified in yaks. These results are significant for designing a breeding strategy to improve the genetic makeup of yak herds.

In search of best fitted composite model to the ALAE data set with transformed Gamma and inversed transformed Gamma families

NASA Astrophysics Data System (ADS)

Maghsoudi, Mastoureh; Bakar, Shaiful Anuar Abu

2017-05-01

In this paper, a recent novel approach is applied to estimate the threshold parameter of a composite model. Several composite models from Transformed Gamma and Inverse Transformed Gamma families are constructed based on this approach and their parameters are estimated by the maximum likelihood method. These composite models are fitted to allocated loss adjustment expenses (ALAE). In comparison to all composite models studied, the composite Weibull-Inverse Transformed Gamma model is proved to be a competitor candidate as it best fit the loss data. The final part considers the backtesting method to verify the validation of VaR and CTE risk measures.

Role of Superoxide Dismutase 2 Gene Ala16Val Polymorphism and Total Antioxidant Capacity in Diabetes and its Complications

PubMed Central

Pourvali, Katayoun; Abbasi, Mehrnaz; Mottaghi, Azadeh

2016-01-01

Diabetes Mellitus (DM) is a chronic heterogeneous disorder and oxidative stress is a key participant in the development and progression of it and its complications. Anti-oxidant status can affect vulnerability to oxidative damage, onset and progression of diabetes and diabetes complications. Superoxide dismutase 2 (SOD2) is one of the major antioxidant defense systems against free radicals. SOD2 is encoded by the nuclear SOD2 gene located on the human chromosome 6q25 and the Ala16Val polymorphism has been identified in exon 2 of the human SOD2 gene. Ala16Val (rs4880) is the most commonly studied SOD2 single nucleotide polymorphism (SNP) in SOD2 gene. This SNP changes the amino acid at position 16 from valine (Val) to alanine (Ala), which has been shown to cause a conformational change in the target sequence of manganese superoxide dismutase (MnSOD) and also affects MnSOD activity in mitochondria. Ala16Val SNP and changes in the activity of the SOD2 antioxidant enzyme have been associated with altered progression and risk of different diseases. Association of this SNP with diabetes and some of its complications have been studied in numerous studies. This review evaluated how rs4880, oxidative stress and antioxidant status are associated with diabetes and its complications although some aspects of this line still remain unclear. PMID:27141263

Sibling-based association study of the PPARgamma2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study. Stanford Asian-Pacific Program in Hypertension and Insulin Resistance.

PubMed

Chuang, L M; Hsiung, C A; Chen, Y D; Ho, L T; Sheu, W H; Pei, D; Nakatsuka, C H; Cox, D; Pratt, R E; Lei, H H; Tai, T Y

2001-11-01

The peroxisome proliferator activated receptor (PPAR) gamma2 is a transcription factor that has been shown to be involved in adipocyte differentiation, adipogenesis, and insulin sensitivity. To address the role of PPARgamma2 in glucose homeostasis and insulin sensitivity, among many other objectives, we conducted a sibling-controlled association study in a multicenter program - the Stanford Asian-Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe). Approximately 2525 subjects in 734 Chinese and Japanese families have been recruited from six field centers for SAPPHIRe. In total, 1702 subjects including parents and siblings from 449 families have been genotyped for PPARgamma2, of which 328 families were Chinese and 121 Japanese. Only 88 subjects of the 1525 siblings screened for the P12A polymorphism were found to be carriers of the A variant, the most common variant of the PPARgamma2 gene. A variant frequencies of the siblings were 4.27% in Chinese and 2.72% in Japanese. A sibling-controlled association study was performed through genetically discordant sibships (i.e., P/P genotype vs. P/A + A/A genotypes). Specifically, we examined whether there were differences in metabolic variables between the discordant siblings within families. In total, 88 subjects carrying either 1 or 2 A alleles had at least one sibling who was discordant for the P12A polymorphism, yielding a total of 180 individuals from 47 families for analyses, among which 92 siblings were homozygous for wild-type P allele. Siblings with the A variant tended to have lower levels of fasting plasma glucose (OG-10), and lower glucose levels at 60 min following oral glucose loading after adjusting for age, gender, and body mass index. Using a mixed model treating family as a random effect, we found that P12A polymorphism of the PPARgamma2 gene contributes significantly to the variance in fasting plasma glucose, glucose level at 60 min, and insulin-resistance homeostasis model assessment. Our

Genetic polymorphisms in extracellular superoxide dismutase Leu53Leu, Arg213Gly, and Ala40Thr and susceptibility to type 2 diabetes mellitus.

PubMed

Yang, Y M; Xie, X R; Jin, A L

2016-12-02

The most common type of endocrine disease is type 2 diabetes mellitus (T2DM); genetic factors contribute to the development to T2DM. In this study, we investigated the role of the Leu53Leu, Arg213Gly, and Ala40Thr polymorphisms in extracellular superoxide dismutase (EC-SOD) gene in the development of T2DM in a Chinese population. DNA was extracted from peripheral blood samples obtained from 256 T2DM patients and 324 control subjects recruited from our hospital between January 2013 and March 2015. DNA was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The obtained data was then statistically analyzed. The chi-square test revealed a statistically significant difference in the genotype frequencies of EC-SOD Ala40Thr (χ 2 = 13.26, P = 0.001) between the patients and controls. Unconditional regression analysis indicated that the GA and AA genotypes of EC-SOD Ala40Thr were associated with an increased risk of T2DM compared to the GG genotype {adjusted odds ratio (OR) [95% confidence interval (CI)] = 1.46 (1.01-2.11) and 2.67 (1.48-4.85), respectively}. In the dominant model, the GA+AA genotype of EC-SOD Ala40Thr was correlated with a higher risk of T2DM, in comparison with the GG genotype (OR = 1.64, 95%CI = 1.16-2.33). In the recessive model, AA of EC-SOD Ala40Thr showed a 2.19-fold higher risk of developing T2DM than the GG+GA genotype. In conclusion, people with the Ala40Thr polymorphism in EC-SOD are at a higher risk of developing T2DM; therefore, this may be utilized as a biomarker for early screening of T2DM in a Chinese population.

Effects of energy expenditure gene polymorphisms on obesity-related traits in obese children.

PubMed

Csernus, Katalin; Pauler, Gábor; Erhardt, Éva; Lányi, Éva; Molnár, Dénes

2015-01-01

To assess the frequencies of common polymorphisms of genes associated with energy expenditure among Hungarian obese children and investigate their influences on obesity-related traits and metabolic complications of common childhood obesity. In a total of 528 obese children (age 13.2±2.6 years) an oral glucose tolerance test and determination of fasting serum lipid levels were carried out, blood pressure and resting energy expenditure were measured and the children were genotyped for the following gene polymorphisms: Trp64Arg of β3-adrenoreceptor (ADRB3), -3826 A/G of uncoupling protein (UCP)-1, exon 8 45 bp del/ins and -866 G/A of UCP-2, -55 C/T of UCP-3, and Pro12Ala of peroxisome-proliferator activated receptor gamma-2. Carriers of the ADRB3 Arg64 allele had a significantly higher relative body weight and relative body mass index compared with non-carriers. The UCP-2 exon 8 del/ins polymorphism was associated with higher degree of obesity, insulin resistance, dyslipideamia and lower adjusted metabolic rate. Children with UCP-3 -55 T/T genotype had a significantly lower adjusted metabolic rate than the C allele carriers. We found evidence for associations between common polymorphisms of the ADRB3, the UCP-2 and UCP-3 genes and basic metabolic rate as well as level and metabolic consequences of common obesity among Hungarian school-aged children. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

PubMed

Abbasi, Mehrnaz; Daneshpour, Maryam S; Hedayati, Mehdi; Mottaghi, Azadeh; Pourvali, Katayoun; Azizi, Fereidoun

2018-01-01

Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P  = 0.006). Median serum TAC in CKD group was 920 μmol/L and was significantly lower ( p  < 0.001) compared to the control group (1045 μmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.

The novel endomorphin degradation blockers Tyr-Pro-DClPhe-Phe-NH (EMDB-1) and Tyr-Pro-Ala-NH (EMDB-2) prolong endomorphin-2 action in rat ileum in vitro.

PubMed

Fichna, Jakub; Perlikowska, Renata; Gach, Katarzyna; do-Rego, Jean-Claude; Cravezic, Aurore; Janecka, Anna; Storr, Martin A

2010-07-01

The endogenous opioid system is involved in the control of gastrointestinal (GI) motility. The potential use of endogenous MOR ligands, endomorphins (EMs), as therapeutics is limited because of their rapid enzymatic degradation and short duration of action. Targeting enzymatic degradation is an approach to prolong EM activity. In the present study, we characterized the effects of novel blockers of EM degradation in GI tissue preparation in vitro. The effects of actinonin, diprotin A (DIP) and the novel peptide EM degradation blockers Tyr-Pro-DClPhe-Phe-NH(2) (EMDB-1), Tyr-Pro-Ala-NH(2) (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3) on EM-2-mediated inhibition of electrically induced cholinergic twitch contractions were compared in rat ileum in vitro using an organ bath. EMDB-1 and EMDB-2 significantly prolonged the inhibitory effect of EM-2 on smooth muscle contractility in rat ileum. EMDB-2 extended the EM-2 action for up to 60 min compared to 10 min in controls and was more potent than the conventional peptidase inhibitor DIP. EMDB-1 and EMDB-2 are potent EM degradation blockers, which prolong the inhibitory effects of EM-2 on smooth muscle contractility in rat ileum. These novel compounds may be of future use when targeting the endogenous opioid system in the treatment of GI motility disorders such as diarrhea.

Evaluating the role of the FSH receptor gene Thr307-Ala and Asn680-Ser polymorphisms in male infertility and their association with semen quality and reproductive hormones.

PubMed

Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Saba

2011-07-01

To determine whether Thr(307)-Asn(680) and Ala(307)-Ser(680) polymorphisms of the follicle-stimulating hormone receptor (FSH-R) gene are associated with male infertility, semen quality, and reproductive hormones. The FSH-R polymorphisms at codons 680 and 307 were analysed by restriction-fragment-length polymorphism (RFLP) in 172 infertile men and in an equal number of age-matched healthy fertile men. Genotyping of the FSH-R gene was performed using the polymerase chain reaction RFLP technique. All of the participants underwent semen analysis, and reproductive hormones were also measured. Allelic frequencies were 29.7% serine (Ser) and 70.3% asparagine (Asn) for fertile men (the control group), and 33.1% Ser and 66.9% Asn for infertile men (P > 0.05). The FSH-R genotype at position 680 was 49.4% (Asn/Asn), 41.9% (Asn/Ser), and 8.7% (Ser/Ser) in the control group and 40.1% (Asn/Asn), 46.5% (Asn/Ser), and 13.4% (Ser/Ser) in infertile men, respectively (P > 0.05, chi-squared test). Allelic frequencies were 33.1% alanine (Ala) and 66.9% threonine (Thr) for the control group, and 37.8% Ala and 62.2% Thr for the infertile men. The frequencies of genotypes at position 307 were 45.5% Thr/Thr, 43% Thr/Ala, and 11.6% Ala/Ala for the control group and 36.1% Thr/Thr, 52.3% Thr/Ala, and 11.6% Ala/Ala for infertile men. No significant association between codon 680 and codon 307 genotypes and infertility was observed (P = 0.076 and P = 0.073, respectively). The odds ratio (OR) values indicated that individuals with the Thr/Thr + Asn/Ser combined genotypes had a > 50% decreased risk for developing infertility (OR = 0.44; 95% confidence interval [CI]: 0.22-0.77; P = 0.006). The patients with heterozygous Thr/Ala + Asn/Ser combined genotype were 2.65 times more susceptible to infertility than the control group (OR = 2.65; 95% CI: 1.74-3.82; P = 0.0053). The FSH-R codon 680 and codon 307 genotypes did not result in different serum FSH levels either in men with normal spermatogenesis

Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tasmin, Saira, E-mail: rimzim1612@yahoo.com; Furusawa, Hana; Ahmad, Sk. Akhtar

Background and objective: Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. Methods: Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected tomore » determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). Results: The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1carriers. Conclusion: This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys. - Highlights: • High blood lead level for the environmentally exposed schoolchildren. • BPb was significantly correlated with U-ALA and Hb. • Effect of ALAD genotype on U-ALA is differed by sex. • Lower U-ALA in ALAD2 than ALAD1 carriers only for boys at same exposure.« less

ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

PubMed

Flores, Ariane Ethur; Pascotini, Eduardo Tanuri; Kegler, Aline; Gabbi, Patricia; Bochi, Guilherme Vargas; Barbisan, Fernanda; Duarte, Thiago; Prado, Ana Lucia Cervi; Duarte, Marta M M F; da Cruz, Ivana B M; Moresco, Rafael Noal; Santos, Adair Roberto Soares; Bresciani, Guilherme; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

2017-09-05

Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer.

PubMed

Hirata, Hiroshi; Hinoda, Yuji; Kawamoto, Ken; Kikuno, Nobuyuki; Suehiro, Yutaka; Okayama, Naoko; Tanaka, Yuichiro; Dahiya, Rajvir

2008-05-01

The mismatch repair system is a DNA repair mechanism that corrects mispaired bases during DNA replication errors. Cancer cells deficient in MMR proteins have a 10(2) to 10(3)-fold increase in the mutation rate. Single nucleotide polymorphisms of mismatch repair genes have been shown to cause a decrease in DNA repair activity. We hypothesized that mismatch repair gene polymorphism could be a risk factor for prostate cancer and p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms. DNA samples from 110 patients with prostate cancer and 110 healthy controls were analyzed by single strand conformational polymorphism and polymerase chain reaction-restriction fragment length polymorphism to determine the genotypic frequency of 5 polymorphic loci on 2 MMR genes (MSH3 and MSH6) and p53 codon72. The chi-square test was applied to compare genotype frequency between patients and controls. A significant increase in the G/A+A/A genotype of MSH3 Pro222Pro was observed in patients compared to controls (OR 1.87, 95% CI 1.0-3.5). The frequency of A/G + G/G genotypes of MSH3 exon23 Thr1036Ala also tended to increase in patients (OR 1.57, 95% CI 0.92-2.72). In p53 codon72 Arg/Pro + Pro/Pro carriers the frequency of the AG + GG genotype of MSH3 exon23 was significantly increased in patients compared to controls (OR 2.1, 95% CI 1.05-4.34). To our knowledge this is the first report of the association of MSH3 gene polymorphisms in prostate cancer. These results suggest that the MSH3 polymorphism may be a risk factor for prostate cancer.

The Antioxidant Enzyme GPX1 Gene Polymorphisms Are Associated with Low BMD and Increased Bone Turnover Markers

PubMed Central

Mlakar, Simona Jurkovic; Osredkar, Josko; Prezelj, Janez; Marc, Janja

2010-01-01

Recently, oxidative stress has been suggested as participating in the development of osteoporosis. Glutathione peroxidase 1 (GPX1) is one of antioxidant enzymes responsible for the defence of cells against oxidative damage and thus for protection against age related diseases such as osteoporosis. The aim of present study was to associate genetic variances of GPX1 enzyme with bone mineral density (BMD) and biochemical bone turnover markers and to show the influence of antioxidative defence system in genetics of osteoporosis. We evaluated 682 Slovenian subjects: 571 elderly women and 111 elderly men. All subjects were genotyped for the presence of GPX1 gene polymorphisms Pro198Leu and polyAla region. BMD and biochemical markers were also measured. General linear model analysis, adjusted to height, and (one-way) analysis of variance were used to assess differences between the genotype.and haplotype subgroups, respectively. The significant or borderline significant associations were found between the polyAla or the Pro198Leu polymorphisms and total hip BMD (0.018; 0.023, respectively), femoral neck BMD (0.117; 0.026, respectively) and lumbar spine BMD (0.032; 0.086, respectively), and with biochemical bone turnover markers such as plasma osteocalcin (0.027; 0.025, respectively) and serum C-terminal telopeptide of type I collagen concentrations (0.114; 0.012, respectively) in whole group. Haplotype analysis revealed that the 6-T haplotype is associated significantly with low BMD values (p > 0.025) at all measured locations of the skeleton, and with high plasma osteocalcin concentrations (p = 0.008). This study shows for the first time that the polymorphisms polyAla and Pro198Leu of the GPX1 gene, individually and in combination, are associated with BMD and therefore may be useful as genetic markers for bone disease. Moreover, it implies the important contribution of the oxidative stress to pathogenesis of osteoporosis. PMID:21045266

The antioxidant enzyme GPX1 gene polymorphisms are associated with low BMD and increased bone turnover markers.

PubMed

Mlakar, Simona Jurkovic; Osredkar, Josko; Prezelj, Janez; Marc, Janja

2010-01-01

Recently, oxidative stress has been suggested as participating in the development of osteoporosis. Glutathione peroxidase 1 (GPX1) is one of antioxidant enzymes responsible for the defence of cells against oxidative damage and thus for protection against age related diseases such as osteoporosis. The aim of present study was to associate genetic variances of GPX1 enzyme with bone mineral density (BMD) and biochemical bone turnover markers and to show the influence of antioxidative defence system in genetics of osteoporosis. We evaluated 682 Slovenian subjects: 571 elderly women and 111 elderly men. All subjects were genotyped for the presence of GPX1 gene polymorphisms Pro198Leu and polyAla region. BMD and biochemical markers were also measured. General linear model analysis, adjusted to height, and (one-way) analysis of variance were used to assess differences between the genotype.and haplotype subgroups, respectively. The significant or borderline significant associations were found between the polyAla or the Pro198Leu polymorphisms and total hip BMD (0.018; 0.023, respectively), femoral neck BMD (0.117; 0.026, respectively) and lumbar spine BMD (0.032; 0.086, respectively), and with biochemical bone turnover markers such as plasma osteocalcin (0.027; 0.025, respectively) and serum C-terminal telopeptide of type I collagen concentrations (0.114; 0.012, respectively) in whole group. Haplotype analysis revealed that the 6-T haplotype is associated significantly with low BMD values (p< 0.025) at all measured locations of the skeleton, and with high plasma osteocalcin concentrations (p=0.008). This study shows for the first time that the polymorphisms polyAla and Pro198Leu of the GPX1 gene, individually and in combination, are associated with BMD and therefore may be useful as genetic markers for bone disease. Moreover, it implies the important contribution of the oxidative stress to pathogenesis of osteoporosis.

BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

PubMed Central

Uegaki, Koichi; Kumanogoh, Haruko; Mizui, Toshiyuki; Hirokawa, Takatsugu; Ishikawa, Yasuyuki; Kojima, Masami

2017-01-01

Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function

Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer

PubMed Central

Hirata, Hiroshi; Hinoda, Yuji; Kawamoto, Ken; Kikuno, Nobuyuki; Suehiro, Yutaka; Okayama, Naoko; Tanaka, Yuichiro; Dahiya, Rajvir

2014-01-01

Purpose The mismatch repair (MMR) system is a DNA repair mechanism that corrects mispaired bases during DNA replication errors. Cancer cells deficient in the MMR proteins have a 102 –103-fold increase in the mutation rate. Single nucleotide polymorphisms (SNPs) of MMR genes have been shown to cause a reduction in DNA repair activity. We hypothesized that mismatch repair gene polymorphism could be a risk factor for prostate cancer (PC) and that p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms. Material and Methods DNA samples from 110 cases of prostate cancer and healthy controls (n=110) were analyzed by SSCP and PCR-RFLP to determine the genotypic frequency of five different polymorphic loci on two MMR genes (MSH3 and MSH6) and p53 codon72. The chi-square test was applied to compare the genotype frequency between patients and controls. Results A significant increase in the G/A+A/A genotype of MSH3 Pro222Pro was observed in patients compared to controls (OR, 1.87; 95% CI, 1.0–3.5). The frequency of A/G + G/G genotypes of MSH3 exon23 Thr1036Ala also tended to increase in patients (OR, 1.57; 95% CI, 0.92–2.72). Among p53 codon72 Arg/Pro + Pro/Pro carriers, the frequency of the AG + GG genotype of MSH3 exon23 was significantly increased in patients compared to controls (OR = 2.1, 95% CI; 1.05–4.34). Conclusion This is the first report on the association of MSH3 gene polymorphisms in prostate cancer. These results suggest that the MSH3 polymorphism may be a risk factor for prostate cancer. PMID:18355840

MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis.

PubMed

Nikzad, Hossein; Karimian, Mohammad; Sareban, Kobra; Khoshsokhan, Maryam; Hosseinzadeh Colagar, Abasalt

2015-11-01

Methylenetetrahydrofolate reductase (MTHFR) functions as a main regulatory enzyme in folate metabolism. The association of MTHFR gene Ala222Val polymorphism with male infertility in an Iranian population was investigated by undertaking a meta-analysis and in-silico approach. A genetic association study included 497 men; 242 had unexplained infertility and 255 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for genotyping MTHFR-Ala222Val. OpenMeta[Analyst] software was used to conduct the analysis; 22 studies were identified by searching PubMed and the currently reported genetic association study. A novel in-silico approach was used to analyse the effects of Ala222Val substitution on the structure of mRNA and protein. Genetic association study revealed a significant association of MTHFR-222Val/Val genotype with oligozoospermia (OR 2.32; 95% CI, 1.12 to 4.78; P = 0.0451) and azoospermia (OR 2.59; 95% CI 1.09 to 6.17; P = 0.0314). Meta-analysis for allelic, dominant and codominant models showed a significant association between Ala222Val polymorphism and the risk of male infertility (P < 0.001). In silico-analysis showed MTHFR-Ala222Val affects enzyme structure and could also change the mRNA properties (P = 0.1641; P < 0.2 is significant). The meta-analysis suggested significant association of MTHFR-Ala222Val with risk of male infertility, especially in Asian populations. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Influence of ALA54THR polymorphism of fatty acid binding protein 2 on lifestyle modification response in obese subjects.

PubMed

de Luis, D A; Aller, R; Izaola, O; Sagrado, M Gonzalez; Conde, R

2006-01-01

It has been found that the expression of fatty acid binding protein 2 (FABP2) mRNA is under dietary control. A G-to-A transition at codon 54 of FABP2 results in an amino acid substitution (from Ala 54 to Thr 54). This polymorphism was associated with high insulin resistance and high fasting insulin concentrations. The aim of our study was to investigate the influence of Thr54 polymorphism in the FABP2 protein on the response to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. A population of 69 obese (body mass index > 30) nondiabetic outpatients was analyzed in a prospective way. Before and after 3 months of the lifestyle modification program, indirect calorimetry, tetrapolar electrical bioimpedance measurement, blood pressure recording, serial assessment of the nutritional intake (3 days of written food records), and biochemical analysis were performed. The lifestyle modification program consisted of a hypocaloric diet (1,520 kcal; 52% carbohydrates, 25% lipids, and 23% proteins). The exercise program consisted of aerobic exercise for at least three times/week (60 min each). Statistical analysis was performed for combined Ala54/Thr54 and Thr54/Thr54 as a mutant group and wild-type Ala54/Ala54 as second group. The mean age was 45.5 +/- 16.7 years, the mean body mass index was 34.1 +/- 5.1, and there were 14 males (20.3%) and 55 females (79.7%) with a weight loss of 3.17 +/- 3.5 kg (3.5%). Thirty-seven patients (53.6%) had the genotype Ala54/Ala54 (wild-type group) and 32 (46.4%) patients either the genotype Ala54/Thr54 (26 patients, 30.2%) or the genotype Thr54/Thr54 (6 patients, 16.2%). The percentage of responders (weight loss) was similar in both groups (89.2 vs. 90.6%). In the wild-type group, body mass index, weight, fat mass, low-density lipoprotein cholesterol level, and waist circumference decreased, whereas the VO2 (oxygen consumption) increased. In the mutant group, glucose, body mass index, weight, waist

The conformation of cyclo(-D-Pro-Ala4-) as a model for cyclic pentapeptides of the DL4 type.

PubMed

Heller, Markus; Sukopp, Martin; Tsomaia, Natia; John, Michael; Mierke, Dale F; Reif, Bernd; Kessler, Horst

2006-10-25

The conformation of the cyclic pentapeptide cyclo(-D-Pro-Ala(4)-) in solution and in the solid state was reinvestigated using modern NMR techniques. To allow unequivocal characterization of hydrogen bonds, relaxation behavior, and intramolecular distances, differently labeled isotopomers were synthesized. The NMR results, supported by extensive MD simulations, demonstrate unambiguously that the preferred conformation previously described by us, but recently questioned, is indeed correct. The validation of the conformational preferences of this cyclic peptide is important given that this system is a template for several bioactive compounds and for controlled "spatial screening" for the search of bioactive conformations.

High frequency of Neuropeptide Y Leu7Pro polymorphism in an Iranian population and its association with coronary artery disease.

PubMed

Masoudi-Kazemabad, Ali; Jamialahmadi, Khadijeh; Moohebati, Mohsen; Mojarrad, Majid; Dehghan-Manshadi, Raheleh; Forghanifard, Mohammad Mahdi; Akhlaghi, Saeed; Ferns, Gordon A; Ghayour-Mobarhan, Majid

2012-03-15

Neuropeptide Y (NPY), a 36-amino acid peptide, is widely expressed in the central and peripheral nervous systems as well as in the heart. A relationship has been reported between NPY gene variants and coronary artery disease (CAD) in some populations. However, there are few data on the NPY gene polymorphism and CAD in the Persian population. In the current study we have investigated the relationship between the NPY Leu7Pro polymorphism and CAD within a population from Iran. A total of 1061 subjects were recruited; 609 patients and 452 healthy subjects. Four hundred and twenty eight of the patients had >50% stenosis; with the remaining 181 patients having <50% stenosis based on angiography. Angiography positive patients were divided into three groups: those with single (n=115), double (n=140), and triple vessel (n=173) disease. DNA analysis for the Leu7Pro polymorphism was performed using a PCR-RFLP technique. A significantly higher frequency of the Leu7Pro genotype was observed in CAD patients compared with the control group (P<0.05). Patients with the Pro7 had significantly higher values for weight (P=0.027), BMI (P=0.001), hip circumference (P=0.003) and prevalence of diabetes mellitus (P=0.018) but reduced prevalence of a history of myocardial infarction (P=0.017). The frequency of Leu7Pro polymorphism of NPY was 5.9% in our Iranian population; higher than reported for other Asian populations. The Leu7Pro polymorphism was associated with CAD in an Iranian population. Copyright © 2012 Elsevier B.V. All rights reserved.

Evidence of Interaction Between PPARG2 and HNF4A Contributing to Variation in Insulin Sensitivity in Mexican Americans

PubMed Central

Black, Mary Helen; Fingerlin, Tasha E.; Allayee, Hooman; Zhang, Weiming; Xiang, Anny H.; Trigo, Enrique; Hartiala, Jaana; Lehtinen, Allison B.; Haffner, Steven M.; Bergman, Richard N.; McEachin, Richard C.; Kjos, Siri L.; Lawrence, Jean M.; Buchanan, Thomas A.; Watanabe, Richard M.

2015-01-01

OBJECTIVE We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes–related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests. RESULTS Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes–related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher SI compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes. PMID:18162503

Common polymorphisms in interleukin genes (IL4, IL6, IL8 and IL12) are not associated with alcoholic liver disease or alcoholism in Spanish men.

PubMed

Marcos, Miguel; Pastor, Isabel; González-Sarmiento, Rogelio; Laso, Francisco-Javier

2009-03-01

Preliminary data suggest that polymorphisms in cytokine genes may be involved in the genetic predisposition to alcoholic liver cirrhosis or alcohol use disorders. We thus analyze the association between these diseases and the following polymorphisms: -33T>C IL4, -174 G>C IL6, -251 T>A IL8 and 1188 A>C IL12B. 258 male alcoholics (161 without liver disease and 97 with liver cirrhosis) and 101 healthy controls were genotyped for the above mentioned polymorphisms. We examined the relationship between genotype and allele frequencies and the presence of disease, as well as the correlation with combinations of putative pro-inflammatory genotypes. Haplotypes were inferred using the expectation-maximization algorithm and haplotype frequencies were compared. We found no statistically significant association between any of these polymorphisms or the combinations of pro-inflammatory polymorphisms and the risk of alcoholic liver cirrhosis or alcohol abuse or dependence. Haplotype analysis of the IL4 and IL12B polymorphisms did not show any statistical relationship either. Our results do not support the hypothesis that the analyzed polymorphisms confer differences in alcoholic liver cirrhosis or alcohol use disorders susceptibility.

Is SOD2 Ala16Val Polymorphism Associated with Migraine with Aura Phenotype?

PubMed Central

Barbanti, Piero; De Marchis, Maria Laura; Egeo, Gabriella; Aurilia, Cinzia; Fofi, Luisa; Ialongo, Cristiano; Valente, Maria Giovanna; Ferroni, Patrizia; Della-Morte, David; Guadagni, Fiorella

2015-01-01

Abstract Several studies suggest a role of oxidative stress in the physiopathology of migraine, particularly in the form with aura. In a case-control study, we investigated the association between migraine and superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) genes in a cohort of 490 consecutive unrelated Caucasian migraineurs (migraine with aura [MwA], n=107; migraine without aura [MwoA], n=246; chronic migraine [CM], n=137) and 246 healthy controls recruited at our Headache and Pain Unit and stored in the Interinstitutional Multidisciplinary BioBank (BioBIM). Migraine phenotype was carefully detailed using face-to-face interviews. We examined polymorphisms of SOD1 gene (A/C substitution—rs2234694) and SOD2 gene (C/T transition—rs4880—Ala16Val). The rs4880 TT (Val/Val) genotype was associated (p=0.042) with the presence of unilateral cranial autonomic symptoms (UAs) in MwA patients. We also found a mild correlation between SOD2 rs4880 genotype and the type of acute migraine treatment (p=0.048) in MwA patients. Our findings suggest that SOD2 is a disease-modifier gene influencing oxidative mechanisms in MwA. These observations lead to the hypothesis that SOD2 polymorphism may cause a defective control of the oxidative phenomena linked to cortical spreading depression, the neurophysiological hallmark of migraine aura, causing an overstimulation of trigeminal neurons and UAs triggering. Antioxid. Redox Signal. 22, 275–279. PMID:25295643

Ala397Asp mutation of myosin VIIA gene segregating in a Spanish family with type-Ib Usher syndrome.

PubMed

Espinós, C; Millán, J M; Sánchez, F; Beneyto, M; Nájera, C

1998-06-01

In the current study, 12 Spanish families affected by type-I Usher syndrome, that was previously linked to chromosome 11q, were screened for the presence of mutations in the N-terminal coding portion of the motor domain of the myosin VIIA gene by single-strand conformation polymorphism analysis of the first 14 exons. A mutation (Ala397Asp) segregating with the disease was identified, and several polymorphisms were also detected. It is presumed that the other USHIB mutations in these families could be located in the unscreened regions of the gene.

[Ala12]MCD peptide: a lead peptide to inhibitors of immunoglobulin E binding to mast cell receptors.

PubMed

Buku, A; Condie, B A; Price, J A; Mezei, M

2005-09-01

An effort was made to discover mast cell degranulating (MCD) peptide analogs that bind with high affinity to mast cell receptors without triggering secretion of histamine or other mediators of the allergic reaction initiated by immunoglobulin E (IgE) after mast cell activation. Such compounds could serve as inhibitors of IgE binding to mast cell receptors. An alanine scan of MCD peptide reported previously showed that the analog [Ala12]MCD was 120-fold less potent in histamine-releasing activity and fivefold more potent in binding affinity to mast cell receptors than the parent MCD peptide. Because this analog showed marginal intrinsic activity and good binding affinity it was subsequently tested in the present study as an IgE inhibitor. In contrast to MCD peptide, [Ala12]MCD showed a 50% inhibition of IgE binding to the Fc epsilon RI alpha mast cell receptor by using rat basophilic leukemia (RBL-2H3) mast cells and fluorescence polarization. Furthermore, in a beta-hexosaminidase secretory assay, the peptide also showed a 50% inhibition of the secretion of this enzyme caused by IgE. An attempt was made to relate structural changes and biologic differences between the [Ala12]MCD analog and the parent MCD peptide. The present results show that [Ala12]MCD may provide a base for designing agents to prevent IgE/Fc epsilon RI alpha interactions and, consequently, allergic conditions.

Meta-analysis of association between the TP53 Arg72Pro polymorphism and risk of endometriosis based on case-control studies.

PubMed

Yan, Yulan; Wu, Renzheng; Li, Shaojing; He, Jinlong

2015-06-01

In the light of the relationship between the TP53 Arg72Pro (rs1042522) polymorphism and the risk of endometriosis remains inclusive or controversial. For better understanding of the effect of TP53 Arg72Pro polymorphism on endometriosis risk, we performed a meta-analysis. The relevant studies were identified through a search of PubMed, Web of Science, EMBASE, Ovid, Springer, China National Knowledge Infrastructure (CNKI), cqvip, Wanfang database, and Chinese Biomedical Literature (CBM) databases up to December, 2014. The association between the TP53 Arg72Pro polymorphism and endometriosis risk was pooled by conducted by odds ratios and 95% confidence intervals. A total of fifteen case-control studies with 2683 cases and 3335 controls were eventually identified. There was significant association between Arg72Pro polymorphism and endometriosis risk in all of the five models in overall populations (C vs. G: OR=1.32, 95%CI=1.14-1.53, p=0.00; CC vs. GG: OR=1.80, 95%CI=1.28-2.53, p=0.001; GC vs. GG: OR=1.52, 95%CI=1.22-1.88, p=0.00; CC vs. OR=1.32, 95%CI=1.05-1.66, p=0.016; CC/GC vs. GG: OR=1.59, 95%CI=1.26-2.00, p=0.00). In the sub-group analysis according to ethnicity, the results suggested that TP53 Arg72Pro polymorphism was not associated with endometriosis risk in Caucasians. However, the significant association was found in Asians and Mixed race (MIX) under the five models. The results of this meta-analysis suggest that the TP53 Arg72Pro polymorphism can increase the risk of endometriosis, especially among Asians and MIX populations. Considering the limited sample size and ethnicities included in the meta-analysis, further larger scaled and well-designed studies are needed to confirm our results. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Glycyl-alanyl-histidine protects PC12 cells against hydrogen peroxide toxicity.

PubMed

Shimura, Hideki; Tanaka, Ryota; Shimada, Yoshiaki; Yamashiro, Kazuo; Hattori, Nobutaka; Urabe, Takao

2017-11-22

Peptides with cytoprotective functions, including antioxidants and anti-infectives, could be useful therapeutics. Carnosine, β-alanine-histidine, is a dipeptide with anti-oxidant properties. Tripeptides of Ala-His-Lys, Pro-His-His, or Tyr-His-Tyr are also of interest in this respect. We synthesized several histidine-containing peptides including glycine or alanine, and tested their cytoprotective effects on hydrogen peroxide toxicity for PC12 cells. Of all these peptides (Gly-His-His, Ala-His-His, Ala-His-Ala, Ala-Ala-His, Ala-Gly-His, Gly-Ala-His (GAH), Ala-His-Gly, His-Ala-Gly, His-His-His, Gly-His-Ala, and Gly-Gly-His), GAH was found to have the strongest cytoprotective activity. GAH decreased lactate dehydrogenase (LDH) leakage, apoptosis, morphological changes, and nuclear membrane permeability changes against hydrogen peroxide toxicity in PC12 cells. The cytoprotective activity of GAH was superior to that of carnosine against hydrogen peroxide toxicity in PC12 cells. GAH also protected PC12 cells against damage caused by actinomycin D and staurosporine. Additionally, it was found that GAH also protected SH-SY5Y and Jurkat cells from damage caused by hydrogen peroxide, as assessed by LDH leakage. Thus, a novel tripeptide, GAH, has been identified as having broad cytoprotective effects against hydrogen peroxide-induced cell damage.

Capping Parallel β-Sheets of Acetyl(Ala)6NH2 with an Acetyl(Ala)5ProNH2 Can Arrest the Growth of the Sheet, Suggesting a Potential for Curtailing Amyloid Growth. An ONIOM and Density Functional Theory Study

PubMed Central

2015-01-01

We present ONIOM calculations using B3LYP/d95(d,p) as the high level and AM1 as the medium level on parallel β-sheets containing four strands of Ac-AAAAAA-NH2 capped with either Ac-AAPAAA-NH2 or Ac-AAAPAA-NH2. Because Pro can form H-bonds from only one side of the peptide linkage (that containing the C=O H-bond acceptor), only one of the two Pro-containing strands can favorably add to the sheet on each side. Surprisingly, when the sheet is capped with AAPAAA-NH2 at one edge, the interaction between the cap and sheet is slightly more stabilizing than that of another all Ala strand. Breaking down the interaction enthalpies into H-bonding and distortion energies shows the favorable interaction to be due to lower distortion energies in both the strand and the four-stranded sheet. Because another strand would be inhibited for attachment to the other side of the capping (Pro-containing) strand, we suggest the possible use of Pro residues in peptides designed to arrest the growth of many amyloids. PMID:24422496

Role of IL-10 -1082, IFN-gamma +874, and TNF-alpha -308 genes polymorphisms in suicidal behavior.

PubMed

Omrani, Mir Davood; Bushehri, Behzad; Bagheri, Morteza; Salari-Lak, Shaker; Alipour, Azize; Anoshae, Mohamad-Reza; Massomi, Reza

2009-01-01

In this study, it was determined whether the IL-10 -1082, IFN-gamma +874, and TNF-alpha -308 polymorphisms were associated with suicidal behavior. One hundred forty five patients with suicidal behavior and 160 normal individuals were genotyped for IL-10 -1082, IFN-gamma +874, and TNF-alpha -308 polymorphisms using ASO-PCR method. TNF-alpha -308 G/G genotype has been increased in males with completed suicide behavior versus control group (p value = 0.017). IL-10 -1082 A/A genotype is higher in both male and female suicide completed groups (p value = 0.017). IFN-gamma (+874) A/A genotype was significantly higher in males with completed suicide behavior versus normal male control (p value = 0.027). It can be concluded that IL-10, IFN-gamma, and TNF-alpha polymorphisms may play a role in suicidal behavior.

Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor.

PubMed

Zou, Xuan; Dong, Fangtian; Zhang, Shuying; Tian, Rong; Sui, Ruifang

2013-05-01

The familial transthyretin (TTR) amyloidosis (FTA) demonstrates variable penetrance of clinical features associated with mutations in the plasma thyroid hormone-binding protein TTR gene. The purpose of this study was to assess the ocular features, to analyze vitreous and serum vascular endothelial growth factor (VEGF) levels, and to identify the genetic defect in a Chinese family with TTR FTA. The pedigree of interest was a three-generation family with eleven members. The primary ocular signs were vitreous opacities, beginning from the third or fourth decade, accompanied by retinal vasculitis, hemorrhages, and widespread pinpoint deposits in the peripheral retina. Two patients underwent vitrectomy with marked improvement of visual acuity postoperatively. Vitreous and serum samples for VEGF were analyzed with an enzyme-linked immunosorbent assay (ELISA). Forty-eight healthy adult volunteers were enrolled as a control group for the analysis of serum VEGF. Eight subjects who underwent vitrectomy for a macular epiretinal membrane or macular hole were enrolled as control for the analysis of vitreous VEGF. Both serum and vitreous VEGF levels of patients were raised compared to that of controls. Venous blood was collected from family members and the genomic DNA was extracted. All exons and exon-intron boundaries of the TTR gene were sequenced. A previously-described pathogenic transversion in exon 2 (c.G106C, p.Ala36Pro) was identified. Within this family eight individuals were confirmed as affected. In conclusion, a Chinese family with TTR Ala36Pro associated FTA is characterized by early ocular involvement. Widespread pinpoint lesions indicate RPE lesions caused by TTR deposition. FTA is associated with increased VEGF levels, both in serum and vitreous. Copyright © 2013 Elsevier Ltd. All rights reserved.

Frequency of the AGT Pro11Leu polymorphism in humans: Does diet matter?

PubMed

Ségurel, Laure; Lafosse, Sophie; Heyer, Evelyne; Vitalis, Renaud

2010-01-01

The Pro11Leu substitution in the AGXT gene, which causes primary hyperoxaluria type 1, is found with high frequency in some human populations (e.g., 5-20% in Caucasians). It has been suggested that this detrimental mutation could have been positively selected in populations with a meat-rich diet. In order to test this hypothesis, we investigated the occurrence of Pro11Leu in both herder and agriculturalist populations from Central Asia. We found a lower frequency of this detrimental mutation in herders, whose diet is more meat-rich, as compared to agriculturalists, which therefore challenges the universality of the previous claim. Furthermore, when combining our original data with previously published results, we could show that the worldwide genetic differentiation measured at the Pro11Leu polymorphism does not depart from neutrality. Hence, the distribution of the variation observed in the AGXT gene could be due to demographic history, rather than local adaptation to diet.

Association of GABA(B)R1 receptor gene polymorphism with obstructive sleep apnea syndrome.

PubMed

Bayazit, Yildirim A; Yilmaz, Metin; Kokturk, Oguz; Erdal, M Emin; Ciftci, Tansu; Gokdogan, Tuba; Kemaloglu, Yusuf; Ileri, Fikret

2007-01-01

GABA(B)R (gamma-amino butyric acid B receptor)-mediated neurotransmission has been implicated in the pathophysiology of a variety of neuropsychiatric disorders. GABA(B)R1 gene variants were identified by single-strand conformation analysis. The nucleotide exchanges cause a substitution of alanine to valine in exon 1a1 (Ala20Val), a substitution of glycine to serine in exon 7 (Gly489Ser) and a silent C to G nucleotide exchange encoding the amino acid phenylalanine in exon 11 (Phe658Phe). The significance of GABA(B)R1a gene polymorphism in obstructive sleep apnea syndrome (OSAS) as well as the association of these polymorphisms with the polysomnography findings in OSAS patients are not known. In this study, we aimed to assess the significance of 3 different GABA(B)R1 gene polymorphisms (Ala20Val, Gly489Ser and Phe658Phe) in OSAS. Seventy-five patients (23 female and 52 male) with OSAS and 99 healthy volunteers (51 female, 48 male) were included in the study to assess Ala20Val, Gly489Ser and Phe658Phe polymorphisms of the GABA(B)R1 gene. For the Ala20Val variants, there was no significant difference between the genotypes and allele frequencies of the patients and controls, nor between both genders (p > 0.05). For Phe658Phe polymorphism, there was no significant difference between genotypes and allele frequencies of the patients and controls (p > 0.05). However, the C/C genotype was overrepresented and the T/C genotype was less frequent in male than female patients (p = 0.03). The C/C genotype was overrepresented and the T/C genotype was less frequent in male patients than male controls (p = 0.01). For GABA(B)R1-Gly489Ser polymorphism, all of the patients and controls had G/G genotype. The apnea arousal index scores of the male patients with C/C genotype were significantly higher than in the patients with C/T genotype (p = 0.01). The percent total sleep time in non-REM 1 scores of the male patients with T/T genotype were significantly higher than in the patients with T

Evaluation of p53 Polymorphism in Patients with Pannus-Derived Prosthetic Dysfunction.

PubMed

Gursoy, Mustafa Ozan; Karakoyun, Suleyman; Kalcik, Macit; Yesin, Mahmut; Gunduz, Sabahattin; Astarcioğlu, Mehmet Ali; Oğuz, Ali Emrah; Ozkan, Mehmet

2015-09-01

Prosthetic valve dysfunction (PVD) due to pannus formation is considered to occur due to a bioreaction to prosthetic material. The p53 gene plays a critical role in apoptosis and cell proliferation. p53 Arg72Pro polymorphism has been found to be associated with coronary stent restenosis, but has not yet been studied in prosthetic heart valve dysfunction. The study aim was to evaluate the association between pannus-derived PVD and p53 G72C(Arg72Pro) polymorphism. This single-center, prospective study included 25 patients (20 females, five males; mean age 45.6 +/- 12.5 years; group 1) who underwent redo valve surgery due to PVD, and 49 age- and gender-matched control patients (44 females, five males; mean age 47.3 +/- 12.2 years; group 2) with normofunctional prostheses. The prostheses were examined using transthoracic and transesophageal echocardiography. Analyses of p53 G72C(Arg72Pro) polymorphism were performed using Roche LightCyler 2.0 Real-time polymerase chain reaction. The most common location of replaced valves was the mitral position in both groups (88% and 89.8%, respectively). In group 1, normal alleles (GG) were observed in 12 patients (48%), while one patient (4%) showed a homozygous mutation (GC) and 12 patients (48%) showed a heterozygous mutation (CC). In group 2, 21 patients (42.9%) had normal alleles (GG), while four (8.2%) had a homozygous mutation (CC) and 24 (48.9%) had a heterozygous mutation (GC). No significant difference was observed between the groups with regards to p53 Arg72Pro polymorphism (p = 0.769). In patients with prosthetic valves, the underlying mechanism behind pannus formation is unrelated to p53 Arg72Pro polymorphism.

Leu7Pro polymorphism of PreproNPY associated with an increased risk for type II diabetes in middle-aged subjects.

PubMed

Ukkola, O; Kesäniemi, Y A

2007-09-01

Neuropeptide Y (NPY) plays a central in energy homeostasis and potentially in the development of obesity-related comorbidities, like type II diabetes. As the PreproNPY Leu7Pro polymorphism probably changes the intracellular processing of the synthesized preproNPY peptide, we assessed the hypothesis that PreproNPY Leu7Pro polymorphism is a risk factor for type II diabetes, impaired glucose tolerance and hypertension. Blood pressure recordings and oral glucose tolerance test were performed in the hypertensive (n=515) and control cohorts (n=525) of our well-defined Oulu Project Elucidating Risk of Atherosclerosis (OPERA) study. The prevalence of type II diabetes was 9% (n=93). The genotypes, insulin and glucose metabolism indexes and plasma ghrelin of the subjects were determined. Pro7 allele frequencies were 5.9, 5.3 and 11.3% in the total cohort, in subjects without and with type II diabetes, respectively. The PreproNPY Pro7 carrier status was a significant risk factor for type II diabetes, and the effect remained significant after adjustment for age, sex, waist circumference and study group (odds ratio=3.02, confidence interval: 1.67-5.44 and P<0.001). Pro7 carriers were more insulin resistant and showed lower ghrelin levels compared to non-carriers. The PreproNPY Pro7 allele is associated with an increased risk for type II diabetes. The risk seems to be associated with a higher insulin resistance among Pro7 carriers whereas low ghrelin concentrations in Pro7 carriers are possibly a consequence of high insulin levels.

Variation in PPARG is associated with longitudinal change in insulin resistance in Mexican Americans at risk for type 2 diabetes.

PubMed

Black, Mary Helen; Wu, Jun; Takayanagi, Miwa; Wang, Nan; Taylor, Kent D; Haritunians, Talin; Trigo, Enrique; Lawrence, Jean M; Watanabe, Richard M; Buchanan, Thomas A; Xiang, Anny H

2015-03-01

Peroxisome proliferator-activated receptor gamma (PPARG) is a susceptibility locus for type 2 diabetes mellitus (T2DM). Although cross-sectional associations have been reported, primarily for Pro12Ala, few longitudinal studies in nondiabetic populations have been conducted. This study aimed to examine whether and to what extent variation in PPARG is associated with longitudinal changes in anthropometric and metabolic traits in Mexican Americans at risk for T2DM. Subjects were participants of BetaGene, a family-based study of obesity, insulin resistance, and β-cell function, who completed a baseline and follow-up study visit (n = 378; mean followup, 4.6 ± 1.5 y). Phenotypes included body fat assessed by dual-energy x-ray absorptiometry; insulin sensitivity (SI), acute insulin response, and β-cell function (disposition index; DI) were estimated from iv glucose tolerance tests with Minimal Model analysis. Eighteen tag single nucleotide polymorphisms (SNPs) capturing variation in a 156-kb region surrounding PPARG were tested for association with changes in longitudinal traits. P-values were Bonferroni-corrected for multiple testing. Six SNPs (rs2972164, rs11128598, rs17793951, rs1151996, rs1175541, rs3856806) were significantly associated with rate of change in SI after adjustment for age, sex, and body fat percentage, but not with changes in adiposity. rs17793951 also had a significant effect on change in DI over time. Association between rs1175541 and change in SI varied by changes in adiposity such that only carriers of the minor allele who reduced body fat over followup improved SI. rs1306470 (captured Pro12Ala, r(2) = 0.9) was not associated with rates of change in any traits and its effects were not modified by changes in adiposity. Variation in PPARG, but not Pro12Ala, contributes to declining SI and concomitant deterioration in β-cell function in Mexican Americans at risk for T2DM.

Electrospray ionization tandem mass spectrometry differentiation of N-phosphoryl-[alpha]-, [beta]- and [gamma]-amino acids

NASA Astrophysics Data System (ADS)

Qiang, Liming; Cao, Shuxia; Zhao, Xiaoyang; Mao, Xiangju; Guo, Yanchun; Liao, Xincheng; Zhao, Yufen

2007-10-01

The fragmentation patterns of N-diisopropyloxyphosphoryl-l-[alpha]-Ala (DIPP-l-[alpha]-Ala), N-diisopropyloxyphosphoryl-d-[alpha]-Ala (DIPP-d-[alpha]-Ala), N-diisopropyloxyphosphoryl-[beta]-Ala (DIPP-[beta]-Ala) and N-diisopropyloxyphosphoryl-[gamma]-amino butyric acid (DIPP-[gamma]-Aba) were investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS). DIPP-d-[alpha]-Ala showed the same fragmentation pathways as DIPP-l-[alpha]-Ala. In the fragmentation of protonated DIPP-[beta]-Ala, the characteristic fragment ion [M + H - 2C3H6 - H2O - CH2CO]+ appeared and could be used to distinguish [beta]-Ala from l-[alpha]-Ala and d-[alpha]-Ala through tandem mass spectra, even though they possess the same molecular weight. In the fragmentation of protonated DIPP-[gamma]-Aba, the break of PN bond occurred and an interesting protonated lactam ion with five-membered ring was generated. Furthermore, in the MS3 spectrum of [M + Na - 2C3H6]+ ion of DIPP-[gamma]-Aba, a strong intensity of unique fragment ion, namely lactam-sodium adduct with five-membered ring, was observed, which could be considered as a mark for [gamma]-amino acids. The stepwise fragmentations of their [M + Na]+ ions and [M - H]- ions showed that they all underwent a PN to PO bond migration through a five-membered or six-membered or even seven-membered ring transition state, respectively, which supported the great affinity of hydroxyl for phosphoryl group.

The Neuronal Ischemic Tolerance Is Conditioned by the Tp53 Arg72Pro Polymorphism.

PubMed

Ramos-Araque, Maria E; Rodriguez, Cristina; Vecino, Rebeca; Cortijo Garcia, Elisa; de Lera Alfonso, Mercedes; Sanchez Barba, Mercedes; Colàs-Campàs, Laura; Purroy, Francisco; Arenillas, Juan F; Almeida, Angeles; Delgado-Esteban, Maria

2018-04-23

Cerebral preconditioning (PC) confers endogenous brain protection after stroke. Ischemic stroke patients with a prior transient ischemic attack (TIA) may potentially be in a preconditioned state. Although PC has been associated with the activation of pro-survival signals, the mechanism by which preconditioning confers neuroprotection is not yet fully clarified. Recently, we have described that PC-mediated neuroprotection against ischemic insult is promoted by p53 destabilization, which is mediated by its main regulator MDM2. Moreover, we have previously described that the human Tp53 Arg72Pro single nucleotide polymorphism (SNP) controls susceptibility to ischemia-induced neuronal apoptosis and governs the functional outcome of patients after stroke. Here, we studied the contribution of the human Tp53 Arg72Pro SNP on PC-induced neuroprotection after ischemia. Our results showed that cortical neurons expressing the Pro72-p53 variant exhibited higher PC-mediated neuroprotection as compared with Arg72-p53 neurons. PC prevented ischemia-induced nuclear and cytosolic p53 stabilization in Pro72-p53 neurons. However, PC failed to prevent mitochondrial p53 stabilization, which occurs in Arg72-p53 neurons after ischemia. Furthermore, PC promoted neuroprotection against ischemia by controlling the p53/active caspase-3 pathway in Pro72-p53, but not in Arg72-p53 neurons. Finally, we found that good prognosis associated to TIA within 1 month prior to ischemic stroke was restricted to patients harboring the Pro72 allele. Our findings demonstrate that the Tp53 Arg72Pro SNP controls PC-promoted neuroprotection against a subsequent ischemic insult by modulating mitochondrial p53 stabilization and then modulates TIA-induced ischemic tolerance.

Unlike type 2 diabetes, type 1 does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene.

PubMed

Georgopoulos, Angeliki; Aras, Omer; Noutsou, Marina; Tsai, Michael Y

2002-08-01

In type 2 diabetes, the threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein 2 gene is associated with elevated fasting and postprandial triglycerides and dyslipidemia when compared with the wild type (Ala-54/Ala-54). To assess whether this is the case in patients with type 1 diabetes, who usually do not manifest the metabolic syndrome, we screened 181 patients with similar glycemic control as the type 2 patients. Thirty percent were heterozygous, and 9% were homozygous for the polymorphism. Mean (+/-SEM) fasting plasma triglyceride levels in patients with the wild type (n = 84), those heterozygous for Ala-54/Thr-54 (n = 44), and those homozygous for the Thr-54 (n = 13) were 1.0 +/- 0.07, 1.1 +/- 0.17, and 1.2 +/- 0.23 mmol/liter, respectively. In addition, there were no differences in total, low-density lipoprotein, high-density lipoprotein, and non-high density lipoprotein cholesterol among the three groups. After a fat load, the postprandial area under the curve of triglyceride in plasma, chylomicrons, and very low-density lipoprotein were similar between the wild type (n = 18) and the Thr-54 homozygotes (n = 12). In conclusion, in contrast to type 2, type 1 diabetes does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene to cause hypertriglyceridemia/dyslipidemia. Insulin resistance could account possibly for this difference.

Moisture-Absorption and Water Dynamics in the Powder of Egg Albumen Peptide, Met-Pro-Asp-Ala-His-Leu.

PubMed

Yang, Shuailing; Liu, Xuye; Zhang, Mingdi; Lin, Songyi; Chen, Feng

2017-01-01

Moisture absorbed into the powder of Met-Pro-Asp-Ala-His-Leu (MPDAHL)-a novel egg albumen antioxidant peptide-profoundly affects its properties. In this study, we elucidated water dynamics in MPDAHL using DVS, DSC, and low-field 1 H NMR. Based on the DVS data, we found that MPDAHL sorption kinetics obey a parallel exponential model. DSC results indicated that both water and heating could change the microstructure of MPDAHL. The T 2 parameters of NMR reflected the different phases of moisture absorption revealed that there were 4 categories of water with different states or mobility in the MPDAHL during the moisture absorption process. The fastest fraction T 2b mainly dominated the hygroscopicity of MPDAHL and the absorbed water significantly changed the proton distribution and structure of MPDAHL. Thus, this study shows that DVS, DSC, and low-field 1 H NMR are effective methods for monitoring water mobility and distribution in synthetic peptides. It can be used to improve the quality assurance of functional peptides. © 2016 Institute of Food Technologists®.

Substitution of the Lys Linker with the β-Ala Linker Dramatically Decreased the Renal Uptake of 99mTc-Labeled Arg-X-Asp-Conjugated and X-Ala-Asp-Conjugated α-Melanocyte Stimulating Hormone Peptides

PubMed Central

2015-01-01

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg11)CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg11)CCMSH (2), RVD-β-Ala-(Arg11)CCMSH (3), RAD-β-Ala-(Arg11)CCMSH (4), NAD-β-Ala-(Arg11)CCMSH (5), and EAD-β-Ala-(Arg11)CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their 99mTc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six 99mTc-peptides. 99mTc-4 exhibited the highest melanoma uptake (15.66 ± 6.19% ID/g) and the lowest kidney uptake (20.18 ± 3.86% ID/g) among these 99mTc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using 99mTc-4 as an imaging probe. PMID:25290883

Substitution of the Lys linker with the β-Ala linker dramatically decreased the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone peptides.

PubMed

Flook, Adam M; Yang, Jianquan; Miao, Yubin

2014-11-13

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg(11))CCMSH (2), RVD-β-Ala-(Arg(11))CCMSH (3), RAD-β-Ala-(Arg(11))CCMSH (4), NAD-β-Ala-(Arg(11))CCMSH (5), and EAD-β-Ala-(Arg(11))CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their (99m)Tc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six (99m)Tc-peptides. (99m)Tc-4 exhibited the highest melanoma uptake (15.66 ± 6.19% ID/g) and the lowest kidney uptake (20.18 ± 3.86% ID/g) among these (99m)Tc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using (99m)Tc-4 as an imaging probe.

Polymorphisms of glutathione peroxidase 1 (GPX1 Pro198Leu) and catalase (CAT C-262T) in women with spontaneous abortion.

PubMed

Sabet, Eliza Eskafi; Salehi, Zivar; Khodayari, Siamak; Zarafshan, Samin Sabouhi; Zahiri, Ziba

2014-10-01

About 10%-15% of conceptions are lost spontaneously prior to 20 weeks. Apart from the clinical problems, genetic variations have also been proposed as a susceptibility factor to miscarriage. Glutathione peroxidase 1 (GPX1) and catalase (CAT) encode two antioxidant enzymes that detoxify H2O2 and protect the cells from oxidative damage. A functional polymorphism at codon 198 of the GPX1 gene causes a C/T substitution in exon 2, which encodes for either proline or leucine (Pro198Leu). The CAT gene has a polymorphic site in the promoter region at position -262 (C-262T) which alters the expression and enzyme blood levels, leading to some pathological clinical conditions. In this study, we evaluated the association of these two polymorphisms with the risk of spontaneous abortion. Genomic DNA from 105 cases with spontaneous abortion and 90 healthy women were genotyped using allele-specific PCR (AS-PCR) and polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). The genetic distributions for GPX1 did not differ significantly between cases and controls (p = 0.680). However, C-262T polymorphism was significantly associated with the risk of the disease (OR, 5.50; 95% CI, 1.43-21.09; p = 0.012). In conclusion, this study indicates that CAT -262T/T genotype confers less susceptibility to spontaneous abortion, while GPX1 Pro198Leu polymorphism may not be correlated with the disease.

Association between polymorphism in the melanocortin 1 receptor gene and E locus plumage color phenotype.

PubMed

Dávila, S G; Gil, M G; Resino-Talaván, P; Campo, J L

2014-05-01

The purpose of this study was to investigate the effect of the melanocortin 1 receptor (MC1R) gene on plumage color in chickens. The gene was sequenced in 77 males and 77 females from 13 Spanish breeds, carrying 6 different alleles in the E locus (E*E, E*R, E*WH, E*N, E*B, E*BC), a recessive wheaten (yellowish-white) tester line (E*Y), and a White Leghorn population (heterozygous E*E). A total of 11 significant SNP were detected. Nine of them were nonsynonymous (T212C, G274A, G376A, T398AC, G409A, A427G, C637T, A644C, and G646A, corresponding to amino acid changes Met72Thr, Glu92Lys, Val126Ile, Leu133GlnPro, Ala137Thr, Thr143Ala, Arg213Cys, His215Pro, and Val216Ile), and 2 were synonymous (C69T and C834T). With respect to the significant SNP, 7 had an allelic frequency of 0.5 or greater for some of the alleles at the E locus. These results indicated a significant correlation between MC1R polymorphism and the presence of different alleles at the E locus. All the populations carrying the E*E or E*R alleles, except the Birchen Leonesa, had the G274A polymorphism. Eleven haplotypes were made with 7 of the significant SNP. The distribution of these haplotypes in the different alleles of the E locus showed that each haplotype was predominantly associated to one allele. The number of haplotypes was greatest for the Black Menorca, Birchen Leonesa, and Blue Andaluza breeds, whereas the Quail Castellana and Red-barred Vasca breeds were monomorphic. Our results suggested that the Glu92Lys mutation may be responsible of the activation of the receptor for eumelanin production, being necessary but not sufficient to express the extended black phenotype. They also suggested that the Arg213Cys mutation may be the cause of the loss or the decrease of function of the receptor to produce eumelanin, and the Ala137Thr mutation may be a candidate to attenuate the Glu92Lys effect. The observed co-segregation of the E locus alleles and polymorphisms in MC1R confirms that the E locus is

Manduca sexta proprophenoloxidase activating proteinase-3 (PAP3) stimulates melanization by activating proPAP3, proSPHs, and proPOs

PubMed Central

Wang, Yang; Lu, Zhiqiang; Jiang, Haobo

2014-01-01

Melanization participates in various insect physiological processes including antimicrobial immune responses. Phenoloxidase (PO), a critical component of the enzyme system catalyzing melanin formation, is produced as an inactive precursor prophenoloxidase (proPO) and becomes active via specific proteolytic cleavage by proPO activating proteinase (PAP). In Manduca sexta, three PAPs can activate proPOs in the presence of two serine proteinase homologs (SPH1 and SPH2). While the hemolymph proteinases (HPs) that generate the active PAPs are known, it is unclear how the proSPHs (especially proSPH1) are activated. In this study, we isolated from plasma of bar-stage M. sexta larvae an Ile-Glu-Ala-Arg-p-nitroanilide hydrolyzing enzyme that cleaved the proSPHs. This proteinase, PAP3, generated active SPH1 and SPH2, which function as cofactors for PAP3 in proPO activation. Cleavage of the purified recombinant proSPHs by PAP3 yielded 38 kDa bands similar in mobility to the SPHs formed in vivo. Surprisingly, PAP3 also can activate proPAP3 to stimulate melanization in a direct positive feedback loop. The enhanced proPO activation concurred with the cleavage activation of proHP6, proHP8, proPAP1, proPAP3, proSPH1, proSPH2, proPOs, but not proHP14 or proHP21. These results indicate that PAP3, like PAP1, is a key factor of the self-reinforcing mechanism in the proPO activation system, which is linked to other immune responses in M. sexta. PMID:24768974

Human beta-globin gene polymorphisms characterized in DNA extracted from ancient bones 12,000 years old.

PubMed

Béraud-Colomb, E; Roubin, R; Martin, J; Maroc, N; Gardeisen, A; Trabuchet, G; Goosséns, M

1995-12-01

Analyzing the nuclear DNA from ancient human bones is an essential step to the understanding of genetic diversity in current populations, provided that such systematic studies are experimentally feasible. This article reports the successful extraction and amplification of nuclear DNA from the beta-globin region from 5 of 10 bone specimens up to 12,000 years old. These have been typed for beta-globin frameworks by sequencing through two variable positions and for a polymorphic (AT) chi (T) gamma microsatellite 500 bp upstream of the beta-globin gene. These specimens of human remains are somewhat older than those analyzed in previous nuclear gene sequencing reports and considerably older than those used to study high-copy-number human mtDNA. These results show that the systematic study of nuclear DNA polymorphisms of ancient populations is feasible.

Arg25Pro polymorphism of transforming growth factor-beta1 and its role in the pathogenesis of essential hypertension in Russian population of the Central Chernozem Region.

PubMed

Ivanov, V P; Solodilova, M A; Polonnikov, A V; Belugin, D A; Shestakov, A M; Ushachev, D V; Khoroshaya, I V; Katargina, L N; Kozhukhov, M A; Kolesnikova, O E

2007-07-01

We studied the relationship between Arg25Pro polymorphism of TGFbeta1 gene and predisposition to essential hypertension in the Russian population of Central Chernozem Region (n=402). An association was found between 25Pro allele and 25ArgPro genotype with low risk of essential hypertension in male individuals.

Association between p53 polymorphism at codon 72 and recurrent spontaneous abortion.

PubMed

Zhang, Ying; Wu, Yuan-Yuan; Qiao, Fu-Yuan; Zeng, Wan-Jiang

2016-06-01

p53 gene plays an important role in apoptosis, which is necessary for successful invasion of trophoblast cells. The change from an arginine (Arg) to a proline (Pro) at codon 72 can influence the biological activity of p53, which predisposes to an increased risk of recurrent spontaneous abortion (RSA). In order to investigate the association between p53 polymorphism at codon 72 and RSA, we conducted this meta-analysis. Pubmed, Embase and Web of science were used to identify the eligible studies. Odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of the association. Six studies containing 937 cases of RSA and 830 controls were included, and there was one study deviated from Hardy-Weinberg equilibrium (HWE). There was a significant association between p53 polymorphism at codon 72 and RSA in recessive model (Pro/Pro vs. Pro/Arg+Arg/Arg; OR=1.60, 95% CI: 1.14-2.24) and co-dominant model (Pro/Pro vs. Arg/Arg; OR=1.47, 95% CI: 1.02-2.12) whether the study that was deviated from HWE was eliminated or not. A significant association was observed in allelic model (Pro vs. Arg; OR=1.28, 95% CI: 1.04-1.57) after exclusion of the study that was deviated from HWE. No association was noted in recessive model (Pro/Pro+Pro/Arg vs. Arg/Arg; OR=1.05, 95% CI: 0.86-1.30) and co-dominant model (Pro/Arg vs. Arg/Arg; OR=0.96, 95% CI: 0.77-1.19). Subgroup analysis by ethnicity also indicated a significant association between p53 polymorphism at codon 72 and RSA in Caucasian group. No heterogeneity and publication bias were found. Our meta-analysis implied that p53 polymorphism at codon 72 carries high maternal risk of RSA.

The transcobalamin codon 259 polymorphism influences the risk of human spontaneous abortion.

PubMed

Zetterberg, H; Regland, B; Palmér, M; Rymo, L; Zafiropoulos, A; Arvanitis, D A; Spandidos, D A; Blennow, K

2002-12-01

The remethylation cycle of methionine is folate and vitamin B(12) (cobalamin) dependent and appears to be crucial for embryonic development, probably through effects on synthesis of DNA, proteins and polyamines. Transcobalamin (TC) transports vitamin B(12) to the tissues. The objective of the present investigation was to explore the putative association between the major TC genetic polymorphism (Pro259Arg) and human spontaneous abortion. The prevalence of the TC Pro259Arg polymorphism was determined in DNA samples from embryos that had been spontaneously aborted between the 6th and 20th week after conception, and adult controls using solid-phase minisequencing technique. The 259-Pro allele was significantly less frequent in the spontaneous abortion group than in the control group (42.2 and 57.0% respectively; P = 0.005), while the frequency of 259-Arg was significantly increased. There was a lower prevalence of 259-Pro homozygotes in the spontaneous abortion group compared with the control group (9.1 and 32.2% respectively; P < 0.001). The 259-Pro allele seems to have beneficial influences during embryogenesis, conceivably through its positive effect on vitamin B(12) intracellular bioavailability. Our results warrant additional investigations addressing the question if vitamin B(12) supplementation in addition to folic acid supplementation may prevent spontaneous abortion in women planning a pregnancy.

Identification of Genetic Polymorphisms of CYP2W1 in the Three Main Chinese Ethnicities: Han, Tibetan, and Uighur.

PubMed

Li, Yanwei; Kang, Xing; Yang, Ge; Dai, Penggao; Chen, Chao; Wang, Huijuan

2016-09-01

CYP2W1 is an orphan member of the cytochrome P450 superfamily. Recently, CYP2W1 has gained great research interest because of its unknown enzymatic function and tumor-specific expression property. This study aims to investigate the genetic polymorphisms of the CYP2W1 gene in Chinese populations and explore the functions of the detected variants. All of the nine exons and exon-intron junction regions of the CYP2W1 gene were sequenced in 150 Chinese subjects, including 50 Han Chinese, 50 Tibetans, and 50 Uighurs. A total of 26 genetic variants were identified in this study, and 19 polymorphisms were detected in each population. Frequency comparison between populations showed that nine variants exhibited significantly different allelic distributions. A total of 12 different haplotypes were inferred from 150 samples by using the genotype data of nine exonic variants found in this study. CYP2W1*1A, *1B, *2, *4, and *6 were detected as the main alleles/haplotypes. Moreover, one, three, and two ethnically specific haplotypes were observed in the Han, Tibetan, and Uighur samples, respectively. Then, the effects of four detected missense mutations (Ala181Thr, Gly376Ser, Val432Ile, and Pro488Leu) on the CYP2W1 protein function were predicted using three in silico tools: Polymorphism Phenotyping v2, Sorts Intolerant from Tolerant, and MutationTaster. The results showed that Gly376Ser and Pro488Leu may have deleterious effects. In summary, this study showed that the genetic pattern of CYP2W1 is interethnically different among the three Chinese populations, and this finding can extend our understanding of population genetics of CYP2W1 in the Chinese population. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

A polymorphism in the bovine gamma-S-crystallin gene revealed by allele-specific amplification.

PubMed

Kemp, S J; Maillard, J C; Teale, A J

1993-04-01

A polymorphism was detected in the 3' untranslated region of the bovine gamma-S-crystallin gene by direct sequencing of polymerase chain reaction (PCR) products from genomic DNA of an N'Dama bull and a Boran cow. A set of three PCR primers was designed to detect this difference and thus give allele-specific amplification. The two allele-specific primers differ in length by 20 nucleotides so that the allelic products may be distinguished by simple agarose gel electrophoresis following a single PCR reaction. This provides a simple and rapid assay for this polymorphism.

Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome

PubMed Central

Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

2015-01-01

Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies. PMID:25987964

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis

PubMed Central

Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

2013-01-01

Background Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. Objectives To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. Methods The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Results Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. Conclusions The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. PMID:23252768

Effect of Gamma Rays on Sophora davidii and Detection of DNA Polymorphism through ISSR Marker

PubMed Central

Wang, Puchang; Mo, Bentian; Luo, Tianqiong

2017-01-01

Sophora davidii (Franch.) Kom. ex Pavol is an important medicinal plant and a feeding scrub with ecological value. The effects of different gamma irradiation doses (20–140 Kr) on seed germination and seedling morphology were investigated in S. davidii, and intersimple sequence repeat (ISSR) markers were used to identify the DNA polymorphism among mutants. Significant variations were observed for seed germination, stem diameter, and number of branches per plant. The improved agronomic traits, such as stem diameter and number of branches per plant, were recorded at 80 Kr dose and 20 Kr dose for seed germination. ISSR analysis generated in total 183 scorable fragments, of which 94 (51.37%) were polymorphic. The percentage of polymorphism ranged from 14.29 to 93.33 with an average of 45.69%. Jaccard's coefficients of dissimilarity varied from 0.6885 to 1.000, indicative of the level of genetic variation among the mutants. The constructed dendrogram grouped the entities into five clusters. Consequently, it was concluded that gamma rays irradiation of seeds generates a sufficient number of induced mutations and that ISSR analysis offered a useful molecular marker for the identification of mutants. PMID:28612030

LRP5 gene polymorphism and cortical bone.

PubMed

Lauretani, Fulvio; Cepollaro, Chiara; Bandinelli, Stefania; Cherubini, Antonio; Gozzini, Alessia; Masi, Laura; Falchetti, Alberto; Del Monte, Francesca; Carbonell-Sala, Silvia; Marini, Francesca; Tanini, Annalisa; Corsi, Anna Maria; Ceda, Gian Paolo; Brandi, Maria Luisa; Ferrucci, Luigi

2010-08-01

There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women. We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21-94 yrs). Trabecular vBMD (vBMDt, mg/cm3), cortical vBMD (vBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women.

Polymorphisms of the peroxisome proliferator-activated receptor-γ (rs1801282) and its coactivator-1 (rs8192673) are associated with obesity indexes in subjects with type 2 diabetes mellitus.

PubMed

Kruzliak, Peter; Haley, Andreana P; Starcevic, Jovana Nikolajevic; Gaspar, Ludovit; Petrovic, Daniel

2015-04-28

The aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with obesity indexes (BMI, waist circumference) in subjects with type 2 diabetes mellitus (T2DM) in Caucasian population. The second aim was to find an association of both polymorphisms with T2DM. Two exonic SNPs of both genes rs1801282 of the PPAR-γ gene and rs8192673 of the PGC-1α gene) were genotyped in 881 unrelated Slovene subjects (Caucasians) with T2DM and in 348 subjects without T2DM (control subjects). Female homozygotes with the CC genotype of the rs8192673 had higher waist circumference in comparison with subjects with other genotypes. Homozygotes (females, males) with wild allele (Pro) of the rs1801282 (Pro12Ala polymorphism) had higher waist circumference in comparison with subjects with other genotypes. In the study, there were no differences in the distributions of the rs8192673 and the rs1801282 genotypes between patients with T2DM and controls. Linear regression analyses for both polymorphisms were performed and demonstrated an independent effect of the rs1801282 of the PPAR-γ on waist circumference in subjects with T2DM, whereas an independent effect on waist circumference was not demonstrated for the rs8192673 of the PGC-1α gene. In a large sample of the Caucasians the rs8192673 of the PGC-1α gene and the rs1801282 of the PPAR-γ gene were associated with waist circumference in subjects with T2DM.

Loss of the Arabidopsis thaliana P4-ATPases ALA6 and ALA7 impairs pollen fitness and alters the pollen tube plasma membrane.

PubMed

McDowell, Stephen C; López-Marqués, Rosa L; Cohen, Taylor; Brown, Elizabeth; Rosenberg, Alexa; Palmgren, Michael G; Harper, Jeffrey F

2015-01-01

Members of the P4 subfamily of P-type ATPases are thought to create and maintain lipid asymmetry in biological membranes by flipping specific lipids between membrane leaflets. In Arabidopsis, 7 of the 12 Aminophospholipid ATPase (ALA) family members are expressed in pollen. Here we show that double knockout of ALA6 and ALA7 (ala6/7) results in siliques with a ~2-fold reduction in seed set with a high frequency of empty seed positions near the bottom. Seed set was reduced to near zero when plants were grown under a hot/cold temperature stress. Reciprocal crosses indicate that the ala6/7 reproductive deficiencies are due to a defect related to pollen transmission. In-vitro growth assays provide evidence that ala6/7 pollen tubes are short and slow, with ~2-fold reductions in both maximal growth rate and overall length relative to wild-type. Outcrosses show that when ala6/7 pollen are in competition with wild-type pollen, they have a near 0% success rate in fertilizing ovules near the bottom of the pistil, consistent with ala6/7 pollen having short and slow growth defects. The ala6/7 phenotypes were rescued by the expression of either an ALA6-YFP or GFP-ALA6 fusion protein, which showed localization to both the plasma membrane and highly-mobile endomembrane structures. A mass spectrometry analysis of mature pollen grains revealed significant differences between ala6/7 and wild-type, both in the relative abundance of lipid classes and in the average number of double bonds present in acyl side chains. A change in the properties of the ala6/7 plasma membrane was also indicated by a ~10-fold reduction of labeling by lipophilic FM-dyes relative to wild-type. Together, these results indicate that ALA6 and ALA7 provide redundant activities that function to directly or indirectly change the distribution and abundance of lipids in pollen, and support a model in which ALA6 and ALA7 are critical for pollen fitness under normal and temperature-stress conditions.

Loss of the Arabidopsis thaliana P4-ATPases ALA6 and ALA7 impairs pollen fitness and alters the pollen tube plasma membrane

PubMed Central

McDowell, Stephen C.; López-Marqués, Rosa L.; Cohen, Taylor; Brown, Elizabeth; Rosenberg, Alexa; Palmgren, Michael G.; Harper, Jeffrey F.

2015-01-01

Members of the P4 subfamily of P-type ATPases are thought to create and maintain lipid asymmetry in biological membranes by flipping specific lipids between membrane leaflets. In Arabidopsis, 7 of the 12 Aminophospholipid ATPase (ALA) family members are expressed in pollen. Here we show that double knockout of ALA6 and ALA7 (ala6/7) results in siliques with a ~2-fold reduction in seed set with a high frequency of empty seed positions near the bottom. Seed set was reduced to near zero when plants were grown under a hot/cold temperature stress. Reciprocal crosses indicate that the ala6/7 reproductive deficiencies are due to a defect related to pollen transmission. In-vitro growth assays provide evidence that ala6/7 pollen tubes are short and slow, with ~2-fold reductions in both maximal growth rate and overall length relative to wild-type. Outcrosses show that when ala6/7 pollen are in competition with wild-type pollen, they have a near 0% success rate in fertilizing ovules near the bottom of the pistil, consistent with ala6/7 pollen having short and slow growth defects. The ala6/7 phenotypes were rescued by the expression of either an ALA6-YFP or GFP-ALA6 fusion protein, which showed localization to both the plasma membrane and highly-mobile endomembrane structures. A mass spectrometry analysis of mature pollen grains revealed significant differences between ala6/7 and wild-type, both in the relative abundance of lipid classes and in the average number of double bonds present in acyl side chains. A change in the properties of the ala6/7 plasma membrane was also indicated by a ~10-fold reduction of labeling by lipophilic FM-dyes relative to wild-type. Together, these results indicate that ALA6 and ALA7 provide redundant activities that function to directly or indirectly change the distribution and abundance of lipids in pollen, and support a model in which ALA6 and ALA7 are critical for pollen fitness under normal and temperature-stress conditions. PMID:25954280

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

PubMed

Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

2013-04-01

Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. © 2012 Biofrontera Bioscience GmbH BJD © 2012 British Association of Dermatologists.

P12.105-ALA GUIDED REMOVAL AND COMBINED TREATMENT IN MALIGNANT GLIOMA

PubMed Central

Oppido, P.A.; Carapella, C.M.; Pompili, A.; Vidiri, A.; Pace, A.; Villani, V.

2014-01-01

INTRODUCTION: Malignant gliomas are the most unfavourable brain tumours. Recent evidence suggests that extensive tumour removal is associated with better survival. The current treatment is complete as possible resection of the contrast-enhancing tumour tissue, followed by adjuvant treatment with radiotherapy and chemotherapy. As it appears difficult to distinguish between infiltration tumour and normal tissue, specially in recurrent tumours, the radical removal becomes harmful. Techniques to visualize the borderline tumour intraoperatively are helpful. More recently, fluorescence guidance has taken advantage of intrinsic metabolic and structural changes that occur within malignant glioma by exploiting the eme biosynthetic pathway and a natural biochemical in that pathway, 5-aminolevulinic acid (5-ALA). METHODS: Since the end of 2009, in our Institute 54 patients were operated on using fluorescence guided tumour resection. Preoperatively, all enrolled patients had MRI showing contrast enhancing lesions. MRI within 72 hours after surgery and thereafter at 3-month interval was performed. 32 patients were newly diagnosed tumour, 22 were recurrent malignant glioma. An oral dose of 20 mg 5-ALA /kg body weight was administered to each patient. By a NC4 OPMI Pentero operating microscope (Zeiss), enabled switching from xenon light to violet-blue light for visualizing fluorescence, the surgical resection was performed. Histology was in 48 glioblastoma (1 gliosarcoma), in 4 anaplastic oligodendroglioma, in 1 oligodendroglioma I WHO and in 1 pleomorphic xanthoastrocytoma. All the patients, as first line treatment, were submitted to radiotherapy and chemotherapy; in recurrent tumours second and in some cases third line treatments were administered. The follow-up ranged from 2 years to 8 months. RESULTS: In all cases the yellow fluorescence due to 5-ALA in cortical vessels was seen. In 47 glioblastoma, 4 anaplastic oligodendroglioma and 1 xanthoastrocytoma the tumour tissue

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine.

PubMed

Meyer, Marleen Julia; Seitz, Tina; Brockmöller, Jürgen; Tzvetkov, Mladen Vassilev

2017-01-01

Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity. In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs. We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 μM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism. We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine's potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed.

Uric acid and obesity-related phenotypes in postmenopausal women.

PubMed

Grygiel-Górniak, B; Mosor, M; Marcinkowska, J; Przysławski, J; Nowak, J

2018-06-01

The aim of this study was to find the genetic, metabolic, and nutritional risk factors, which can be associated with uric acid (UA) level. The risk factors related to uricemia were assessed among 271 postmenopausal women without cardiometabolic disorders and hypolipidemic/hypoglycemic treatment selected from a cohort of 1423 obese postmenopausal women. The bioimpedance analysis and biochemical and genetic analyses were performed in two groups characterized by serum UA ≥ 4 mg/dL (238 μmol/L) and < 4 mg/dL. The TaqMan-based real-time PCR method was applied to assess the role of Pro12Ala of peroxisome proliferation-activated receptor (PPAR)gamma-2 and Trp64Arg of beta-3-adrenergic receptor (ADRB) polymorphisms. Women with UA level ≥ 4 mg/dL were characterized by larger body mass, triceps skinfold, waist circumference, body fat amount, and serum insulin, glucose, and triglyceride levels. There was no difference in dietary habits between the analyzed groups. Body mass, waist circumference, body fat amount, diastolic blood pressure, and serum insulin, glucose, high-density lipoprotein, and triglyceride levels, Homeostasis Model Assessment-Insulin Resistance, and energy from the dietary fat influence the UA level ≥ 4 mg/dL; however, the serum UA was not determined by Pro12Ala and Trp64Arg polymorphism analyses. The model of linear regression revealed that the group characterized by body mass index  ≥ 25 kg/m 2 and glucose ≥ 100 mg/dL has 4 times increased risk of UA level (p = 0.0009); after adding triglycerides ≥ 150 mg/dL, the risk of UA increased 7 times (p = 0.0216). Increasing the level of UA ≥ 4 mg/dL is associated with overweight, hyperglycemia, and hypertriglyceridemia in women without a history of cardiometabolic disorders. A better management of metabolic factors could help prevent further increase in UA levels.

The IFN-gamma +874T/A gene polymorphism is associated with retinochoroiditis toxoplasmosis susceptibility.

PubMed

Albuquerque, Maíra Cavalcanti de; Aleixo, Ana Luisa Quintella do Couto; Benchimol, Eliezer Israel; Leandro, Ana Cristina Câmara S; das Neves, Leandro Batista; Vicente, Regiane Trigueiro; Bonecini-Almeida, Maria da Glória; Amendoeira, Maria Regina Reis

2009-05-01

Toxoplasmosis is a worldwide zoonosis that generally produces an asymptomatic infection. In some cases, however, toxoplasmosis infection can lead to ocular damage. The immune system has a crucial role in both the course of the infection and in the evolution of toxoplasmosis disease. In particular, IFN-gamma plays an important role in resistance to toxoplasmosis. Polymorphisms in genes encoding cytokines have been shown to have an association with susceptibility to parasitic diseases. The aim of this work was to analyse the occurrence of polymorphisms in the gene encoding IFN-gamma (+874T/A) among Toxoplasma gondii seropositive individuals, including those with ocular lesions caused by the parasite, from a rural population of Santa Rita de Cássia, Barra Mansa, state of Rio de Janeiro, Brazil. Further, we verified which of these polymorphisms could be related to susceptibility to the development of ocular toxoplasmosis. This study included 34 individuals with ocular toxoplasmosis (ocular group) and 134 without ocular lesions (control group). The differences between A and T allele distributions were not statistically significant between the two groups. However, we observed that a higher frequency of individuals from the ocular group possessed the A/A genotype, when compared with the control group, suggesting that homozygocity for the A allele could enhance susceptibility to ocular toxoplasmosis in T. gondii infection.

Structural Perturbations in the Ala → Val Polymorphism of Methylenetetrahydrofolate Reductase: How Binding of Folates May Protect against Inactivation†‡

PubMed Central

Pejchal, Robert; Campbell, Elizabeth; Guenther, Brian D.; Lennon, Brett W.; Matthews, Rowena G.; Ludwig, Martha L.

2006-01-01

In human methylenetetrahydrofolate reductase (MTHFR) the Ala222Val (677C → T) polymorphism encodes a heat-labile gene product that is associated with elevated levels of homocysteine and possibly with risk for cardiovascular disease. Generation of the equivalent Ala to Val mutation in Escherichia coli MTHFR, which is 30% identical to the catalytic domain of the human enzyme, creates a protein with enhanced thermolability. In both human and E. coli MTHFR, the A → V mutation increases the rate of dissociation of FAD, and in both enzymes, loss of FAD is linked to changes in quaternary structure [Yamada, K., Chen, Z., Rozen, R., and Matthews, R. G. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14853–14858; Guenther, B. D., Sheppard, C. A., Tran, P., Rozen, R., Matthews, R. G., and Ludwig, M. L. (1999) Nat. Struct. Biol. 6, 359–365]. Folates have been shown to protect both human and bacterial enzymes from loss of FAD. Despite its effect on affinity for FAD, the A → V mutation is located at the bottom of the (βα)8 barrel of the catalytic domain in a position that does not contact the bound FAD prosthetic group. Here we report the structures of the Ala177Val mutant of E. coli MTHFR and of its complex with the 5,10-dideazafolate analogue, LY309887, and suggest mechanisms by which the mutation may perturb FAD binding. Helix α5, which immediately precedes the loop bearing the mutation, carries several residues that interact with FAD, including Asn168, Arg171, and Lys172. In the structures of the mutant enzyme this helix is displaced, perturbing protein–FAD interactions. In the complex with LY309887, the pterin-like ring of the analogue stacks against the si face of the flavin and is secured by hydrogen bonds to residues Gln183 and Asp120 that adjoin this face. The direct interactions of bound folate with the cofactor provide one mechanism for linkage between binding of FAD and folate binding that could account in part for the protective action of folates

LRP5 gene polymorphism and cortical bone

PubMed Central

Lauretani, Fulvio; Cepollaro, Chiara; Bandinelli, Stefania; Cherubini, Antonio; Gozzini, Alessia; Masi, Laura; Falchetti, Alberto; Del Monte, Francesca; Carbonell-Sala, Silvia; Marini, Francesca; Tanini, Annalisa; Corsi, Anna Maria; Ceda, Gian Paolo; Brandi, Maria Luisa; Ferrucci, Luigi

2016-01-01

Background and aims There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro-architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women. Methods We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21–94 yrs). Trabecular vBMD (vBMDt, mg/cm3), cortical vBMD (vBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. Conclusion These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women. PMID:21116122

Engineering an ATP-dependent D-Ala:D-Ala ligase for synthesizing amino acid amides from amino acids.

PubMed

Miki, Yuta; Okazaki, Seiji; Asano, Yasuhisa

2017-05-01

We successfully engineered a new enzyme that catalyzes the formation of D-Ala amide (D-AlaNH 2 ) from D-Ala by modifying ATP-dependent D-Ala:D-Ala ligase (EC 6.3.2.4) from Thermus thermophilus, which catalyzes the formation of D-Ala-D-Ala from two molecules of D-Ala. The new enzyme was created by the replacement of the Ser293 residue with acidic amino acids, as it was speculated to bind to the second D-Ala of D-Ala-D-Ala. In addition, a replacement of the position with Glu performed better than that with Asp with regards to specificity for D-AlaNH 2 production. The S293E variant, which was selected as the best enzyme for D-AlaNH 2 production, exhibited an optimal activity at pH 9.0 and 40 °C for D-AlaNH 2 production. The apparent K m values of this variant for D-Ala and NH 3 were 7.35 mM and 1.58 M, respectively. The S293E variant could catalyze the synthesis of 9.3 and 35.7 mM of D-AlaNH 2 from 10 and 50 mM D-Ala and 3 M NH 4 Cl with conversion yields of 93 and 71.4 %, respectively. This is the first report showing the enzymatic formation of amino acid amides from amino acids.

Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model

NASA Astrophysics Data System (ADS)

Maytin, Edward; Anand, Sanjay; Sato, Nobuyuki; Mack, Judith; Ortel, Bernhard

2005-04-01

During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

Expression Levels of ALA Dehydratase as a Marker of ALA-PDT Efficacy

NASA Astrophysics Data System (ADS)

Avital, Schauder; Tamar, Feuerstein; Zvi, Malik

2010-05-01

Accelerated synthesis of protoporphyrinIX (PpIX) following ALA pre-treatment followed by light irradiation is the principle of ALA-PDT. Several limiting enzymes were suggested to control PpIX accumulation and PDT efficacy, among them porphobilinogen deaminase (PBGD) and ferrochelatase. Here we reveal the centrality of ALA dehydratase (ALAD) activity in predicting ALA-PDT efficacy. Silencing of ALAD expression and activity was carried out in leukemic cells using shRNA plasmid transfection or Pb2+ intoxication. ALAD activity, porphyrin synthesis and mitochondrial activity were determined versus PDT efficacy. In K562 ALAD-silenced cells, ALAD activity and expression were reduced and as a result, PpIX synthesis was almost abolished. Following ALA treatment and irradiation, ALAD-silenced cells depicted normal mitochondrial activity, in contrast to control and non-silencing transfected cells where accumulated PpIX and irradiation caused ROS formation and mitochondrial damage. Morphological analysis by scanning electron microscopy (SEM) of ALA-PDT treated cells showed no morphological changes in ALAD-silenced cells, while controls exhibited cell deformations and lysis. Annexin V-FITC/PI staining as well as LDH-L leakage testing showed that membrane integrity was undamaged following ALA-PDT in ALAD silenced cells. Pb2+ treatment in MEL cells impaired ALAD activity and reduced PpIX synthesis but to a lesser extent. In conclusion, we show that a dramatic reduction in PpIX accumulation following down regulation of ALAD expression prevents an efficient PDT. Thus, ALAD has a major role in regulating PpIX synthesis and ALA-PDT therapeutic outcome. Monitoring ALAD expression or activity in various tumors may be useful as prognostic tool to predict PDT efficacy.

Association of mRNA expression of TP53 and the TP53 codon 72 Arg/Pro gene polymorphism with colorectal cancer risk in Asian population: a bioinformatics analysis and meta-analysis.

PubMed

Dong, Zhiyong; Zheng, Longzhi; Liu, Weimin; Wang, Cunchuan

2018-01-01

The relationship between TP53 codon 72 Pro/Arg gene polymorphism and colorectal cancer risk in Asians is still controversial, and this bioinformatics analysis and meta-analysis was performed to assess the associations. The association studies were identified from PubMed, and eligible reports were included. RevMan 5.3.1 software, Oncolnc, cBioPortal, and Oncomine online tools were used for statistical analysis. A random/fixed effects model was used in meta-analysis. The data were reported as risk ratios or mean differences with corresponding 95% CI. We confirmed that TP53 was associated with colorectal cancer, the alteration frequency of TP53 was 53% mutation and 7% deep deletion, and TP53 mRNA expression was different in different types of colorectal cancer based on The Cancer Genome Atlas database. Then, 18 studies were included that examine the association of TP53 codon 72 gene polymorphism with colorectal cancer risk in Asians. The meta-analysis indicated that TP53 Pro allele and Pro/Pro genotype were associated with colorectal cancer risk in Asian population, but Arg/Arg genotype was not (Pro allele: odds ratios [OR]=1.20, 95% CI: 1.06 to 1.35, P =0.003; Pro/Pro genotype: OR=1.39, 95% CI: 1.15 to 1.69, P =0.0007; Arg/Arg genotype: OR=0.86, 95% CI: 0.74 to 1.00, P =0.05). Interestingly, in the meta-analysis of the controls from the population-based studies, we found that TP53 codon 72 Pro/Arg gene polymorphism was associated with colorectal cancer risk (Pro allele: OR=1.33, 95% CI: 1.15 to 1.55, P =0.0002; Pro/Pro genotype: OR=1.61, 95% CI: 1.28 to 2.02, P <0.0001; Arg/Arg genotype: OR=0.77, 95% CI: 0.63 to 0.93, P =0.009). TP53 was associated with colorectal cancer, but the different value levels of mRNA expression were not associated with survival rate of colon and rectal cancer. TP53 Pro allele and Pro/Pro genotype were associated with colorectal cancer risk in Asians.

Association of mRNA expression of TP53 and the TP53 codon 72 Arg/Pro gene polymorphism with colorectal cancer risk in Asian population: a bioinformatics analysis and meta-analysis

PubMed Central

Liu, Weimin; Wang, Cunchuan

2018-01-01

Background The relationship between TP53 codon 72 Pro/Arg gene polymorphism and colorectal cancer risk in Asians is still controversial, and this bioinformatics analysis and meta-analysis was performed to assess the associations. Methods The association studies were identified from PubMed, and eligible reports were included. RevMan 5.3.1 software, Oncolnc, cBioPortal, and Oncomine online tools were used for statistical analysis. A random/fixed effects model was used in meta-analysis. The data were reported as risk ratios or mean differences with corresponding 95% CI. Results We confirmed that TP53 was associated with colorectal cancer, the alteration frequency of TP53 was 53% mutation and 7% deep deletion, and TP53 mRNA expression was different in different types of colorectal cancer based on The Cancer Genome Atlas database. Then, 18 studies were included that examine the association of TP53 codon 72 gene polymorphism with colorectal cancer risk in Asians. The meta-analysis indicated that TP53 Pro allele and Pro/Pro genotype were associated with colorectal cancer risk in Asian population, but Arg/Arg genotype was not (Pro allele: odds ratios [OR]=1.20, 95% CI: 1.06 to 1.35, P=0.003; Pro/Pro genotype: OR=1.39, 95% CI: 1.15 to 1.69, P=0.0007; Arg/Arg genotype: OR=0.86, 95% CI: 0.74 to 1.00, P=0.05). Interestingly, in the meta-analysis of the controls from the population-based studies, we found that TP53 codon 72 Pro/Arg gene polymorphism was associated with colorectal cancer risk (Pro allele: OR=1.33, 95% CI: 1.15 to 1.55, P=0.0002; Pro/Pro genotype: OR=1.61, 95% CI: 1.28 to 2.02, P<0.0001; Arg/Arg genotype: OR=0.77, 95% CI: 0.63 to 0.93, P=0.009). Conclusion TP53 was associated with colorectal cancer, but the different value levels of mRNA expression were not associated with survival rate of colon and rectal cancer. TP53 Pro allele and Pro/Pro genotype were associated with colorectal cancer risk in Asians. PMID:29872345

The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility.

PubMed

Hung, Yi-Wen; Tsai, Chia-Wen; Wu, Cheng-Nan; Shih, Liang-Chun; Chen, Yen-Yu; Liu, Yen-Fang; Hung, Huey-Shan; Shen, Ming-Yi; Chang, Wen-Shin; Bau, DA-Tian

2017-01-01

Metalloproteinases (MMPs) are a family of multifunctional proteins reported to be overexpressed in several types of cancers. However, the contribution of MMP8 genotype to oral cancer has not been elucidated. In this study, we focused on the contribution of polymorphisms in the promoter region of MMP-8 (C-799T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to Taiwanese oral cancer. In this case-control study, MMP-8 genotype, was examined among 788 patients with oral cancer and 956 gender- and age-matched healthy controls regarding its potential to determine oral cancer risk. The distributions of MMP-8 C-799T, Val436Ala and Lys460Thr genotypes were not different between the oral cancer and non-cancer control groups. We also analyzed the allelic frequency distributions and no significant difference was found. As for gene-environment interaction analysis, there was an increased risk for smokers, alcohol drinkers or betel quid chewers with variant MMP-8 C-799T or Val436Ala genotypes. Our findings suggest that the polymorphisms at MMP-8 C-799T or Val436Ala may not play a major role in mediating personal risk of oral cancer; however, the detailed mechanisms require further investigation. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

IL-8 -251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population.

PubMed

Liu, S; Yin, C; Chu, N; Han, L; Li, C

2013-01-01

Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate NALP3 and mediate interleukin (IL)-1β generation from its inactive pro-form, resulting in cellular activation and an IL-8-mediated neutrophil influx into the joint. IL-8 and IL-12 are important chemokines related to the initiation and amplification of acute and chronic inflammatory processes. In this study, we investigated whether the IL-8 -251T/A and IL-12 1188A/C polymorphisms are associated with susceptibility to gout in a Chinese Han male population. Overall, 387 patients with gout and 576 controls were included in this study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). An association analysis was carried out using the χ2 test. A genotype-phenotype analysis was also conducted. The T allele of IL-8 -251 was associated with risk of gout [p = 0.031 (odds ratio (OR) 1.229, 95% confidence interval (CI) 1.019-1.483]. There was a clear link between the IL-12 1188 AA and AC genotypic and A allelic frequencies between gout cases and controls (p < 0.001, df = 2 by genotype; p < 0.001, OR 1.404, 95% CI 1.165-1.691 by allele). Our results suggest that the IL-8 -251T/A and IL-12B 1188A/C polymorphisms may be relevant host susceptibility factors for the development of gout.

GPX1 Pro198Leu polymorphism and GSTM1 deletion do not affect selenium and mercury status in mildly exposed Amazonian women in an urban population.

PubMed

Rocha, Ariana V; Rita Cardoso, Bárbara; Zavarize, Bruna; Almondes, Kaluce; Bordon, Isabella; Hare, Dominic J; Teixeira Favaro, Déborah Inês; Franciscato Cozzolino, Silvia Maria

2016-11-15

Mercury is potent toxicant element, but its toxicity can be reduced by forming a complex with selenium for safe excretion. Considering the impact of mercury exposure in the Amazon region and the possible interaction between these two elements, we aimed to assess the effects of Pro198Leu polymorphism to GPX1 and GSTM1 deletion, on mercury levels in a population from Porto Velho, an urban locality in the Brazilian Amazon region. Two hundred women from the capital city of Rondônia state were recruited for this study with 149 deemed suitable to participate. We assessed dietary intake using 24-hour recall. Selenium levels in plasma and erythrocytes were measured using hydride generation quartz tube atomic absorption spectroscopy and total hair mercury using cold vapor atomic absorption spectrometry. Oxidative stress parameters (GPx activity, oxygen radical absorbency capacity [ORAC] and malondialdehyde [MDA]) were also analyzed. All participants were genotyped for Pro198Leu polymorphism and GSTM1 deletion. We observed that this population presented high prevalence of selenium deficiency, and also low levels of mercury, likely due to food habits that did not include selenium-rich food sources or significant consumption of fish (mercury biomagnifiers) regularly. Univariate statistical analysis showed that Pro198Leu and GSTM1 genotypes did not affect selenium and mercury levels in this population. Pro198Leu polymorphism and GSTM1 deletion had no effect on mercury levels in mildly exposed people, suggesting these genetic variants impact mercury levels only in highly exposed populations. Copyright © 2016 Elsevier B.V. All rights reserved.

Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12

PubMed Central

Landouré, Guida; Zhu, Peng-Peng; Lourenço, Charles M.; Johnson, Janel O.; Toro, Camilo; Bricceno, Katherine V.; Rinaldi, Carlo; Meilleur, Katherine G.; Sangaré, Modibo; Diallo, Oumarou; Pierson, Tyler M.; Ishiura, Hiroyuki; Tsuji, Shoji; Hein, Nichole; Fink, John K.; Stoll, Marion; Nicholson, Garth; Gonzalez, Michael; Speziani, Fiorella; Dürr, Alexandra; Stevanin, Giovanni; Biesecker, Leslie G.; Accardi, John; Landis, Dennis M. D.; Gahl, William A.; Traynor, Bryan J.; Marques, Wilson; Züchner, Stephan; Blackstone, Craig; Fischbeck, Kenneth H.; Burnett, Barrington G.

2013-01-01

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly-conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. PMID:23857908

Regional Brain Shrinkage over Two Years: Individual Differences and Effects of Pro-Inflammatory Genetic Polymorphisms

PubMed Central

Persson, N.; Ghisletta, P.; Dahle, C.L.; Bender, A.R.; Yang, Y.; Yuan, P.; Daugherty, A.M.; Raz, N.

2014-01-01

We examined regional changes in brain volume in healthy adults (N = 167, age 19-79 years at baseline; N = 90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (HC), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the HC, CbH, In, OF, and the PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants mediated shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1βC-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFRC677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan. PMID:25264227

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine

PubMed Central

Meyer, Marleen Julia; Seitz, Tina; Brockmöller, Jürgen

2017-01-01

Background Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity. Aim In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs. Methods and results We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 μM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism. Conclusions We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine’s potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine

Analysis of common transforming growth factor beta-1 gene polymorphisms in gastric and duodenal ulcer disease: pilot study.

PubMed

Polonikov, Alexey V; Ivanov, Vladimir P; Belugin, Dmitry A; Khoroshaya, Irina V; Kolchanova, Inessa O; Solodilova, Mariya A; Tutochkina, Margarita P; Stepchenko, Alexander A

2007-04-01

Transforming growth factor-beta1 (TGF-beta1) has been shown to be an important cytokine that plays a role in cell proliferation, differentiation, tissue injury repair and ulcer healing. The purpose of this pilot study was to investigate if common polymorphisms Leu10Pro, Arg25Pro and C-509T within the TGF-beta1 gene are associated with susceptibility to gastric and duodenal ulcer disease in Russians. Blood samples from 377 unrelated patients with gastric and duodenal ulcer disease and 226 sex- and age-matched healthy controls were used to determine TGF-beta1 gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Leu10Pro substitution in the signal peptide of TGF-beta1 has been found to be associated with susceptibility to gastric ulcer (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.12-2.77). A genotype combination of 10Leu/Leu x 25Arg/Arg x -509C/C was also associated with susceptibility to gastric ulcer disease (OR 1.81, P = 0.01). In addition, the frequency of a combination of genotypes 10Pro/Pro x 25Arg/Pro x -509C/T was statistically lower in patients with duodenal ulcer than in controls (OR 0.42, P = 0.05). A significant difference (P = 0.04) in the distribution of rare haplotypes of the TGF-beta1 gene between patients with duodenal ulcer and healthy controls has been found. Polymorphism Leu10Pro was in positive linkage disequilibrium with C-509T polymorphism (coefficient D = 0.191; P < 0.0001). These findings indicate that the Leu10Pro and C-509T polymorphisms may be involved in the modulation of expression of the TGF-beta1 gene, and therefore a predisposition to peptic ulcer disease could be linked to particular alleles of this gene. In particular, a possible role of TGF-beta1 in the pathogenesis of gastric ulcer disease is discussed.

Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template.

PubMed

Wilczynski, Andrzej; Wilson, Krista R; Scott, Joseph W; Edison, Arthur S; Haskell-Luevano, Carrie

2005-04-21

The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

PubMed Central

Kailainathan, Sumangali; Piers, Thomas M.; Yi, Jee Hyun; Choi, Seongmin; Fahey, Mark S.; Borger, Eva; Gunn-Moore, Frank J.; O’Neill, Laurie; Lever, Michael; Whitcomb, Daniel J.; Cho, Kwangwook; Allen, Shelley J.

2016-01-01

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. PMID:26687096

Transcobalamin 776C-->G polymorphism is associated with peripheral neuropathy in elderly with high folate intake

USDA-ARS?s Scientific Manuscript database

Background: The 776C-->G polymorphism of the vitamin B-12 transport protein transcobalamin gene (TCN2) (rs1801198; Pro259Arg) is associated with a lower holotranscobalamin concentration in plasma. This effect may reduce the availability of vitamin B-12 to tissues even when vitamin B-12 intake is ade...

ALA-Butyrate prodrugs for Photo-Dynamic Therapy

NASA Astrophysics Data System (ADS)

Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

2010-05-01

The use of 5-aminolevulinic acid (ALA) administration has led to many applications of photodynamic therapy (PDT) in cancer. However, the hydrophilic nature of ALA limits its ability to penetrate the cells and tissues, and therefore the need for ALA derivatives became an urgent research target. In this study we investigated the activity of novel multifunctional acyloxyalkyl ester prodrugs of ALA that upon metabolic hydrolysis release active components such as, formaldehyde, and the histone deacetylase inhibitory moiety, butyric acid. Evaluation of these prodrugs under photo-irradiation conditions showed that butyryloxyethyl 5-amino-4-oxopentanoate (ALA-BAC) generated the most efficient photodynamic destruction compared to ALA. ALA-BAC stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells which resulted in generation of intracellular ROS, reduction of mitochondrial activity, leading to apoptotic and necrotic death of the cells. The apoptotic cell death induced by ALA / ALA-BAC followed by PDT equally activate intrinsic and extrinsic apoptotic signals and both pathways may occur simultaneously. The main advantage of ALA-BAC over ALA stems from its ability to induce photo-damage at a significantly lower dose than ALA.

Adiponectin levels are reduced, independent of polymorphisms in the adiponectin gene, after supplementation with alpha-linolenic acid among healthy adults.

PubMed

Nelson, Tracy L; Stevens, James R; Hickey, Matthew S

2007-09-01

Our first aim was to determine whether an isocaloric intervention using alpha-linolenic acid (ALA) in the form of flaxseed oil would alter adiponectin levels among overweight, otherwise healthy, males and females, and our second aim was to test for any potential modification of this intervention by 2 single nucleotide polymorphisms (276 and 45) in the adiponectin gene. Subjects included healthy adult males and females (approximately 81% female; average age, 38 years) with increased waist circumference (mean, 99 cm) and body mass index (mean, 30 kg/m(2)) who were free of chronic disease, not taking medications, and sedentary. Subjects met weekly with a registered dietician for 8 weeks. The control subjects (n = 27) were instructed not to alter their habitual diet and the ALA group (n = 30) was instructed to follow an enriched ALA diet by using flaxseed oil capsules (increasing ALA to 5% of total energy intake) and to lower their dietary fat consumption by a commensurate amount. Diets were analyzed using the Food Intake and Analysis System (v. 3.0, University of Texas School of Public Health, 1998). Fasting blood samples were obtained before and after the 8-week intervention. We found significant decreases (P = .02) in adiponectin (10.12 microg/mL pre, 9.23 microg/mL post) in the ALA group as compared with the control group (7.93 microg/mL pre, 8.10 microg/mL post) after the intervention. We also saw a decline in adiponectin in all genotype groups with the greatest decline among those carrying the rare T allele of single nucleotide polymorphism 276. There were no significant changes in fasting insulin, glucose, or quantitative insulin sensitivity check index values as a result of this intervention. In conclusion, this study suggests that supplementing with ALA for 8 weeks may lower adiponectin levels among healthy individuals, and this effect appears to be independent of polymorphisms in the adiponectin gene. Although the change in adiponectin in response to the

α-Linolenic acid (ALA) is an anti-inflammatory agent in inflammatory bowel disease.

PubMed

Reifen, Ram; Karlinsky, Anna; Stark, Aliza H; Berkovich, Zipi; Nyska, Abraham

2015-12-01

Studies suggest that consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) plays a protective role in inflammatory bowel disease; however, the use of plant-derived oils rich in α-linolenic acid (ALA) has not been widely investigated. The aims of this study were to test the effects of two different sources of (n-3) PUFA, fish and plant-derived oils, in two animal models of experimental colitis and to determine whether the (n-3) PUFA-enriched diets could ameliorate the inflammatory status. Rats were fed diets rich in corn, fish or sage oil with or without vitamin A supplementation for 3weeks then colitis was induced by adding dextran sodium sulfate to the drinking water or by injecting 2,4,6-trinitrobenzene sulfonic acid. We show that colitic rats fed the sage oil diets had a lower inflammatory response, improved histological repair and had less necrotic damage in the mucosa when compared to the corn and fish oil groups. Colonic damage and myeloperoxidase activity were significantly lower. Colonic mRNA levels of pro-inflammatory genes including interleukin IL-6, cyclooxygenase 2 and tumor necrosis factor α were markedly down-regulated in rats fed fish and sage oils compared to control. These results were supported by experiments in the human colonic epithelial cell line Caco-2, where ALA supplementation was shown to be effective in inhibiting inflammation induced by IL-1β by down-regulating mRNA levels of pro-inflammatory genes including IL-8, COX2 and inducible nitric oxide synthase. Taken together, these results suggest that plant-derived oil rich in ALA could ameliorate the inflammatory damage in colitis. Copyright © 2015 Elsevier Inc. All rights reserved.

Modeling dynamic beta-gamma polymorphic transition in Tin

NASA Astrophysics Data System (ADS)

Chauvin, Camille; Montheillet, Frank; Petit, Jacques; CEA Gramat Collaboration; EMSE Collaboration

2015-06-01

Solid-solid phase transitions in metals have been studied by shock waves techniques for many decades. Recent experiments have investigated the transition during isentropic compression experiments and shock-wave compression and have highlighted the strong influence of the loading rate on the transition. Complementary data obtained with velocity and temperature measurements around the polymorphic transition beta-gamma of Tin on gas gun experiments have displayed the importance of the kinetics of the transition. But, even though this phenomenon is known, modeling the kinetic remains complex and based on empirical formulations. A multiphase EOS is available in our 1D Lagrangian code Unidim. We propose to present the influence of various kinetic laws (either empirical or involving nucleation and growth mechanisms) and their parameters (Gibbs free energy, temperature, pressure) on the transformation rate. We compare experimental and calculated velocities and temperature profiles and we underline the effects of the empirical parameters of these models.

Evaluation of the Urine Protein/Creatinine Ratio Measured with the Dipsticks Clinitek Atlas PRO 12.

PubMed

Hermida, Fernando J; Soto, Sonia; Benitez, Alfonso J

2016-01-01

Screening for urine proteins is recommended for the detection of albuminuria in high risk groups. The aim of this study was to compare the Clinitek Atlas PRO12 reagent urine strip with quantitative methods for the determination of protein/creatinine ratio and to evaluate the usefulness of the semi-quantitative Clinitek Atlas PRO12 reagent urine strip as a tool in the early detection of albuminuria among the general population. Six hundred first morning urine specimens were collected from outpatients with various clinical conditions. The results showed that the test data for the urine dipstick Clinitek Atlas PRO12 show good agreement with the quantitative measurement of protein, creatinine and protein/creatinine ratio. In addition, this study shows that 97.2% of the samples which gave "normal" protein/creatinine ratios by the semi-quantitative method, showed albumin/creatinine ratio < 30 mg/g by the quantitative methods. Our results show that Clinitek Atlas PRO12 reagent strips can be used for the purposes of albuminuria screening in the general population.

IL-10 and IL-12B gene polymorphisms in a multiethnic Malaysian population.

PubMed

Sam, S S; Teoh, B T; AbuBakar, S

2015-04-13

Inheritance of polymorphisms in the interleukin (IL)-10 promoter and IL-12B genes, which influence cytokine production and activities, may define the balance in T helper response in infection and autoimmune diseases. In the present study, we investigated the distribution of the IL-10 promoter and IL-12B gene polymorphisms in a multiethnic Malaysian population. Overall, our findings suggest that the IL-12B and IL-10 -592 genotypes were distributed homogenously across all major ethnic groups, including Malays, Chinese, and Indians, except for polymorphisms at IL-10 -1082. At this gene locus, the ethnic Chinese showed a significantly lower allele frequency of -1082G (2.1%) compared to the Malay (12.2%) and Indian (15.3%) populations. Results for the IL-12B and IL-10 gene polymorphisms were consistent with those reported for the Asian population, but markedly different from those of the African and Caucasian populations. Our findings suggest that there are specific genetic variations between different ethnic groups, which should be examined in all gene population-based association studies.

Progesterone-associated proteins PP12 and PP14 in the human endometrium.

PubMed

Rutanen, E M; Koistinen, R; Seppälä, M; Julkunen, M; Suikkari, A M; Huhtala, M L

1987-01-01

Two proteins, designated as PP12 and PP14 were originally isolated from soluble extracts of the human placenta and its adjacent membranes. We have shown that they are synthesized by decidualized/secretory endometrium and not by placenta. Both proteins occur at high concentrations in human amniotic fluid, which is therefore an excellent source for purification. PP12 is a 34-kDa glycoprotein, which has an N-terminal amino acid sequence of Ala-Pro-Trp-Gln-Cys-Ala-Pro-Cys-Ser-Ala. This is identical with that of somatomedin-binding protein purified from the amniotic fluid. PP12 too binds somatomedin-C, or IGF-I (insulin-like growth factor-I). Human secretory endometrium synthesizes and secretes PP12, and progesterone stimulates its secretion. PP14 is a 28-kDa glycoprotein. Its N-terminal sequence shows homology to that of beta-lactoglobulins from various species. We have found PP14 in the human endometrium, serum and milk. Immunologically, PP14 is related to progestagen-associated endometrial protein (PEP), alpha-2 pregnancy-associated endometrial protein (alpha-2, PEG), endometrial protein 15 (EP15), alpha-uterine protein (AUP) and chorionic alpha-2 microglobulin (CAG-2). In ovulatory menstrual cycles, the concentration of PP14 increases in endometrial tissue as the secretory changes advance. In serum, the PP14 concentration begins to rise later than the progesterone levels, and high serum PP14 levels are maintained for the first days of the next cycle. By contrast, no elevation of serum PP14 level is seen in anovulatory cycles. Our results show that progesterone-associated proteins are synthesized by the human endometrium and appear in the peripheral circulation, where they can be quantitatively measured using immunochemical techniques.

Polymorphisms of pro-inflammatory cytokine genes and the risk for acute suppurative or chronic nonsuppurative apical periodontitis in a Colombian population.

PubMed

Amaya, M P; Criado, L; Blanco, B; Gómez, M; Torres, O; Flórez, L; González, C I; Flórez, O

2013-01-01

To determine the association of functional single nucleotide polymorphisms in genes of the pro-inflammatory cytokines tumour necrosis factor-α, interleukin-1β, interleukin-8 and interleukin-12B with the development of two clinical forms of apical periodontitis (AP): acute suppurative and chronic nonsuppurative. The study included 120 patients from Bucaramanga City, Colombia, 63 diagnosed with acute suppurative AP (ASAP) and 57 diagnosed with chronic nonsuppurative AP (CNAP). Genotyping for IL1B +3954 (rs1143634), IL8 / CXCL8 -251 (rs4073), IL12B +1188 (rs3212227) and TNFA -308 (rs1800629) was performed by the PCR-restriction fragment length polymorphisms method. The statistical analysis was performed using STATA 10.0 and PLINK V1.07 software. Significant differences in the distribution of IL8 / CXCL8 -251 A allele (P adjusted = 0.041; OR adjusted = 0.41, CI adjusted = 0.31-0.97) and IL8 / CXCL -251 TT genotype (P adjusted = 0.04; OR adjusted = 2.24, CI adjusted = 1.04-4.84) were observed comparing patients diagnosed with ASAP and CNAP. No association was observed in genotype and allele distribution for other genetic polymorphisms analysed. This study provides molecular epidemiological evidence that suggests in the present cohort that IL8 / CXCL8 -251 T allele, which is associated with higher production of IL8/CXCL8, is also associated with a higher risk of developing acute suppurative form of AP, whereas IL8 / CXCL8 -251 A allele, which is associated with lower production of IL8/CXCL8, is associated with chronic nonsuppurative form of AP. This suggests a pivotal role for IL-8/CXCL8 in periapical disease because of its ability to induce chemotaxis and modulating the directed migration of neutrophils to the site of inflammation in response to microbial infection of pulp. © 2012 International Endodontic Journal.

Alpha lipoic acid (ALA) modulates expression of apoptosis associated proteins in hippocampus of rats exposed during postnatal period to sodium arsenite (NaAsO2).

PubMed

Dixit, Shilpi; Dhar, Pushpa; Mehra, Raj D

2015-01-01

The present study focused on the role of exogenous alpha lipoic acid (ALA) in amelioration of inorganic arsenic ( iAs ) induced effects on apoptosis and apoptosis associated proteins in developing rat hippocampus. NaAsO 2 (1.5/2.0 mg/kg bw) alone or along with ALA (70 mg/kg bw) was administered to rat pups (experimental groups) by intraperitoneal (i.p.) route from postnatal day (PND) 4-15. Controls received no treatment/distilled water/ALA. On PND 16, the animals were perfusion fixed and the brains were processed for paraffin embedding (CV and TUNEL staining) and cryopreservation (immunohistochemistry). The fresh brain tissue was used for Western blotting. Significant increase was observed in TUNEL positive cells and Bax (pro-apoptotic protein) expression in hippocampal sub-regions of iAs alone treated groups, whereas Bcl-2 expression was intensified in animals receiving ALA with iAs . Densitometric analysis (Western blots) revealed optimal restoration of Bax and Bcl-2 ratio in animals receiving ALA with iAs , thereby suggesting the protective role of ALA in iAs induced developmental neurotoxicity.

The UCP2 -866G/A, Ala55Val and UCP3 -55C/T polymorphisms are associated with premature coronary artery disease and cardiovascular risk factors in Mexican population.

PubMed

Gamboa, Ricardo; Huesca-Gómez, Claudia; López-Pérez, Vanessa; Posadas-Sánchez, Rosalinda; Cardoso-Saldaña, Guillermo; Medina-Urrutia, Aida; Juárez-Rojas, Juan Gabriel; Soto, María Elena; Posadas-Romero, Carlos; Vargas-Alarcón, Gilberto

2018-05-21

We examined the role of UCP gene polymorphisms as susceptibility markers for premature coronary artery disease (pCAD). The UCP2 Ala55Val (C/T rs660339), UCP2 -866G/A (rs659366), and UCP3 -55C/T (rs1800849) polymorphisms were genotyped in 948 patients with pCAD, and 763 controls. The distribution of the UCP2 A55V (C/T rs660339) and UCP3 -55 (rs1800849) was similar in patients and controls. However, under a recessive model, the UCP2 -866 (rs659366) A allele was associated with increased risk of developing pCAD (OR = 1.43, Pc = 0.003). On the other hand, patients with pCAD and UCP2 A55V (rs660339) TT showed high levels of visceral abdominal fat (VAF) (Pc = 0.002), low levels of subcutaneous abdominal fat (SAF) (Pc = 0.001) and high VAT/SAT ratio (Pc < 0.001). Also, patients with UCP2 -866 (rs659366) AA showed increased levels of VAF (Pc = 0.003), low levels of SAF (Pc = 0.001) and a high VAT/SAT ratio (Pc = 0.002), whereas patients with the UCP3 -55 (rs1800849) TT presented high levels of VAF (Pc = 0.002). The results suggest the association of the UCP2 -866 (rs659366) polymorphism with risk of developing pCAD. Some polymorphisms were associated with abdominal fat levels and cardiovascular risk factors.

Evidence that PC2 is the endogenous pro-neurotensin convertase in rMTC 6-23 cells and that PC1- and PC2-transfected PC12 cells differentially process pro-neurotensin.

PubMed

Rovère, C; Barbero, P; Kitabgi, P

1996-05-10

The neuropeptide precursor proneurotensin/neuromedin N (pro-NT/NN) is mainly expressed and differentially processed in the brain and in the small intestine. We showed previously that rMTC 6-23 cells process pro-NT/NN with a pattern similar to brain tissue and increase pro-NT/NN expression in response to dexamethasone, and that PC12 cells also produce pro-NT/NN but are virtually unable to process it. In addition, PC12 cells were reported to be devoid of the prohormone convertases PC1 and PC2. The present study was designed to identify the proprotein convertase(s) (PC) involved in pro-NT/NN processing in rMTC 6-23 cells and to compare PC1- and PC2-transfected PC12 cells for their ability to process pro-NT/NN. rMTC 6-23 cells were devoid of PC1, PC4, and PC5 but expressed furin and PC2. Stable expression of antisense PC2 RNA in rMTC 6-23 cells led to a 90% decrease in PC2 protein levels that correlated with a > 80% reduction of pro-NT/NN processing. PC2 expression was stimulated by dexamethasone in a time- and concentration-dependent manner. Stable PC12/PC2 transfectants processed pro-NT/NN with a pattern similar to that observed in the brain and in rMTC 6-23 cells. In contrast, stable PC12/PC1 transfectants reproduced the pro-NT/NN processing pattern seen in the gut. We conclude that (i) PC2 is the major pro-NT/NN convertase in rMTC 6-23 cells; (ii) its expression is coregulated with that of pro-NT/NN in this cell line; and (iii) PC2 and PC1 differentially process pro-NT/NN with brain and intestinal phenotype, respectively.

No association of the neuropeptide Y (Leu7Pro) and ghrelin gene (Arg51Gln, Leu72Met, Gln90Leu) single nucleotide polymorphisms with eating disorders.

PubMed

Kindler, Jochen; Bailer, Ursula; de Zwaan, Martina; Fuchs, Karoline; Leisch, Friedrich; Grün, Bettina; Strnad, Alexandra; Stojanovic, Mirjana; Windisch, Julia; Lennkh-Wolfsberg, Claudia; El-Giamal, Nadja; Sieghart, Werner; Kasper, Siegfried; Aschauer, Harald

2011-06-01

Genetic factors likely contribute to the biological vulnerability of eating disorders. Case-control association study on one neuropeptide Y gene (Leu7Pro) polymorphism and three ghrelin gene (Arg51Gln, Leu72Met and Gln90Leu) polymorphisms. 114 eating disorder patients (46 with anorexia nervosa, 30 with bulimia nervosa, 38 with binge eating disorder) and 164 healthy controls were genotyped. No differences were detected between patients and controls for any of the four polymorphisms in allele frequency and genotype distribution (P > 0.05). Allele frequencies and genotypes had no significant influence on body mass index (P > 0.05) in eating disorder patients. Positive findings of former case-control studies of associations between ghrelin gene polymorphisms and eating disorders could not be replicated. Neuropeptide Y gene polymorphisms have not been investigated in eating disorders before.

Peroxisome proliferator-activated receptor gamma co-activator 1 gene Gly482Ser polymorphism is associated with the response of low-density lipoprotein cholesterol concentrations to exercise training in elderly Japanese.

PubMed

Tobina, Takuro; Mori, Yukari; Doi, Yukiko; Nakayama, Fuki; Kiyonaga, Akira; Tanaka, Hiroaki

2017-09-01

Muscle peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1)α gene expression is influenced by the Gly482Ser gene polymorphism, which is a candidate genetic risk factor for diabetes mellitus and obesity. This study investigated the effects of PGC-1 gene Gly482Ser polymorphisms on alterations in glucose and lipid metabolism induced by exercise training. A 12-week intervention study was performed for 119 participants who were more than 65 years of age and completed exercise training at lactate threshold intensity. Total cholesterol and low-density lipoprotein cholesterol were significantly reduced in Gly/Gly but not in Gly/Ser and Ser/Ser participants after exercise. The Gly/Gly genotype of the PGC-1 gene Gly482Ser polymorphism influences the effects of moderate-intensity exercise training on low-density lipoprotein cholesterol and total cholesterol concentrations in older people.

GLUTATHIONE PEROXIDASE-1 PRO200LEU POLYMORPHISM (RS1050450) IS ASSOCIATED WITH MORBID OBESITY INDEPENDENTLY OF THE PRESENCE OF PREDIABETES OR DIABETES IN WOMEN FROM CENTRAL MEXICO.

PubMed

Hernández Guerrero, César; Hernández Chávez, Paulina; Martínez Castro, Noemí; Parra Carriedo, Alicia; García Del Rio, Sandra; Pérez Lizaur, Ana

2015-10-01

obesity affects more than a third of Mexican population. Oxidative stress participates actively in the etiology of this phenomenon. Glutathione peroxidase-1 (GPX-1) plays a protective role against oxidative stress. The SNP Pro200Leu (rs10504050) has been reported to affect the activity of the enzyme. to determine the frequency of rs10504050 polymorphism in women with obesity and normal weight control, asses the concentration of peripheral TBARS and evaluate the consumption of pro and antioxidants. 104 women with obesity and 70 healthy controls (CG) were included in the study. Anthropometric, biochemical, clinical and dietary features were evaluated. GPx-1 rs10504050 was determined by PCR/RFLP method. TBARS was assayed spectrophotometrically in plasma. The subjects were stratified and compared by obesity grades and by subgroups of prediabetes and diabetes condition. Statistical analysis included ANOVA of Kruskal Wallis, Xi squared and Pearson correlation. for rs10504050 polymorphism there were differences (Xi2 = 6; p = 0.01) between frequency (0.61) of obese carriers (Pro/Leu plus Leu/Leu) and CG carriers (0.42), and between (Xi2 = 8; p = 0.004) morbid (IMC > 40) obesity (0.74) and CG carriers. The obese group (OB) showed a prevalence of 66% of prediabetes plus diabetes. There were no differences in frequencies of rs10504050 in OB with pre or diabetes versus CG, or versus obese participants without diabetes. TBARS concentration was greater in all the degrees of OB versus CG. GPx-1 Pro200Leu polymorphism was associated with obesity especially with morbid obesity, but not with obese participants with prediabetes or diabetes. Oxidative stress is present in all grades of obesity significantly. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Association between environmental tobacco smoke exposure and lung cancer susceptibility: modification by antioxidant enzyme genetic polymorphisms.

PubMed

Fathy, Mona; Hamed, Mai; Youssif, Omnia; Fawzy, Nahla; Ashour, Wafa

2014-02-01

Environmental tobacco smoke (ETS) is the primary etiologic factor responsible for lung cancer. However, only 10-15 % of smokers develop lung cancer, suggesting a genetic role in modifying individual susceptibility to lung cancer. Antioxidant enzymes and genetic polymorphisms should be considered. The present study aimed to evaluate the role of antioxidant enzyme activity and genetic polymorphisms in modifying the susceptibility to lung cancer among individuals exposed to ETS. A total of 150 male subjects were divided into three groups: 50 lung cancer patients, 50 chronic smokers, and 50 passive smokers. Genotyping of microsomal epoxide hydrolase (mEH) exon 3 (Tyr(113)Hist) and exon 4 (Hist(139)Arg) polymorphisms were done by the polymerase chain reaction-restriction fragment length polymorphism technique. MnSOD (Val(16)Ala) polymorphism was detected by the real time-TaqMan assay. Erythrocyte MnSOD activity was measured spectrophotometrically. ETS-exposed individuals (both active and passive smokers) who carried the His allele of mEH exon3 have a 2.9-fold increased risk of lung cancer (odds ratio [OR] 2.9, P < 0.001). In addition, ETS-exposed carriers of the Arg allele of mEH exon 4 have a 2.1-fold increased risk of lung cancer (OR 2.1, P = 0.024). However, no association between the MnSOD Val(16)Ala polymorphism and lung cancer was detected among ETS-exposed individuals (OR 1.6, P = 0.147), although the lung cancer group had significantly lower MnSOD activity than the chronic or passive smoker groups (P = 0.03). Exons 3 and 4 polymorphisms of the mEH gene may contribute to lung cancer susceptibility through disturbed antioxidant balance. However, this was not the case with the MnSOD Val(16)Ala single-nucleotid polymorphism. Antioxidant enzymes may modulate the influence of ETS exposure on lung cancer risk.

Association between TPO Asn698Thr and Thr725Pro gene polymorphisms and serum anti-TPO levels in Iranian patients with subclinical hypothyroidism.

PubMed

Khoshi, Amirhosein; Sirghani, Alireza; Ghazisaeedi, Mehran; Mahmudabadi, Ali Zare; Azimian, Amir

2017-01-01

Subclinical hypothyroidism (SCH) is defined as high levels of TSH in the presence of normal levels of serum FT4. Since thyroid peroxidase (TPO) plays a key role in thyroid hormone synthesis, variations in the TPO gene can change the enzyme structure and result in the production of anti-TPO antibodies. The aim of this study was to examine the relationship between the Asn698Thr (A2095C) and Thr725Pro (A2173C) polymorphisms of the TPO gene and anti-TPO levels in patients with SCH. In this study, 150 individuals (75 cases and 75 controls), aged 19-75 years, were selected randomly by a clinician. The thyroid function tests included were FT3, FT4, TSH and anti-TPO antibodies using ELISA. The TPO gene polymorphisms were examined by PCR-RFLP. Anti-TPO levels in the experimental group was significantly increased (P=0.020). The A2095C genotype frequency in the experimental and control groups were 37.3% vs 34.7% for the AA healthy genotype, 20% vs 46.7% for AC and 42.7% vs 18.6% for CC, respectively (P=0.001). The A2173C genotype frequency in the experimental and control groups were 22.6% vs 68% for healthy AA, 40% vs 25.3% for AC and 37.4% vs 6.7% for CC, respectively (P <0.001). The increased anti-TPO antibodies were significantly associated with the A2173C polymorphism (P=0.035). The findings showed that the chance (odds ratio) of developing subclinical hypothyroidism in individuals who had C alleles was 1.5 and 5.6-fold higher than in individuals without these alleles in the A2095C and A2173C regions, respectively. Determination of anti-TPO antibody levels and exon 12 TPO gene polymorphisms in patients with SCH can be helpful for prediction of overt hypothyroidism.

A study of parallelism of the occlusal plane and ala-tragus line.

PubMed

Sadr, Katayoun; Sadr, Makan

2009-01-01

Orientation of the occlusal plane is one of the most important clinical procedures in prostho-dontic rehabilitation of edentulous patients. The aim of this study was to define the best posterior reference point of ala-tragus line for orientation of occlusal plane for complete denture fabrication. Fifty-three dental students (27 females and 26 males) with complete natural dentition and Angel's Class I occlusal relationship were selected. The subjects were photographed in natural head position while clenching on a Fox plane. After tracing the photographs, the angles between the following lines were measured: the occlusal plane (Fox plane) and the superior border of ala-tragus, the occlusal plane (Fox plane) and the middle of ala-tragus as well as the occlusal plane (Fox plane) and the inferior border of ala-tragus. Descriptive statistics, one sample t-test and independent t-test were used. P value less than 0.05 was considered significant. There was no parallelism between the occlusal plane and ala-tragus line with three different posterior ends and one sample t-test showed that the angles between them were significantly different from zero (p<0.05). However, the supe-rior border of ala-tragus line had the lowest mean angle, 1.80° (3.12) and was almost parallel to the occlusal plane. The superior border of the tragus is suggested as the posterior reference for ala-tragus line.

ALA Pretreatment Improves Waterlogging Tolerance of Fig Plants

PubMed Central

An, Yuyan; Qi, Lin; Wang, Liangju

2016-01-01

5-aminolevulinic acid (ALA), a natural and environmentally friendly plant growth regulator, can improve plant tolerance to various environmental stresses. However, whether ALA can improve plant waterlogging tolerance is unknown. Here, we investigated the effects of ALA pretreatment on the waterlogging-induced damage of fig (Ficus carica Linn.) plants, which often suffer from waterlogging stress. ALA pretreatment significantly alleviated stress-induced morphological damage, increased leaf relative water content (RWC), and reduced leaf superoxide anion (O2⋅¯) production rate and malonaldehyde (MDA) content in fig leaves, indicating ALA mitigates waterlogging stress of fig plants. We further demonstrated that ALA pretreatment largely promoted leaf chlorophyll content, photosynthetic electron transfer ability, and photosynthetic performance index, indicating ALA significantly improves plant photosynthetic efficiency under waterlogging stress. Moreover, ALA pretreatment significantly increased activities of leaf superoxide dismutase (SOD) and peroxidase (POD), root vigor, and activities of root alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH), indicating ALA also significantly improves antioxidant ability and root function of fig plants under waterlogging stress. Taken together, ALA pretreatment improves waterlogging tolerance of fig plants significantly, and the promoted root respiration, leaf photosynthesis, and antioxidant ability may contribute greatly to this improvement. Our data firstly shows that ALA can improve plant waterlogging tolerance. PMID:26789407

A Study of Parallelism of the Occlusal Plane and Ala-Tragus Line

PubMed Central

Sadr, Katayoun; Sadr, Makan

2009-01-01

Background and aims Orientation of the occlusal plane is one of the most important clinical procedures in prostho-dontic rehabilitation of edentulous patients. The aim of this study was to define the best posterior reference point of ala-tragus line for orientation of occlusal plane for complete denture fabrication. Materials and methods Fifty-three dental students (27 females and 26 males) with complete natural dentition and Angel’s Class I occlusal relationship were selected. The subjects were photographed in natural head position while clenching on a Fox plane. After tracing the photographs, the angles between the following lines were measured: the occlusal plane (Fox plane) and the superior border of ala-tragus, the occlusal plane (Fox plane) and the middle of ala-tragus as well as the occlusal plane (Fox plane) and the inferior border of ala-tragus. Descriptive statistics, one sample t-test and independent t-test were used. P value less than 0.05 was considered significant. Results There was no parallelism between the occlusal plane and ala-tragus line with three different posterior ends and one sample t-test showed that the angles between them were significantly different from zero (p<0.05). However, the supe-rior border of ala-tragus line had the lowest mean angle, 1.80° (3.12) and was almost parallel to the occlusal plane. Conclusion The superior border of the tragus is suggested as the posterior reference for ala-tragus line. PMID:23230496

A base substitution in the donor site of intron 12 of KIT gene is responsible for the dominant white coat colour of blue fox (Alopex lagopus).

PubMed

Yan, S Q; Hou, J N; Bai, C Y; Jiang, Y; Zhang, X J; Ren, H L; Sun, B X; Zhao, Z H; Sun, J H

2014-04-01

The dominant white coat colour of farmed blue fox is inherited as a monogenic autosomal dominant trait and is suggested to be embryonic lethal in the homozygous state. In this study, the transcripts of KIT were identified by RT-PCR for a dominant white fox and a normal blue fox. Sequence analysis showed that the KIT transcript in normal blue fox contained the full-length coding sequence of 2919 bp (GenBank Acc. No KF530833), but in the dominant white individual, a truncated isoform lacking the entire exon 12 specifically co-expressed with the normal transcript. Genomic DNA sequencing revealed that a single nucleotide polymorphism (c.1867+1G>T) in intron 12 appeared only in the dominant white individuals and a 1-bp ins/del polymorphism in the same intron showed in individuals representing two different coat colours. Genotyping results of the SNP with PCR-RFLP in 185 individuals showed all 90 normal blue foxes were homozygous for the G allele, and all dominant white individuals were heterozygous. Due to the truncated protein with a deletion of 35 amino acids and an amino acid replacement (p.Pro623Ala) located in the conserved ATP binding domain, we propose that the mutant receptor had absent tyrosine kinase activity. These findings reveal that the base substitution at the first nucleotide of intron 12 of KIT gene, resulting in skipping of exon 12, is a causative mutation responsible for the dominant white phenotype of blue fox. © 2013 Stichting International Foundation for Animal Genetics.

ALA-PDT mediated DC vaccine for skin squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Ji, Jie; Fan, Zhixia; Zhou, Feifan; Wang, Xiaojie; Shi, Lei; Zhang, Haiyan; Wang, Peiru; Yang, Degang; Zhang, Linglin; Wang, Xiuli; Chen, Wei R.

2015-03-01

Dendritic cell (DC) based vaccine has emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have only achieved limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secret INF-Υ and IL-12). ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumor in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing DC-based cancer vaccine, which could improve the clinical application of PDT- DC vaccines.

Evaluation of Effect CAT -262C/T, SOD + 35A/C, GPx1 Pro197Leu Polymorphisms in Patients with IBD in the Polish Population.

PubMed

Mrowicki, Jerzy; Mrowicka, Małgorzata; Majsterek, Ireneusz; Mik, Michał; Dziki, Adam; Dziki, Łukasz

2016-12-01

Inflammatory bowel disease (IBD) are a heterogeneous group of disorders in the course dominated by chronic, recurrent gastrointestinal inflammation. It is believed that the activation of IBD occurs in patients with a genetic predisposition to their development. Chronic inflammation develops as a result of an excessive reaction of the immune system principally under the influence of environmental risk factors. Among them, it has been shown that the mechanism of oxidative stress is associated with the pathophysiology of inflammatory bowel disease, responsible for the commencement and progress of these diseases. The aim of the study was the relationship between single nucleotide polymorphisms (SNPs) of individual antioxidant enzymes, and the prevalence of inflammatory bowel disease that may be associated with increased levels of oxidative stress. A total of 111 IBD patients, including 65 patients with ulcerative colitis (UC) and 46 with Crohn's disease (CD) and 125 healthy controls recruited from the Polish population, were genotyped for CAT -262C / T (rs1001179), SOD + 35A / C (rs2234694), GPx Pro 197 Leu polymorphisms. Genotyping of CAT, SOD, GPx gene polymorphism was performed by a RFLP-PCR. The performed analysis of genetic polymorphisms of antioxidant enzymes showed that polymorphic variant of the CAT -262 C / T may have protective effects in patients with ulcerative colitis in the range of genotype C / T; OR = 0.49 (0.25-0.99), p = 0.044. Trend protective, but statistically unrelated, it was also observed for genotype T / T and T allele of the same polymorphism and genotypes and alleles + 35A / C SOD1 in UC as well as polymorphic variants CAT -262 C / T, Pro197Leu of GPx1, + 35A / C SOD1 in CD. The results were compared with a control group of potentially healthy individuals without such diseases. It has been shown that the polymorphism of antioxidant enzymes CAT gene -262 C / T may have protective effects in patients who are carriers of a genotype C / T at the

Ala67Thr mutation in the poliovirus receptor CD155 is a potential risk factor for vaccine and wild-type paralytic poliomyelitis.

PubMed

Kindberg, Elin; Ax, Cecilia; Fiore, Lucia; Svensson, Lennart

2009-05-01

Poliovirus infections can be asymptomatic or cause severe paralysis. Why some individuals develop paralytic poliomyelitis is unknown, but a role for host genetic factors has been suggested. To investigate if a polymorphism, Ala67Thr, in the poliovirus receptor, which has been found to facilitate increased resistance against poliovirus-induced cell lysis and apoptosis, is associated with increased risk of paralytic poliomyelitis, poliovirus receptor genotyping was undertaken among Italian subjects with vaccine-associated (n = 9), or with wild-type paralytic poliomyelitis (n = 6), and control subjects (n = 71), using RFLP-PCR and pyrosequencing. Heterozygous poliovirus receptor Ala67Thr genotype was found in 13.3% of the patients with paresis and in 8.5% of the controls (Odds Ratio = 1.667). The frequency of Ala67Thr among the controls is in agreement with earlier published data. It is concluded that the Ala67Thr mutation in the poliovirus receptor is a possible risk factor for the development of vaccine-associated or paralytic poliomyelitis associated with wild-type virus. Copyright 2009 Wiley-Liss, Inc.

[Association between Fok I vitamin D receptor (VDR) gene polymorphism and plasmatic concentrations of transforming growth factor-beta1 and interferon gamma in type 1 diabetes mellitus].

PubMed

López, Tatiana; García, Diego; Angel, Bárbara; Carrasco, Elena; Codner, Ethel; Ugarte, Francisca; Pérez-Bravo, Francisco

2008-02-02

In order to assess whether Fok I vitamin D receptor gene (VDR) polymorphism is involved in the genetic susceptibility of type 1 diabetes, a case-control study was conducted and VDR genotypes were related to serum concentrations of 25(OH) vitamin D and cytokines transforming growth factor beta1 (TGF-beta1) and interferon gamma (INF-gamma). 151 incident cases of type 1 diabetes and 182 non related healthy controls from Santiago were studied for VDR polymorphisms in peripheral blood DNA. Exon 2 (Fok I) segments were amplified by polimerase chain reaction and analyzed by means of restriction fragment length polymorphism to determine each corresponding genotype. Differences for allele, genotype and serological markers as 25(OH) vitamin D, TGF-beta1 and INF-gamma levels distribution between patients and controls were analyzed. Fok I polymorphism distribution analysis showed no differences between patients and controls. Among diabetics, higher levels of TGF-beta1 (median, 282.6 pg/ml; range, 131.8-3,031.4) were observed compared with healthy children (median, 232.2 pg/ml; range, 135.7-506.5) (p < 0.0038). Similar results were observed for INF-gamma concentrations (median, 121.1 pg/ml, and range, 5.3-228.8, in cases, and median, 89.6 pg/ml, and range, 10.9-117.2 in controls) (p < 0.0004). The diabetic carriers of the ff genotype showed low levels of 25(OH) vitamin D compared with the carriers of the F allele: mean (standard deviation), 23.1 (5.9) versus 27.9 (10.3) ng/ml (p < 0.03). A similar result was observed for TGF-beta1 concentrations in diabetic carriers of ff genotype and patients carriers of the F allele (298.5 versus 276.6; p < 0.05). Fok I polymorphism of VDR could have a marginal role in the immunologic disturbance in type 1 diabetes.

The role of DAMPS in ALA-PDT for skin squamous cell carcinoma (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wang, Xiuli; Wang, Xiaojie; Ji, Jie; Zhang, Haiyan; Shi, Lei

2016-03-01

5-Aminolevulinic acid mediated photodynamic therapy (ALA-PDT) is an established local approach for skin squamous cell carcinoma. It is believed that dangerous signals damage-associated molecular patterns (DAMPs) play an important role in ALA-PDT. In this study, we evaluated in vitro and in vivo expressions of major DAMPs, calreticulin (CRT), heat shock proteins 70 (HSP70), and high mobility group box 1 (HMGB1), induced by ALA-PDT using immunohistochemistry, western blot, and ELISA in a squamous cell carcinoma (SCC) mouse model. The role of DAMPs in the maturation of DCs potentiated by ALA-PDT-treated tumor cells was detected by FACS and ELISA. Our results showed that ALA-PDT enhanced the expression of CRT, HSP70, and HMGB1. These induced DAMPs played an important role in activating DCs by PDT-treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, CD80, and CD86) and functional maturation (enhanced capability to secrete IFN-γ and IL-12). Furthermore, injecting ALA-PDT-treated tumor cells into naïve mice resulted in complete protection against cancer cells of the same origin. Our findings indicate that ALA-PDT can upregulate DAMPs and enhance tumor immunogenicity, providing a promising strategy for inducing a systemic anticancer immune response.

Expression of the alaE gene is positively regulated by the global regulator Lrp in response to intracellular accumulation of l-alanine in Escherichia coli.

PubMed

Ihara, Kohei; Sato, Kazuki; Hori, Hatsuhiro; Makino, Yumiko; Shigenobu, Shuji; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

2017-04-01

The alaE gene in Escherichia coli encodes an l-alanine exporter that catalyzes the active export of l-alanine using proton electrochemical potential. In our previous study, alaE expression was shown to increase in the presence of l-alanyl-l-alanine (Ala-Ala). In this study, the global regulator leucine-responsive regulatory protein (Lrp) was identified as an activator of the alaE gene. A promoter less β-galactosidase gene was fused to an alaE upstream region (240 nucleotides). Cells that were lacZ-deficient and harbored this reporter plasmid showed significant induction of β-galactosidase activity (approximately 17-fold) in the presence of 6 mM l-alanine, l-leucine, and Ala-Ala. However, a reporter plasmid possessing a smaller alaE upstream region (180 nucleotides) yielded transformants with strikingly low enzyme activity under the same conditions. In contrast, lrp-deficient cells showed almost no β-galactosidase induction, indicating that Lrp positively regulates alaE expression. We next performed an electrophoretic mobility shift assay (EMSA) and a DNase I footprinting assay using purified hexahistidine-tagged Lrp (Lrp-His). Consequently, we found that Lrp-His binds to the alaE upstream region spanning nucleotide -161 to -83 with a physiologically relevant affinity (apparent K D , 288.7 ± 83.8 nM). Furthermore, the binding affinity of Lrp-His toward its cis-element was increased by l-alanine and l-leucine, but not by Ala-Ala and d-alanine. Based on these results, we concluded that the gene expression of the alaE is regulated by Lrp in response to intracellular levels of l-alanine, which eventually leads to intracellular homeostasis of l-alanine concentrations. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

SOD2 gene polymorphism and response of oxidative stress parameters in young wrestlers to a three-month training.

PubMed

Jówko, Ewa; Gierczuk, Dariusz; Cieśliński, Igor; Kotowska, Jadwiga

2017-05-01

The aim of the study was to analyse the effect of Val 16Ala polymorphism in SOD2 gene on oxidative stress parameters and lipid profile of the blood during a three-month wrestling training. The study included 53 Polish young wrestlers. Blood samples were collected at the beginning of the programme and following three months of the training. The list of analysed parameters included erythrocyte and serum activities of superoxide dismutase (SOD), whole blood glutathione peroxidase (GPx) activity, total glutathione (tGSH) level, concentration of lipid hydroperoxides (LHs), total antioxidant capacity (TAC) and creatine kinase (CK) activity in the serum, as well as lipid profile parameters: triglycerides (TG), total cholesterol (TC), high-density (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Three-month training resulted in a decrease in CK activity, an increase in serum SOD activity, as well as in unfavourable changes in serum lipid profile: an increase in TC, LDL-C, and TG, and a decrease in HDL-C. Aside from CK activity, all these changes seemed to be associated with presence of Val allele. Prior to the training programme, subjects with Ala/Ala genotype presented with lower levels of LHs, lower whole blood GPx activity, and lower serum concentrations of TC than the individuals with Ala/Val genotype. Both prior to and after three-month training, higher levels of tGSH were observed in Val/Val genotype as compared to Ala/Val genotype carriers. Moreover, multiple regression analysis demonstrated that SOD2 genotype was a significant predictor of pre-training whole blood GPx activity and erythrocyte SOD activity (Val/Val > Ala/Val > Ala/Ala). Altogether, these findings suggest that Val 16Ala polymorphism in SOD2 gene contributes to individual variability in oxidative stress status and lipid profile of the blood in young wrestlers, and may modulate biochemical response to training.

ALA-PDT of the normal rat esophagus: efficiency and safety largely depends on the timing of illumination

NASA Astrophysics Data System (ADS)

van den Boogert, Jolanda; de Bruin, Ron W. F.; van Staveren, Hugo J.; Siersema, Peter D.; van Hillegersberg, Richard

1999-02-01

Photodynamic therapy (PDT) is an experimental treatment modality for (pre)malignant oesophageal lesions. 5- Aminolevulinic acid (ALA)-induced, protoporphyrin IX (PpIX)- mediated photo-sensitization could be very useful as ALA- induced porphrin accumulation selectively occurs in the oesophageal epithelium. The present study aimed to optimize the time between illumination and the administration of ALA. 200 mg/kg ALA was given orally to 24 rats (allocated to 6 groups of 4 animals each). Four animals served as controls and received phosphate buffered saline orally. The animals were illuminated at various time-points (either 1, 2, 3, 4, 6, or 12 hours) after ALA administration. Illumination was performed with a cylindrical diffuser placed in a balloon catheter. The device was originally made for percutaneous transluminal coronary angioplasty and consisted of a semi-flexible catheter and an inflatable cylindric optically clear balloon. The diffuser was placed centrally in the catheter. The same illumination parameters (633 nm, 25 J radiant energy/cm diffuser, power output 100 mW/cm diffuser) were used for each animal. During illumination, fluorescence measurements and light dosimetry were performed. The animals were sacrificed at 48 hours after PDT for histological assessment. Highest PpIX fluorescence was found at 2, 3, and 4 hours after ALA administration. Dosimetric measurements showed a 2 - 3 times higher in vivo fluence rate compared to the estimated fluence rate. Histology at 48 hours after PDT showed diffuse epithelial damage at the laser site only in rats illuminated at 2 hours after ALA administration. Illumination at 3, 4, and 6 hours after ALA administration resulted in diffuse epithelial damage in only one of four rats. In none of the rats illuminated at 1 and 12 hours after administration of ALA epithelial damage was found. These results show that illumination at 2 hours after oral ALA administration provides an efficient and safe scheme for ALA-PDT in the

Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample.

PubMed

Ojeda, Diego A; Forero, Diego A

2014-10-01

Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome-wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations.

Functional polymorphisms in the sigma1 receptor gene associated with alcoholism.

PubMed

Miyatake, Ryosuke; Furukawa, Aizo; Matsushita, Sachio; Higuchi, Susumu; Suwaki, Hiroshi

2004-01-01

Sigma1 receptors are involved in the pathogenesis of drug abuse. Two polymorphisms (GC-241-240TT and Gln2Pro) in the sigma1 receptor gene (SIGMAR1) have been identified. To investigate the role of SIGMAR1 in conveying susceptibility to alcoholism, we performed a functional analysis of polymorphisms in the SIGMAR1 and a case-control study. We initially screened for polymorphisms in the 5'-upstream region. The effects of the polymorphisms on transcriptional activity were determined using a gene reporter assay. The distribution of SIGMAR1 polymorphisms was analyzed in 307 alcoholic and 302 control subjects. A novel T-485A polymorphism was identified. The transcriptional activity of the A-485 allele and the TT-241-240 allele was significantly reduced compared with that of the T-485 allele and the GC-241-240 allele. The frequencies of the A-485 allele (chi2=5.575, df=1, p=.0205) and the TT-241-240/Pro2 haplotype (chi2=21.464, df=1, p<.0001) were significantly higher in control subjects compared with alcoholic subjects. The T-485A and the GC-241-240TT may be functional polymorphisms, and the A-485 allele and TT-241-240/Pro2 haplotype are possible protective factors for the development of alcoholism.

Restriction fragment length polymorphisms for growth hormone, prolactin, osteonectin, alpha crystallin, gamma crystallin, fibronectin and 21-steroid hydroxylase in cattle.

PubMed

Theilmann, J L; Skow, L C; Baker, J F; Womack, J E

1989-01-01

Genomic DNAs from animals representing six breeds of cattle (Angus, Brahman, Hereford, Holstein, Jersey and Texas Longhorn) were screened with cloned gene probes in a search for restriction fragment length polymorphisms (RFLPs). Eleven RFLPs were identified using seven different probes: growth hormone, prolactin, osteonectin, alpha A-crystallin, gamma crystallin, fibronectin and 21-steroid hydroxylase. The frequencies of the alleles identified by each probe were calculated and compared in a limited sampling of the six bovine breeds. These polymorphisms greatly enhance the pool of immunogenetic, biochemical and molecular markers available in cattle for linkage analysis, testing of parentage, and distinction of breeds.

Lack of association between the fatty acid binding protein 2 (FABP2) polymorphism with obesity and insulin resistance in two aboriginal populations from Chile.

PubMed

Pérez-Bravo, F; Fuentes, M; Angel, B; Sanchez, H; Carrasco, E; Santos, J L; Lera, L; Albala, C

2006-12-01

The aim of this study was to assess the frequency of fatty acid binding protein 2 (FABP2) Ala54Thr genetic polymorphism and to evaluate its association with obesity and insulin resistance in Chilean aboriginal populations. A sample of 96 urban Aymara and 111 urban Mapuche subjects aged 20-80 years were recruited for this cross-sectional study. Glucose, insulin and lipid profile were measured in fasting plasma samples. Insulin resistance was estimated through the HOMA-IR model. FABP2 Ala54Thr genotypes were determined by PCR followed by RFLP analysis. The allele frequency of Thr54 variant was estimated as 18.2% in Aymara subjects, which is one of the lowest reported to date. The corresponding frequency in Mapuche subjects was 31.9% (p<0.002). Regarding genotype-phenotype associations, no significant differences were found in any of the anthropometric or metabolic variables according to Ala54Thr genotypes. After adjustment by BMI and metabolic variables through a logistic regression analysis, the association of the FABP2 polymorphism with ethnic group persisted (Mapuche group: OR=2.37, 95% CI 1.319-4.277, p=0.004) It is unlikely that Ala54Thr polymorphism of the FABP2 gene plays a relevant role in obesity and insulin resistance in Chilean ethnic groups.

Periodic gamma-ray emissions from Geminga at or = 10(12) eV

NASA Technical Reports Server (NTRS)

Kaul, R. K.; Rawat, H. S.; Sanecha, V. K.; Rannot, R. C.; Sapru, M.; Tickoo, A. K.; Qazi, R. A.; Bhat, C. L.; Razdan, H.; Tonwar, S. C.

1985-01-01

Analysis of data from an atmospheric Cerenkov telescope indicated the periodic emission of gamma rays of energy 10 to the 12th power eV, at 60.25 second period, from 2CG 195+4. The gamma ray flux at 99% confidence level is estimated to be 9.5 x 10 to 12 photons/sq cm/s.

Processing and population genetic analysis of multigenic datasets with ProSeq3 software.

PubMed

Filatov, Dmitry A

2009-12-01

The current tendency in molecular population genetics is to use increasing numbers of genes in the analysis. Here I describe a program for handling and population genetic analysis of DNA polymorphism data collected from multiple genes. The program includes a sequence/alignment editor and an internal relational database that simplify the preparation and manipulation of multigenic DNA polymorphism datasets. The most commonly used DNA polymorphism analyses are implemented in ProSeq3, facilitating population genetic analysis of large multigenic datasets. Extensive input/output options make ProSeq3 a convenient hub for sequence data processing and analysis. The program is available free of charge from http://dps.plants.ox.ac.uk/sequencing/proseq.htm.

TNF-alpha -308G>A polymorphism is associated with suicide attempts in major depressive disorder.

PubMed

Kim, Yong-Ku; Hong, Jin-Pyo; Hwang, Jung-A; Lee, Heon-Jeong; Yoon, Ho-Kyoung; Lee, Bun-Hee; Jung, Han-Yong; Hahn, Sang-Woo; Na, Kyoung-Sae

2013-09-05

Despite the substantial role of the cytokine network in depression and suicide, few studies have investigated the role of genetic polymorphisms of pro- and anti-inflammatory cytokines in suicide in major depressive disorder (MDD). The aim of this study was to investigate whether tumor necrosis factor-alpha (TNF-alpha) -308G>A, interferon-gamma (IFN-gamma) +874A>T, and interleukin-10 (IL-10) -1082A>G are associated with increased risk for suicide attempts in MDD. Among patients with MDD, 204 patients who had attempted suicide and 97 control patients who had not attempted suicide were recruited. A chi-square test was used to identify a possible risk genotype or allele type for suicide. A subsequent multivariate logistic regression analysis was conducted to investigate the influence of a risk genotype or allele type adjusted for other environmental factors. The lethality of the suicide attempt was also tested between genotype and allele types among suicidal patients with MDD. The GG genotype of the TNF-alpha -308G>A polymorphism was found to significantly increase risk for suicide attempt (adjusted OR=2.630, 95% CI=1.206 to 5.734). IFN-gamma +874A>T and IL-10 -1082A>G were not associated with risk for suicide. Lethality of the suicide attempt was not associated with any of the three cytokine genotypes or allele types. Limitations include a relatively small sample size and a cross-sectional design. TNF-alpha -308G>A polymorphism is an independent risk factor for suicide attempts in MDD. Future studies should clarify the neural mechanisms by which the GG genotype of TNF-alpha -308G>A influences suicide in MDD. Copyright © 2013 Elsevier B.V. All rights reserved.

Impact of charged amino acid substitution in the transmembrane domain of L-alanine exporter, AlaE, of Escherichia coli on the L-alanine export.

PubMed

Kim, Seryoung; Ihara, Kohei; Katsube, Satoshi; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

2017-01-01

The Escherichia coli alaE gene encodes the L-alanine exporter, AlaE, that catalyzes active export of L-alanine using proton electrochemical potential. The transporter comprises only 149 amino acid residues and four predicted transmembrane domains (TMs), which contain three charged amino acid residues. The AlaE-deficient L-alanine non-metabolizing cells (ΔalaE cells) appeared hypersusceptible to L-alanyl-L-alanine showing a minimum inhibitory concentration (MIC) of 2.5 µg/ml for the dipeptide due to a toxic accumulation of L-alanine. To elucidate the mechanism by which AlaE exports L-alanine, we replaced charged amino acid residues in the TMs, glutamic acid-30 (TM-I), arginine-45 (TM-II), and aspartic acid-84 (TM-III) with their respective charge-conserved amino acid or a net neutral cysteine. The ΔalaE cells producing R45K or R45C appeared hypersusceptible to the dipeptide, indicating that arginine-45 is essential for AlaE activity. MIC of the dipeptide in the ΔalaE cells expressing E30D and E30C was 156 µg/ml and >10,000 µg/ml, respectively, thereby suggesting that a negative charge at this position is not essential. The ΔalaE cells expressing D84E or D84C showed an MIC >10,000 and 78 µg/ml, respectively, implying that a negative charge is required at this position. These results were generally consistent with that of the L-alanine accumulation experiments in intact cells. We therefore concluded that charged amino acid residues (R45 and D84) in the AlaE transmembrane domain play a pivotal role in L-alanine export. Replacement of three cysteine residues at C22, C28 (both in TM-I), and C135 (C-terminal region) with alanine showed only a marginal effect on L-alanine export.

Interleukin-12- and interferon-gamma-mediated natural killer cell activation by Agaricus blazei Murill.

PubMed

Yuminamochi, Eri; Koike, Taisuke; Takeda, Kazuyoshi; Horiuchi, Isao; Okumura, Ko

2007-06-01

Dried fruiting bodies of Agaricus blazei Murill (A. blazei) and its extracts have generally used as complementary and alternative medicines (CAMs). Here, we report that the oral administration of A. blazei augmented cytotoxicity of natural killer (NK) cells in wild-type (WT) C57BL/6, C3H/HeJ, and BALB/c mice. Augmented cytotoxicity was demonstrated by purified NK cells from treated wild-type (WT) and RAG-2-deficient mice, but not from interferon-gamma (IFN-gamma) deficient mice. NK cell activation and IFN-gamma production was also observed in vitro when dendritic cell (DC)-rich splenocytes of WT mice were coincubation with an extract of A. blazei. Both parameters were largely inhibited by neutralizing anti-interleukin-12 (IL-12) monoclonal antibody (mAb) and completely inhibited when anti-IL-12 mAb and anti-IL-18 mAb were used in combination. An aqueous extract of the hemicellulase-digested compound of A. blazei particle; (ABPC) induced IFN-gamma production more effectively, and this was completely inhibited by anti-IL-12 mAb alone. NK cell cytotoxicty was augmented with the same extracts, again in an IL-12 and IFN-gamma-dependent manner. These results clearly demonstrated that A. blazei and ABPC augmented NK cell activation through IL-12-mediated IFN-gamma production.

Bacterial DNA-induced NK cell IFN-gamma production is dependent on macrophage secretion of IL-12.

PubMed

Chace, J H; Hooker, N A; Mildenstein, K L; Krieg, A M; Cowdery, J S

1997-08-01

Bacterial DNA (bDNA) activates B cells and macrophages and can augment inflammatory responses by inducing release of proinflammatory cytokines. We found that bDNA stimulation of mouse spleen cells induced NK cell IFN-gamma production that was dependent upon the presence of unmethylated CpG motifs, and oligonucleotides with internal CpG motifs could also induce splenocytes to secrete IFN-gamma. The bDNA-induced IFN-gamma response was strictly macrophages dependent. While splenocytes from SCID mice secreted IFN-gamma in response to bDNA, depletion of macrophages eliminated this response. Additionally, purified NK cells did not respond to bDNA; however, addition of macrophages restored the NK cell IFN-gamma response. Coculture of NK cells with preactivated macrophages further increased bDNA-induced NK cell IFN-gamma production. Anti-IL-12 or IL-10 inhibited bDNA-induced IFN-gamma response. Treatment of purified macrophages with bDNA resulted in IL-12 secretion accompanied by an increase in IL-12 p40 mRNA level. Although isolated NK cells did not make IFN-gamma in response to bDNA, NK cells costimulated with IL-12 gained the ability to respond to bDNA. These experiments show that bDNA induces macrophage IL-12 production which, in turn, stimulates NK cell IFN-gamma production. Macrophage-derived IL-12 renders NK cells responsive to bDNA permitting an even greater IFN-gamma response to bDNA.

Peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 C>G polymorphism is associated with cancer susceptibility in asians: an updated meta-analysis

PubMed Central

Wang, Yafeng; Chen, Yu; Jiang, Heping; Tang, Weifeng; Kang, Mingqiang; Liu, Tianyun; Guo, Zengqing; Ma, Zhiqiang

2015-01-01

Peroxisome proliferator-activated receptor gamma (PPARG) is related to inflammation and plays an important role in the development of cancer. PPARG rs1801282 C>G polymorphism might influence the risk of cancer by regulating production of PPARG gene. Hence, a comprehensive meta-analysis was conducted to explore the association of PPARG rs1801282 C>G polymorphism with cancer susceptibility. An extensive search of PubMed and Embase databases for all relevant publications was carried out. A total of 38 publications with 16,844 cancer cases and 23,736 controls for PPARG rs1801282 C>G polymorphism were recruited in our study. Our results indicated that PPARG rs1801282 C>G variants were associated with an increased cancer risk in Asian populations and gastric cancer. In summary, the findings suggest that PPARG rs1801282 C>G polymorphism may play a crucial role in malignant transformation and the development of cancer. PMID:26550180

Peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 C>G polymorphism is associated with cancer susceptibility in asians: an updated meta-analysis.

PubMed

Wang, Yafeng; Chen, Yu; Jiang, Heping; Tang, Weifeng; Kang, Mingqiang; Liu, Tianyun; Guo, Zengqing; Ma, Zhiqiang

2015-01-01

Peroxisome proliferator-activated receptor gamma (PPARG) is related to inflammation and plays an important role in the development of cancer. PPARG rs1801282 C>G polymorphism might influence the risk of cancer by regulating production of PPARG gene. Hence, a comprehensive meta-analysis was conducted to explore the association of PPARG rs1801282 C>G polymorphism with cancer susceptibility. An extensive search of PubMed and Embase databases for all relevant publications was carried out. A total of 38 publications with 16,844 cancer cases and 23,736 controls for PPARG rs1801282 C>G polymorphism were recruited in our study. Our results indicated that PPARG rs1801282 C>G variants were associated with an increased cancer risk in Asian populations and gastric cancer. In summary, the findings suggest that PPARG rs1801282 C>G polymorphism may play a crucial role in malignant transformation and the development of cancer.

Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

NASA Astrophysics Data System (ADS)

Yang, Deng-Fu; Hsu, Yih-Chih

2012-03-01

In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

Impact of an AlAs window layer upon the optical properties of Al x Ga1-x As photodiodes

NASA Astrophysics Data System (ADS)

Kang, T.; Chen, X. J.; Johnson, E. B.; Christian, J. F.; Lee, K.; Hammig, M. D.

2016-05-01

Recently developed advanced scintillators, which have the ability to distinguish gamma-ray interaction events from those that accompany neutron impact, require improved quantum efficiency in the blue to near UV region of the spectrum. We utilize GaAs/Al0.8Ga0.2As photodiode elements as components in a wide band-gap solid-state photomultiplier as a lower-cost, lower logistical burden, and higher quantum efficiency replacement for the photomultiplier tube. An AlAs window layer is employed as a means to increase the diode’s optical performance. Relative to structures absent the window layer, simulations and measurements demonstrate that the AlAs layer produces a spatial coincidence between regions of large drift fields with regions of high photon absorption. In addition to the AlAs layer, secondary ion mass spectrometry measurements show that an unexpected high degree of inter-diffusion of GaAs and AlAs quenches the photon-detection efficiency, a decrease that can be avoided by its post-growth removal. With the AlAs layer, the peak external quantum efficiency of 49% is achieved at 450 nm with 10 V reverse bias, which does not fully deplete the device. Simulations show that full depletion can result in efficiencies exceeding 90%. In order to enhance the optical response, a simple anti-reflective coating layer is designed using the existing passivation layer components that successfully minimizes the reflection at the wavelength range of interest (300 nm-500 nm).

Association of angiotensin-converting enzyme (ACE) and fatty acid binding protein 2 (FABP2) genes polymorphism with type 2 diabetes mellitus in Northern India.

PubMed

Raza, Syed Tasleem; Fatima, Jalees; Ahmed, Faisal; Abbas, Shania; Zaidi, Zeashan Haider; Singh, Seema; Mahdi, Farzana

2014-12-01

Type 2 diabetes mellitus (T2DM) is growing in an epidemic manner across the world with an expected doubling of the incidence to millions of affected individuals in the last decades. At present, adequate data are not available regarding the ACE and FABP2 polymorphisms and their susceptibility with T2DM cases in the North Indian population. Thus we conceived the need for further study of ACE (I/D) and FABP2 (Ala54Thr) genes polymorphism and its susceptibility to T2DM in the North Indian population. In this study, a total of 300 subjects (including 190 T2DM cases and 110 controls) participated. ACE and FABP2 gene polymorphisms in the cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism. The frequencies of ACE I/I, I/D and D/D genotypes in T2DM cases and controls were 28.73%, 55.17%, 16.09% and 13.63%, 57.95%, 28.40%, respectively. The frequencies of FABP2 Ala54Ala, Ala54Thr and Thr54Thr in T2DM cases were 18.39%, 66.66%, 14.94% and 22.72%, 61.36%, 15.90% in controls, respectively. ACE I/I genotype was significantly more frequent in cases as compared to controls (p = 0.003, χ(2) = 9.13). It appears that the ACE I/I genotype frequency was significantly higher in the T2DM cases as compared to the controls. © The Author(s) 2013.

Escherichia coli K-12 can utilize an exogenous gamma-glutamyl peptide as an amino acid source, for which gamma-glutamyltranspeptidase is essential.

PubMed

Suzuki, H; Hashimoto, W; Kumagai, H

1993-09-01

Escherichia coli K-12 can utilize a gamma-glutamyl peptide as an amino acid source, for which gamma-glutamyltranspeptidase (EC 2.3.2.2) is essential. We suggest that the gamma-glutamyl linkage of a gamma-glutamyl peptide is hydrolyzed by gamma-glutamyltranspeptidase located in the periplasmic space, and the released amino acid is taken up and utilized by E. coli.

Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease

PubMed Central

Rohatgi, Soma; Gohil, Shruti; Kuniholm, Mark H.; Schultz, Hannah; Dufaud, Chad; Armour, Kathryn L.; Badri, Sheila; Mailliard, Robbie B.; Pirofski, Liise-anne

2013-01-01

ABSTRACT Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4+ T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4+ T cell decline, and nadir CD4+ T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation. PMID:23982074

Compartmentalized bronchoalveolar IFN-gamma and IL-12 response in human pulmonary tuberculosis.

PubMed

Herrera, Maria Teresa; Torres, Martha; Nevels, Denarra; Perez-Redondo, Carlos Núñez; Ellner, Jerrold J; Sada, Eduardo; Schwander, Stephan K

2009-01-01

Human tuberculosis (TB) principally involves the lungs, where local immunity impacts on the load of Mycobacterium tuberculosis (M.tb). Because concomitants of local Th1 immunity are still under-explored in humans, we characterized immune responses in bronchoalveolar cells (BACs) and systemically in peripheral blood mononuclear cells (PBMCs) in persons with active pulmonary TB and in healthy community controls. PPD- and live M.tb-induced IFN-gamma-production were observed in CD4(+), CD8(+), gammadeltaTCR(+), and CD56(+) alveolar T cell subpopulations and NK cells (CD3(-)CD56(+)). IFN-gamma-producing CD4(+) T cells (mostly CD45RO(+)) were more abundant (p<0.05). M.tb-induced IL-12p70, but interestingly also IL-4, was increased (p<0.05) in BACs from TB patients. Constitutive expression of IL-12Rbeta1 and IL-12Rbeta2 mRNA in BACs and PBMCs and IFN-gammaR1 in BACs was similar in both study groups. Data were normalized to account for differences in proportions of alveolar T cells and macrophages in the study groups. IFN-gamma-production and its induction by IL-12R engagement occur virtually unimpaired in the bronchoalveolar spaces of patients with pulmonary TB. The reasons for the apparent failure to control M. tuberculosis growth during active pulmonary TB disease is unknown but could be the expression of locally acting immunosuppressive mechanisms that subvert the antimycobacterial effects of IFN-gamma.

IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk.

PubMed

Jemli, Achraf; Inoubli, Oumaima; Trifa, Fatma; Mechri, Anouar; Zaafrane, Ferid; Gaha, Lotfi; Jrad, Besma Bel Hadj

2017-01-01

Considering current scientific evidence about the significant role of chronic low grade inflammation in the physiopathology of schizophrenia, it has been hypothesized that changes in pro-inflammatory cytokines such as interferon gamma may have a significant role in the predisposition to schizophrenia. This study focuses on identifying whether the functional polymorphism of interferon gamma receptor 2 (IFNGR2) is a risk factor for the development of schizophrenia. This study was conducted by the RFLP-PCR on a Tunisian population composed of 225 patients with different sub-types of schizophrenia and 166 controls. The IFNGR2 (Q64R) polymorphism analysis showed higher frequencies of minor homozygous genotype (RR) and allele (R) in all patients compared to controls (21.8% vs 10.2%; p = .006, OR = 2.54) and (44% vs 34.9%; p = .01; OR = 1.46), respectively. This correlation was confirmed only for males. This study also noted a significant increase of the mutated homozygous (RR) genotype and (R) allele frequencies of IFNGR2 in paranoid schizophrenics compared to controls (31.4% vs 10.2%; p = .001; OR = 3.34 and 47.2% vs 34.9%; p = .009; OR = 1.66, respectively). This increase remains significant after using binary logistic regression to eliminate confounding factors such as age and sex. Additionally, carriers of RR genotype have significant lower scores on the Scale of Assessment of Positive (SAPS) and negative (SANS) symptoms comparatively to the carrier of the QQ + QR genotypes, suggesting that the R recessive allele carriers could have milder symptoms. The IFNGR2Q64R polymorphism is correlated with male sex and paranoid schizophrenia. It is suggested that a chronic neuroinflammation may predispose to the paranoid schizophrenia development in men.

Significant Synergistic Effect of Peroxisome Proliferator–Activated Receptor γ C-2821T and Diabetes on the Risk of Ischemic Stroke

PubMed Central

Hsieh, Fang-I; Lo, Wei-Cheng; Lin, Huey-Juan; Hsieh, Yi-Chen; Lien, Li-Ming; Bai, Chyi-Huey; Tseng, Hung-Pin; Chiou, Hung-Yi

2009-01-01

OBJECTIVE To explore the relationship between the genetic polymorphisms of PPARγ (Pro12Ala, C1431T, and C-2821T) and the risk of ischemic stroke and to investigate whether these genetic polymorphisms of PPARγ would modify the risk of ischemic stroke among patients with hypertension or diabetes. RESEARCH DESIGN AND METHODS The case-control study was conducted with 537 ischemic stroke patients and 537 control subjects. A structured questionnaire was used to collect information on conventional cardiovascular risk factors and laboratory results. The genetic polymorphisms of PPARγ were determined by PCR–restriction fragment–length polymorphism. RESULTS A significant interaction was seen between the −2821C allele and diabetes but not between this allele and hypertension. A markedly elevated risk of ischemic stroke (odds ratio 9.7) was found in the subjects with diabetes and the −2821C allele compared with that in those without these two risk factors. CONCLUSIONS The −2821C allele of PPARγ was a strong predictor of ischemic stroke for diabetic patients. PMID:19651920

TGF{beta}1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruyck, Kim de; Van Eijkeren, Marc; Claes, Kathleen

2006-07-15

Purpose: To investigate the association between six transforming growth factor {beta}1 gene (TGF{beta}1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). Methods and Materials: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites inmore » TGF{beta}1. Results: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p = 0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. Conclusions: The present study shows that homozygous variant TGF{beta}1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.« less

Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance.

PubMed

Mammen, Cherry; Rupps, Rosemarie; Trnka, Peter; Boerkoel, Cornelius F

2012-02-01

We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Measurement of the {sup 12}C({alpha},{gamma}){sup 16}O reaction at TRIAC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makii, H.; Miyatake, H.; Wakabayashi, Y.

2012-11-12

We have measured the {gamma}-ray angular distribution of the {sup 12}C({alpha},{gamma}){sup 16}O reaction at TRIAC (Tokai Radioactive Ion Accelerator Complex) to accurately determine the E1 and E2 cross sections. In this experiment, we used high efficiency anti-Compton NaI(T1) spectrometers to detect a {gamma}-ray from the reaction with large S/N ratio, intense pulsed {alpha}-beams to discriminate true event from background events due to neutrons from {sup 13}C({alpha},n){sup 16}O reaction with a time-of-flight (TOF) method. We succeeded in removing a background events due to neutrons and clearly detected {gamma}-ray from the {sup 12}C({alpha}{gamma}){sup 16}O reaction with high statistics.

Monitoring blood flow responses during topical ALA-PDT

PubMed Central

Becker, Theresa L.; Paquette, Anne D.; Keymel, Kenneth R.; Henderson, Barbara W.; Sunar, Ulas

2011-01-01

Photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA) is currently used as a clinical treatment for nonmelanoma skin cancers. In order to optimize PDT treatment, vascular disruption early in treatment must be identified and prevented. We present blood flow responses to topical ALA-PDT in a preclinical model and basal cell carcinoma patients assessed by diffuse correlation spectroscopy (DCS). Our results show that ALA-PDT induced early blood flow changes and these changes were irradiance dependent. It is clear that there exists considerable variation in the blood flow responses in patients from lesion to lesion. Monitoring blood flow parameter may be useful for assessing ALA-PDT response and planning. PMID:21326642

Vitamin D Combined with Aminolevulinate (ALA)-Mediated Photodynamic Therapy (PDT) for Human Psoriasis: A Proof-of-Principle Study

PubMed Central

Maytin, Edward V.; Honari, Golara; Khachemoune, Amor; Taylor, Charles R.; Ortel, Bernhard; Pogue, Brian W.; Sznycer-Taub, Nathaniel; Hasan, Tayyaba

2012-01-01

We previously showed that select agents (methotrexate or Vitamin D), when administered as a preconditioning regimen, are capable of promoting cellular differentiation of epithelial cancer cells while simultaneously enhancing the efficacy of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). In solid tumors, pretreatment with Vitamin D simultaneously promotes cellular differentiation and leads to selective accumulation of target porphyrins (mainly protoporphyrin IX, PpIX) within diseased tissue. However, questions of whether or not the effects upon cellular differentiation are inexorably linked to PpIX accumulation, and whether these effects might occur in hyperproliferative noncancerous tissues, have remained unanswered. In this paper, we reasoned that psoriasis, a human skin disease in which abnormal cellular proliferation and differentiation plays a major role, could serve as a useful model to test the effects of pro-differentiating agents upon PpIX levels in a non-neoplastic setting. In particular, Vitamin D, a treatment for psoriasis that restores (increases) differentiation, might increase PpIX levels in psoriatic lesions and facilitate their responsiveness to ALA-PDT. This concept was tested in a pilot study of 7 patients with bilaterally-matched psoriatic plaques. A regimen in which calcipotriol 0.005% ointment was applied for 3 days prior to ALA-PDT with blue light, led to preferential increases in PpIX (~130%), and reductions in thickness, redness, scaling, and itching in the pretreated plaques. The results suggest that a larger clinical trial is warranted to confirm a role for combination treatments with Vitamin D and ALA-PDT for psoriasis. PMID:23264699

p16 gene silencing along with p53 single-nucleotide polymorphism and risk of esophageal cancer in Northeast India.

PubMed

Das, Mandakini; Sharma, Santanu Kumar; Sekhon, Gaganpreet Singh; Mahanta, Jagadish; Phukan, Rup Kumar; Jalan, Bimal Kumar

2017-05-01

The high incidence of esophageal cancer in Northeast India and the unique ethnic background and dietary habits provide a great opportunity to study the molecular genetics behind esophageal squamous cell carcinoma in this part of the region. We hypothesized that in addition to currently known environmental risk factors for esophageal cancer, genetic and epigenetic factors are also involved in esophageal carcinogenesis in Northeast India. Therefore, in this study, we explored the possible association between the two important G1 cell cycle regulatory genes p16 and p53 and environmental risk factors and risk of esophageal carcinogenesis. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age-, sex-, and ethnicity-matched controls were included in this study. Methylation-specific polymerase chain reaction was used to determine the p16 promoter methylation status. Single-nucleotide polymorphism at codon 72 of p53 gene was assessed by the polymerase chain reaction-restriction fragment length polymorphism method. Aberrant methylation of p16 gene was seen in 81% of esophageal cancer cases. Hypermethylation of p16 gene was not found in healthy controls. p53 Pro/Pro genotype was found to be a risk genotype in Northeast India compared with Arg/Pro and Arg/Arg. p53 variant/polymorphism was significantly associated with esophageal cancer risk in the study population under all three genetic models, namely, dominant model (Arg/Pro + Pro/Pro vs Arg/Arg odds ratio = 2.25, confidence interval = 1.19-4.26; p = 0.012), recessive model (Arg/Arg + Arg/Pro vs Pro/Pro odds ratio = 2.35, confidence interval = 1.24-4.44; p = 0.008), and homozygous model (Pro/Pro vs Arg/Arg odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). However, p53 variant/polymorphism was not statistically associated with esophageal cancer risk under the heterozygous model (Pro/Pro vs Arg/Pro). In the case-only analysis based on p16

RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy.

PubMed

Kaufman, Beth D; Auerbach, Scott; Reddy, Sushma; Manlhiot, Cedric; Deng, Liyong; Prakash, Ashwin; Printz, Beth F; Gruber, Dorota; Papavassiliou, Dimitrios P; Hsu, Daphne T; Sehnert, Amy J; Chung, Wendy K; Mital, Seema

2007-12-01

Hypertrophic Cardiomyopathy (HCM) is a disease with variable rate of progression. Young age is an independent risk factor for poor outcome in HCM. The influence of renin-angiotensin-aldosterone (RAAS) genotype on the progression of HCM in children is unknown. Children with HCM (n = 65) were enrolled prospectively across two centers (2001-2005). All subjects were genotyped for five RAAS gene polymorphisms previously associated with LV hypertrophy (pro-LVH): AGT M235T, ACE DD, CMA-1903 A/G, AGTR1 1666 A/C and CYP11B2-344 C/T. Linear regression models, based on maximum likelihood estimates, were created to assess the independent effect of RAAS genotype on LV hypertrophy (LVH). Forty-six subjects were homozygous for <2 and 19 were homozygous for > or =2 pro-LVH RAAS polymorphisms. Mean age at presentation was 9.6 +/- 6 years. Forty children had follow-up echocardiograms after a median of 1.5 years. Indexed LV mass (LVMI) and LV mass z-scores were higher at presentation and follow-up in subjects with > or =2 pro-LVH genotypes compared to those with <2 (P < 0.05). Subjects with > or =2 pro-LVH genotypes also demonstrated a greater increase in septal thickness (IVST) and in LV outflow tract (LVOT) obstruction on follow-up (P < 0.05). On multivariate analysis, a higher number of pro-LVH genotypes was associated with a larger effect size (P < 0.05). Pro-LVH RAAS gene polymorphisms are associated with progressive septal hypertrophy and LVOT obstruction in children with HCM. Identification of RAAS modifier genes may help to risk-stratify patients with HCM.

Controlling the crystal polymorph by exploiting the time dependence of nucleation rates.

PubMed

Little, Laurie J; King, Alice A K; Sear, Richard P; Keddie, Joseph L

2017-10-14

Most substances can crystallise into two or more different crystal lattices called polymorphs. Despite this, there are no systems in which we can quantitatively predict the probability of one competing polymorph forming instead of the other. We address this problem using large scale (hundreds of events) studies of the competing nucleation of the alpha and gamma polymorphs of glycine. In situ Raman spectroscopy is used to identify the polymorph of each crystal. We find that the nucleation kinetics of the two polymorphs is very different. Nucleation of the alpha polymorph starts off slowly but accelerates, while nucleation of the gamma polymorph starts off fast but then slows. We exploit this difference to increase the purity with which we obtain the gamma polymorph by a factor of ten. The statistics of the nucleation of crystals is analogous to that of human mortality, and using a result from medical statistics, we show that conventional nucleation data can say nothing about what, if any, are the correlations between competing nucleation processes. Thus we can show that with data of our form it is impossible to disentangle the competing nucleation processes. We also find that the growth rate and the shape of a crystal depend on it when nucleated. This is new evidence that nucleation and growth are linked.

Interleukin-12 (-1188) A/C and interferon-γ (+874) A/T gene polymorphisms in subacute sclerosing panencephalitis patients.

PubMed

Dundar, Nihal Olgac; Gencpinar, Pinar; Sallakci, Nilgun; Duman, Ozgur; Haspolat, Senay; Anlar, Banu; Yegin, Olcay

2016-10-01

The two polymorphisms [IL-12 (-1188) A/C and the IFN-γ (+874) A/T)] are known to have functional consequences and henceforth were analyzed in subacute sclerosing panencephalitis (SSPE) patients to reveal a possible relation with these polymorphisms and this debilitating disease. For the IL-12 (-1188) A/C polymorphism, 78 patients and 90 healthy individuals were analyzed. An increase in the AA genotype was determined (p = 0.02, OR = 2.06). There was also a statistically significant difference between the control group and the patients with respect to the allele frequencies (p = 0.04, OR = 1.65). For the IFN-γ (+874) A/T polymorphism, 69 SSPE patients and 115 controls were studied and there was not a significant difference between the two groups. Our findings suggested that not the IFN-γ (+874) A/T but the IL-12 (-1188) A/C polymorphism is correlated with SSPE and having an AA genotype or A allele decreases the risk of developing SSPE by 2.06- and 1.65-fold, respectively.

Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility: a case-control analysis.

PubMed

Huo, Xiang; Hu, Zhibin; Zhai, Xiangjun; Wang, Yan; Wang, Shui; Wang, Xuechen; Qin, Jianwei; Chen, Wenseng; Jin, Guangfu; Liu, Jiyong; Gao, Jun; Wei, Qingyi; Wang, Xinru; Shen, Hongbing

2007-05-01

The BRCA1 Associated RING Domain (BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common (minor allele frequency (MAF)>0.10) non-synonymous polymorphisms (Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes (24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P(int )= 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR=1.81, 95% CI=1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk (adjusted OR=0.74, 95% CI=0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor (PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.

Association of the Genetic Polymorphisms in Transcription Factor 7-Like 2 and Peroxisome Proliferator-Activated Receptors-γ2 with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status in Emirati Population

PubMed Central

Al-Safar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Afandi, Bachar; Rais, Naushad

2015-01-01

Background. Transcription factor 7-like 2 gene (TCF7L2) and peroxisome proliferator-activated receptors-γ2 (PPAR-γ2) have a profound effect on the incidence of type 2 diabetes mellitus (T2DM) and had previously been found to be associated with T2DM risk in various ppopulations. However, studies in the Arab population are inconsistent. We conducted a case control study to confirm the association of variants rs10885409 of TCF7L2 and Pro12Ala (rs1801282) of PPAR-γ2 with risk of T2DM and related complications in Emirati population of Arab origin. We also investigated the interaction of these associations with obesity status. Methods. DNA was extracted from the saliva samples of 272 T2DM patients and 216 nondiabetic Emiratis. Genotyping for rs10885409 (TCF7L2) and rs1801282 (PPAR-γ2 P12A) variants was accomplished with a TaqMan assay. The subgroups were constituted according to obesity status. Results. In the nonobese group, the rs10885409 C allele in the recessive model was significantly associated with the incidence of T2DM (OR 1.975 [95% CI 1.127–3.461], P = 0.017), but this association was not observed in the obese group or when BMI was not considered. PPAR-γ2 risk allele Pro12 frequency (0.96) was similar in the groups tested and more than 90% population was homozygous for this allele. Conclusions. Our case-control study is the first of its kind in Emiratis which establishes TCF7L2 rs10885409 C allele as a T2DM risk factor in Emiratis and this association is modulated by obesity status. We also confirmed that Pro12Ala mutation in PPAR-γ2 is not associated with T2DM risk in this population. PMID:26273662

Association of the Genetic Polymorphisms in Transcription Factor 7-Like 2 and Peroxisome Proliferator-Activated Receptors- γ 2 with Type 2 Diabetes Mellitus and is Interaction with Obesity Status in Emirati Population.

PubMed

Al-Safar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Afandi, Bachar; Rais, Naushad

2015-01-01

Transcription factor 7-like 2 gene (TCF7L2) and peroxisome proliferator-activated receptors-γ2 (PPAR-γ2) have a profound effect on the incidence of type 2 diabetes mellitus (T2DM) and had previously been found to be associated with T2DM risk in various ppopulations. However, studies in the Arab population are inconsistent. We conducted a case control study to confirm the association of variants rs10885409 of TCF7L2 and Pro12Ala (rs1801282) of PPAR-γ2 with risk of T2DM and related complications in Emirati population of Arab origin. We also investigated the interaction of these associations with obesity status. DNA was extracted from the saliva samples of 272 T2DM patients and 216 nondiabetic Emiratis. Genotyping for rs10885409 (TCF7L2) and rs1801282 (PPAR-γ2 P12A) variants was accomplished with a TaqMan assay. The subgroups were constituted according to obesity status. In the nonobese group, the rs10885409 C allele in the recessive model was significantly associated with the incidence of T2DM (OR 1.975 [95% CI 1.127-3.461], P = 0.017), but this association was not observed in the obese group or when BMI was not considered. PPAR-γ2 risk allele Pro12 frequency (0.96) was similar in the groups tested and more than 90% population was homozygous for this allele. Our case-control study is the first of its kind in Emiratis which establishes TCF7L2 rs10885409 C allele as a T2DM risk factor in Emiratis and this association is modulated by obesity status. We also confirmed that Pro12Ala mutation in PPAR-γ2 is not associated with T2DM risk in this population.

Association between alcohol dehydrogenase 1C gene *1/*2 polymorphism and pancreatitis risk: a meta-analysis.

PubMed

Fang, F; Pan, J; Su, G H; Xu, L X; Li, G; Li, Z H; Zhao, H; Wang, J

2015-11-30

Numerous studies have focused on the relationship be-tween alcohol dehydrogenase 1C gene (ADH1C) *1/*2 polymorphism (Ile350Val, rs698, also known as ADH1C *1/*2) and pancreatitis risk, but the results have been inconsistent. Thus, we conducted a meta-anal-ysis to more precisely estimate this association. Relevant publications were searched in several widely used databases and 9 eligible studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Significant associations between ADH1C *1/*2 poly-morphism and pancreatitis risk were observed in both overall meta-analysis for 12 vs 22 (OR = 1.53, 95%CI = 1.12-2.10) and 11 + 12 vs 22 (OR = 1.44, 95%CI = 1.07-1.95), and the chronic alcoholic pancre-atitis subgroup for 12 vs 22 (OR = 1.64, 95%CI = 1.17-2.29) and 11 + 12 vs 22 (OR = 1.53, 95%CI = 1.11-2.11). Significant pancreatitis risk variation was also detected in Caucasians for 11 + 12 vs 22 (OR = 1.45, 95%CI = 1.07-1.98). In conclusion, the ADH1C *1/*2 polymorphism is likely associated with pancreatitis risk, particularly chronic alcoholic pancreatitis risk, with the *1 allele functioning as a risk factor.

Development and characterization of 12 polymorphic microsatellite loci in the sea sandwort, Honckenya peploides

USGS Publications Warehouse

Gravley, Megan C.; Sage, George K.; Talbot, Sandra L.; Carlson, Matthew L.

2018-01-01

Codominant marker systems are better suited to analyze population structure and assess the source of an individual in admixture analyses. Currently, there is no codominant marker system using microsatellites developed for the sea sandwort, Honckenya peploides (L.) Ehrh., an early colonizer in island systems. We developed and characterized novel microsatellite loci from H. peploides, using reads collected from whole genome shotgun sequencing on a 454 platform. The combined output from two shotgun runs yielded a total of 62,669 reads, from which 58 loci were screened. We identified 12 polymorphic loci that amplified reliably and exhibited disomic inheritance. Microsatellite data were collected and characterized for the 12 polymorphic loci in two Alaskan populations of H. peploides: Fossil Beach, Kodiak Island (n = 32) and Egg Bay, Atka Island (n = 29). The Atka population exhibited a slightly higher average number of alleles (3.9) and observed heterozygosity (0.483) than the Kodiak population (3.3 and 0.347, respectively). The overall probability of identity values for both populations was PID = 2.892e−6 and PIDsib = 3.361e−3. We also screened the 12 polymorphic loci in Wilhelmsia physodes (Fisch. ex Ser.) McNeill, the most closely related species to H. peploides, and only one locus was polymorphic. These microsatellite markers will allow future investigations into population genetic and colonization patterns of the beach dune ruderal H. peploides on new and recently disturbed islands.

P2Y12 Polymorphisms and the Risk of Adverse Clinical Events in Patients Treated with Clopidogrel: A Meta-Analysis.

PubMed

Zhao, Kun; Yang, Ming; Lu, Yanxia; Sun, Shusen; Li, Wei; Li, Xingang; Zhao, Zhigang

2018-05-23

Some studies have reported an association between P2Y12 gene polymorphisms and clopidogrel adverse outcomes with inconsistent results. We aimed to explore the relationship between P2Y12 polymorphisms and the risk of adverse clinical events in patients treated with clopidogrel through a meta-analysis. A systematic search of PubMed, Web of Science and the Cochrane Library was conducted. Retrieved articles were comprehensively reviewed and eligible studies were included, and the relevant data was extracted for this meta-analysis. All statistical tests were performed by the Review Manager 5.3 software. A total of 14 studies involving 8,698 patients were included. In the Han Chinese population, ischemic events were associated with P2Y12 T744C polymorphism in the CC vs TT+CT genetic model (OR=3.32, 95%CI=1.62-6.82, P =0.001), and the events were associated with P2Y12 C34T polymorphism in the TT+TC vs CC genetic model (OR=1.70, 95%CI=1.22-2.36, P =0.002). However, ischemic events were not related to P2Y12 G52T polymorphism (TT+TG vs GG: OR=1.13, 95%CI=0.76-1.68, P =0.56; TT vs GG+TG: OR=2.02, 95%CI=0.65-6.28, P =0.22). The associations between the P2Y12 polymorphism and ischemic events were not significant in T744C, G52T and C34T genotype for another subgroup of the Caucasian population ( P >0.05). Only two studies referring to bleeding events were included in this analysis of C34T polymorphism, and no significant association was found (TT+TC vs CC: OR=1.07, 95%CI=0.37-3.15, P =0.90). In the Caucasian population, P2Y12 gene polymorphisms are not associated with clinical events. However, in the Chinese Han population, P2Y12 T744C and C34T polymorphisms are significantly associated with adverse clinical events. © Georg Thieme Verlag KG Stuttgart · New York.

TGFbeta1 (Leu10Pro), p53 (Arg72Pro) can predict for increased risk for breast cancer in south Indian women and TGFbeta1 Pro (Leu10Pro) allele predicts response to neo-adjuvant chemo-radiotherapy.

PubMed

Rajkumar, Thangarajan; Samson, Mani; Rama, Ranganathan; Sridevi, Veluswami; Mahji, Urmila; Swaminathan, Rajaraman; Nancy, Nirmala K

2008-11-01

The breast cancer incidence has been increasing in the south Indian women. A case (n=250)-control (n=500) study was undertaken to investigate the role of Single Nucleotide Polymorphisms (SNP's) in GSTM1 (Present/Null); GSTP1 (Ile105Val), p53 (Arg72Pro), TGFbeta1 (Leu10Pro), c-erbB2 (Ile655Val), and GSTT1 (Null/Present) in breast cancer. In addition, the value of the SNP's in predicting primary tumor's pathologic response following neo-adjuvant chemo-radiotherapy was assessed. Genotyping was done using PCR (GSTM1, GSTT1), Taqman Allelic discrimination assay (GSTP1, c-erbB2) and PCR-CTPP (p53 and TGFbeta1). None of the gene SNP's studied were associated with a statistically significant increased risk for the breast cancer. However, combined analysis of the SNP's showed that p53 (Arg/Arg and Arg/Pro) with TGFbeta1 (Pro/Pro and Leu/Pro) were associated with greater than 2 fold increased risk for breast cancer in Univariate (P=0.01) and Multivariate (P=0.003) analysis. There was no statistically significant association for the GST family members with the breast cancer risk. TGFbeta1 (Pro/Pro) allele was found to predict complete pathologic response in the primary tumour following neo-adjuvant chemo-radiotherapy (OR=6.53 and 10.53 in Univariate and Multivariate analysis respectively) (P=0.004) and was independent of stage. This study suggests that SNP's can help predict breast cancer risk in south Indian women and that TGFbeta1 (Pro/Pro) allele is associated with a better pCR in the primary tumour.

Matrix metalloproteinase-1 and matrix metalloproteinase-12 gene polymorphisms and the risk of ischemic stroke in a Tunisian population.

PubMed

Chehaibi, Khouloud; Hrira, Mohamed Yahia; Nouira, Samir; Maatouk, Faouzi; Ben Hamda, Khaldoun; Slimane, Mohamed Naceur

2014-07-15

Matrix metalloproteinases (MMPs) play an important role in early atherosclerosis, extracellular matrix remodeling, plaque rupture and myocardial infarction. MMP gene polymorphisms contribute to the risk of developing cardiovascular diseases. In this study, we investigated, for the first time, the association between MMP-1-16071G/2G, MMP-12 -82A/G and MMP-12 1082A/G genotypes and haplotypes and the risk of ischemic stroke (IS) among patients with type 2 diabetes mellitus (T2DM). To examine whether these genetic polymorphisms are associated with susceptibility to IS, 196 patients with IS and 192 controls were examined by PCR-based RFLP. When the analyses were adjusted for multiple risk factors, no interaction between T2DM and MMP-1-1607 1G/2G polymorphism on the risk of ischemic stroke was found (p=0.074). However, MMP-12 polymorphisms genotypes were associated with the higher risk of IS in diabetic patients compared with total patients. The -82G-1082G haplotype of MMP-12 polymorphisms was associated with higher risk of ischemic stroke in diabetic patients [AOR=2.33; 95% CI (1.25-3.62), P=0.032]. These findings showed that there was an important joint effect of the MMP-12 polymorphisms and T2DM on the risk of IS and therefore it can be considered as a potential marker of cerebrovascular disorders in diabetic patients. Copyright © 2014 Elsevier B.V. All rights reserved.

No evidence of association between NOD2/CARD15 gene polymorphism and atherosclerotic events after renal transplantation

PubMed Central

Courivaud, Cécile; Ferrand, Christophe; Deschamps, Marina; Tiberghien, Pierre; Chalopin, Jean-Marc; Duperrier, Anne; Saas, Philippe; Ducloux, Didier

2006-01-01

Stable renal transplant recipients (RTR) display high rates of atherosclerotic events (AE). Innate immunity and especially vascular inflammation play a role in the pathogenesis of atherosclerosis. It is illustrated both by an increased occurrence of post-renal transplant cardiovascular events in patients with elevated levels of C-reactive protein and by a correlation between post-transplant AE and Toll-like receptor-4 Asp299Gly polymorphism. Here, we analyze the influence NOD2/CARD15 gene polymorphism since NOD2 can modulate macrophage pro-inflammatory activity and macrophage is present in early atherosclerotic lesions. The incidence of single nucleotide polymorphism (SNP) in the three major polymorphic region of NOD2 gene (SNP8, SNP12 and SNP13) was assessed in 182 RTR and the correlation between such polymorphism and the development of AE was analyzed. No correlation was observed between NOD2 gene polymorphism and the occurrence of AE after renal transplantation. NOD2 gene polymorphism thus does not appear to influence cardiovascular complications in RTR. PMID:16641610

The association between leptin receptor gene polymorphisms and type 2 diabetes mellitus: A systematic review and meta-analysis.

PubMed

Su, Shu; Zhang, Chunhua; Zhang, Fan; Li, Hui; Yang, Xuewei; Tang, Xiaojun

2016-11-01

Several case-control studies have demonstrated a relationship between leptin receptor (LEPR) gene polymorphism and type 2 diabetes mellitus (T2DM) risk, though the results have not always been consistent among diverse populations. This meta-analysis was designed to assess a more accurate association between LEPR polymorphism and T2DM. Eight electronic databases were consulted and researchers searched for Chinese and English peer-reviewed articles, published between 2000 and 2015, that referred to the association between LEPR polymorphism and T2DM. Pooled odds ratios (OR) with a 95% confidence interval (CI) were calculated in allele contrast, recessive, dominant and additive genetic models to assess this association. Four repeatedly reviewed polymorphisms, taken from 22 studies on Arg109Lys, Asn656Lys, Gln223Arg and Pro1019Pro with 31,260 controls and 25,560 cases, were included in the meta-analysis model. The meta-result demonstrated that only the Pro1019Pro polymorphism was substantially associated with T2DM risk-G vs. A: OR with 95% CI 0.58 (0.43-0.79), Z=3.51, p=0.0005; GG vs. AG+AA: 0.57 (0.42-0.77), Z=3.66, p=0.0002; GG+AG vs. AA: 0.55 (0.37-0.81), Z=3.01, p=0.003; GG vs. AA: 0.51 (0.37-0.69), Z=4.24, p<0.001. Our meta-analysis suggested a significant association between the LEPR Pro1019Pro polymorphism and T2DM risk. Thus, targeted healthcare should be strengthened with regard to this gene carrier in order to prevent T2DM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Uncoupling protein 2 gene polymorphisms are associated with obesity

PubMed Central

2012-01-01

Background Uncoupling protein 2 (UCP2) gene polymorphisms have been reported as genetic risk factors for obesity and type 2 diabetes mellitus (T2DM). We examined the association of commonly observed UCP2 G(−866)A (rs659366) and Ala55Val (C > T) (rs660339) single nucleotide polymorphisms (SNPs) with obesity, high fasting plasma glucose, and serum lipids in a Balinese population. Methods A total of 603 participants (278 urban and 325 rural subjects) were recruited from Bali Island, Indonesia. Fasting plasma glucose (FPG), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were measured. Obesity was determined based on WHO classifications for adult Asians. Participants were genotyped for G(−866)A and Ala55Val polymorphisms of the UCP2 gene. Results Obesity prevalence was higher in urban subjects (51%) as compared to rural subjects (23%). The genotype, minor allele (MAF), and heterozygosity frequencies were similar between urban and rural subjects for both SNPs. All genotype frequencies were in Hardy-Weinberg equilibrium. A combined analysis of genotypes and environment revealed that the urban subjects carrying the A/A genotype of the G(−866)A SNP have higher BMI than the rural subjects with the same genotype. Since the two SNPs showed strong linkage disequilibrium (D’ = 0.946, r2 = 0.657), a haplotype analysis was performed. We found that the AT haplotype was associated with high BMI only when the urban environment was taken into account. Conclusions We have demonstrated the importance of environmental settings in studying the influence of the common UCP2 gene polymorphisms in the development of obesity in a Balinese population. PMID:22533685

Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients.

PubMed

Genazzani, A D; Shefer, K; Della Casa, D; Prati, A; Napolitano, A; Manzo, A; Despini, G; Simoncini, T

2018-05-01

To evaluate the efficacy of alpha-lipoic acid (ALA) administration on hormonal and metabolic parameters of obese PCOS patients. A group of 32 obese PCOS patients were selected after informed consent. 20 patients referred to have first grade relatives with diabetes type I or II. Hormonal and metabolic parameters as well as OGTT were evaluated before and after 12 weeks of ALA integrative administration (400 mg per os every day). ALA administration significantly decreased insulin, glucose, BMI and HOMA index. Hyperinsulinemia and insulin response to OGTT decreased both as maximal response (Δmax) and as AUC. PCOS with diabetes relatives showed the decrease also of triglyceride and GOT. Interestingly in all PCOS no changes occurred on all hormonal parameters involved in reproduction such as LH, FSH, and androstenedione. ALA integrative administration at a low dosage as 400 mg daily improved the metabolic impairment of all PCOS patients especially in those PCOS with familiar diabetes who have a higher grade of risk of NAFLD and predisposition to diabetes.

Association of ACE, FABP2 and GST genes polymorphism with essential hypertension risk among a North Indian population.

PubMed

Abbas, Shania; Raza, Syed Tasleem; Chandra, Anu; Rizvi, Saliha; Ahmed, Faisal; Eba, Ale; Mahdi, Farzana

2015-01-01

Hypertension has a multi-factorial background based on genetic and environmental interactive factors. ACE, FABP2 and GST genes have been suggested to be involved in the development of hypertension. However, the results have been inconsistent. The present study was carried out to investigate the association of ACE (rs4646994), FABP2 (rs1799883) and GST (GSTM1 null or positive genotype and GSTT1 null or positive genotype) genes polymorphism with essential HTN cases and controls. This study includes 138 essential hypertension (HTN) patients and 116 age-, sex- and ethnicity-matched control subjects. GST (GSTM1 null or positive genotype and GSTT1 null or positive genotype) genes polymorphisms were evaluated by multiplex PCR, ACE (rs4646994) gene polymorphisms by PCR and FABP2 (rs1799883) gene polymorphisms by PCR-RFLP method. Significant differences were obtained in the frequencies of ACE DD, II genotype (p = 0.006, 0.003), GSTT1 null, GSTM1 positive genotype (p = 0.048, 0.010) and FABP2 Ala54/Ala54 genotype (p = 0.049) between essential HTN cases and controls. It is concluded that ACE (rs 4646994), FABP2 (rs1799883) and GST (GSTM1 null or positive genotype and GSTT1 null or positive genotype) genes polymorphism are associated with HTN. Further investigation with a larger sample size may be required to validate this study.

THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION.

PubMed

Khan, Kamron N; Islam, Farrah; Moore, Anthony T; Michaelides, Michel

2018-03-01

To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P < 0.05). Despite their older age, the final recorded acuity seemed to be better in the p.Ala243Val group (median = 0.55, interquartile range = 0.6475; median = 0.33, interquartile range = 0.358), although this did not reach statistical significance (Mann-Whitney U test; P > 0.05). The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes.

Computational and experimental investigations into the conformations of cyclic tetra-α/β-peptides.

PubMed

Oakley, Mark T; Oheix, Emmanuel; Peacock, Anna F A; Johnston, Roy L

2013-07-11

We present a combined computational and experimental study of the energy landscapes of cyclic tetra-α/β-peptides. We have performed discrete path sampling calculations on a series of cyclic tetra-α/β-peptides to obtain the relative free energies and barriers to interconversion of their conformers. The most stable conformers of cyclo-[(β-Ala-Gly)2] contain all-trans peptide groups. The relative energies of the cis isomers and the cis-trans barriers are lower than in acyclic peptides but not as low as in the highly strained cyclic α-peptides. For cyclic tetra-α/β-peptides containing a single proline residue, of the type cyclo-[β-Ala-Xaa-β-Ala-Pro], the energy landscapes show that the most stable isomers containing cis and trans β-Ala-Pro have similar free energies and are separated by barriers of approximately 15 kcal mol(-1). We show that the underlying energy landscapes of cyclo-[β-Ala-Lys-β-Ala-Pro] and cyclo-[β-Ala-Ala-β-Ala-Pro] are similar, allowing the substitution of the flexible side chain of Lys with Ala to reduce the computational demand of our calculations. However, the steric bulk of the Val side chain in cyclo-[β-Ala-Val-β-Ala-Pro] affects the conformations of the ring, leading to significant differences between its energy landscape and that of cyclo-[β-Ala-Ala-β-Ala-Pro]. We have synthesized the cyclic peptide cyclo-[β-Ala-Lys-β-Ala-Pro], and NMR spectroscopy shows the presence of conformers that interconvert slowly on the NMR time scale at temperatures up to 80 °C. Calculated circular dichroism (CD) spectra for the proposed major isomer of cyclo-[β-Ala-Ala-β-Ala-Pro] are in good agreement with the experimental spectra of cyclo-[β-Ala-Lys-β-Ala-Pro], suggesting that the Ala cyclic tetrapeptide is a viable model for the Lys analogue.

Polymorphism of the p53 tumor suppressor gene is associated with susceptibility to uterine leiomyoma.

PubMed

Denschlag, Dominik; Bettendorf, Herta; Watermann, Dirk; Keck, Christoph; Tempfer, Clemens; Pietrowski, Detlef

2005-07-01

To evaluate the association between the presence of uterine leiomyoma and two single nuclear polymorphisms of the p53 tumor suppressor and the angiopoietin-2 (ANGPT2) genes. Prospective case control study. Academic research institution. One hundred thirty-two women with clinically and surgically diagnosed uterine leiomyomas and 280 controls. Peripheral venous puncture. Genotyping was performed by polymerase chain reaction-based amplification of the Arg and Pro variants at codon 72 of the p53 gene and by restriction fragment length polymorphism analysis of the G/G and G/A alleles in exon 4 of the ANGPT2 gene. Comparing women with uterine leiomyomas and controls, no statistically significant difference with respect to allele frequency and genotype distribution were ascertained for the ANGPT2 polymorphism (P=.2 and P=.5, respectively). However, for the p53 tumor suppressor gene polymorphism, statistically significant differences in terms of a higher Pro allele frequency and a higher prevalence of the Pro/Pro genotype among women with uterine leiomyoma (32.0% vs. 16.0%, respectively, and 21.3% vs. 4.7%, respectively) were ascertained (P=.001, OR 1.74; 95% CI 1.24-2.45, P=.001; OR 3.84, 95% CI 1.81-8.14; respectively). Carriage of the p53 polymorphism at codon 72 predicts the susceptibility to leiomyoma in a Caucasian population and may contribute to the pathogenesis of uterine leiomyoma.

Microstructure and Mechanical Properties in Gamma(face-centered cubic) + Gamma Prime(L12) Precipitation-Strengthened Cobalt-based Superalloys

NASA Astrophysics Data System (ADS)

Bocchini, Peter J.

High-temperature structural alloys for aerospace and energy applications have long been dominated by Ni-based superalloys, whose high-temperature strength and creep resistance can be attributed to a two-phase microstructure consisting of a large volume fraction of ordered gamma'(L12)-precipitates embedded in a disordered gamma(f.c.c.)-matrix. These alloys exhibit excellent mechanical behavior and thermal stability, but after decades of incremental improvement, are nearing the theoretical limit of their operating temperatures. In 2006, an analogous gamma(f.c.c.) + gamma'(L12) microstructure was identified in the Co-Al-W ternary system with liquidus and solidus temperatures 50-150 °C higher than conventional Ni-based superalloys. The work herein focuses on assessing the effects of alloying additions on microstructure and mechanical behavior in an effort to lay the foundations for understanding this emerging alloy system. A variety of Co-based superalloys are investigated in order to study fundamental materials properties and to address key engineering challenges. Coarsening rate constants and temporal exponents are measured for gamma'(L1 2)-precipitates in a ternary Co-Al-W alloy aged at 650 °C and 750 °C. A series of Co-Al-W-B-Zr alloys are cast to study the influence of segregation of B and Zr to grain boundaries (GBs) on mechanical properties. Co-Ni-Al-W-Ti alloys with various amounts of Al, W, and Ti are cast in order to fabricate Co-based superalloys with decreased density and increased gamma'(L1 2)-solvus temperature. 2-D dislocation dynamics modeling is employed to predict how gamma'(L12)-precipitate size and volume fraction affect the mechanical properties of Ni- and Co-based superalloys. Compositional information such as phase concentrations, partitioning behavior, and GB segregation are measured with local electrode atom probe (LEAP) tomography in alloys with fine microstructures and with scanning electron microscope (SEM) electron dispersive x

Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients.

PubMed

Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca; Sani, Cristina; Biti, Giampaolo; Livi, Lorenzo; Barletta, Emanuela; Costantini, Adele Seniori; Gorini, Giuseppe

2011-09-01

Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52). To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic

Lack of correlation between p53 codon 72 polymorphism and anal cancer risk

PubMed Central

Contu, Simone S; Agnes, Grasiela; Damin, Andrea P; Contu, Paulo C; Rosito, Mário A; Alexandre, Claudio O; Damin, Daniel C

2009-01-01

AIM: To investigate the potential role of p53 codon 72 polymorphism as a risk factor for development of anal cancer. METHODS: Thirty-two patients with invasive anal carcinoma and 103 healthy blood donors were included in the study. p53 codon 72 polymorphism was analyzed in blood samples through polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. RESULTS: The relative frequency of each allele was 0.60 for Arg and 0.40 for Pro in patients with anal cancer, and 0.61 for Arg and 0.39 for Pro in normal controls. No significant differences in distribution of the codon 72 genotypes between patients and controls were found. CONCLUSION: These results do not support a role for the p53 codon 72 polymorphism in anal carcinogenesis. PMID:19777616

Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.

PubMed

Berkson, Burton M; Rubin, Daniel M; Berkson, Arthur J

2009-12-01

The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms

PubMed Central

Paul, Cristiana; Brady, David M.

2017-01-01

Context Three natural forms of vitamin B12 are commercially available: methylcobalamin (MeCbl), adenosylcobalamin (AdCbl), and hydroxycobalamin (OHCbl), all of which have been shown in clinical studies to improve vitamin B12 status. They are bioidentical to the B12 forms occurring in human physiology and animal foods. In contrast, cyanocobalamin (CNCbl), a synthetic B12 compound used for food fortification and in some supplements, occurs only in trace amounts in human tissues as a result of cyanide intake from smoking or other sources. Objective This study had 3 objectives: (1) To summarize and compare assimilation pathways for 4 B12 forms; (2) to determine whether supplementation with a particular B12 form (or combination of forms) presents any advantages for the general population or for individuals with single nucleotide polymorphisms (SNPs) in B12-related pathways; and (3) to address misconceptions regarding B12 forms, methylation pathways, and various SNPs reported in commercially available tests. Design PubMed was systematically searched for articles published up to June 2016 using specific key words. Human, animal, and in vitro studies that were published in English, French, and German were included. Other studies considered were found by selecting in PubMed the suggested “related studies” and also some referenced studies. Setting The study occurred in Los Angeles, CA, USA. Results The studies reviewed provide evidence that all supplemental or food-derived B12 forms are reduced to a core cobalamin molecule, which converts to the intracellular active forms: MeCbl and AdCbl, in a ratio not influenced by the form of B12 ingested. The methyl and adenosyl components of supplemental MeCbl and AdCbl are cleaved inside cells and are not used in the synthesis of intracellular MeCbl and AdCbl, respectively. However, the overall bioavailability of each form of supplemental B12 may be influenced by many factors such as gastrointestinal pathologies, age, and genetics

Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.

PubMed

Paul, Cristiana; Brady, David M

2017-02-01

Three natural forms of vitamin B 12 are commercially available: methylcobalamin (MeCbl), adenosylcobalamin (AdCbl), and hydroxycobalamin (OHCbl), all of which have been shown in clinical studies to improve vitamin B 12 status. They are bioidentical to the B 12 forms occurring in human physiology and animal foods. In contrast, cyanocobalamin (CNCbl), a synthetic B 12 compound used for food fortification and in some supplements, occurs only in trace amounts in human tissues as a result of cyanide intake from smoking or other sources. This study had 3 objectives: (1) To summarize and compare assimilation pathways for 4 B 12 forms; (2) to determine whether supplementation with a particular B 12 form (or combination of forms) presents any advantages for the general population or for individuals with single nucleotide polymorphisms (SNPs) in B 12 -related pathways; and (3) to address misconceptions regarding B 12 forms, methylation pathways, and various SNPs reported in commercially available tests. PubMed was systematically searched for articles published up to June 2016 using specific key words. Human, animal, and in vitro studies that were published in English, French, and German were included. Other studies considered were found by selecting in PubMed the suggested "related studies" and also some referenced studies. The study occurred in Los Angeles, CA, USA. The studies reviewed provide evidence that all supplemental or food-derived B 12 forms are reduced to a core cobalamin molecule, which converts to the intracellular active forms: MeCbl and AdCbl, in a ratio not influenced by the form of B 12 ingested. The methyl and adenosyl components of supplemental MeCbl and AdCbl are cleaved inside cells and are not used in the synthesis of intracellular MeCbl and AdCbl, respectively. However, the overall bioavailability of each form of supplemental B 12 may be influenced by many factors such as gastrointestinal pathologies, age, and genetics. Polymorphisms on B 12 -related

Subunit association of gamma-glutamyltranspeptidase of Escherichia coli K-12.

PubMed

Hashimoto, W; Suzuki, H; Nohara, S; Tachi, H; Yamamoto, K; Kumagai, H

1995-12-01

gamma-Glutamyltranspeptidase [EC 2.3.2.2] of Escherichia coli K-12 consists of one large subunit and one small subunit, which can be separated from each other by high-performance liquid chromatography. Using ion spray mass spectrometry, the masses of the large and the small subunit were determined to be 39,207 and 20,015, respectively. The large subunit exhibited no gamma-glutamyltranspeptidase activity and the small subunit had little enzymatic activity, but a mixture of the two subunits showed partial recovery of the enzymatic activity. The results of native-polyacrylamide gel electrophoresis suggested that they could partially recombine, and that the recombined dimer exhibited enzymatic activity. The gene of gamma-glutamyltranspeptidase encoded a signal peptide, and the large and small subunits in a single open reading frame in that order. Two kinds of plasmid were constructed encoding the signal peptide and either the large or the small subunit. A gamma-glutamyltranspeptidase-less mutant of E. coli K-12 was transformed with each plasmid or with both of them. The strain harboring the plasmid encoding each subunit produced a small amount of the corresponding subunit protein in the periplasmic space but exhibited no enzymatic activity. The strain transformed with both plasmids together exhibited the enzymatic activity, but its specific activity was approximately 3% of that of a strain harboring a plasmid encoding the intact structural gene. These results indicate that a portion of the separated large and small subunits can be reconstituted in vitro and exhibit the enzymatic activity, and that the expressed large and small subunits independently are able to associate in vivo and be folded into an active structure, though the specific activity of the associated subunits was much lower than that of native enzyme. This suggests that the synthesis of gamma-glutamyltranspeptidase in a single precursor polypeptide and subsequent processing are more effective to construct

[Effect of promoter polymorphism of organic cation transporter OCTN1/2 on the susceptibility to Crohns disease: a Meta-analysis].

PubMed

Ma, Mu-yuan; Ma, Zhi-bin; Xu, Hong-yu; Zhao, Jing-bo; Li, Ying; Gao, Meng

2013-03-01

To investigate the associations between polymorphisms of organic cation transporter OCTN1/2 (organic cation transporter 1/2) and the susceptibility of Crohn's disease (CD) through a meta-analysis. Databases of PubMed, EMBASE, MedLine, and CNKI (Chinese), Wanfang (Chinese) were searched for published case control studies on the association between polymorphisms of OCTN1/2 gene and the susceptibility of CD which were published before September 2012. The meta-analysis was applied with Review Manager 4.2 software and Stata 10.0 software. Nineteen eligible studies, including 14 from Europeans, 3 from Asians, 1 from Oceania, and 1 from the US were included in the meta-analysis. In total, significant associations were found between OCTN1/2 polymorphisms and the susceptibility of CD for all genetic models. In subgroup analyses, significant associations were found in the European population for OCTN1/2. Associations were not significant in the non-European population for OCTN1 (TT vs. CT: OR = 1.25, 95%CI: 0.75 - 1.98, P = 0.34; TT vs. CC + CT: OR = 1.48, 95%CI: 0.95 - 2.29, P = 0.08) and for OCTN2 (CC vs. GC: OR = 1.03, 95%CI: 0.68 - 1.56, P = 0.89; CC vs. GG + GC: OR = 1.23, 95%CI: 0.83 - 1.82, P = 0.31). However, there were significant associations found between OCTN1/2 (TT vs. CC, TT + CT vs. CC, CC vs. GG, CC + GC vs. GG) polymorphisms and the susceptibility of CD found in the non-European population. Results from this meta-analysis suggested that OCTN1/2 polymorphisms were associated with the susceptibility of CD in the European population. Associations between OCTN1/2 polymorphisms and the susceptibility of CD in the non-European population required searching for large samples to confirm the findings.

Evidence for a Contribution of ALA Synthesis to Plastid-To-Nucleus Signaling

PubMed Central

Czarnecki, Olaf; Gläßer, Christine; Chen, Jin-Gui; Mayer, Klaus F. X.; Grimm, Bernhard

2012-01-01

The formation of 5-aminolevulinic acid (ALA) in tetrapyrrole biosynthesis is widely controlled by environmental and metabolic feedback cues that determine the influx into the entire metabolic path. Because of its central role as the rate-limiting step, we hypothesized a potential role of ALA biosynthesis in tetrapyrrole-mediated retrograde signaling and exploited the direct impact of ALA biosynthesis on nuclear gene expression (NGE) by using two different approaches. Firstly, the Arabidopsis gun1, hy1 (gun2), hy2 (gun3), gun4 mutants showing uncoupled NGE from the physiological state of chloroplasts were thoroughly examined for regulatory modifications of ALA synthesis and transcriptional control in the nucleus. We found that reduced ALA-synthesizing capacity is common to analyzed gun mutants. Inhibition of ALA synthesis by gabaculine (GAB) that inactivates glutamate-1-semialdehyde aminotransferase and ALA feeding of wild-type and mutant seedlings corroborate the expression data of gun mutants. Transcript level of photosynthetic marker genes were enhanced in norflurazon (NF)-treated seedlings upon additional GAB treatment, while enhanced ALA amounts diminish these RNA levels in NF-treated wild-type in comparison to the solely NF-treated seedlings. Secondly, the impact of posttranslationally down-regulated ALA synthesis on NGE was investigated by global transcriptome analysis of GAB-treated Arabidopsis seedlings and the gun4-1 mutant, which is also characterized by reduced ALA formation. A common set of significantly modulated genes was identified indicating ALA synthesis as a potential signal emitter. The over-represented gene ontology categories of genes with decreased or increased transcript abundance highlight a few biological processes and cellular functions, which are remarkably affected in response to plastid-localized ALA biosynthesis. These results support the hypothesis that ALA biosynthesis correlates with retrograde signaling-mediated control of NGE

The TP53 gene polymorphisms and survival of sporadic breast cancer patients.

PubMed

Bišof, V; Salihović, M Peričić; Narančić, N Smolej; Skarić-Jurić, T; Jakić-Razumović, J; Janićijević, B; Rudan, P

2012-06-01

The TP53 gene polymorphisms, Arg72Pro and PIN3 (+16 bp), can have prognostic and predictive value in different cancers including breast cancer. The aim of the present study is to investigate a potential association between different genotypes of these polymorphisms and clinicopathological variables with survival of breast cancer patients in Croatian population. Ninety-four women with sporadic breast cancer were retrospectively analyzed. Median follow-up period was 67.9 months. The effects of basic clinical and histopathological characteristics of tumor on survival were tested by Cox's proportional hazards regression analysis. The TNM stage was associated with overall survival by Kaplan-Meier analysis, univariate, and multivariate Cox's proportional hazards regression analysis, while grade was associated with survival by Kaplan-Meier analysis and univariate Cox's proportional hazards regression analysis. Different genotypes of the Arg72Pro and PIN3 (+16 bp) polymorphisms had no significant impact on survival in breast cancer patients. However, in subgroup of patients treated with chemotherapy without anthracycline, the A2A2 genotype of the PIN3 (+16 bp) polymorphism was associated with poorer overall survival than other genotypes by Kaplan-Meier analysis (P = 0.048). The TP53 polymorphisms, Arg72Pro and PIN3 (+16 bp), had no impact on survival in unselected sporadic breast cancer patients in Croatian population. However, the results support the role of the A2A2 genotype of the PIN3 (+16 bp) polymorphism as a marker for identification of patients that may benefit from anthracycline-containing chemotherapy.

Atg12 Maintains Skeletal Integrity by Modulating Pro-Osteoclastogenic Signals and Chondrocyte Differentiation

NASA Technical Reports Server (NTRS)

Tahimic, Candice; Bahl, Disha; Shirazi-Fard, Yasaman; Marsh, Timothy; Schreurs, Anne-Sofie; Rael, Victoria E.; Glikbarg, Chloe; Debnath, Jayantha; Globus, Ruth K.

2016-01-01

Weightlessness and radiation, two unique elements of space, profoundly decreases bone mass. This bone loss is attributed to increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Our long-term goal is to identify signaling pathways that may be targeted to mitigate bone loss in scenarios of space exploration, radiotherapy and accidental radiation exposure. We have previously shown that exposure of MLO-Y4 osteocyte-like cells to simulated space radiation (56Fe) increased the expression of the pro-osteoclastogenic gene rankl and decreased protein levels of LC3B-II, a key player in autophagy. In this current study, we aimed to further elucidate the role of autophagy in maintaining structural integrity of the skeleton. We hypothesize that loss of autophagy in bone leads to an imbalance in pro-osteoclastogenic and pro-osteogenic signals, resulting in net bone loss. To test our hypothesis we performed global postnatal deletion of Atg12 using tamoxifeninducible Cre recombinase under the control of the CAG promoter. Six-week-old CAGCreERT2/ FloxAtg12 animals were treated daily with Tamoxifen or Vehicle (Control, oil only) for five days and euthanasia performed two weeks after the onset of treatment. Percent change in body weights (prior to treatment and at euthanasia) was not significantly different between treatment groups within the same gender. Compared to Vehicle (Control) groups, Tamoxifen (Atg12 iKO) groups showed decreased LC3B-I to II conversion and increased p62 protein levels, consistent with loss of autophagy. Quantitative PCR revealed increased expression of proosteoclastogenic cytokines mcp1 and rankl in bone and marrow respectively in male iKOs compared to male controls. Expression levels of these genes were not significantly altered in the Atg12 iKO females compared to females controls. Microcomputed tomography of tibiae revealed decreased cortical bone volume, cortical

Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease.

PubMed

Domingo, Pere; Muñiz-Diaz, Eduardo; Baraldès, Maria A; Arilla, Marina; Barquet, Nicolau; Pericas, Roser; Juárez, Cándido; Madoz, Pedro; Vázquez, Guillermo

2002-01-01

In vitro studies have shown that the neutrophil Fc gamma receptor IIA (FcgammaRIIA) polymorphism influences the phagocytic capacity of neutrophils and the removal of encapsulated bacteria from the bloodstream. In particular, the R/R131 allotype is associated with less phagocytic activity. We performed a case-control study to determine the influence of the FcgammaRIIA polymorphism (R/R131, R/H131, H/H131) on the risk and outcome of meningococcal disease. The polymorphisms were measured in 130 patients with microbiologically proven meningococcal disease diagnosed from 1987 to 1998 (cases) and 260 asymptomatic sex-matched blood donors (controls). Clinical manifestations and complications of meningococcal disease were recorded, and a prognostic score (based on age, hemorrhagic diathesis, neurologic signs, and the absence of preadmission antibiotic) therapy was calculated. The distributions of FcgammaRIIA allotypes were similar in cases and controls. However, among patients with meningococcal infection, fulminant meningococcal disease (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 1.0 to 16; P = 0.04) and meningococcemia without meningitis (OR = 3.0; 95% CI: 1.4 to 7.8; P = 0.004) were more common in those with the FcgammaRIIA-R/R131 allotype. Complications were also significantly more frequent in these patients. Of the 42 patients with the R/R131 allotype, 31 (74%) had an adverse prognostic score, compared with 7% (4 of 59) of those with the R/H131 allotype and 3% (1 of 29) of those with the H/H131 allotype (P <0.0001). The FcgammaRIIA-R/R131 allotype is associated with more severe forms of meningococcal disease.

Inferior oblique muscle origin: horizontal location in relation to ala nasi and its gender difference.

PubMed

Takahashi, Yasuhiro; Kakizaki, Hirohiko; Kohjima, Kiwamu; Nakano, Takashi; Asamoto, Ken; Ichinose, Akihiro; Iwaki, Masayoshi

2013-01-01

We studied the horizontal location of the inferior oblique muscle (IOM) origin in relation to the ipsilateral ala nasi and compared the results between genders in 76 orbits of 38 Japanese cadavers. Consequently, the IOM origin was located 1.2 mm laterally to the vertical line through the lateral margin of the ipsilateral ala nasi. No significant difference was noted between genders (males, 1.3 mm; females, 0.9 mm; P = 0.257, Student t test) or between sides (right, 1.1 mm; left, 1.3 mm; P = 0.570, Student t test). In contrast, the mean interalae-nasi distance was 39.8 mm and was significantly greater in males than that in females (males, 40.8 mm; females, 38.6 mm; P = 0.049, Student t test). The ala nasi can be used as a reference point irrespective of gender or side for identifying the IOM origin during oculoplastic surgery.

Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

PubMed

Abhinand, P A; Shaikh, Faraz; Bhakat, Soumendranath; Radadiya, Ashish; Bhaskar, L V K S; Shah, Anamik; Ragunath, P K

2016-01-01

Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

ON THE RELATIONSHIPS OF SUBSTRATE ORIENTATION, HYDROGEN ABSTRACTION AND PRODUCT STEREOCHEMISTRY IN SINGLE AND DOUBLE DIOXYGENATIONS BY SOYBEAN LIPOXYGENASE-1 AND ITS ALA542GLY MUTANT*

PubMed Central

Coffa, Gianguido; Imber, Ann N.; Maguire, Brendan C.; Laxmikanthan, Gurunathan; Schneider, Claus; Gaffney, Betty J.; Brash, Alan R.

2005-01-01

Recent findings associate the control of stereochemistry in lipoxygenase (LOX) catalysis with a conserved active site alanine for S configuration hydroperoxide products, or a corresponding glycine for R stereoconfiguration. To further elucidate the mechanistic basis for this stereocontrol we compared the stereoselectivity of the initiating hydrogen abstraction in soybean LOX-1 and an Ala542Gly mutant that converts linoleic acid to both 13S and 9R configuration hydroperoxide products. Using 11R-3H- and 11S-3H-labeled linoleic acid substrates to examine the initial hydrogen abstraction, we found that all the primary hydroperoxide products were formed with an identical and highly stereoselective proS hydrogen abstraction from C-11 of the substrate (97–99% pro-S selective). This strongly suggests that 9R and 13S oxygenations occur with the same binding orientation of substrate in the active site, and as the equivalent 9R and 13S products were formed from a bulky ester derivative (1-palmitoyl-2-linoleoyl-phosphatidylcholine), one can infer that the orientation is tail-first. Both the EPR spectrum and the reaction kinetics were altered by the R product-inducing Ala-Gly mutation, indicating a substantial influence of this Ala-Gly substitution extending to the environment of the active site iron. To examine also the reversed orientation of substrate binding, we studied oxygenation of the 15S-hydroperoxide of arachidonic acid by the Ala542Gly mutant soybean LOX-1. In addition to the usual 5S,15S- and 8S,15S-dihydroperoxides, a new product was formed and identified by HPLC, UV, GC-MS and NMR as 9R , 1 5 S -dihydroperoxy-eicosa-5Z,7E,11Z,13E-tetraenoic acid, the R configuration “partner” of the normal 5S,15S product. This provides evidence that both tail-first and carboxylate end-first binding of substrate can be associated with S or R partnerships in product formation in the same active site. PMID:16157595

Delta-ALA urine test

MedlinePlus

... hours. Normal value ranges may vary slightly from one lab to another. Some labs use different measurements or test different samples. Talk to your provider about the meaning of your specific test results. What Abnormal Results Mean An increased level of urinary delta-ALA may ...

ALA-induced fluorescence in the canine oral cavity.

PubMed

Vaidyanathan, Vijay; Wiggs, Robert; Stohl, Josh; Baxi, Mehul

2006-06-01

We examined whether 5-aminolevulinic acid (ALA) could enhance the spectroscopic contrast between normal and diseased oral tissues, without prolonged photosensitivity. ALA is a promising photosensitizing agent. Adose of 25 mg/kg of ALA was administered intravenously to five dogs with gingivitis and three dogs with oral cancer, respectively. Fluorescence was recorded from the diseased sites in the oral cavity in addition to normal sites. ALA-induced proto-porphyrin IX fluorescence at all gingivitis sites reached a peak in 2-3 h and returned to baseline in 24 h. Fluorescence from the gingivitis site was observed earlier and was higher than the fluorescence from the normal site. For dogs with cancer, fluorescence from the cancerous sites occurred earlier in time compared to gingivitis sites and was comparatively higher in intensity. The fluorescence from the diseased sites was found to be higher than the normal site. Clinical and fluorescence data suggest that a dose of 25 mg/kg may be satisfactory for diagnostic purposes and would have minimal side effects.

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population.

PubMed

Rivu, Sanzana Fareen; Apu, Mohd Nazmul Hasan; Shabnaz, Samia; Nahid, Noor Ahmed; Islam, Md Reazul; Al-Mamun, Mir Md Abdullah; Nahar, Zabun; Rabbi, Sikder Nahidul Islam; Ahmed, Maizbha Uddin; Islam, Mohammad Safiqul; Hasnat, Abul

2017-08-01

Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160Cpolymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR=2.58, 95% CI=1.77-3.77, p<0.05) and Pro/Pro mutant homozygosity (adjusted OR=2.92, 95% CI=1.78-4.78, p<0.05) along with the combined genotype (Arg/Pro+Pro/Pro) (adjusted OR=2.70, 95% CI=1.90-3.82, p<0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p<0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR=2.02, 95% CI=1.42-2.87, p<0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acquisition of pro-oxidant activity of fALS-linked SOD1 mutants as revealed using circular dichroism and UV-resonance Raman spectroscopy

NASA Astrophysics Data System (ADS)

Fujimaki, Nobuhiro; Nishiya, Ken; Miura, Takashi; Nakabayashi, Takakazu

2016-11-01

The acquisition of pro-oxidant activity of the mutated form of human Cu, Zn-superoxide dismutase (SOD1) has been investigated to clarify the relationship between mutations in SOD1 and the pathogenesis of amyotrophic lateral sclerosis (ALS). Ala4 → Val (A4V) and Gly93 → Ala (G93A) mutants, which are representative ALS-linked SOD1 mutants, have been found to exhibit both the denaturation and the gain of pro-oxidant activity after incubation in the apo-form at a physiological condition of 37 °C and pH 7.4 and the rebinding of Cu2+. These characteristics are similar to those previously reported for the His43 → Arg (H43R) mutant. UV-resonance Raman spectra indicated that the coordination structure of the Cu-binding site catalyzing the oxidation reaction is the same among the denatured A4V, G93A, and H43R. Since wild-type SOD1 does not exhibit the denaturation in its apo-form at 37 °C and pH 7.4, the instability of the protein structure due to mutation can be considered as a significant factor that induces the denaturation and the subsequent pro-oxidant activity.

ALOX12 polymorphisms are associated with fat mass but not peak bone mineral density in Chinese nuclear families.

PubMed

Xiao, W-J; He, J-W; Zhang, H; Hu, W-W; Gu, J-M; Yue, H; Gao, G; Yu, J-B; Wang, C; Ke, Y-H; Fu, W-Z; Zhang, Z-L

2011-03-01

Arachidonate 12-lipoxygenase (ALOX12) is a member of the lipoxygenase superfamily, which catalyzes the incorporation of molecular oxygen into polyunsaturated fatty acids. The products of ALOX12 reactions serve as endogenous ligands for peroxisome proliferator-activated receptor γ (PPARG). The activation of the PPARG pathway in marrow-derived mesenchymal progenitors stimulates adipogenesis and inhibits osteoblastogenesis. Our objective was to determine whether polymorphisms in the ALOX12 gene were associated with variations in peak bone mineral density (BMD) and obesity phenotypes in young Chinese men. All six tagging single-nucleotide polymorphisms (SNPs) in the ALOX12 gene were genotyped in a total of 1215 subjects from 400 Chinese nuclear families by allele-specific polymerase chain reaction. The BMD at the lumbar spine and hip, total fat mass (TFM) and total lean mass (TLM) were measured using dual-energy X-ray absorptiometry. The pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both the individual SNP markers and the haplotypes were tested for an association with the peak BMD, body mass index, TFM, TLM and percentage fat mass (PFM) using the quantitative transmission disequilibrium test (QTDT). Using the QTDT, significant within-family association was found between the rs2073438 polymorphism in the ALOX12 gene and the TFM and PFM (P=0.007 and 0.012, respectively). Haplotype analyses were combined with our individual SNP results and remained significant even after correction for multiple testing. However, we failed to find significant within-family associations between ALOX12 SNPs and the BMD at any bone site in young Chinese men. Our present results suggest that the rs2073438 polymorphism of ALOX12 contributes to the variation of obesity phenotypes in young Chinese men, although we failed to replicate the association with the peak BMD variation in this sample. Further independent studies are needed to confirm our

Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

PubMed Central

Kaneko, Sadahiro

2016-01-01

Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

ALA PDT for high grade dysplasia in Barrett's oesophagus: review of a decade's experience

NASA Astrophysics Data System (ADS)

Bown, Stephen G.; Mackenzie, Gary D.; Dunn, Jason M.; Thorpe, Sally M.; Lovat, Laurence B.

2009-06-01

We have been investigating PDT with 5 aminolaevulinic acid (ALA) for the treatment of high grade dysplasia (HGD) in Barrett's oesophagus (BO) for over a decade. This drug has inherent advantages over porfimer sodium (Photofrin), the current approved photosensitiser in the UK and USA, which causes strictures in 18-50% and light sensitivity for up to three months. ALA has a lower rate of oesophageal strictures due to its preferential activity in the mucosa, sparing the underlying muscle, and patients are only light sensitive for 1-2 days. Within a randomised controlled trial, we demonstrated that an ALA dose of 60mg/kg activated by 1000J/cm red laser light is the most effective. Using these values we achieved complete reversal of HGD at 1 year in 89% of 27 patients. A randomised controlled trial of ALA vs porfimer sodium PDT for HGD is currently under way with end points of efficacy and safety. 50 of 66 patients have been recruited. Preliminary data suggest ALA PDT is safer with a trend to higher efficacy. Late relapse can occur in 20% of patients. New prognostic markers, in particular aneuploidy, are helping us to identify and target patients at risk of late relapse. Furthermore optical biopsy techniques such as elastic scattering spectroscopy (ESS) may allow detection of nuclear abnormalities in vivo and enable us to target areas of interest whilst reducing sampling error. PDT faces new challenges for the treatment of HGD in BO, with the recent introduction of balloon based radiofrequency ablation. This technique appears simpler and as effective as PDT, but follow up is currently short and long term safety data is lacking. In our experience ALA PDT is currently the most effective minimally invasive treatment for HGD in BO. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

Association of cytokine gene polymorphisms in CWP and its severity in Turkish coal workers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ates, I.; Suzen, H.S.; Yucesoy, B.

2008-10-15

Cytokines appear to play a key role in some inflammatory reactions affecting the interactions among pro- and anti-inflammatory mechanisms that result in several diseases such as coal workers' pneumoconiosis (CWP). In this study, to determine the cytokine gene profiles of Turkish coal miners, we performed genotyping analysis to investigate the polymorphisms of CWP-related pro-inflammatory (TNFA, IL1A, IL1B, and IL6) and anti-inflammatory cytokines (IL-1RN and TGFB1). Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. TNFA (-238) gene polymorphism principally affected CWP development and severity (OR=3.47: 95% CI, 1.12-10.77 and OR=4.30: 95% CI, 1.25-14.74, respectively) and alsomore » risk of CWP (OR=3.79: 95% CI, 1.37-10.46). The TNFA (-308) variant was associated with a risk for the CWP severity (OR = 2.84: 95% CI, 1.08-7.39). A protective effect of IL6 was found on the development (OR = 0.48: 95% CI, 0.21-0.93) and severity of CWP (OR = 0.37: 95% CI, 0.15-0.91). We suggest that TNFA (-238) variant may be a risk factor in both development and the severity, of CWP while TNFA (-308) variant seems to be important only in disease severity On the other hand, IL6 variant may have a protective effect on the development and disease severity.« less

33 CFR 110.194 - Mobile Bay, Ala., at entrance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Mobile Bay, Ala., at entrance. 110.194 Section 110.194 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY ANCHORAGES ANCHORAGE REGULATIONS Anchorage Grounds § 110.194 Mobile Bay, Ala., at entrance. (a) The anchorage...

Requirement for IFN-gamma in IL-12 production induced by collaboration between v(alpha)14(+) NKT cells and antigen-presenting cells.

PubMed

Yang, Y F; Tomura, M; Ono, S; Hamaoka, T; Fujiwara, H

2000-12-01

Two cytokines IL-4 and IL-12 are known to determine the balance between T(h)1 and T(h)2 development. In addition to IL-4 production of V(alpha)14(+) NKT cells, they have recently been demonstrated to have the capacity to stimulate IL-12 production by antigen-presenting cells (APC). This study demonstrates that IFN-gamma is absolutely required for the NKT cell-stimulated IL-12 production. Culture of B cell-depleted spleen cells from C57BL/6 mice with alpha-galactosylceramide (alpha-GalCer) capable of selectively stimulating V(alpha)14/J(alpha)281(+) NKT cells resulted in the production of IL-12 together with IL-4. Whereas IL-4 production occurred in culture of IFN-gamma(-/-) C57BL/6 splenocytes, the same culture failed to generate IL-12 production. While IL-12 production induced during culture of V(alpha)14(+) NKT cells and APC depended on the interaction between CD40 ligand on NKT cells and CD40 on APC, the expression levels of these key molecules were comparable in cells from wild-type and IFN-gamma(-/-) mice. Addition of rIFN-gamma to alpha-GalCer stimulated IFN-gamma(-/-) splenocyte culture, and administration of rIFN-gamma to alpha-GalCer-injected IFN-gamma(-/-) mice resulted in the restoration of IL-12 production in vitro and in vivo. These results illustrate a mandatory role for IFN-gamma in V(alpha)14(+) NKT cell-stimulated IL-12 production by APC.

Effect of gamma irradiation on the change of solubility and anti-inflammation activity of chrysin in macrophage cells and LPS-injected endotoxemic mice

NASA Astrophysics Data System (ADS)

Byun, Eui-Baek; Jang, Beom-Su; Byun, Eui-Hong; Sung, Nak-Yun

2016-10-01

This study evaluated the changes of solubility and anti-inflammatory properties of structurally modified gamma-irradiated chrysin. Chrysin was irradiated at various doses for a physical analysis and determining any structural changes and solubility. As shown through the physical analysis, the main peak of the chrysin was decreased as the irradiation dose increased, and it was concomitant with the appearance of several new peaks, which were highly increased in 50 kGy gamma-irradiated chrysin. The solubility was markedly increased in the gamma-irradiated groups. As shown through a physiological analysis, both gamma-irradiated- (15-50 kGy) and intact-chrysin (0 kGy) did not exert cytotoxicity to bone-marrow derived macrophages. The treatment of LPS-stimulated macrophages with 50 kGy gamma-irradiated chrysin resulted in a dose-dependent decrease in pro-inflammatory mediators, such as iNOS-mediated NO, PGE2, COX-2, and cell surface marker (CD80 and CD86), as well as pro-inflammatory cytokines (TNF-α and IL-6), when compared to the intact-chrysin treated group. Mechanically, we found that the inhibition of these pro-inflammatory mediators induced by gamma-irradiated chrysin occurred through an inhibition of MAPKs (ERK1/2 and p38) and the NF-κB signaling pathways. Furthermore, the anti-inflammatory activity remained in the LPS-injected animal model. In this model, gamma-irradiated chrysin treatment highly increased the mouse survival, and significantly decreased the serum cytokine (TNF-α, IL-6 and IL-1β) levels. From these findings, the anti-inflammatory action by gamma-irradiated chrysin may be closely mediated with structural modification. It seems likely that gamma irradiation can be an effective tool for improvement of the physical and physiological properties of polyphenols.

Effects of BDNF polymorphisms on antidepressant action.

PubMed

Tsai, Shih-Jen; Hong, Chen-Jee; Liou, Ying-Jay

2010-12-01

Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidepressant treatment and since genetic factors may contribute to this inter-individual variability in antidepressant response, pharmacogenetic studies have tested the associations between genetic polymorphisms in candidate genes related to antidepressant therapeutic action. In human BDNF gene, there is a common functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF. Because of the potentially important role of BDNF in the antidepressant mechanism, many pharmacogenetic studies have tested the association between this polymorphism and the antidepressant therapeutic response, but they have produced inconsistent results. A recent meta-analysis of eight studies, which included data from 1,115 subjects, suggested that the Val/Met carriers have increased antidepressant response in comparison to Val/Val homozygotes, particularly in the Asian population. The positive molecular heterosis effect (subjects heterozygous for a specific genetic polymorphism show a significantly greater effect) is compatible with animal studies showing that, although BDNF exerts an antidepressant effect, too much BDNF may have a detrimental effect on mood. Several recommendations are proposed for future antidepressant pharmacogenetic studies of BDNF, including the consideration of multiple polymorphisms and a haplotype approach, gene-gene interaction, a single antidepressant regimen, controlling for age and gender interactions, and pharmacogenetic

Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China.

PubMed

Zhou, Sheng Li; Cui, Juan; Fan, Zong Min; Li, Xue Min; Li, Ji Lin; Liu, Bao Chi; Zhang, Dong Yun; Liu, Hong Yan; Zhao, Xue Ke; Song, Xin; Wang, Ran; Yan, Ze Chen; Yi, Hui Xing; Wang, Li Dong

2013-05-25

The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method. The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09-3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78-12.52) and GCA (OR=7.50, 95% CI= 2.78-20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10-8.73; for differentiation: OR=0.29, 95% CI=0.12-0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03-0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57-167.74). The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia

The n-3 long-chain PUFAs modulate the impact of the GCKR Pro446Leu polymorphism on triglycerides in adolescents[S

PubMed Central

Rousseaux, Julien; Duhamel, Alain; Dumont, Julie; Dallongeville, Jean; Molnar, Denes; Widhalm, Kurt; Manios, Yannis; Sjöström, Michael; Kafatos, Anthony; Breidenassel, Christina; Gonzales-Gross, Marcela; Cuenca-Garcia, Magdalena; Censi, Laura; Ascensión, Marcos; De Henauw, Stefaan; Moreno, Luis A.; Meirhaeghe, Aline; Gottrand, Frédéric

2015-01-01

Dietary n-3 long-chain PUFAs (LC-PUFAs) are associated with improvement in the parameters of the metabolic syndrome (MetS). Glucokinase regulatory protein (GCKR) is a key protein regulating intracellular glucose disposal. Our aim was to investigate: i) the relationship between the GCKR rs1260326 (Pro446Leu) polymorphism and parameters of the MetS; and ii) a potential influence of n-3 and n-6 LC-PUFA levels on this relationship in the HELENA study (1,155 European adolescents). Linear regression analyses were performed to study the association between rs1260326 and the outcomes of interest. Interactions between rs1260326 and LC-PUFA levels on outcomes were explored. The T allele of rs1260326 was associated with higher serum TG concentrations compared with the C allele. In contrast to n-6 LC-PUFA levels, a significant interaction (P = 0.01) between rs1260326 and total n-3 LC-PUFA levels on serum TG concentrations was observed. After stratification on the n-3 LC-PUFA median values, the association between rs1260326 and TG concentration was significant only in the group with high n-3 LC-PUFA levels. In conclusion, this is the first evidence that n-3 LC-PUFAs may modulate the impact of the GCKR rs1260326 polymorphism on TG concentrations in adolescents. Several molecular mechanisms, in link with glucose uptake, could explain these findings. PMID:26136510

Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high-risk region.

PubMed

Hedayatizadeh-Omran, Akbar; Alizadeh-Navaei, Reza; Janbabaei, Ghasem; Omrani-Nava, Versa; Hasheminasab, Yahya; Amjadi, Omolbanin; Tehrani, Mohsen

2018-05-01

Gastric cancer has the fourth highest morbidity rate of all cancers worldwide. Genetic factors including alterations in oncogenes and tumor suppressor genes serve an important role in gastric cancer development and progression. The P53 gene acts as a tumor suppressor gene by regulating the cell cycle, DNA transcription and repair, apoptosis, senescence and genome stability. In addition to somatic P53 mutations in cancer development, germline polymorphisms are also involved in different malignancies. The polymorphism of P53 at codon 72 (Arg72Pro) is established as a common variant that increases susceptibility to various cancers. The present case-control study was conducted to evaluate the possible association between this P53 polymorphism and gastric cancer in the Iranian population. A total of 59 patients with gastric cancer and 59 healthy controls were enrolled in the present study. Genomic DNA was extracted from peripheral blood mononuclear cells and genotype analysis was performed using a polymerase chain reaction-based restriction fragment length polymorphism assay. Genotype frequencies did not differ significantly between the patients and controls (P=0.4); the frequencies of the three genotypes Arg/Arg, Arg/Pro and Pro/Pro in gastric cancer patients were 28.8, 49.2 and 22.0%, and in controls were 37.3, 49.2 and 13.6%. Additionally, there were no differences in genotype frequencies based on tumor location, histological differentiation or tumor stage. Based on these findings, it may be concluded that the P53 codon 72 polymorphism does not contribute to gastric cancer susceptibility in Northern Iran.

The n-3 long-chain PUFAs modulate the impact of the GCKR Pro446Leu polymorphism on triglycerides in adolescents.

PubMed

Rousseaux, Julien; Duhamel, Alain; Dumont, Julie; Dallongeville, Jean; Molnar, Denes; Widhalm, Kurt; Manios, Yannis; Sjöström, Michael; Kafatos, Anthony; Breidenassel, Christina; Gonzales-Gross, Marcela; Cuenca-Garcia, Magdalena; Censi, Laura; Ascensión, Marcos; De Henauw, Stefaan; Moreno, Luis A; Meirhaeghe, Aline; Gottrand, Frédéric

2015-09-01

Dietary n-3 long-chain PUFAs (LC-PUFAs) are associated with improvement in the parameters of the metabolic syndrome (MetS). Glucokinase regulatory protein (GCKR) is a key protein regulating intracellular glucose disposal. Our aim was to investigate: i) the relationship between the GCKR rs1260326 (Pro446Leu) polymorphism and parameters of the MetS; and ii) a potential influence of n-3 and n-6 LC-PUFA levels on this relationship in the HELENA study (1,155 European adolescents). Linear regression analyses were performed to study the association between rs1260326 and the outcomes of interest. Interactions between rs1260326 and LC-PUFA levels on outcomes were explored. The T allele of rs1260326 was associated with higher serum TG concentrations compared with the C allele. In contrast to n-6 LC-PUFA levels, a significant interaction (P = 0.01) between rs1260326 and total n-3 LC-PUFA levels on serum TG concentrations was observed. After stratification on the n-3 LC-PUFA median values, the association between rs1260326 and TG concentration was significant only in the group with high n-3 LC-PUFA levels. In conclusion, this is the first evidence that n-3 LC-PUFAs may modulate the impact of the GCKR rs1260326 polymorphism on TG concentrations in adolescents. Several molecular mechanisms, in link with glucose uptake, could explain these findings. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Ex-vivo absorption study of lysine R-lipoate salt, a new pharmaceutical form of R-ALA.

PubMed

Amenta, Francesco; Buccioni, Michela; Ben, Diego Dal; Lambertucci, Catia; Navia, Aleix Martí; Ngouadjeu Ngnintedem, Michael A; Ricciutelli, Massimo; Spinaci, Andrea; Volpini, Rosaria; Marucci, Gabriella

2018-06-15

Alpha-lipoic acid (ALA) oral supplements were used in many pathologies associated with increased oxidative stress. Although only R-ALA is considered the biologically active form, R,S-ALA is used in therapeutic applications even showing poor water solubility. The aim of this work was to study the absorption and transport mechanism across the intestinal barrier of new R-ALA stable and water soluble form, consisting in the lysine R-ALA salt, in presence and absence of specific inhibitors of Na + /multivitamin (SMVT) and monocarboxylic acids (MCT). The absorption of a new ALA form was investigated at rat everted sacs in comparison with R-ALA, S-ALA, and R,S-ALA. Results showed that duodenum is the best portion of intestine for ALA forms absorption. The absorption percentage of R-ALA, S-ALA, R,S-ALA, and lysine R-ALA salt was 66%, 43%, 55%, and 70%, respectively. The modest effect of the SMVT inhibitor biotin demonstrated that this transporter system is not principally involved in the absorption of lysine R-lipoate salt across the rat intestinal barrier. On the contrary, the MCT inhibitor octanoic acid significantly reduced the transport of this salt, whit an absorption decrease of R-ALA and lysine R-lipoate salt of 28% and 24%, respectively. Since the highest concentration of these inhibitors did not completely inhibit the absorption of lysine R-lipoate salt, other transport mechanisms probably operate for its intracellular delivery. The new form of ALA, lysine R-lipoate salt, was the most absorbed respect to the other ALA forms demonstrating that this compound is more suitable for oral administration. This new salt could represent a promising candidate for ALA oral supplementation. Copyright © 2018 Elsevier B.V. All rights reserved.

Evaluation of ALA-induced PpIX as a photosensitizer for PDT in cats

NASA Astrophysics Data System (ADS)

Lucroy, Michael D.; Edwards, Benjamin F.; Peavy, George M.; Krasieva, Tatiana B.; Griffey, Stephen M.; Madewell, Bruce R.

1998-07-01

Given exogenously, ALA defeats intrinsic regulatory feedback mechanisms allowing intracellular accumulation of protoporphyrin IX (PpIX), a highly efficient photosensitizer. In vivo, PpIX synthesis in neoplastic mammary tissues averages 20-fold higher than in normal mammary tissues. PpIX is retained intracellularly, unlike perivascular localization of other photosensitizers, and it is then cleared quickly from the body. In vitro, ALA induced PpIX production in our laboratory in 6 cell lines tested, including an established feline kidney cell line and dermal fibroblasts from primary skin biopsy explant, resulting in photosensitization. Fluorescent microscopy confirmed PpIX production in skin adnexae following ALA administration in a normal cat. To evaluate toxicity, three cats were treated with a single i.v. dose of ALA (either 100, 200, of 400 mg/kg) and followed for 7 days. Cats receiving 100 or 200 mg/kg ALA i.v. had elevated liver enzymes and bilirubin within 24 hours. Histopathology revealed hydropic changes in the liver and renal fibrosis. The cat receiving 400 mg/kg ALA intravenously had cutaneous flush, bradycardia and apnea associated with ALA administration; within 24 hours the cat was lethargic, anorectic and icteric. ALT, AST and bilirubin concentrations had increased significantly. At necropsy the liver had a prominent lobular pattern; histopathology revealed severe periportal hepatitis and splenic necrosis. Systemically administered ALA induces PpIX production, but toxicity may preclude its clinical application in the cat. PpIX levels seem to be more time dependent than those dependent at these three ALA doses and they are well beyond the saturation point for adequate PpIX conversion. The literature is scant regarding toxicity associated with parenteral administration of ALA.

Association between a polymorphism in the IL-12p40 gene and cytomegalovirus reactivation after kidney transplantation.

PubMed

Hoffmann, Thomas W; Halimi, Jean-Michel; Büchler, Mathias; Velge-Roussel, Florence; Goudeau, Alain; Al Najjar, Azmi; Boulanger, Marie-Denise; Houssaini, Tarik Sqalli; Marliere, Jean-Frédéric; Lebranchu, Yvon; Baron, Christophe

2008-05-27

Cytomegalovirus (CMV) infection is associated with a significant rate of morbidity after organ transplantation. The genetic factors influencing its occurrence have been little investigated. IL-12 plays a crucial role in anti-infectious immune responses, especially by stimulating IFNgamma production. An A-to-C single nucleotide polymorphism (SNP) within the 3'-untranslated region of the IL-12p40 gene has been characterized and was reported to be both functionally and clinically relevant. However, the impact of this single nucleotide polymorphism on events after organ transplantation has never been reported. In this study, we investigated the impact of the 3'-untranslated region polymorphism on the occurrence of CMV infection in 469 kidney recipients transplanted at the University Hospital of Tours between 1995 and 2005. The polymorphism was genotyped using the restriction fragment length polymorphism method and CMV infection was determined by pp65 antigenemia. Multifactorial Cox regression analysis demonstrated that the presence of the C allele was an independent risk factor for CMV infection (OR=1.52, P=0.043), the risk being even higher when study was restricted to patients with positive CMV serological status before the graft and who did not receive any CMV prophylaxis (OR=1.88, P=0.028). This study identified a new genetic risk factor for CMV reactivation after kidney transplantation. The results of our study suggest that C carriers might especially benefit from CMV prophylaxis.

In vivo study of ALA PLGA nanoparticles-mediated PDT for treating cutaneous squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Wang, Xiaojie; Shi, Lei; Huang, Zheng; Wang, Xiuli

2014-09-01

Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still a challenge. Although topical photodynamic therapy (PDT) is effective for treating in situ and superficial SCC, the effectiveness of topical ALA delivery to thick SCC can be limited by its bioavailability. Polylactic-co-glycolic acid nanopartieles (PLGA NPs) might provide a promising ALA delivery strategy. The aim of this study was to evaluate the efficacy of ALA PLGA NPs PDT for the treatment of cutaneous SCC in a mouse model. Methods: ALA loaded PLGA NPs were prepared and characterized. The therapeutic efficacy of ALA PLGA NP mediated PDT in treating UV-induced cutaneous SCC in the mice model were examined. Results: In vivo study showed that ALA PLGA NPs PDT were more effective than free ALA of the same concentration in treating mouse cutaneous SCC. Conclusion: ALA PLGA NPs provides a promising strategy for delivering ALA and treating cutaneous SCC.

GIS-based accident location and analysis system (GIS-ALAS) : project report : phase I

DOT National Transportation Integrated Search

1998-04-06

This report summarizes progress made in Phase I of the geographic information system (GIS) based Accident Location and Analysis System (GIS-ALAS). The GIS-ALAS project builds on PC-ALAS, a locationally-referenced highway crash database query system d...

Potent inhibition of endopeptidase 24.16 and endopeptidase 24.15 by the phosphonamide peptide N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid.

PubMed Central

Barelli, H; Dive, V; Yiotakis, A; Vincent, J P; Checler, F

1992-01-01

A phosphonamide peptide, N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid, previously shown to block Clostridium histolyticum collagenases, was examined as a putative inhibitor of endopeptidase 24.16 and endopeptidase 24.15. Hydrolysis of two endopeptidase 24.16 substrates, i.e. 3-carboxy-7-methoxycoumarin (Mcc)-Pro-Leu-Gly-Pro-D-Lys-dinitrophenyl (Dnp) and neurotensin, were completely and dose-dependently inhibited by the phosphonamide inhibitor with KI values of 0.3 and 0.9 nM respectively. In addition, the phosphonamide peptide inhibited the hydrolysis of benzoyl (Bz)-Gly-Ala-Ala-Phe-(pAB) p-aminobenzoate and neurotensin by endopeptidase 24.15 with about a 10-fold lower potency (KI values of 5 and 7.5 nM respectively). The selectivity of this inhibitor towards several exo- and endo-peptidases belonging to the zinc-containing metallopeptidase family established that a 1 microM concentration of this inhibitor was unable to affect leucine aminopeptidase, carboxypeptidase A, angiotensin-converting enzyme and endopeptidase 24.11. The present paper therefore reports on the first hydrophilic highly potent endopeptidase 24.16 inhibitor and describes the most potent inhibitory agent directed towards endopeptidase 24.15 developed to date. These tools should allow one to assess the contribution of endopeptidase 24.16 and endopeptidase 24.15 to the physiological inactivation of neurotensin as well as other neuropeptides. PMID:1332678

Pro-Inflammatory Cytokines in Psychiatric Disorders in Children and Adolescents: A Review.

PubMed

Miłkowska, Paulina; Popko, Katarzyna; Demkow, Urszula; Wolańczyk, Tomasz

2017-04-30

Cytokines are a large group of small proteins which play a significant role in cell signaling and regulate a variety of processes in organisms, including proliferation and differentiation of many cells, mediation in defense reactions and regulation of hematopoiesis. Cytokines can be divided into those with pro- and those with anti-inflammatory properties. In the group of pro-inflammatory cytokines the most important are: IL-1 beta, IL-6, TNF-alpha, and IFN-gamma. Pro-inflammatory cytokines might be involved in the pathophysiology of many psychiatric conditions in adults, but their role in children and adolescents is less clear. The aim of this article is to demonstrate the patterns of pro-inflammatory cytokines in children and adolescents.

Pro-inflammatory Cytokines in Psychiatric Disorders in Children and Adolescents: A Review.

PubMed

Miłkowska, Paulina; Popko, Katarzyna; Demkow, Urszula; Wolańczyk, Tomasz

2017-01-01

Cytokines are a large group of small proteins which play a significant role in cell signaling and regulate a variety of processes in organisms, including proliferation and differentiation of many cells, mediation in defense reactions and regulation of hematopoiesis. Cytokines can be divided into those with pro- and those with anti-inflammatory properties. In the group of pro-inflammatory cytokines the most important are: IL-1 beta, IL-6, TNF-alpha, and IFN-gamma. Pro-inflammatory cytokines might be involved in the pathophysiology of many psychiatric conditions in adults, but their role in children and adolescents is less clear. The aim of this article is to demonstrate the patterns of pro-inflammatory cytokines in children and adolescents.

Association of a coding polymorphism in Fc gamma receptor 2A and graft survival in re-transplant candidates.

PubMed

Arnold, Marie-Luise; Fuernrohr, Barbara G; Weiß, Katrin M; Harre, Ulrike; Wiesener, Michael S; Spriewald, Bernd M

2015-10-01

The family of Fc gamma receptors (FcγRs) is involved in mediating immunological effector functions. FcγRs are differentially expressed on immune cells and can act either activating or inhibitory, with FcγR2A belonging to the first group. The polymorphism H131R (rs1801274) in FCGR2A has been associated with acute rejection and can shift the overall balance between activating and inhibitory FcγRs. Anti-HLA allo-antibodies in transplant recipients have been identified as risk factor for organ survival after transplantation. In this study we genotyped FCGR2A H131R in 200 patients who had undergone kidney transplantation and experienced loss of graft function. FCGR2A polymorphism was related to graft survival and anti-HLA antibodies. Graft survival was calculated as the time interval between transplantation and return to chronic dialysis after transplantation. The gene frequency of FCGR2A R/R131 was found significantly more often in patients with earlier (⩽60months) compared to patients with later (>60months) graft failure. Overall patients homozygous for R/R131 had a significantly shorter graft survival, compared to H/H131 or H/R131 which is even more pronounced, when anti-HLA antibodies were present. These data suggest, that FCGR2A polymorphisms constitute a risk factor for graft loss following kidney transplantation and that this effect is related to anti-HLA antibodies. Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Frequency and Clinicopathological Characteristics of Presenilin 1 Gly206Ala Mutation in Puerto Rican Hispanics with Dementia

PubMed Central

Arnold, Steven E.; Vega, Irving E.; Karlawish, Jason H.; WoIk, David A.; Nunez, Jessica; Negron, Mirna; Xie, Sharon X.; Wang, Li-San; Dubroff, Jacob G.; McCarty-Wood, Elisabeth; Trojanowski, John Q.; Van Deerlin, Vivianna

2012-01-01

The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania’s Alzheimer’s Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly 206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study. PMID:23114514

Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208).

PubMed

De Marco, Rossella; Bedini, Andrea; Spampinato, Santi; Cavina, Lorenzo; Pirazzoli, Edoardo; Gentilucci, Luca

2016-10-13

Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging macrocycle size, giving the μ-agonist 9 or the δ-antagonist 10 characterized by low nanomolar affinity. In particular, the μ-agonist c[β-Ala-d-Pro-Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.

Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion.

PubMed

Barišić, Anita; Pereza, Nina; Hodžić, Alenka; Kapović, Miljenko; Peterlin, Borut; Ostojić, Saša

2017-03-01

The aim of this study was to investigate the potential association of matrix metalloproteinase 7 (MMP7) -181 A/G and MMP12 -82 A/G functional single nucleotide polymorphisms (SNP) with idiopathic recurrent spontaneous abortion (IRSA) in Slovenian reproductive couples. A case-control study was conducted on 149 couples with 3 or more consecutive idiopathic spontaneous pregnancy loses and 149 women and men with at least 2 live births and no history of pregnancy complications. Genotyping of MMP7 -181 A/G and MMP12 -82 A/G SNPs was performed using polymerase chain reaction and restriction fragment length polymorphism methods. There were no statistically significant differences in the distribution of MMP7 -181 A/G and MMP12 -82 A/G genotype, allele, or haplotype frequencies between IRSA patients and controls, as well as patients' primary and secondary IRSA. We also found no association of MMP7 -181 A/G and MMP12 -82 A/G genotypes, alleles, and haplotypes with IRSA. We found no evidence to support the association between IRSA and MMP7 -181 A/G and MMP12 -82 A/G SNPs in Slovenian reproductive couples.

Alpha-linolenic acid (ALA) is inversely related to development of adiposity in school-age children

PubMed Central

Perng, Wei; Villamor, Eduardo; Mora-Plazas, Mercedes; Marin, Constanza; Baylin, Ana

2015-01-01

Background/Objectives Studies in adults indicate that dietary polyunsaturated fatty acid (PUFA) composition may play a role in development of adiposity. Because adipocyte quantity is established between late childhood and early adolescence, understanding the impact of PUFAs on weight gain during the school-age years is crucial to developing effective interventions. Subjects/Methods We quantified N-3 and N-6 PUFAs in serum samples of 668 Colombian schoolchildren aged 5–12 years at the time of recruitment into a cohort study, using gas-liquid chromatography. Serum concentrations of N-3 (ALA, EPA, DHA) and N-6 PUFAs (LA, GLA, DGLA, AA) were determined as % total fatty acids. Children’s anthropometry was measured annually for a median of 30 months. We used mixed-effects models with restricted cubic splines to construct population body mass index-for-age z-score (BAZ) growth curves for age-and sex-specific quartiles of each PUFA. Results N-3 ALA was inversely related to BAZ gain after adjustment for sex, baseline age and weight status, and household socioeconomic level. Estimated BAZ change between 6 and 14 years among children in the highest quartile of ALA compared to those in the lowest quartile was 0.45 (95% CI: 0.07, 0.83) lower (P-trend=0.006). Conclusions N-3 ALA may be protective against weight gain in school-age children. Whether improvement in PUFA status reduces adiposity in pediatric populations deserves evaluation in randomized trials. PMID:25271016

Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-gamma: a role for intrinsic tumor immunogenicity and IL-15.

PubMed

Gri, Giorgia; Chiodoni, Claudia; Gallo, Elena; Stoppacciaro, Antonella; Liew, Foo Y; Colombo, Mario P

2002-08-01

IFN-gamma knockout mice (GKO) rejected C26 colon carcinoma cells transduced to secrete interleukin(IL)-12 but do not reject similarly transduced TSA mammary adenocarcinoma (C26/12 and TSA/12 cells, respectively). To determine whether such difference could be because of a different tumor response to IFN-gamma, we injected BALB/c mice with TSA, C26, and their IL-12-transduced counterparts rendered unresponsive to IFN-gamma by stable transduction of a dominant negative (DN), truncated IFN-gamma receptor alpha chain. TSA/DN and C26/DN showed the same in vivo growth kinetics as parental cells, whereas coexpression of IL-12 induced rejection independent of tumor-cell responsiveness to IFN-gamma. This suggests that the role of IFN-gamma is primarily in activating the host immune response, which appears to depend on the intrinsic immunogenicity of the target tumor. C26 and TSA share a common tumor-associated antigen, yet C26 cells are more immunogenic than TSA. C26/12 expressed 10-fold higher levels of class I MHC molecules and induced higher CTL activity compared with TSA/12 cells in GKO mice. Moreover, whereas in GKO mice the TSA/12 tumor was associated with a greater number of infiltrating T cells, only those infiltrating C26/12 tumor expressed the activation marker OX40. The search for cytokine(s) that might contribute in determining the different T-cell response to these IL-12-transduced tumors in GKO mice revealed a role of IL-15. In situ hybridization showed IL-15 expression in C26/12 but not in TSA/12 tumors. In addition, injection of GKO mice with soluble IL-15 receptor-alpha to block IL-15 expression prevented rejection of C26/12 cells. Together, the results suggest that in the absence of IFN-gamma, IL-12 can exert antitumor activity through alternative mechanisms, depending on the tumor cell type and the availability of cytokines that can replace IFN-gamma in sustaining T-cell functions.

Association of the IFN-γ (+874A/T) Genetic Polymorphism with Paranoid Schizophrenia in Tunisian Population.

PubMed

Jemli, Achraf; Eshili, Awatef; Trifa, Fatma; Mechri, Anouar; Zaafrane, Ferid; Gaha, Lotfi; Juckel, George; Tensaout, Besma Bel Hadj Jrad

2017-02-01

Since growing evidence suggests a significant role of chronic low-grade inflammation in the physiopathology of schizophrenia, we have hypothesized that functional genetic variant of the IFN gamma (IFN-γ; +874A/T; rs2430561) gene may be involved in the predisposition to schizophrenia. This research is based on a case-control study which aims to identify whether polymorphism of the IFN-γ gene is a risk factor for the development of schizophrenia. The RFLP-PCR genotyping of the IFN-γ gene was conducted on a Tunisian population composed of 218 patients and 162 controls. The IFN-γ (+874A/T) polymorphism analysis showed higher frequencies of minor homozygous genotype (TT) and allele (T) in all patients compared with controls (11.5 vs. 4.9%; p = 0.03, OR = 2.64 and 30.7 vs. 24.1%, p = 0.04, OR = 1.4, respectively). This correlation was confirmed for male but not for female patients. Also, the T allele was significantly more common among patients with paranoid schizophrenia when compared with controls (25.8 vs. 4.9%, p = 0.0001; OR = 6.7). Using the binary regression analysis to eliminate confounding factors as age and sex, only this last association remained significant (p = 0.03; OR = 1.76, CI = 1.05-2.93). In conclusion, our results showed a significant association between +874A/T polymorphism of IFN-γ and paranoid schizophrenia, suggesting that this single nucleotide polymorphism (SNP) or another at proximity could predispose to paranoid schizophrenia. Since the minor allele of this polymorphism was correlated with an increased expression of their product, our study validates the hypothesis of excessive pro-inflammatory cytokine in the physiopathology of paranoid schizophrenia.

Evaluation of Partial Cut-out of Sacroiliac Screws From the Sacral Ala Slope via Pelvic Inlet and Outlet View.

PubMed

Zhang, Jingwei; Hamilton, Ryan; Li, Ming; Ebraheim, Nabil A; He, Xianfeng; Liu, Jiayong; Zhu, Limei

2015-12-01

An anatomic and radiographic study of placement of sacroiliac screws. The aim of this study was to quantitatively assess the risk of partial cut-out of sacroiliac screws from the sacral ala slope via inlet and outlet view. The partial cut-out of sacroiliac screws from the superior surface of sacral ala can jeopardize the L5 nerve root, which is difficult to identify on the pelvic inlet and outlet views. Computed tomography images of 60 patients without pelvic ring deformity or injury were used to measure the width (on inlet view) and height (on outlet view) of the sacral ala. The angle of the sacral ala slope was measured on lateral view. According to the measured parameters, the theoretical safe trajectories of screw placement were calculated using inverse trigonometric functions. Under fluoroscopic guidance, a sacroiliac screw was placed close to the midline on both inlet and outlet views, including posterosuperior, posteroinferior, anterosuperior, and anteroinferior regions to the midline. The incidence of screw partial cut-out from the superior surface of sacral ala was identified. The measured widths and heights of the sacral alas were 28.1 ± 2.8 and 29.8 ± 3.1 mm, respectively. The average angle between the superior aspect of the S1 vertebral body and the superior aspect of the sacral ala was 37.2 ± 2.5 degrees. The rate of partial cut-out of the screws from the superior surface of sacral ala slope was 12.5% (5/40) in posterosuperior, 0% (0/40) in posteroinferior, 70% (28/40) in anterosuperior, and 20% (8/40) in anteroinferior. To avoid the risk of partial cut-out from sacroiliac screw placement, more precise description should be added to the conventional description: the sacroiliac screws should be placed at the inferior half portion on outlet view and at the posterior half portion on inlet view. 4.

IFN-gamma-mediated inhibition of human IgE synthesis by IL-21 is associated with a polymorphism in the IL-21R gene.

PubMed

Pène, Jérôme; Guglielmi, Laurence; Gauchat, Jean-François; Harrer, Nathalie; Woisetschläger, Maximilian; Boulay, Vera; Fabre, Jean-Michel; Demoly, Pascal; Yssel, Hans

2006-10-15

IL-21 is a cytokine produced by CD4+ T cells that has been reported to regulate human, as well as, mouse T and NK cell function and to inhibit Ag-induced IgE production by mouse B cells. In the present study, we show that human rIL-21 strongly enhances IgE production by both CD19+ CD27- naive, and CD19+ CD27+ memory B cells, stimulated with anti-CD40 mAb and rIL-4 and that it promotes the proliferative responses of these cells. However, rIL-21 does not significantly affect anti-CD40 mAb and rIL-4-induced Cepsilon promoter activation in a gene reporter assay, nor germline Cepsilon mRNA expression in purified human spleen or peripheral blood B cells. In contrast, rIL-21 inhibits rIL-4-induced IgE production in cultures of PBMC or total splenocytes by an IFN-gamma-dependent mechanism. The presence of a polymorphism (T-83C), in donors heterozygous for this mutation was found to be associated not only with lower rIL-21-induced IFN-gamma production levels, but also with a lower sensitivity to the inhibitory effects of IL-21 on the production of IgE, compared with those in donors expressing the wild-type IL-21R. Taken together, these results show that IL-21 differentially regulates IL-4-induced human IgE production, via its growth- and differentiation-promoting capacities on isotype-, including IgE-, committed B cells, as well as via its ability to induce IFN-gamma production, most likely by T and NK cells, whereas the outcome of these IL-21-mediated effects is dependent on the presence of a polymorphism in the IL-21R.

Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsieh, Yi-Chen; Lien, Li-Ming; School of Medicine, Taipei Medical University, Taipei, Taiwan

2011-08-15

Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study.more » Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis

TNF-alpha and IL-10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population.

PubMed

Javor, J; Chmurova, N; Parnicka, Z; Ferencik, S; Grosse-Wilde, H; Buc, M; Svecova, D

2010-01-01

Pemphigus vulgaris is a rare chronic autoimmune disease of skin and mucous membranes, with several cytokines participating in its development. The role of their gene polymorphisms in susceptibility to the disease is, however, not fully understood. The aim of our case-control study was to investigate whether some of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes (IL-1alpha, IL-1beta, IL-1RI, IL-1Ra, IL-4Ralpha, IL-12, IFN-gamma, TGF-beta1, TNF-alpha, IL-2, IL-4, IL-6 and IL-10) are associated with pemphigus vulgaris in the Slovak population. DNA samples were obtained from 34 pemphigus vulgaris patients and 140 healthy controls of Slovak origin. Cytokine gene SNPs were determined using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Results We found a weak association between pemphigus vulgaris and polymorphic variants in TNF-alpha and IL-10 genes only, with haplotypes TNF-alpha-308G/-238G and IL-10 -1082A/-819C/-592C being significantly overrepresented in pemphigus vulgaris patients (TNF-alpha GG: 94.12% vs. 82.86%, P = 0.0216; IL-10 ACC: 44.12% vs. 30.00%, P = 0.0309). Our preliminary results suggest that certain TNF-alpha and IL-10 gene polymorphisms might contribute to genetic susceptibility to pemphigus vulgaris; however, their overall impact on disease development will be rather limited.

Lack of association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian, African American, and Asian children and adults.

PubMed

Onel, K B; Huo, D; Hastings, D; Fryer-Biggs, J; Crow, M K; Onel, K

2009-01-01

The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE (n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE.

Lack of Association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian, African American, and Asian children and adults

PubMed Central

Onel, KB; Huo, D; Hastings, D; Fryer-Biggs, J; Crow, MK; Onel, K

2009-01-01

The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE (n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE. PMID:19074170

ALA-induced PpIX fluorescence in epileptogenic tissue

NASA Astrophysics Data System (ADS)

Kleen, Jonathan K.; Valdes, Pablo A.; Harris, Brent T.; Holmes, Gregory L.; Paulsen, Keith D.; Roberts, David W.

2011-03-01

Astrogliotic tissue displays markedly increased levels of ALA-induced PpIX fluorescence, making it useful for fluorescence-guided resection in glioma surgery. In patients with temporal lobe epilepsy (TLE) and corresponding animal models, there are areas of astrogliosis that often co-localize with the epileptic focus, which can be resected to eliminate seizures in the majority of treated patients. If this epileptogenic tissue can exhibit PpIX fluorescence that is sufficiently localized, it could potentially help identify margins in epilepsy surgery. We tested the hypothesis that ALA-induced PpIX fluorescence could visually accentuate epileptogenic tissue, using an established animal model of chronic TLE. An acute dose of pilocarpine was used to induce chronic seizure activity in a rat. This rat and a normal control were given ALA, euthanized, and brains examined post-mortem for PpIX fluorescence and neuropathology. Preliminary evidence indicates increased PpIX fluorescence in areas associated with chronic epileptic changes and seizure generation in TLE, including the hippocampus and parahippocampal areas. In addition, strong PpIX fluorescence was clearly observed in layer II of the piriform cortex, a region known for epileptic reorganization and involvement in the generation of seizures in animal studies. We are further investigating whether ALA-induced PpIX fluorescence can consistently identify epileptogenic zones, which could warrant the extension of this technique to clinical studies for use as an adjuvant guidance technology in the resection of epileptic tissue.

Conformational analysis of α-helical polypeptide included L-proline residue by high-resolution solid-state NMR measurement and quantum chemical calculation

NASA Astrophysics Data System (ADS)

Souma, Hiroyuki; Shoji, Akira; Kurosu, Hiromichi

2008-10-01

We challenged the problem about the stabilization mechanism of an α-helix formation for polypeptides containing L-proline (Pro) residue. We computed the optimized structure of α-helical poly( L-alanine) molecules including a Pro residue, H-(Ala) 8-Pro-(Ala) 9-OH, based on the molecular orbital calculation with density functional theory, B3LYP/6-31G(d) and the 13C and 15N chemical shift values based on the GIAO-CHF method with B3LYP/6-311G(d,p), respectively. It was found that two kinds of optimized structures, 'Bent structure' and 'Included α-helix structure', were preferred structures in H-(Ala) 8-Pro-(Ala) 9-OH. In addition, based on the precise 13C and 15N chemical shift data of the simple model, we successfully analyzed the secondary structure of well-defined synthetic polypeptide H-(Phe-Leu-Ala) 3-Phe C-Pro-Ala N-(Phe-Leu-Ala) 2-OH (FLA-11P), the secondary structure of which was proven to the 'Included α-helix structure'.

Computational Prediction of the Protonation Sites of Ac-Lys-(Ala)n-Lys-NH2 Peptides through Conceptual DFT Descriptors.

PubMed

Sastre, Sebastián; Frau, Juan; Glossman-Mitnik, Daniel

2017-03-13

Six density functionals (M11, M11L, MN12L, MN12SX, N12, and N12SX) in connection with the Def2TZVP basis set and the SMD solvation model (water as a solvent) have been assessed for the calculation of the molecular structure and properties of several peptides with the general formulaAc-Lys-(Ala)n-Lys-NH2,withn=0to5  [...].

Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo.

PubMed

García-Martín, Elena; Ramos, María I; Cornejo-García, José A; Galván, Segismundo; Perkins, James R; Rodríguez-Santos, Laura; Alonso-Navarro, Hortensia; Jiménez-Jiménez, Félix J; Agúndez, José A G

2018-01-01

Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals. Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses. Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os . Reaction and motor times were determined before ethanol challenge (basal), and when participants reached peak ethanol concentrations. We analyzed all common missense polymorphisms described in the 19 genes coding for the GABA-A receptor subunits by using TaqMan probes. Results: The GABRA6 rs4454083 T/C polymorphisms were related to motor times, with individuals carrying the C/C genotype having faster motor times, both, at basal and at peak ethanol concentrations. The GABRA4 rs2229940 T/T genotype was associated to faster reaction times and with lower ethanol effects, determined as the difference between basal reaction time and reaction time at peak concentrations. All these associations remained significant after correction for multiple comparisons. No significant associations were observed for the common missense SNPs GABRB3 rs12910925, GABRG2 rs211035, GABRE rs1139916, GABRP rs1063310, GABRQ rs3810651, GABRR1 rs12200969 or rs1186902, GABRR2 rs282129, and GABRR3 rs832032. Conclusions: This study provides novel information supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo .

Prevalence of the rs1801282 single nucleotide polymorphism of the PPARG gene in patients with metabolic syndrome.

PubMed

Rocha, Renato Marano; Barra, Gustavo Barcelos; Rosa, Érica Carine Campos Caldas; Garcia, Érica Correa; Amato, Angélica Amorim; Azevedo, Monalisa Ferreira

2015-08-01

This study aimed to get the genotypic and allelic frequencies of rs1801282 in 179 volunteer donors and 154 patients with Metabolic syndrome (MetS) in Brasilia, Brazil and also examine the association with anthropometric, biochemical and hemodynamic variables in the latter group. MetS comprises a group of diseases resulting from insulin resistance, in-creased risk of type 2 diabetes and atherosclerotic cardiovascular disease. MetS is defined by the presence of increased visceral fat, atherogenic dyslipidemia (elevated triglycerides (TGL)), with decreased high density lipoprotein (HDL) and increased low density lipoprotein (LDL) levels, hypertension (BPH) and disturbances in glucose homeostasis representing a significant burden across the world due to the alarming increase in the incidence over the last decades besides their significant morbidity and mortality. Peroxisome proliferator activated receptor-gamma (PPARg) has been mentioned as a candidate gene for determining the risk of MetS. It is a member of the nuclear receptors superfamily and a ligand-activated transcription factor, which regulates the expression of genes involved in the network lipogenesis and adipogenesis, insulin sensitivity, energy balance, inflammation, angiogenesis and atherosclerosis. Among the PPARG genetic variants, single nucleotide polymorphism rs1801282 has been the most extensively studied one since it was first described by Yen and cols. in 1997. This polymorphism is characterized by the replacement of a proline (CCC) to an alanine (GCA) at codon 12 of exon B, due to the exchange of a cytosine with a guanine. The Ala allele frequency varies in different ethnic groups. DNA was extracted using Chelex-100 method and determinations of genotypes were performed by allele-specific chain reaction. The distribution of genotype frequency of the MetS group was not statistically different from the frequency in the donor population at large. In the first group, genotype frequency was CC to 0

Relationship between a GABAA alpha 6 Pro385Ser substitution and benzodiazepine sensitivity.

PubMed

Iwata, N; Cowley, D S; Radel, M; Roy-Byrne, P P; Goldman, D

1999-09-01

In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABAA alpha 6 receptor. The authors detected a Pro385Ser [1236C > T] amino acid substitution in the human GABAA alpha 6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait.

Stimulation of respiratory changes in alae nasi length by chemoreceptor activation.

PubMed

Van Lunteren, E; Haxhiu, M A; Cherniack, N S

1986-03-01

Respiratory-related changes in length of the nasal dilator muscle, the alae nasi muscle, were measured using sonomicrometry in ten anesthetized (pentobarbital), tracheostomized, spontaneously breathing dogs. Piezoelectric crystals were inserted 7-25 mm apart along the direction of the alae nasi muscle fibers, and the effects of progressive hyperoxic hypercapnia and a peripheral and central chemoreceptor stimulant, nicotine (10-500 micrograms intravenously), were ascertained. The alae nasi shortened during inspiration in all animals, started to lengthen again towards the end of inspiration, returned to resting length during the first portion of expiration (Te-1), and remained at resting length for the remainder of expiration (Te-2). The amount of alae nasi inspiratory shortening was increased by occluding the airway for a single breath. Progressive hypercapnia caused progressive increases in the amount and velocity of nasal muscle inspiratory shortening during both unoccluded and occluded breaths; similar stimulatory effects on inspiratory shortening were seen following nicotine administration. Furthermore, both chemoreceptor stimulants caused a delay in the return of the muscle to its resting length during expiration, resulting in a significant increase in Te-1 relative to Te (Te-1/Te), and a greater amount of nasal muscle shortening to be present during Te-1. In some animals these agents also caused tonic shortening of the alae nasi, so that the muscle never returned to its resting length. These results suggest that inspiratory shortening of the alae nasi is inhibited by vagal inputs, but that chemoreceptor activation increases the amount of muscle shortening during both inspiration and early expiration.

Interferon-gamma +874 T/A and interleukin-10 -1082 A/G single nucleotide polymorphism in Egyptian children with tuberculosis.

PubMed

Mosaad, Y M; Soliman, O E; Tawhid, Z E; Sherif, D M

2010-10-01

The aim was to investigate the association of interferon-gamma (IFN-γ) +874 T/A and interleukin-10 (IL-10)-1082 A/G single nucleotide polymorphisms with tuberculous infection and post-BCG lymphadenitis in Egyptian children. IFN-γ +874 T/A and IL-10 -1082 A/G polymorphism detection by amplification refractory mutation system technique was carried out for 110 patients with TB, 40 patients with post-BCG lymphadenitis and 118 healthy controls. IFN-γ +874 A allele was higher in TB and post-BCG patients than those in healthy controls (Pc=0.006 and 0.002, respectively). IFN-γ +874 genotype AA was significantly higher in patients with TB than that in control (Pc=0.015), in extrapulmonary than patients with pulmonary TB (PTB) (Pc=0.009), and young children with TB below 5 years (Pc=0.024). No statistically significant differences were observed between patients with TB and controls for the frequency of IL-10(-1082) alleles or genotypes (P>0.05); however, a statistically significant difference in the frequency of IL-10 (-1082) GG genotype was found between patients with pulmonary and extrapulmonary TB (Pc=0.003). Low producer IFN-γ +874 A/A genotype is associated with post-BCG lymphadenitis and TB disease especially in younger children below 5 years. IL-10-1082 G/G genotype did not exhibit significant association except for increased GG frequency in PTB. Both cytokine polymorphisms have no relation to tuberculin reaction in patients with TB. © 2010 The Authors. Scandinavian Journal of Immunology © 2010 Blackwell Publishing Ltd.

Influence of the 48867A>C (Asp358Ala) IL6R polymorphism on response to a lifestyle modification intervention in individuals with metabolic syndrome.

PubMed

Vargas, V R A; Bonatto, S L; Macagnan, F E; Feoli, A M P; Alho, C S; Santos, N D V; Schmitt, V M

2013-02-28

We evaluated the response of individuals with metabolic syndrome to lifestyle modification intervention and examined the influence of the 48867A>C (Asp358Ala) IL6R (rs2228145) polymorphism on this response. Participants were randomly divided into two groups: NI, nutritional intervention; NIE, nutritional intervention and exercise practice. Intervention lasted three months and participants completed a comprehensive evaluation and had blood collected for biochemical measurements. Eighty-two sedentary individuals with at least three criteria for metabolic syndrome were included. Comparing metabolic syndrome parameters before and after intervention, a reduction of waist circumference was observed, although significant only for AA and AC genotypes. Also, a decrease in triglyceride levels was observed (significant for AA genotype individuals; for the AC genotype, only in the NIE group). Significant reduction of fasting glucose level was observed in all AA genotype individuals; for the AC genotype, only in the NI group. Systolic blood pressure showed significant reduction in AA and AC genotype individuals. After three months of lifestyle modification intervention, improvement in some of the metabolic syndrome parameters was observed, some associated with the IL6R genotype. At enrollment, participants with genotypes AA and AC showed more severe conditions regarding metabolic syndrome inclusion criteria, supporting previous reports that the A allele is a genetic risk factor. These individuals, however, had a better response to intervention compared to individuals with the CC genotype, suggesting that nutritional control and exercise practice could prevent risks associated with metabolic syndrome more efficiently in individuals bearing the A allele.

Meta-Analysis on Associations of RGS1 and IL12A Polymorphisms with Celiac Disease Risk.

PubMed

Guo, Cong-Cong; Wang, Man; Cao, Feng-Di; Huang, Wei-Huang; Xiao, Di; Ye, Xing-Guang; Ou, Mei-Ling; Zhang, Na; Zhang, Bao-Huan; Liu, Yang; Yang, Guang; Jing, Chun-Xia

2016-03-30

The pathogenesis of celiac disease (CD) has been related to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but the existing findings are inconsistent. Our aim is to investigate the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 in RGS1 and rs17810546 in IL12A) with CD risk using meta-analysis. We searched PubMed and Web of Science on RGS1 rs2816316 and IL12A rs17810546 with CD risk. Odds ratio (OR) and 95% confidence interval (CI) of each SNP were estimated. All statistical analyses were performed on Stata 12.0. A total of seven studies were retrieved and analyzed. The available data indicated the minor allele C of rs2816316 was negatively associated with CD (C vs. A: OR = 0.77, 95% CI = 0.74-0.80), and a positive association was found for the minor allele G of rs17810546 (G vs. A: OR = 1.37, 95% CI = 1.31-1.43). The co-dominant model of genotype effect confirmed the significant associations between RGS1 rs2816316/IL12A rs17810546 and CD. No evidence of publication bias was observed. Our meta-analysis supports the associations of RGS1 and IL12A with CD and strongly calls for further studies to better understand the roles of RGS1 and IL12A in the pathogenesis of CD.

Transforming growth factor beta1 gene variation Leu10Pro affects secretion and function in hepatic cells.

PubMed

Gu, Xing; Ji, Xin; Shi, Le-Hua; Yi, Chang-Hong; Zhao, Yun-Peng; Wang, Ai-Hua; Lu, Lun-Gen; Yu, Wen-Bo; Gao, Chun-Fang

2012-11-01

Our previous work revealed transforming growth factor beta1 (TGFβ1) gene polymorphisms are associated with susceptibility to hepatocellular carcinoma and liver cirrhosis. However, no further study of functional substitution in hepatic cells has yet been reported. This study was designed to uncover the functional mechanisms of TGFβ1 gene polymorphisms in the pathogenesis of liver diseases. Two recombinant TGFβ1 expression plasmids containing TGFβ1 codon 10 Leu/Pro variation were constructed with CMV promoter and transfected into human hepatoma cell lines (HepG2 and SMMU 7721), hepatic stellate cells (LX-2), and immortalized hepatocytes (L02). The secretion capacities of TGFβ1 protein in the transfected cells were determined by ELISA. Apoptosis, proliferative activity, and expression of CD 105, CD83, and CD80 were also measured by use of flow cytometry. The ELISA results showed that cells transfected with CMV-Pro10 were more capable of TGFβ1 secretion than those transfected with CMV-Leu10. Functionally, CMV-Pro10 was more apoptosis-protective and induced more proliferation than CMV-Leu10 in transfected hepatic cells. Pro10 up-regulated expression of CD105 and down-regulated expression of CD83. TGFβ1 gene Leu10Pro variation in signal peptide has significant effects on TGFβ1 secretion and functions in hepatic cells.

Crystallization and transformation of polymorphic forms of trioleoyl glycerol and 1,2-dioleoyl-3-rac-linoleoyl glycerol.

PubMed

Bayés-García, Laura; Calvet, Teresa; Cuevas-Diarte, Miquel Àngel; Ueno, Satoru; Sato, Kiyotaka

2013-08-08

This study examined the influence of different thermal treatments on the crystallization and transformation of trioleoyl glycerol (OOO) and 1,2-dioleoyl-3-rac-linoleoyl glycerol (OOL). Two triacylglycerol (TAG) samples were cooled at 0.5-15 °C·min(-1) and heated at 2 and 15 °C·min(-1). The polymorphic characteristics of the two TAGs were analyzed in situ using differential scanning calorimetry, Raman spectroscopy, and synchrotron radiation X-ray diffraction. Multiple polymorphic forms were identified in OOO (α, β'2, β'1, β2, and β1) and OOL (α, β'2, and β'1). Larger quantities of more stable forms (e.g., β2 and β1 of OOO and β'1 of OOL) were obtained when the samples were slowly cooled and heated. In contrast, less stable polymorphs were obtained with increased cooling and heating rates. Polymorphic transformations occurred in either solid-state or melt-mediation and were influenced by heating rates. The results were analyzed by considering the activation energies for crystallization and transformation of stable and less stable polymorphic forms in comparison with previous studies on 1,3-dipalmitoyl-2-oleoyl-glycerol and 1, 3-dioleoyl-2-palmitoyl-glycerol.

Ala-7, His-10 and Arg-12 are crucial amino acids for activity of a synthetically engineered μ-conotoxin.

PubMed

Lebbe, Eline K M; Peigneur, Steve; Brullot, Ward; Verbiest, Thierry; Tytgat, Jan

2014-03-01

Cone snail toxins or conotoxins are often small cysteine-rich peptides which have shown to be highly selective ligands for a wide range of ion channels such as voltage-gated sodium channels (Na(V)s). Na(V)s participate in a wide range of electrophysiological processes. Consequently, their malfunction has been associated with numerous diseases. The development of subtype-selective modulators of Na(V)s remains highly important in the treatment of such disorders. In order to expand our knowledge in the search for novel therapeutics to treat Na(V)-related diseases, we explored the field of peptide engineering. In the current study, the impact of well considered point mutations into a bioactive peptide that was found to be a very potent and selective inhibitor of Na(V)s (i.e. Midi R2) was examined. We designed two peptides, named Midi R2[A7G] and Midi R2[H10A, R12A] which have mutations at position 7, and both 10 and 12, respectively. Electrophysiological recordings indicated that an Ala to Gly mutation at position 7 increased IC50-values from the nanomolar range to the micromolar range. For Midi R2[H10A, R12A] at a concentration of 10 μM, activity is even reduced to 0-10% for all of the tested Na(V)-channels. Circular dichroism measurements proved that overall structural conformations did not change. These findings suggest that the minimal space between the second and the third intercysteine loop of Midi R2 is the sequence RRWARDHSR and that His at position 10 and Arg at position 12 are crucial amino acids for the potency and specificity of Midi R2. In this way, new insights into the structure-activity relationships of μ-conotoxins were found. Copyright © 2013 Elsevier Inc. All rights reserved.

Treating cutaneous squamous cell carcinoma using ALA PLGA nanoparticle-mediated photodynamic therapy in a mouse model

NASA Astrophysics Data System (ADS)

Wang, Xiaojie; Shi, Lei; Tu, Qingfeng; Wang, Hongwei; Zhang, Haiyan; Wang, Peiru; Zhang, Linglin; Huang, Zheng; Wang, Xiuli; Zhao, Feng; Luan, Hansen

2015-03-01

Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP)-assisted ALA delivery for topical photodynamic therapy (PDT) of cutaneous SCC. Methods: UV-induced cutaneous SCCs were established in hairless mice. ALA loaded polylactic-co-glycolic acid (PLGA) NPs were prepared and characterized. The kinetics of ALA PLGA NPs-induced protoporphyrin IX (PpIX) fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined. Results: PLGA NPs could enhance PpIX production in SCC. ALA PLGA NP mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC. Conclusion: PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC.

The role of loop ZA and Pro371 in the function of yeast Gcn5p bromodomain revealed through molecular dynamics and experiment.

PubMed

Pizzitutti, Francesco; Giansanti, Andrea; Ballario, Paola; Ornaghi, Prisca; Torreri, Paola; Ciccotti, Giovanni; Filetici, Patrizia

2006-01-01

Biological experiments were combined with molecular dynamics simulations to understand the importance of amino acidic residues present in the bromodomain of the yeast histone acetyltransferase Gcn5p. It was found that residue Pro371 plays an important role in the molecular recognition of the acetylated histone H4 tail by Gcn5p bromodomain. Crystallographic analysis of the complex showed that this residue does not directly interact with the histone substrate. It has been demonstrated that a double mutation Pro371Thr and Met372Ala in the Gcn5p bromodomain impairs chromatin remodeling activity. It is demonstrated here that, in this double mutant and in the fully deleted bromodomain strain, there is lower growth under amino acid deprivation conditions. By in vitro surface plasmon resonance (Biacore) experiments it is shown that the binding affinity of the double mutation to acetyl lysine 16 histone H4 peptide decreases. Molecular dynamics simulations were used to explain this loss in acetyl lysine-Gcn5p bromodomain affinity, in the double mutant. By comparing nanosecond molecular dynamics trajectories of the native as well as the single and doubly mutated bromodomain, it is concluded that the presence of Pro371 is important to the functionality of the Gcn5p bromodomain. In the simulation a point mutation involving this highly conserved residue induced an increase in the flexibility of the ZA loop, which in turn modulated the exposure of the binding pocket to the acetyl lysine. The combined double mutations (Pro371Thr-Met372Ala) not only markedly perturb the motion of the ZA loop but also destabilize the entire structure of the bromodomain. Copyright 2005 John Wiley & Sons, Ltd.

Polymorphism in alkali metal uranyl nitrates: Synthesis and crystal structure of gamma-K(UO2)(NO3)3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jouffret, Laurent J.; Krivovichev, Sergey V.; Burns, Peter C.

2011-07-20

Single crystals of γ-K(UO₂)(NO₃)₃ were prepared from aqueous solutions by evaporation. The crystal structure [orthorhombic, Pbca (61), a = 9.2559(3) Å, b = 12.1753(3) Å, c = 15.8076(5) Å, V = 1781.41(9) ų, Z = 8] was determined by direct methods and refined to R₁ = 0.0267 on the basis of 3657 unique observed reflections. The structure is composed of isolated anionic uranyl trinitrate units, [(UO₂)(NO₃)₃] –, that are linked through eleven-coordinated K + cations. Both known polymorphs of K(UO₂)(NO₃)₃ (α- and γ-phases) can be considered as based upon sheets of isolated complex [(UO₂)(NO₃)₃] – ions separated by K +more » cations. The existence of polymorphism in the two K[UO₂(NO₃)₃] polymorphs is due to the different packing modes of uranyl trinitrate clusters that adopt the same two-dimensional but different three-dimensional arrangements.« less

Proteomic identification of Drosophila melanogaster male accessory gland proteins, including a pro-cathepsin and a soluble gamma-glutamyl transpeptidase.

PubMed

Walker, Michael J; Rylett, Caroline M; Keen, Jeff N; Audsley, Neil; Sajid, Mohammed; Shirras, Alan D; Isaac, R Elwyn

2006-05-02

In Drosophila melanogaster, the male seminal fluid contains proteins that are important for reproductive success. Many of these proteins are synthesised by the male accessory glands and are secreted into the accessory gland lumen, where they are stored until required. Previous studies on the identification of Drosophila accessory gland products have largely focused on characterisation of male-specific accessory gland cDNAs from D. melanogaster and, more recently, Drosophila simulans. In the present study, we have used a proteomics approach without any sex bias to identify proteins in D. melanogaster accessory gland secretions. Thirteen secreted accessory gland proteins, including seven new accessory gland proteins, were identified by 2D-gel electrophoresis combined with mass spectrometry of tryptic fragments. They included protein-folding and stress-response proteins, a hormone, a lipase, a serpin, a cysteine-rich protein and two peptidases, a pro-enzyme form of a cathepsin K-like cysteine peptidase and a gamma-glutamyl transpeptidase. Enzymatic studies established that accessory gland secretions contain a cysteine peptidase zymogen that can be activated at low pH. This peptidase may have a role in the processing of female and other male-derived proteins, but is unlikely to be involved in the processing of the sex peptide. gamma-Glutamyl transpeptidases are type II integral membrane proteins; however, the identified AG gamma-glutamyl transpeptidase (GGT-1) is unusual in that it is predicted to be a soluble secreted protein, a prediction that is supported by biochemical evidence. GGT-1 is possibly involved in maintaining a protective redox environment for sperm. The strong gamma-glutamyl transpeptidase activity found in the secretions provides an explanation for the observation that glutamic acid is the most abundant free amino acid in accessory gland secretions of D. melanogaster. We have applied biochemical approaches, not used previously, to characterise

Analysis of cytotoxic T lymphocyte associated antigen 4 gene polymorphisms in patients with ulcerative colitis.

PubMed

Lankarani, Kamran B; Karbasi, Ashraf; Kalantari, Tahereh; Yarmohammadi, Hooman; Saberi-Firoozi, Mehdi; Alizadeh-Naeeni, Mahvash; Taghavi, Ali R; Fattahi, Mahammad R; Ghaderi, Abbas

2006-02-01

Ulcerative colitis (UC) is a multifactorial disease associated with dysregulated immunity. Recently, cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms have been reported in association with several autoimmune diseases in several populations. In the present study, the possible implication of the CTLA-4 gene as a risk factor for UC in the Iranian population was investigated. One hundred UC patients and 100 healthy subjects were studied. CTLA-4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphisms were investigated by polymerase chain reaction single strand confirmation polymorphism method. Four of the patients and one of the healthy controls were excluded from the study because of incomplete DNA extraction. The allele frequencies of A and G in 96 patients (A: 66.1%; G: 33.9%) were not significantly different from the 99 control subjects (A: 63.1%; G: 36.9%, P > 0.05). No significant differences in the distribution of genotype frequencies were observed between A + 49G gene polymorphisms and UC in the Iranian population (P > 0.05). CTLA-4 polymorphism is not associated with UC in the Iranian population.

Superoxide dismutase, catalase, glutathione peroxidase and gluthatione S-transferases M1 and T1 gene polymorphisms in three Brazilian population groups.

PubMed

de Oliveira Hiragi, Cássia; Miranda-Vilela, Ana Luisa; Rocha, Dulce Maria Sucena; de Oliveira, Silviene Fabiana; Hatagima, Ana; de Nazaré Klautau-Guimarães, Maria

2011-01-01

Antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX1) reduce the oxidation rates in the organism. Gluthatione S-transferases (GSTs) play a vital role in phase 2 of biotransformation of many substances. Variation in the expression of these enzymes suggests individual differences for the degree of antioxidant protection and geographical differences in the distribution of these variants. We described the distribution frequency of CAT (21A/T), SOD2 (Ala9Val), GPX1 (Pro198Leu), GSTM1 and GSTT1 polymorphisms in three Brazilian population groups: Kayabi Amerindians (n = 60), Kalunga Afro-descendants (n = 72), and an urban mixed population from Federal District (n = 162). Frequencies of the variants observed in Kalunga (18% to 58%) and Federal District (33% to 63%) were similar to those observed in Euro and Afro-descendants, while in Kayabi (3% to 68%), depending on the marker, frequencies were similar to the ones found in different ethnic groups. Except for SOD2 in all population groups studied here, and for GPX1 in Kalunga, the genotypic distributions were in accordance with Hardy-Weinberg Equilibrium. These data can clarify the contribution of different ethnicities in the formation of mixed populations, such as that of Brazil. Moreover, outcomes will be valuable resources for future functional studies and for genetic studies in specific populations. If these studies are designed to comprehensively explore the role of these genetic polymorphisms in the etiology of human diseases they may help to prevent inconsistent genotype-phenotype associations in pharmacogenetic studies.

Application of 5-ALA for differential diagnostics of stomach diseases

NASA Astrophysics Data System (ADS)

Okhotnikova, Natalja L.; Dadvany, Sergey A.; Kuszin, Michail I.; Kharnas, Sergey S.; Zavodnov, Victor Y.; Sklyanskaya, Olga A.; Loschenov, Victor B.; Volkova, Anna I.; Agafonov, Valery V.

2001-01-01

59 patients with stomach diseases including gastric cancer or polyp, gastritis, esofagus disease were investigated. Before gastroscopy all patients were given 5-ALA in doses 5mg, 10mg and 20mg per 1kg of body weight orally. Fluorescence diagnostics which estimates concentration of ALA-induced PPIX in regular and alternated tissues of gastric mucosa were carried out in 2-4 hours. Using of 5-ALA has shown high diagnostic effectiveness for differential diagnostics of stomach diseases. This technique has proved 10 diagnosis of cancer and revealed 15 malignant stomach diseases including 4 cancer in situ for patients with preliminary diagnosis of gastric ulcer. It also revealed 5 patients with enhanced fluorescence for which aimed biopsy has shown high degree of inflammation process. The latter were assigned as a risk group.

Latest results of 5-ALA-based fluorescence diagnosis and other medical disciplines

NASA Astrophysics Data System (ADS)

Baumgartner, Reinhold

1999-02-01

Preclinical and clinical studies on 5-aminolevulinic acid (5- ALA) induced Protoporphyrin IX (PPIX) are performed in various departments now following promising clinical results for the detection of bladder cancer in urology. This paper provides an overview on the progress of 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynecology and ENT coordinated by the Laser Research Laboratory of the Ludwig-Maximilians-University in Munich. 5-ALA can be applied either topically or systematically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumor visible with naked eyes. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolor remission and fluorescence imaging, therefore, should improve tumor localization in future.

Conversion of the agent-oriented domain-specific language ALAS into JavaScript

NASA Astrophysics Data System (ADS)

Sredojević, Dejan; Vidaković, Milan; Okanović, Dušan; Mitrović, Dejan; Ivanović, Mirjana

2016-06-01

This paper shows generation of JavaScript code from code written in agent-oriented domain-specific language ALAS. ALAS is an agent-oriented domain-specific language for writing software agents that are executed within XJAF middleware. Since the agents can be executed on various platforms, they must be converted into a language of the target platform. We also try to utilize existing tools and technologies to make the whole conversion process as simple as possible, as well as faster and more efficient. We use the Xtext framework that is compatible with Java to implement ALAS infrastructure - editor and code generator. Since Xtext supports Java, generation of Java code from ALAS code is straightforward. To generate a JavaScript code that will be executed within the target JavaScript XJAF implementation, Google Web Toolkit (GWT) is used.

Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis.

PubMed

Deraos, George; Rodi, Maria; Kalbacher, Hubert; Chatzantoni, Kokona; Karagiannis, Fotios; Synodinos, Loukas; Plotas, Panayiotis; Papalois, Apostolos; Dimisianos, Nikolaos; Papathanasopoulos, Panagiotis; Gatos, Dimitrios; Tselios, Theodore; Apostolopoulos, Vasso; Mouzaki, Athanasia; Matsoukas, John

2015-08-28

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system, and it has been established that autoreactive T helper (Th) cells play a crucial role in its pathogenesis. Myelin basic protein (MBP) epitopes are major autoantigens in MS, and the sequence MBP87-99 is an immunodominant epitope. We have previously reported that MBP87-99 peptides with modifications at principal T-cell receptor (TCR) contact sites suppressed the induction of EAE symptoms in rats and SJL/J mice, diverted the immune response from Th1 to Th2 and generated antibodies that did not cross react with the native MBP protein. In this study, the linear and cyclic analogs of the MBP87-99 epitope, namely linear (Ala91,Ala96)MBP87-99 (P2) and cyclo(87-99)(Ala91,Ala96)MBP87-99 (P3), were evaluated for their binding to HLA-DR4, stability to lysosomal enzymes, their effect on cytokine secretion by peripheral blood mononuclear cells (PBMC) derived from MS patients or healthy subjects (controls), and their effect in rat EAE. P1 peptide (wild-type, MBP87-99) was used as control. P2 and P3 did not alter significantly the cytokine secretion by control PBMC, in contrast to P1 that induced moderate IL-10 production. In MS PBMC, P2 and P3 induced the production of IL-2 and IFN-γ, with a simultaneous decrease of IL-10, whereas P1 caused a reduction of IL-10 secretion only. The cellular response to P3 indicated that cyclization did not affect the critical TCR contact sites in MS PBMC. Interestingly, the cyclic P3 analog was found to be a stronger binder to HLA-DR4 compared to linear P2. Moreover, cyclic P3 was more stable to proteolysis compared to linear P2. Finally, both P2 and P3 suppressed EAE induced by an encephalitogenic guinea pig MBP74-85 epitope in Lewis rats whereas P1 failed to do so. In conclusion, cyclization of myelin altered peptide ligand (Ala91,Ala96)MBP87-99 improved binding affinity to HLA-DR4, resistance to proteolysis and antigen-specific immunomodulation

Prediction about severity and outcome of sepsis by pro-atrial natriuretic peptide and pro-adrenomedullin.

PubMed

Wang, Rui-lan; Kang, Fu-xin

2010-06-01

Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. The aim of the present study was to evaluate the prognostic value of pro-atrial natriuretic peptide (pro-ANP) and pro-adrenomedullin (pro-ADM) levels in a cohort of medical intensive care patients and to compare it with that of other known biomarkers and physiological scores. Blood samples of 51 consecutive critically ill patients admitted to the intensive care unit and 53 age-matched healthy control people were evaluated in this prospective study. The prognostic value of pro-ANP and pro-ADM levels was compared with that of acute physiology and chronic health evaluation (APACHE) II scores and various biomarkers such as C-reactive protein, interleukin-6 and procalcitonin. Pro-ANP and pro-ADM were detected by a new sandwich immunoassay. On admission, 25 patients had systemic inflammatory response syndrome (SIRS), 12 sepsis, 9 severe sepsis and 5 septic shock. At that time, the median levels (ng/ml) of pro-ANP and pro-ADM were 87.22 and 0.34 respectively in patients with SIRS, 1533.30 and 2.23 in those with sepsis, 1098.73 and 4.57 in those with severe sepsis, and 1933.94 and 8.21 in those with septic shock. With the increasing severity of disease, the levels of pro-ANP and pro-ADM were gradually increased. On admission, the circulating levels of pro-ANP and pro-ADM in patients with sepsis, severe sepsis, or septic shock were significantly higher in non-survivors than in survivors (P less than 0.05). In a receiver operating characteristic curve analysis for the survival of patients with sepsis, the areas under the curve (AUCs) for pro-ANP and pro-ADM were 0.89 and 0.87 respectively, which was similar to the AUCs for procalcitonin and APACHE II scores. Pro-ANP and pro-ADM are valuable biomarkers for prediction of severity of septic patients.

Thermodynamic effects of replacements of Pro residues in helix interiors of maltose-binding protein.

PubMed

Prajapati, R S; Lingaraju, G M; Bacchawat, Kiran; Surolia, Avadhesha; Varadarajan, Raghavan

2003-12-01

Introduction of Pro residues into helix interiors results in protein destabilization. It is currently unclear if the converse substitution (i.e., replacement of Pro residues that naturally occur in helix interiors would be stabilizing). Maltose-binding protein is a large 370-amino acid protein that contains 21 Pro residues. Of these, three nonconserved residues (P48, P133, and P159) occur at helix interiors. Each of the residues was replaced with Ala and Ser. Stabilities were characterized by differential scanning calorimetry (DSC) as a function of pH and by isothermal urea denaturation studies as a function of temperature. The P48S and P48A mutants were found to be marginally more stable than the wild-type protein. In the pH range of 5-9, there is an average increase in T(m) values of P48A and P48S of 0.4 degrees C and 0.2 degrees C, respectively, relative to the wild-type protein. The other mutants are less stable than the wild type. Analysis of the effects of such Pro substitutions in MBP and in three other proteins studied to date suggests that substitutions are more likely to be stabilizing if the carbonyl group i-3 or i-4 to the mutation site is not hydrogen bonded in the wild-type protein. Copyright 2003 Wiley-Liss, Inc.

Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene.

PubMed

Beamer, B A; Negri, C; Yen, C J; Gavrilova, O; Rumberger, J M; Durcan, M J; Yarnall, D P; Hawkins, A L; Griffin, C A; Burns, D K; Roth, J; Reitman, M; Shuldiner, A R

1997-04-28

We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.

Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: preliminary clinical results.

PubMed

Porcaro, G; Brillo, E; Giardina, I; Di Iorio, R

2015-09-01

The clinic use of alpha Lipoic Acid (ALA) is linked to its capability to exert antioxidant effects and, more interestingly, to counteract the pathologic changes of complex networks of cytokines, chemokines and growth factors, restoring their physiological state. The aim of this randomized controlled clinical trial was to test the contribution of oral supplementation of ALA to the standard treatment with Progesterone vaginal suppositories, in healing subchorionic hematomas in patients with threatened miscarriage. Controls were administered only Progesterone suppositories. Nineteen pregnant women in the first trimester of gestation, with threatened miscarriage and ultrasound evidence of subchorionic hematoma, were included in the trial and randomly divided in two groups: controls, treated with 400 mg Progesterone (200 mg 2 times per day), given by vaginal suppositories, and case study treated with the same Progesterone dosage, plus ALA, given orally at the dose of 600 mg (300 mg 2 times per day, DAV®, Lo.Li. Pharma srl, Italy). Sixteen patients completed the trial. Treatment was performed until complete resolution of the clinical picture. In both groups, the subjects improved significantly but, in general, a better and faster evolution in the major signs of threatened miscarriage was observed in the subjects treated with ALA and Progesterone. In these patients, the speed of resorption of subchorionic hematoma was significantly (p ≤ 0.05) superior compared to controls. The ALA and Progesterone group showed a faster decrease or disappearance of all symptoms than that observed in the control group, however the difference was not significant. These preliminary results suggest that ALA supplementation significantly contributes to speed up the process of restoration of physiological conditions in threatened miscarriage and ameliorates the medical conditions of both the mothers and the foetus, probably modulating the networks of cytokines, growth factors and other

Glacier lake outburst floods caused by glacier shrinkage: case study of Ala-Archa valley, Kyrgyz Ala Too, northern Tian Shan, Kyrgyzstan

NASA Astrophysics Data System (ADS)

Petrakov, D.; Erochin, S. A.; Harbor, J.; Ivanov, M.; Rogozhina, I.; Stroeven, A. P.; Usubaliev, R.

2012-12-01

Changes in glacier extent and runoff in Central Asia increase socio-economic stress and may result in political conflict between donors of freshwater (Kyrgyzstan, Tajikistan) and recipients of freshwater (Uzbekistan, China). Glaciers in the Pamir and Tian Shan regions have experienced an unprecedented downwasting due to regional climate changes over the past decades. This is because air temperature increases are in some areas accompanied by a decrease in precipitation. Such conditions have already resulted in a reduction of glacier runoff, especially in the northern and western Tian Shan, and an increase of the number and area of glacial lakes in Kyrgyzstan. Even though glacial lakes in the mountains are in general relatively small and located far from densely populated areas, their outbursts often produce destructive debris flows. Such debris flows are especially common in Kyrgyzstan because of its steep river channels and abundance of Holocene and Quaternary glacier deposits that can be remobilized. The glacial lake outburst flood (GLOF) in the Shakhimardan river catchment in 1999, for example, resulted in 100 fatalities in Uzbekistan, and the GLOF from the Zyndan glacial lake led to substantial economic losses in 2009. According to the latest inventory, there are more than 350 glacial lakes in Kyrgyzstan of which about 70 occur in the Kyrgyz Ala Too. The Ala-Archa valley is among the most important glacierized catchments in Kyrgyzstan. Despite the presence of a relatively small glacier-covered area of 36 km2, the Ala-Archa river is of critical importance to the Bishkek area, its agriculture, and its population which currently exceeds one million. GLOFs are therefore a threat to both numerous settlements of touristic value in the Ala-Archa headwaters and to Bishkek. The Teztor lake in the Adygene catchment of the Ala-Archa river system experienced an outburst during 1988 and 2005. On the early morning of July 31, 2012, this lake began draining through a dam

5-Aminolevulinic Acid (ALA) Alleviated Salinity Stress in Cucumber Seedlings by Enhancing Chlorophyll Synthesis Pathway.

PubMed

Wu, Yue; Jin, Xin; Liao, Weibiao; Hu, Linli; Dawuda, Mohammed M; Zhao, Xingjie; Tang, Zhongqi; Gong, Tingyu; Yu, Jihua

2018-01-01

5-Aminolevulinic acid (ALA) is a common precursor of tetrapyrroles as well as a crucial growth regulator in higher plants. ALA has been proven to be effective in improving photosynthesis and alleviating the adverse effects of various abiotic stresses in higher plants. However, little is known about the mechanism of ALA in ameliorating the photosynthesis of plant under abiotic stress. In this paper, we studied the effects of exogenous ALA on salinity-induced damages of photosynthesis in cucumber ( Cucumis sativus L.) seedlings. We found that the morphology (plant height, leave area), light utilization capacity of PS II [qL, Y(II)] and gas exchange capacity (Pn, gs, Ci, and Tr) were significantly retarded under NaCl stress, but these parameters were all recovered by the foliar application of 25 mg L -1 ALA. Besides, salinity caused heme accumulation and up-regulation of gene expression of ferrochelatase ( HEMH ) with suppression of other genes involved in chlorophyll synthesis pathway. Exogenously application of ALA under salinity down-regulated the heme content and HEMH expression, but increased the gene expression levels of glutamyl-tRNA reductase ( HEMA1 ), Mg-chelatase ( CHLH ), and protochlorophyllide oxidoreductase ( POR ). Moreover, the contents of intermediates involved in chlorophyll branch were increased by ALA, including protoporphyrin IX (Proto IX), Mg-protoporphyrin IX (Mg-Proto IX, protochlorophyllide (Pchlide), and chlorophyll (Chl a and Chl b ) under salt stress. Ultrastructural observation of mesophyll cell showed that the damages of photosynthetic apparatus under salinity were fixed by ALA. Collectively, the chlorophyll biosynthesis pathway was enhanced by exogenous ALA to improve the tolerance of cucumber under salinity.

Effects of CYP2C19 and P2Y12 Gene Polymorphisms on Clinical Results of Patients Using Clopidogrel after Acute Ischemic Cerebrovascular Disease

PubMed Central

Sen, HM; Silan, F; Silan, C; Degirmenci, Y; Ozisik Kamaran, HI

2014-01-01

The CY2C19 and P2Y12 gene polymorphisms are responsible for resistance to clopidogrel, known as drug unresponsiveness. In this study we researched the effect of gene polymorphism on clinical results of patients who began clopidogrel therapy after acute ischemic cerebrovascular disease. The study included 51 patients. The patient group included patients who had begun prophylactic clopidogrel due to acute ischemic cerebrovascular disease in the last 2 years. All patients were monitored by the Neurology Outpatient Clinic at Çanakkale Onsekiz Mart Üniversity Research Hospital, Çanakkale, Turkey, and only those monitored for at least 1 year were included in the study. When the *1, *2 and *3 alleles of the CYP2C19 gene polymorphism were evaluated, two patients were homozygotes for *2/*2, 13 patients were heterozygous for *1/*2 and 36 patients were homozygotes for the wild type *1/*1. No patient had the *3 allele. Three heterozygous patients, one for *2/*2 and two for *1/*2, stopped clopidogrel therapy due to repeated strokes and began taking warfarin. When evaluating P2Y12 52 (G>T) and 34 (C>T) polymorphisms, all alleles were of the wild type. The CYP2C19 and P2Y12 gene polymorphisms may cause recurring strokes linked to insufficient response to treatment of ischemic cerebrovascular disease. In our patient group, three patients suffered repeated strokes and these patients had the CYP2C19*2 gene polymorphism. As a result, before medication use, genetic testing is important for human life, quality of life and economic burden. PMID:25937796

Mutation analysis of BRCA1/2 mutations with special reference to polymorphic SNPs in Indian breast cancer patients.

PubMed

Shah, Nidhi D; Shah, Parth S; Panchal, Yash Y; Katudia, Kalpesh H; Khatri, Nikunj B; Ray, Hari Shankar P; Bhatiya, Upti R; Shah, Sandip C; Shah, Bhavini S; Rao, Mandava V

2018-01-01

Germline mutations BRCA1 and BRCA2 contribute almost equally in the causation of breast cancer (BC). The type of mutations in the Indian population that cause this condition is largely unknown. In this cohort, 79 randomized BC patients were screened for various types of BRCA1 and BRCA2 mutations including frameshift, nonsense, missense, in-frame and splice site types. The purified extracted DNA of each referral patient was subjected to Sanger gene sequencing using Codon Code Analyzer and Mutation Surveyor and next-generation sequencing (NGS) methods with Ion torrent software, after appropriate care. The data revealed that 35 cases were positive for BRCA1 or BRCA2 (35/79: 44.3%). BRCA2 mutations were higher (52.4%) than BRCA1 mutations (47.6%). Five novel mutations detected in this study were p.pro163 frameshift, p.asn997 frameshift, p.ser148 frameshift and two splice site single-nucleotide polymorphisms (SNPs). Additionally, four nonsense and one in-frame deletion were identified, which all seemed to be pathogenic. Polymorphic SNPs contributed the highest percentage of mutations (72/82: 87.8%) and contributed to pathogenic, likely pathogenic, likely benign, benign and variant of unknown significance (VUS). Young age groups (20-60 years) had a high frequency of germline mutations (62/82;75.6%) in the Indian population. This study suggested that polymorphic SNPs contributed a high percentage of mutations along with five novel types. Younger age groups are prone to having BC with a higher mutational rate. Furthermore, the SNPs detected in exons 10, 11 and 16 of BRCA1 and BRCA2 were higher than those in other exons 2, 3 and 9 polymorphic sites in two germline genes. These may be contributory for BC although missense types are known to be susceptible for cancer depending on the type of amino acid replaced in the protein and associated with pathologic events. Accordingly, appropriate counseling and treatment may be suggested.

PC5-A-mediated processing of pro-neurotensin in early compartments of the regulated secretory pathway of PC5-transfected PC12 cells.

PubMed

Barbero, P; Rovère, C; De Bie, I; Seidah, N; Beaudet, A; Kitabgi, P

1998-09-25

Among the members of the proprotein convertase (PC) family, PC1 and PC2 have well established roles as prohormone convertases. Another good candidate for this role is PC5-A that has been shown to be present in the regulated secretory pathway of certain neuroendocrine tissues, but evidence that it can process prohormones is lacking. To determine whether PC5-A could function as a prohormone convertase and to compare its cleavage specificity with that of PC1 and PC2, we stably transfected the rat pheochromocytoma PC12 cell line with PC5-A and analyzed the biosynthesis and subcellular localization of the enzyme, as well as its ability to process pro-neurotensin/neuromedin N (pro-NT/NN) into active peptides. Our data showed that in transfected PC12 cells, PC5-A was converted from its 126-kDa precursor form into a 117-kDa mature form and, to a lesser extent, into a C-terminally truncated 65-kDa form of the 117-kDa product. Metabolic and immunochemical studies showed that PC5-A was sorted to early compartments of the regulated secretory pathway where it colocalized with immunoreactive NT. Furthermore, pro-NT/NN was processed in these compartments according to a pattern that differed from that previously described in PC1- and PC2-transfected PC12 cells. This pattern resembled that previously reported for pro-NT/NN processing in the adrenal medulla, a tissue known to express high levels of PC5-A. Altogether, these data demonstrate for the first time the ability of PC5-A to function as a prohormone convertase in the regulated secretory pathway and suggest a role for this enzyme in the physiological processing of pro-NT/NN.

Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study.

PubMed

Terrell, Thomas Roland; Abramson, Ruth; Barth, Jeffery T; Bennett, Ellen; Cantu, Robert C; Sloane, Richard; Laskowitz, Daniel T; Erlanger, David M; McKeag, Douglas; Nichols, Gregory; Valentine, Verle; Galloway, Leslie

2018-02-01

To evaluate the association of genetic polymorphisms APOE, APOE G-219T promoter, microtubule associated protein(MAPT)/ tau exon 6 Ser 53 Pro, MAPT/ tau Hist 47 Tyr, IL-6 572 G/C and IL-6R Asp 358 Ala with the risk of concussion in college athletes. A 23-centre prospective cohort study of 1056 college athletes with genotyping was completed between August 2003 and December 2012. All athletes completed baseline medical and concussion questionnaires, and post-concussion data were collected for athletes with a documented concussion. The study cohort consisted of 1056 athletes of mean±SD age 19.7±1.5 years , 89.3% male, 59.4% Caucasian, 35.0% African-American, 5.6% other race. The athletes participated in American football, soccer, basketball, softball, men's wrestling and club rugby. A total of 133 (12.1% prevalence) concussions occurred during an average surveillance of 3 years per athlete. We observed a significant positive association between IL-6R CC (p=0.001) and a negative association between APOE 4 (p=0.03) and the risk of concussion. Unadjusted and adjusted logistic regression analysis showed a significant association between IL-6R CC and concussion (OR 3.48; 95% CI 1.58 to 7.65; p=0.002) and between the APOE4 allele and concussion (OR 0.61; 95% CI 0.38 to 0.96; p=0.04), which persisted after adjustment for confounders. IL-6R CC was associated with a three times greater concussion risk and APOE 4 with a 40% lower risk. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor

PubMed Central

2013-01-01

Background To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. Results ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. Conclusion C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor. PMID:24341457

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor.

PubMed

Sanders, Jarred; Nagy, Stanislav; Fetterman, Graham; Wright, Charles; Treinin, Millet; Biron, David

2013-12-17

To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor.

Transcobalamin 776C→G polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake.

PubMed

Sawaengsri, Hathairat; Bergethon, Peter R; Qiu, Wei Qiao; Scott, Tammy M; Jacques, Paul F; Selhub, Jacob; Paul, Ligi

2016-12-01

The 776C→G polymorphism of the vitamin B-12 transport protein transcobalamin gene (TCN2) (rs1801198; Pro259Arg) is associated with a lower holotranscobalamin concentration in plasma. This effect may reduce the availability of vitamin B-12 to tissues even when vitamin B-12 intake is adequate. Clinical outcomes associated with vitamin B-12 insufficiency could potentially be worsened by high folate intake. We determined the association of the TCN2 776C→G polymorphism and folate intake with peripheral neuropathy in elders with normal plasma concentrations of vitamin B-12. Participants in this cross-sectional study (n = 171) were from a cohort of community-based, home-bound elderly individuals aged ≥60 y who underwent an evaluation by physicians including an assessment for peripheral neuropathy. Participants were administered food-frequency and general health status questionnaires, anthropometric measurements were taken, and a fasting blood sample from each subject was collected. Odds of neuropathy were 3-fold higher for GG genotypes than for CC genotypes (OR: 3.33; 95% CI: 1.15, 9.64). When folate intake was >2 times the Recommended Dietary Allowance (800 μg), GG genotypes had 6.9-fold higher odds of neuropathy than CC genotypes (OR: 6.9; 95% CI: 1.31, 36.36). There was no difference between the genotypes in the odds of peripheral neuropathy when folate intake was ≤800 μg (OR: 1.5; 95% CI: 0.18, 12.33). The TCN2 776C→G polymorphism is associated with increased odds of peripheral neuropathy in the elderly, even with a normal vitamin B-12 status, especially if their folate intake is >2 times the Recommended Dietary Allowance. © 2016 American Society for Nutrition.

proBAMconvert: A Conversion Tool for proBAM/proBed.

PubMed

Olexiouk, Volodimir; Menschaert, Gerben

2017-07-07

The introduction of new standard formats, proBAM and proBed, improves the integration of genomics and proteomics information, thus aiding proteogenomics applications. These novel formats enable peptide spectrum matches (PSM) to be stored, inspected, and analyzed within the context of the genome. However, an easy-to-use and transparent tool to convert mass spectrometry identification files to these new formats is indispensable. proBAMconvert enables the conversion of common identification file formats (mzIdentML, mzTab, and pepXML) to proBAM/proBed using an intuitive interface. Furthermore, ProBAMconvert enables information to be output both at the PSM and peptide levels and has a command line interface next to the graphical user interface. Detailed documentation and a completely worked-out tutorial is available at http://probam.biobix.be .

Improve efficacy of topical ALA-PDT by calcipotriol through up-regulation of coproporphyrinogen oxidase.

PubMed

Yang, Deng-Fu; Chen, Jia-Haur; Chiang, Chun-Pin; Huang, Zheng; Lee, Jeng-Woei; Liu, Chung-Ji; Chang, Junn-Liang; Hsu, Yih-Chih

2014-09-01

Topical 5-aminolevulinic acid-mediated photodynamic therapy (topical ALA-PDT) is effective for treating oral precancerous lesions. The aim of this in vivo and in vitro study was to examine whether the efficacy of topical ALA-PDT could be further improved by calcipotriol (CAL). Precancerous lesions in the buccal pouch of hamsters were induced by dimethylbenz(a)anthracene (DMBA). Lesions were treated with multiple topical ALA-PDT with or without CAL pretreatment. ALA-induced protoporphyrine IX (PpIX) was monitored by in situ fluorescence measurement. The effect of CAL on heme-related enzymes (CPOX, PPOX, and FECH) were examined in an in vitro model using human squamous cell carcinoma (SCC) cells (SCC4, SAS) using Western blots. Fluorescence spectroscopy revealed that PpIX reached its peak level in precancerous epithelial cells of buccal pouch at 2.5 or 3.5h without or with CAL pretreatment, respectively. Both treatment regimens showed similar response rates, but the complete response was achieved after 5 times of ALA-PDT and 3 times of CAL-ALA-PDT (p<0.001). Pretreatment of SCC cells with 10(-8) or 10(-7)M CAL could result in a significant cell death (p<0.05) and an elevation of CPOX protein level. Topical CAL can improve the efficacy of ALA-PDT in treating precancerous lesions, likely through the increase in CPOX level and in PpIX production. Copyright © 2014 Elsevier B.V. All rights reserved.

P53 gene codon 72 polymorphism in patients with oral squamous cell carcinoma in the population of northern Iran.

PubMed

Sina, Mahmud; Pedram, Mehrdad; Ghojazadeh, Morteza; Kochaki, Ahmad; Aghbali, Amirala

2014-11-01

Squamous cell carcinoma is the most common cancer of the oral cavity, and several etiologic factors are involved in its developing. Single nucleotide polymorphism (SNP) of the P53 gene codon 72 (P53c72) changes the structure of the protein and affects its activity. The prevalence of P53c72 different genotypes, which seems to vary with race and geographic location, has shown a strong correlation with many types of human cancers. The aim of this study was to investigate the correlation between P53c72polymorphism and risk of oral squamous cell carcinoma (OSCC) in the heavily populated Gilan Province in northern Iran. This case-control study was done on 55 paraffin-embedded samples from OSCC patients and 100 samples of non-dysplastic oral cavity lesions. The P53c72 genotypes were determined using the ARMS-PCR method. SPSS-15 software was used for statistical analysis. There were no significant statistical differences found between the prevalence of different P53c72 genotypes in the OSCC group vs. the control. However, the Pro/Pro genotype in OSCC samples showed a strong correlation with age, as 70% of such patients were below 50 years old. Interestingly, a large portion (40%) of the patients with the Pro/Pro genotype had the tumor in the lip area. Although P53c72 polymorphism does not appear to be a predisposing factor for OSCC in the population of Northern Iran, the Pro/Pro genotype could be considered as a risk factor for OSCC in adults below 50 years old and the anatomical location of the tumor.

In vitro antioxidant activities of the novel pentapeptides Ser-His-Glu-Cys-Asn and Leu-Pro-Phe-Ala-Met and the relationship between activity and peptide secondary structure.

PubMed

Yang, Ruiwen; Wang, Jia; Lin, Songyi; Ye, Haiqing; Chen, Feng

2017-04-01

Using high-performance liquid chromatography/tandem mass spectrometry, two novel antioxidant pentapeptides [Ser-His-Glu-Cys-Asn (SHECN) and Leu-Pro-Phe-Ala-Met (LPFAM)] were identified from 1-3-kDa soybean protein hydrolysates (SPH). The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was used to evaluate cytotoxicity in HepG2 cells. Antioxidant activity was measured using in vitro assays, including the cellular antioxidant activity assay (CAA), 2,2-diphenyl-1-picrylhydrazyl or 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) inhibition, and oxygen radical absorbance capacity (ORAC) assays. Finally, the secondary structure was determined using circular dichroism (CD). The results revealed that two novel peptides were nontoxic and possessed antioxidant activity. SHECN had significantly higher antioxidant activity than LPFAM (P < 0.05). The CAA value of SHECN was 776.22 µmol QE 100 g -1 . SHECN also showed significant DPPH inhibition (70.18 ± 4.06%) and ABTS inhibition (88.16 ± 0.76%). It had normalized ORAC values of 0.3000 ± 0.0070 µmol GE mg -1 and 0.0900 ± 0.0020 µmol TE mg -1 , respectively. The results of the CD analysis demonstrated that, compared to LPFAM, which had much lower antioxidant activity, SHECN had a high β-sheet content and reduced α-helix content. The results indicated that SHECN possessed high antioxidant activity. A higher β-sheet content and lower content levels of α-helix appear to be correlated with antioxidant activity. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Temperature- and Length-Dependent Energetics of Formation for Polyalanine Helices in Water: Assignment of wAla(n,T) and Temperature-Dependent CD Ellipticity Standards

PubMed Central

Job, Gabriel E.; Kennedy, Robert J.; Heitmann, Björn; Miller, Justin S.; Walker, Sharon M.; Kemp*, Daniel S.

2006-01-01

Length-dependent helical propensities wAla(n,T) at T = 10, 25, and 60 °C are assigned from t/c values and NMR 13C chemical shifts for series 1 peptides TrpLysmInp2tLeu–AlantLeuInp2LysmNH2, n = 15, 19, and 25, m = 5, in water. Van’t Hoff analysis of wAla(n,T) show that α-helix formation is primarily enthalpy-driven. For series 2 peptides Ac–Trp Lys5Inp2tLeu–βAspHel–Alan–beta–tLeuInp2Lys5NH2, n = 12 and 22, which contain exceptionally helical Alan cores, protection factor-derived fractional helicities FH are assigned in the range 10–30 °C in water and used to calibrate temperature-dependent CD ellipticities [θ]λ,H,n,T. These are applied to CD data for series 1 peptides, 12 ≤ n ≤ 45, to confirm the wAla(n,T) assignments at T = 25 and 60 °C. The [θ]λ,H,n,T are temperature dependent within the wavelength region, 222 ± 12 nm, and yield a temperature correction for calculation of FH from experimental values of [θ]222,n,T,Exp. PMID:16787087

Enterovirus RNA in Peripheral Blood May Be Associated with the Variants of rs1990760, a Common Type 1 Diabetes Associated Polymorphism in IFIH1

PubMed Central

Cinek, Ondrej; Tapia, German; Witsø, Elisabet; Kramna, Lenka; Holkova, Katerina; Rasmussen, Trond; Stene, Lars C.; Rønningen, Kjersti S.

2012-01-01

Objective Polymorphisms in the IFIH1 (common rs1990760 and four rare rs35667974, rs35337543, rs35744605, rs35732034) have been convincingly associated with type 1 diabetes. The encoded protein (interferon-induced helicase C domain-containing protein 1) senses double-stranded RNA during replication of Picornavirales, including Enterovirus, a genus suspected in the etiology of type 1 diabetes. We therefore investigated whether the polymorphisms are associated with differences in the frequency of enterovirus RNA in blood. Research Design and Methods The study included 1001 blood samples, each from a child participating in the Norwegian ‘Environmental Triggers of Type 1 Diabetes: the MIDIA study’. The enterovirus RNA was tested using qualitative semi-nested real-time reverse transcriptase PCR on RNA extracted from frozen cell packs after removal of plasma. Stool samples previously analyzed for enterovirus RNA were available in 417 children. Results The genotypes of IFIH1 rs1990760 were associated with different frequencies of enterovirus RNA in blood (7.0%, 14.4% and 9.5% bloods were enterovirus positive among children carrying the Ala/Ala, Ala/Thr and Thr/Thr genotypes, respectively, p = 0.012). This association remained essentially unchanged after adjustment for age and calendar year. The presence of enterovirus in the concomitantly sampled stool further increased the likelihood of enterovirus RNA in blood (odds ratio 2.40, CI 95% 1.13–4.70), but did not affect the association with IFIH1 rs1990760. The rare polymorphisms (individually, or pooled) were not significantly associated with enterovirus RNA in blood. Conclusions The common IFIH1 SNP may modify the frequency of enterovirus RNA in blood of healthy children. This effect can help explain the association of IFIH1 with type 1 diabetes. PMID:23144876

Allelic polymorphism in the T cell receptor and its impact on immune responses.

PubMed

Gras, Stephanie; Chen, Zhenjun; Miles, John J; Liu, Yu Chih; Bell, Melissa J; Sullivan, Lucy C; Kjer-Nielsen, Lars; Brennan, Rebekah M; Burrows, Jacqueline M; Neller, Michelle A; Khanna, Rajiv; Purcell, Anthony W; Brooks, Andrew G; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R

2010-07-05

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.

5-ALA photopreparation using pulsed NIR enhances skin fluorescence via temperature-independent cell signaling pathways

NASA Astrophysics Data System (ADS)

Barolet, Augustin C.; Cormack, Gregory; Barolet, Daniel

2018-02-01

The effect of near infrared light (940 nm) on the conversion of 5-aminolevulinic acid (5-ALA) to PpIX, a compound involved in photodynamic therapy (PDT), was examined. The back skin of three test subjects was irradiated with continuous wavelength and pulsed infrared light at 940 nm. These irradiations took place 50-53, 24-29, and 8-14 hours prior to the application of the 5-ALA. After a three-hour incubation period with 5-ALA, a FluoDerm™device was used to measure the fluorescence of the skin (emitting wavelength: 400-420 nm; measuring excitation wavelength: 610-720 nm), a direct indication of the activity of 5-ALA. 5-ALA must penetrate the skin and then be converted to PpIX before any fluorescence increase can be observed. Results: For two patients (one was disqualified), the continuous wavelength, 50 hour pre-irradiation condition, the FluoDerm readings showed a 19 to 23% increase in fluorescence (p = 0.05) compared to the no-irradiation, 5-ALA only control.

Pro-Anorexia and Anti-Pro-Anorexia Videos on YouTube: Sentiment Analysis of User Responses.

PubMed

Oksanen, Atte; Garcia, David; Sirola, Anu; Näsi, Matti; Kaakinen, Markus; Keipi, Teo; Räsänen, Pekka

2015-11-12

Pro-anorexia communities exist online and encourage harmful weight loss and weight control practices, often through emotional content that enforces social ties within these communities. User-generated responses to videos that directly oppose pro-anorexia communities have not yet been researched in depth. The aim was to study emotional reactions to pro-anorexia and anti-pro-anorexia online content on YouTube using sentiment analysis. Using the 50 most popular YouTube pro-anorexia and anti-pro-anorexia user channels as a starting point, we gathered data on users, their videos, and their commentators. A total of 395 anorexia videos and 12,161 comments were analyzed using positive and negative sentiments and ratings submitted by the viewers of the videos. The emotional information was automatically extracted with an automatic sentiment detection tool whose reliability was tested with human coders. Ordinary least squares regression models were used to estimate the strength of sentiments. The models controlled for the number of video views and comments, number of months the video had been on YouTube, duration of the video, uploader's activity as a video commentator, and uploader's physical location by country. The 395 videos had more than 6 million views and comments by almost 8000 users. Anti-pro-anorexia video comments expressed more positive sentiments on a scale of 1 to 5 (adjusted prediction [AP] 2.15, 95% CI 2.11-2.19) than did those of pro-anorexia videos (AP 2.02, 95% CI 1.98-2.06). Anti-pro-anorexia videos also received more likes (AP 181.02, 95% CI 155.19-206.85) than pro-anorexia videos (AP 31.22, 95% CI 31.22-37.81). Negative sentiments and video dislikes were equally distributed in responses to both pro-anorexia and anti-pro-anorexia videos. Despite pro-anorexia content being widespread on YouTube, videos promoting help for anorexia and opposing the pro-anorexia community were more popular, gaining more positive feedback and comments than pro-anorexia videos

Surviving the Tremors: ALA in San Francisco.

ERIC Educational Resources Information Center

Wilson Library Bulletin, 1992

1992-01-01

Reports on the American Library Association (ALA) 1992 Annual Conference. Highlights include awards given; libraries' futures; bibliographic instruction; NREN (National Research and Education Network); telecommunications; lack of status in librarianship; proposed guidelines for patron behavior; interlibrary loan; the Americans with Disabilities…

Topical application of ALA PDT for the treatment of moderate to severe acne vulgaris

NASA Astrophysics Data System (ADS)

Wang, Xiu-Li; Wang, Hong-Wei; Zhang, Ling-Lin; Su, Lina; Guo, Ming-Xia; Huang, Zheng

2009-06-01

Objectives: To evaluate the effectiveness of topical 5-aminolevulinic acid (ALA)- medicated photodynamic therapy (ALA PDT) for the treatment of moderate to severe acne vulgaris. Methods: Sixteen Chinese patients with moderate to severe facial acne were treated with 1-3 courses of ALA PDT. ALA cream (3%) was freshly prepared and applied to acne lesions for 3-4 h. The lesions were irradiated by a 635 nm diode laser at dose levels of 60 - 80 J/cm2 at 100 mW/cm2. Clinical assessments were conducted before and after treatment up to 3 months. Results: All patents showed response to ALA PDT. Complete clearance was seen in 10 patients (62.5%) and partial clearance in 6 patients (37.5%). One case showed recurrence after complete clearance at 2 months and another two showed recurrence after complete clearance at 3 months. However, the number of new lesions were significantly reduced. Adverse effects were minimal. Conclusions: The results of this preliminary clinical study is encouraging. ALA PDT is a simple, safe and useful therapeutic option for the treatment of moderate to severe acne. Further studies to evaluate the treatment with a larger number of patients and for a longer period of follow-up are needed.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

PubMed

Naranjo-Galvis, C A; de-la-Torre, A; Mantilla-Muriel, L E; Beltrán-Angarita, L; Elcoroaristizabal-Martín, X; McLeod, R; Alliey-Rodriguez, N; Begeman, I J; López de Mesa, C; Gómez-Marín, J E; Sepúlveda-Arias, J C

2018-04-01

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii , which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1β (IL-1β) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls ( P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients ( P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT ( P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1β gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT ( P = 0.0494). The IL-10, IFN-γ, and IL-1β polymorphisms influence the development of OT in the Colombian population. Copyright © 2018 American Society for Microbiology.

Influence of DGAT1 K232A polymorphism on milk fat percentage and fatty acid profiles in Romanian holstein cattle.

PubMed

Tăbăran, A; Balteanu, V A; Gal, E; Pusta, D; Mihaiu, R; Dan, S D; Tăbăran, A F; Mihaiu, M

2015-01-01

Milk and dairy products are considered the main sources of saturated fatty acids, which are a valuable source of nutrients in the human diet. Fat composition can be adjusted through guided nutrition of dairy animals but also through selective breeding. Recently, a dinucleotide substitution located in the exon 8 of the gene coding for acyl CoA: diacylglycerol acyltransferase 1 (DGAT1), that alters the amino acid sequence from a lysine to an alanine (p.Lys232Ala) in the mature protein, was shown to have a strong effect on milk fat content in some cattle breeds. Therefore, the objectives of this work were to study the occurrence of the DGAT1 p.Lys232Ala polymorphism in Romanian Holstein cattle and Romanian Buffalo breeds and to further investigate its possible influence on fat percentage and fatty acid profiles. The results obtained in this study show that in Romanian Holstein cattle the K allele is associated with increased fat percentage and higher levels of C16:0 and C18:0 fatty acids. The ratio of saturated fatty acids versus unsaturated fatty acids (SFA/UFA) was also higher in KK homozygous individuals, whereas the fractions of C14:0, unsaturated C18 decreased. The DGAT1 p.Lys232Ala polymorphism revealed a high genetic variance for fat percentage, unsaturated C18, C16:0, and SFA/UFA. Although the effect of this polymorphism was not so evident for short chain fatty acids such as C4:0-C8:0, it was significant for C14:0 fatty acids. We concluded that selective breeding of carriers of the A allele in Romanian Holsteins can contribute to improvement in unsaturated fatty acids content of milk. However, in buffalo, the lack of the A allele makes selection inapplicable because only the K allele, associated with higher saturated fatty acids contents in milk, was identified.

Associations between glutathione S-transferase pi Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy.

PubMed

Kanai, Masashi; Yoshioka, Akira; Tanaka, Shiro; Nagayama, Satoshi; Matsumoto, Shigemi; Nishimura, Takafumi; Niimi, Miyuki; Teramukai, Satoshi; Takahashi, Ryo; Mori, Yukiko; Kitano, Toshiyuki; Ishiguro, Hiroshi; Yanagihara, Kazuhiro; Chiba, Tsutomu; Fukushima, Masanori; Matsuda, Fumihiko

2010-04-01

Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase pi (GSTP1) Ile(105)Val, and glyoxylate aminotransferase (AGXT) Pro(11)Leu and AGXT Ile(340)Met. Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1(105)Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P=0.098). There were similar numbers of patients carrying at least one AGXT(105)Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P=0.725). The AGXT(11)Leu allele was not found in any of our patients or controls. We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile(105)Val and AGXT Ile(340)Met polymorphisms. Given that no AGXT(11)Leu allele was found among our study population (n=177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

Synthesis and characterization of 12-aminolauric acid-modified montmorillonite for catalytic application

NASA Astrophysics Data System (ADS)

Pagtalunan, Cris Angelo M.; Sumera, Florentino C.; Conato, Marlon T.

2018-05-01

The simple cation-exchange preparation of 12-aminolauric acid-modified montmorillonite (ALA-Mt), an aluminosilicate clay modified with the alkylammonium surfactant, is reported. Different loadings of 12-aminolauric acid (12-ALA) from 100 to 400 times the cation exchange capacity (CEC) in montmorillonite (Mt) was prepared and studied. Successful intercalation of the organic surfactant was monitored by the increase in basal (d001) spacing of the organoclay compared to the pure Mt. The clay mineral composite have increased surfactant loading resulting to lower degradation temperatures, rougher surface morphology, increased particle size, and increased organophilicity of the organoclay compared to the native Mt. The improved properties of ALA-Mt present it as an attractive catalyst material for polymerization reactions.

The 1993 AIA/ALA Building Award Recipients.

ERIC Educational Resources Information Center

Muller, Karen

1993-01-01

Describes the eight library buildings that won the 1993 Awards of Excellence for Library Architecture from the American Institute of Architects (AIA) and the American Library Association (ALA) including one adaptive reuse, four expansions, two new buildings, and one temporary building. (EAM)

Genetic polymorphism of antioxidant enzymes in eosinophilic and non-eosinophilic nasal polyposis.

PubMed

Akyigit, Abdulvahap; Keles, Erol; Etem, Ebru Onalan; Ozercan, Ibrahim; Akyol, Hatice; Sakallioglu, Oner; Karlidag, Turgut; Polat, Cahit; Kaygusuz, Irfan; Yalcin, Sinasi

2017-01-01

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the paranasal sinuses, and its pathophysiology is not yet precisely known. It is suggested that oxygen free radicals play an important role in the pathogenesis of nasal polyposis. This study aimed to identify genetic polymorphisms of superoxide dismutase (SOD 2), catalase (CAT), and inducible nitric oxide synthase (iNOS) enzymes in eosinophilic CRSwNP and non-eosinophilic CRSwNP patients; the study also aimed to evaluate the effect of genetic polymorphism of antioxidant enzymes on CRSwNP etiopathogenesis. One hundred thirty patients, who received endoscopic sinus surgery due to CRSwNP, and 188 control individuals were included in this study. Nasal polyp tissues were divided into two groups histopathologically as eosinophilic CRSwNP and non-eosinophilic CRSwNP. Venous blood samples were taken from the patient and control groups. Polymorphisms in the Ala16Va1 gene, which is the most common variation of SOD-2 gene, and 21 A/T polymorphisms in catalase gene were evaluated with the restriction fragment length polymorphism method and -277 C/T polymorphism in the iNOS gene was evaluated with the DNA sequencing method. The GG genotype distribution for the (-277) A/G polymorphism in the iNOS gene was a statistically significant difference between eosinophilic CRSwNP and control groups (p < 0.05). The CC genotype distribution for the SOD2 A16V (C/T) polymorphism was not statistically significant in all groups (p > 0.05). The TT genotype distribution for the A/T polymorphism in catalase gene at position -21 was statistically significant differences in eosinophilic CRSwNP and control groups (p < 0.05). Increased free oxygen radical levels, which are considered effective factors in the pathogenesis of CRSwNP, can occur due to genetic polymorphism of enzymes in the antioxidant system and genetic polymorphism of antioxidant enzymes in eosinophilic CRSwNP patients might contribute to the

Pro-inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease.

PubMed

Assari, Raheleh; Aghighi, Yahya; Ziaee, Vahid; Sadr, Maryam; Rahmani, Farzaneh; Rezaei, Arezou; Sadr, Zeinab; Moradinejad, Mohammad Hassan; Raeeskarami, Seyed Reza; Rezaei, Nima

2016-07-25

Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T-cells. IL-1 gene cluster, IL-6 and TNF-α polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD. Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1α at -889 (rs1800587), IL-1β at -511 (rs16944), IL-1β at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-α at -308 (rs1800629), TNF-α at -238, IL-6 at -174 (rs1800795) and IL-6 at +565. Twenty-one percent of the control group had A allele at TNF-α -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14-0.71]). Consistently, TNF-α genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-α (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD. TNF-α GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Preparation of antioxidative corn protein hydrolysates, purification and evaluation of three novel corn antioxidant peptides.

PubMed

Jin, Du-Xin; Liu, Xiao-Lan; Zheng, Xi-Qun; Wang, Xiao-Jie; He, Jun-Fang

2016-08-01

Corn gluten meal is a major co-product of corn wet milling. Corn gluten meal was hydrolyzed with Alcalase, Flavourzyme, Alcalase+Flavourzyme and Flavourzyme+Alcalase. At the substrate concentration of 10%, corn protein hydrolysate catalyzed by Alcalase had a degree of hydrolysis of 17.83%, which was higher than that by Flavourzyme (3.65%). The hydrolysate catalyzed by Alcalase+Flavourzyme exhibited better antioxidant activities and was further purified. Three novel antioxidant peptides were purified by a series of chromatographic techniques. Sequences of the three peptides were identified as Cys-Ser-Gln-Ala-Pro-Leu-Ala, Tyr-Pro-Lys-Leu-Ala-Pro-Asn-Glu and Tyr-Pro-Gln-Leu-Leu-Pro-Asn-Glu, respectively. Among the three peptides, Cys-Ser-Gln-Ala-Pro-Leu-Ala exhibited good reducing power and excellent scavenging capacities for DPPH radical and superoxide anion radical, with IC50 values of 0.116 and 0.39mg/ml, respectively. The results from our study indicate antioxidant potency of corn protein hydrolysates and peptides separated from corn gluten meal and can provide basic understanding for the application of corn protein hydrolysates as natural antioxidants. Copyright © 2016 Elsevier Ltd. All rights reserved.

Purification and Characterization of an X-Prolyl-Dipeptidyl Peptidase from Lactobacillus sakei

PubMed Central

Sanz, Yolanda; Toldrá, Fidel

2001-01-01

An X-prolyl-dipeptidyl peptidase has been purified from Lactobacillus sakei by ammonium sulfate fractionation and five chromatographic steps, which included hydrophobic interaction, anion-exchange chromatography, and gel filtration chromatography. This procedure resulted in a recovery yield of 7% and an increase in specificity of 737-fold. The enzyme appeared to be a dimer with a subunit molecular mass of approximately 88 kDa. Optimal activity was shown at pH 7.5 and 55°C. The enzyme was inhibited by serine proteinase inhibitors and several divalent cations (Cu2+, Hg2+, and Zn2+). The enzyme almost exclusively hydrolyzed X-Pro from the N terminus of each peptide as well as fluorescent and colorimetric substrates; it also hydrolyzed X-Ala at the N terminus, albeit at lower rates. Km s for Gly-Pro- and Lys-Ala-7-amido-4-methylcoumarin were 29 and 88 μM, respectively; those for Gly-Pro- and Ala-Pro-p-nitroanilide were 192 and 50 μM, respectively. Among peptides, β-casomorphin 1-3 was hydrolyzed at the highest rates, while the relative hydrolysis of the other tested peptides was only 1 to 12%. The potential role of the purified enzyme in the proteolytic pathway by catalyzing the hydrolysis of peptide bonds involving proline is discussed. PMID:11282638

The 72Pro Variant of the Tumor Protein 53 Is Associated with an Increased Breast Cancer Risk in the Moroccan Population.

PubMed

Ayoubi, Salah Eddine; Elkarroumi, Mohamed; El Khachibi, Meryam; Hassani Idrissi, Hind; Ayoubi, Hasnaa; Ennachit, Simohamed; Arazzakou, Mounia; Nadifi, Sellama

2018-06-25

The purpose of our case control study is to explore the potential association of tumor protein 53 (TP53) c.215G>C, p. (Arg72Pro) polymorphism (rs1042522) with the risk of breast cancer (BC) development in the Moroccan population. The study population consisted of 125 female patients with confirmed BC and 126 healthy controls. DNA samples were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism assay method using BstUI restriction enzyme. We showed that the homozygous genotype of TP53 72Pro variant was significantly associated with increased BC risk (OR 2.2, 95% CI 1.07-4.54, p = 0.03). The dominant and additive models of TP53 Pro allele were also correlated to the risk of BC (OR 2.13, 95% CI 1.07-4.23, p = 0.02 and OR 1.49, 95% CI 1.03-2.16, p = 0.03, respectively). Furthermore, the TP53 Arg72 variant was associated with protection against BC, either in the homozygous genotype, the dominant or the additive models (OR 0.45, 95% CI 0.22-0.93, p = 0.03; OR 0.46, 95% CI 0.23-0.92, p = 0.029 and OR 0.67, 95% CI 0.46-0.97, p = 0.03, respectively). Our results suggest that TP53 c.215G>C, p. (Arg72Pro) polymorphism may be considered as a genetic marker for predisposition to BC in Moroccan population. © 2018 S. Karger AG, Basel.

New developments in fluorescence detection of ALA-induced protoporphyrin IX for cancer localization

NASA Astrophysics Data System (ADS)

Stepp, Herbert G.; Baumgartner, Reinhold; Betz, Christian; Bise, Karl; Brand, P.; Gamarra, Fernando; Haeussinger, Karl; Hillemanns, Peter; Huber, Rudolf M.; Knuechel, Ruth; Kriegmair, M.; Leunig, Andreas; Pichler, J.; Rick, Kai; Schulz, H.; Stanzel, F.; Stocker, Susanne; Wagner, Simon; Weigandt, H.

1997-12-01

After the very promising clinical results for the detection of bladder cancer in urology, preclinical and clinical studies on aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) are preformed in various disciplines now. This paper provides a brief overview of the progress on 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynecology and ENT performed in collaboration with the Laser Research Laboratory at the Department of Urology of the Ludwig-Maximilians-University in Munich. Five-ALA can be applied either topically or systemically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumor. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolor remission and fluorescence imaging, therefore, seems to be indispensable for a reliable tumor localization.

Acute myeloid leukemia outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients.

PubMed

Strom, Sara S; Estey, Elihu; Outschoorn, Ubaldo Martinez; Garcia-Manero, Guillermo

2010-04-01

In acute myeloid leukemia (AML), cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to interindividual differences in DNA repair capacity, influencing outcome. We studied the role of six polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) in overall and disease-free survival among 170 adult de novo patients with intermediate cytogenetics (diploid [n = 117]; non-diploid [n = 53]), treated with induction chemotherapy. Kaplan-Meier and Cox proportional hazards models were performed. Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type genotype (median survival 22 vs. 40 months, p = 0.03). Diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type genotype (median survival 15 vs. 30 months, p = 0.02). After adjusting for clinical and sociodemographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying, compared to those with the wild-type genotypes (HR = 2.49; 95% CI: 1.06-5.85). No associations were observed for disease-free survival. This combined genotype may modulate treatment effect, decreasing overall survival. These findings could in the future help select treatments for patients with normal cytogenetics.

Scavengers modifying the phototoxicity induced by ALA-mediated photodynamic therapy

NASA Astrophysics Data System (ADS)

Casas, Adriana; Perotti, Christian; Fukuda, Haydee; Batlle, Alcira

2001-04-01

The exogenously stimulated formation of intracellularly generated Protoporphyrin IX, a precursor of heme, is becoming one of the fastest developing areas in the field of Photodynamic Therapy (PDT). We have examined the degree of protection of several scavengers, aminoacids and compounds related to glutathione metabolism, to the photodamage induced by 5-aminolevulinic acid (ALA)-mediated PDT, employing the LM2 cell line, derived from a mammary murine adenocarcinoma. We have exposed the cells to different concentrations of the scavengers, 24 before PDT, during PDT, and 19 hr after treatment. We defined the protection grade (PG) as the ratio between cell survival after ALA-PDT treatment in the presence of the protector and cell survival after ALA-PDT treatment. We found that L-tryptophan (PG=8.3 at 2mM), N-acetyl-L-cysteine (PG= 7.9 at 30 mM), L-cysteine (PG=7.81 at 8mM), S-adenosyl-L-methionine (PG= 7.86 at 8mM), melatonin (PG=6.81 at 8mM) and glycine (PG=6.8 at 40 mM) are the best protectors to PDT damage, followed by L-methionine (PG=4.38 at 0.8 mM), mannitol (PG=2.32 at 2 mM) and reduced glutathione (PG=3.41 at 0.8 mM), whereas oxidized glutathione does not exert any protection. The implications of these results in the photodamage induced by ALA-PDT is discussed.

Bacterial resistance to vancomycin: overproduction, purification, and characterization of VanC2 from Enterococcus casseliflavus as a D-Ala-D-Ser ligase.

PubMed

Park, I S; Lin, C H; Walsh, C T

1997-09-16

The VanC phenotype for clinical resistance of enterococci to vancomycin is exhibited by Enterococcus gallinarum and Enterococcus casseliflavus. Based on the detection of the cell precursor UDP-N-acetylmuramic acid pentapeptide intermediate terminating in D-Ala-D-Ser instead of D-Ala-D-Ala, it has been predicted that the VanC ligase would be a D-Ala-D-Ser rather than a D-Ala-D-Ala ligase. Overproduction of the E. casseliflavus ATCC 25788 vanC2 gene in Escherichia coli and its purification to homogeneity allowed demonstration of ATP-dependent D-Ala-D-Ser ligase activity. The kcat/Km2 (Km2 = Km for D-Ser or C-terminal D-Ala) ratio for D-Ala-D-Ser/D-Ala-D-Ala dipeptide formation is 270/0.69 for a 400-fold selection against D-Ala in the C-terminal position. VanC2 also has substantial D-Ala-D-Asn ligase activity (kcat/Km2 = 74 mM-1min-1).

Pro-Anorexia and Anti-Pro-Anorexia Videos on YouTube: Sentiment Analysis of User Responses

PubMed Central

Garcia, David; Sirola, Anu; Näsi, Matti; Kaakinen, Markus; Keipi, Teo; Räsänen, Pekka

2015-01-01

Background Pro-anorexia communities exist online and encourage harmful weight loss and weight control practices, often through emotional content that enforces social ties within these communities. User-generated responses to videos that directly oppose pro-anorexia communities have not yet been researched in depth. Objective The aim was to study emotional reactions to pro-anorexia and anti-pro-anorexia online content on YouTube using sentiment analysis. Methods Using the 50 most popular YouTube pro-anorexia and anti-pro-anorexia user channels as a starting point, we gathered data on users, their videos, and their commentators. A total of 395 anorexia videos and 12,161 comments were analyzed using positive and negative sentiments and ratings submitted by the viewers of the videos. The emotional information was automatically extracted with an automatic sentiment detection tool whose reliability was tested with human coders. Ordinary least squares regression models were used to estimate the strength of sentiments. The models controlled for the number of video views and comments, number of months the video had been on YouTube, duration of the video, uploader’s activity as a video commentator, and uploader’s physical location by country. Results The 395 videos had more than 6 million views and comments by almost 8000 users. Anti-pro-anorexia video comments expressed more positive sentiments on a scale of 1 to 5 (adjusted prediction [AP] 2.15, 95% CI 2.11-2.19) than did those of pro-anorexia videos (AP 2.02, 95% CI 1.98-2.06). Anti-pro-anorexia videos also received more likes (AP 181.02, 95% CI 155.19-206.85) than pro-anorexia videos (AP 31.22, 95% CI 31.22-37.81). Negative sentiments and video dislikes were equally distributed in responses to both pro-anorexia and anti-pro-anorexia videos. Conclusions Despite pro-anorexia content being widespread on YouTube, videos promoting help for anorexia and opposing the pro-anorexia community were more popular, gaining more

Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao Guixiang; Etherton, Terry D.; Department of Dairy and Animal Science, Pennsylvania State University, University Park, PA

2005-10-28

The effects of linoleic acid (LA), {alpha}-linolenic acid (ALA), and docosahexaenoic acid (DHA) were compared to that of palmitic acid (PA), on inflammatory responses in human monocytic THP-1 cells. When cells were pre-incubated with fatty acids for 2-h and then stimulated with lipopolysaccharide for 24-h in the presence of fatty acids, secretion of interleukin (IL)-6, IL-1{beta}, and tumor necrosis factor-{alpha} (TNF{alpha}) was significantly decreased after treatment with LA, ALA, and DHA versus PA (P < 0.01 for all); ALA and DHA elicited more favorable effects. These effects were comparable to those for 15-deoxy-{delta}{sup 12,14}-prostaglandin J2 (15d-PGJ2) and were dose-dependent. Inmore » addition, LA, ALA, and DHA decreased IL-6, IL-1{beta}, and TNF{alpha} gene expression (P < 0.05 for all) and nuclear factor (NF)-{kappa}B DNA-binding activity, whereas peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) DNA-binding activity was increased. The results indicate that the anti-inflammatory effects of polyunsaturated fatty acids may be, in part, due to the inhibition of NF-{kappa}B activation via activation of PPAR{gamma}.« less

Effect of fatty acid-binding protein 2 Ala54Thr genotype on weight loss and cardiovascular risk factors after a high-polyunsaturated fat diet in obese patients.

PubMed

de Luis, Daniel; Aller, Rocio; Izaola, Olatz; Sagrado, Manuel Gonzalez; de la Fuente, Beatriz; Conde, Rosa; Primo, David

2012-12-01

It has been found that the expression of fatty acid-binding protein 2 messenger RNA is under dietary control. The aim of our study was to investigate the influence of Thr54 polymorphism in the FABP2 gene on weight loss and secondarily in cardiovascular risk factors and serum adipokine after an enriched polyunsaturated fat hypocaloric diet in obese patients. A sample of 111 obese patients was analyzed. The enriched polyunsaturated fat hypocaloric diet during 3 months' intervention consisted of 1459 kcal, 45.7% carbohydrates, 34.4% lipids, and 19.9% proteins. The distribution of fats was as follows: 21.8% saturated fats, 55.5% monounsaturated fats, and 22.7% polyunsaturated fats. Level of significance was P < 0.05. In Ala54Ala genotype, body mass index (-1.6 ± 1.5 kg/m(2)), weight (-3.2 ± 3.3 kg), fat mass (-3.1 ± 3.5 kg), and waist circumference (-3.3 ± 2.1 cm) decreased. In carriers of the Thr54 allele, body mass index (-1.9 ± 1.6 kg/m(2)), weight (- 4.7 ± 1.4 kg), and waist circumference (-3.9 ± 3.7 cm) decreased. These changes were significantly higher in the carriers of the Thr54 allele than noncarriers. Only in the carriers of Thr54 allele, total cholesterol levels (-11.4 ± 20.6 mg/dl), low-density lipoprotein cholesterol levels (-5.4 ± 10.6 mg/dL), insulin (-2.6 ± 3.4 MUI/L), and the level of homeostasis model assessment for insulin sensitivity (-0.9 ± 1.7 U) decreased. Carriers of Thr54 allele have a better metabolic response than obese carriers with Ala54Ala genotype, with a decrease of total cholesterol, low-density lipoprotein cholesterol, insulin levels, leptin levels, and homeostasis model assessment for insulin sensitivity.

Association study between GAS6 gene polymorphisms and risk of preeclampsia in Chinese population.

PubMed

Ye, Liyan; Guan, Linbo; Fan, Ping; Liu, Xinghui; Liu, Rui; Chen, Jinxin; Zhu, Yue; Wei, Xing; Liu, Yu; Bai, Huai

2017-04-01

Preeclampsia is a pregnancy-specific disorder associated with pro-inflammatory and pro-thrombotic events. The growth arrest-specific 6 (GAS6) has been implicated in systemic inflammation and coagulation. Common genetic polymorphisms of GAS6 gene have previously been reported. The aim of this study was to investigate the association of GAS6 gene polymorphisms with the risk of preeclampsia in Chinese subjects. The case-control population consists of 551 subjects. The genotyping of the single-nucleotide polymorphisms of GAS6 gene, GAS6 834 +7G/A(rs8191974) and +1332C/T (rs1803628), was carried out on genomic DNA using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) analysis. There were significant differences in the +1332C/T genotype and allele frequencies between the patients with preeclampsia and the controls (P=0.03 and 0.02, respectively). The +1332 TT genotype was found to be protective from the development of preeclampsia (odds ratios 0.271, 95% confidence interval 0.077-0.953; P=0.03). Further analysis showed that the TT genotype of the GAS6 +1332C/T conferred a risk of severe preeclampsia (OR=0.597, 95% confidence interval 0.416-0.855; P=0.01). However, there were no differences in the 834+7G/A genotype and allele frequencies between the patients with preeclampsia and the controls. Our data suggest that a TT genotype at +1332C/T polymorphism might be associated with decreased risk for preeclampsia, but the 834+7G/A polymorphism is not associated with the disorder, in the Chinese population. Copyright © 2017. Published by Elsevier B.V.

Effect of oscillation dynamics on long-range electron transfer in a helical peptide monolayer.

PubMed

Matsushita, Daisuke; Uji, Hirotaka; Kimura, Shunsaku

2018-06-06

Electron transfer (ET) reactions via helical peptides composed of -(Aib-Pro)n- were studied in self-assembled monolayers and compared with -(Ala-Aib)n- peptides. Short Aib-Pro peptides showed slightly higher ET rates due to the better electronic coupling of the Pro residue. But, the 24mer Aib-Pro peptide showed a smaller ET rate than the corresponding Ala-Aib peptide. On the basis of DFT calculations, the deceleration of the ET rate of the longer Aib-Pro peptide is considered to be due to the smaller number of active modes of accordion-like oscillations than the Ala-Aib peptide, which has a strong influence on a long-range ET reaction.

Primary structure of pancreatic polypeptide from four species of Perissodactyla (Przewalski's horse, zebra, rhino, tapir).

PubMed

Henry, J S; Lance, V A; Conlon, J M

1991-12-01

Pancreatic polypeptide (PP) has been purified from extracts of the pancreas of four species of odd-toed ungulates (Perissodactyla): Przewalski's horse, mountain zebra, white rhinoceros, and mountain tapir. The amino acid sequence of Przewalski's horse pancreatic polypeptide was established as Ala-Pro-Met-Glu-Pro-Val-Tyr-Pro-Gly-Asp10-Asn- Ala-Thr-Pro-Glu-Gln-Met-Ala-Gln-Tyr20-Ala-Ala-Glu-Leu-Arg-Arg-Tyr- Ile-Asn-Met30 - Leu-Thr-Arg-Pro-Arg-Tyr.NH2. Zebra PP was identical to Przewalski's horse PP, rhinoceros PP contained three substitutions relative to the horse (Ser for Ala1, Leu for Met3, and Glu for Gln16), and tapir PP contained one substitution relative to the horse (Leu for Met3). On the basis of morphological characteristics and the fossil record, the rhinocerotids are classified with the tapirids in the suborder Ceratomorpha, whereas the horse and zebra belong to a separate suborder, Hippomorpha. On the basis of structural similarity of the PP molecules, however, it would appear that the tapir is more closely related to the horse than to the rhinoceros. These observations provide a further example of the need for extreme caution when inferring taxonomic or phylogenetic relationships between species from the structures of homologous peptides.

Genetic variations in NADPH-CYP450 oxidoreductase in a Czech Slavic cohort

PubMed Central

Tomková, Mária; Panda, Satya Prakash; Šeda, Ondřej; Baxová, Alice; Hůlková, Martina; Masters, Bettie Sue Siler; Martásek, Pavel

2015-01-01

Background Gene polymorphisms encoding the enzyme NADPH–cytochrome P450 oxidoreductase (POR) contribute to inter-individual differences in drug response. Aim To estimate polymorphic allele frequencies of the POR gene in a Czech Slavic population. Materials & Methods The gene POR was analyzed in 322 Czech Slavic individuals from a control cohort by sequencing and HRM analysis. Results Twenty-five SNP genetic variations were identified. Of these variants, 7 were new, unreported SNPs, including two SNPs in the 5´flanking region (g.4965 C>T and g.4994 G>T), one intronic variant (c.1899 −20C>T), one synonymous SNP (p.20Ala=) and three nonsynonymous SNPs (p.Thr29Ser, p.Pro384Leu and p.Thr529Met). The p.Pro384Leu variant exhibited reduced enzymatic activities compared to wild type. Conclusion New POR variant identification indicates that the number of uncommon variants might be specific for each subpopulation being investigated, particularly germane to the singular role that POR plays in providing reducing equivalents to all CYPs in the endoplasmic reticulum. PMID:25712184

Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism.

PubMed

Boullu-Sanchis, S; Leprêtre, F; Hedelin, G; Donnet, J P; Schaffer, P; Froguel, P; Pinget, M

1999-06-01

We studied by PCR-RFLP 6 polymorphisms in these 5 candidate genes: Ala54Thr in the fatty acid binding protein 2 gene (FABP2), A to G substitution in the uncoupling protein type 1 gene (UCP1), Asp905Tyr in the protein phosphatase type 1 gene (PP1G), Trp64Arg in the human beta 3 adrenergic receptor gene (beta 3AR) and 2 RFLP sites of the vitamin D receptor (VDR) gene (VDRTaq1 and VDRApa1). This study was conducted among 89 cases and 100 controls matched according to age, gender and absence of first degree family link (11 triplets with 2 controls for 1 case and 78 pairs with 1 control for 1 case). Cases and controls were taken among a sample of 429 individuals selected for the study of the prevalence of diabetes in this ethnic group from Guadeloupe. By conditional logistic regression analysis, there was a significant relation (p = 0.02) between the Ala54Thr FABP2 polymorphism and Type 2 DM. Multivariate analysis discriminate the FABP2 polymorphism (p = 0.10), a triglyceridemia over 2 g/l (p < 10(-3)) and high blood pressure (p = 10(-2)) as variables associated with Type 2 DM in this population. These findings suggest that FABP2 does not represent a major gene for Type 2 DM in this migrant Indian population living in Guadeloupe, but seems to be related to the metabolic insulin resistance syndrome.

Solid-state NMR characterization of copolymers of nylon 11 and nylon 12.

PubMed

Johnson, C G; Mathias, L J

1997-05-01

Solid-state 13C and 15N NMR spectroscopy, in conjunction with differential scanning calorimetry, wide-angle X-ray diffraction and infrared spectroscopy, were used to characterize a series of nylon 11 and 12 copolymers with mole percentages of nylon 12 monomer of 0, 15, 35, 50, 65, 85, and 100%. Monotonic melting point (Tm) and heat of fusion depressions were observed for the copolymer series with the 65 mol% nylon 12 copolymer having the lowest apparent crystallinity and Tm at 148 degrees C. Solid-state 15N NMR spectra showed a smooth shift of the main peak position for the as-prepared copolymers from 84 ppm for the alpha-form of pure nylon 11 to 89 ppm for the gamma-form of pure nylon 12. Similar behavior was seen for FTIR amide V and VI modes which are also sensitive to the alpha- and gamma-crystal forms. 13C NMR T1 measurements showed that the overall most mobile sample was the 65:35 copolymer. The amide group of the 1:1 copolymer was labelled using 15N-labelled amino acids available through the Gabriel synthesis; an annealed, solution-cast film of this sample showed a T1N value of 349 s, similar to values seen for annealed nylon 11 and nylon 12 homopolymers. The WAXS pattern for the 65 mol% nylon 12 sample showed a sharp peak at 2 theta = 21.3, overlapping a broad peak centered at 2 theta = 21.0. These are consistent with the values seen for gamma-form nylon 12. The 1:1 copolymer (15N labelled) was shown to be polymorphic, like the homopolymers after specific treatments, with a gamma-like phase formed upon solvent casting, and an alpha-like phase dominating for as-polymerized material and precipitated flakes.

A comparative analysis of MC4R gene sequence, polymorphism, and chromosomal localization in Chinese raccoon dog and Arctic fox.

PubMed

Skorczyk, Anna; Flisikowski, Krzysztof; Switonski, Marek

2012-05-01

Numerous mutations of the human melanocortin receptor type 4 (MC4R) gene are responsible for monogenic obesity, and some of them appear to be associated with predisposition or resistance to polygenic obesity. Thus, this gene is considered a functional candidate for fat tissue accumulation and body weight in domestic mammals. The aim of the study was comparative analysis of chromosome localization, nucleotide sequence, and polymorphism of the MC4R gene in two farmed species of the Canidae family, namely the Chinese raccoon dog (Nycterutes procyonoides procyonoides) and the arctic fox (Alopex lagopus). The whole coding sequence, including fragments of 3'UTR and 5'UTR, shows 89% similarity between the arctic fox (1276 bp) and Chinese raccoon dog (1213 bp). Altogether, 30 farmed Chinese raccoon dogs and 30 farmed arctic foxes were searched for polymorphisms. In the Chinese raccoon dog, only one silent substitution in the coding sequence was identified; whereas in the arctic fox, four InDels and two single-nucleotide polymorphisms (SNPs) in the 5'UTR and six silent SNPs in the exon were found. The studied gene was mapped by FISH to the Chinese raccoon dog chromosome 9 (NPP9q1.2) and arctic fox chromosome 24 (ALA24q1.2-1.3). The obtained results are discussed in terms of genome evolution of species belonging to the family Canidae and their potential use in animal breeding.

Polymorphisms in the phosducin (PDC) gene on chromosome 1q25-32

DOE Office of Scientific and Technical Information (OSTI.GOV)

Humphries, P.; Mansergh, F.C.; Farrar, G.J.

1994-09-01

Phosducin (33 kDa protein or MEKA) is a principal water-soluble phosphoprotein in the rod and cone photoreceptor cells and pinealocytes. This protein modulates the phototransduction cascade by binding to the beta and gamma subunit complexes of transducin. The PDC gene has been mapped to 1q25-32, the region of linkage of two hereditary retinal degenerative disorders; autosomal dominant juvenile-onset open-angle glaucoma and one form of autosomal recessive RP. Using previously published sequence data, PCR primers were designed to amplify the coding and 5{prime} flanking regions of the PDC gene. Direct sequencing revealed three polymorphisms in the 5{prime} flanking region, two ofmore » which were in regions highly homologous between humans and mice. Analysis of the polymorphisms was then extended to larger population samples using SSCPE and denaturing gel analysis. The first polymorphism PDC1 resulted from an insertion of a G residue at position -653/4. Allele frequencies were determined to be 0.51 (insG) and 0.49 (normal) giving a PIC value of 0.50. A deletion of a T residue at position -488 was the basis of the PDC2 polymorphism with allele frequencies of 0.88 (normal) and 0.12 (delT) and a PIC value of 0.21. Interestingly, the allele with an inserted G residue in PDC1 always segregrated with the deleted T allele in PDC2. The third polymorphism PDC3 was caused by a T or G residue at position -1083. Allele frequencies of 0.26 (G residue) and 0.74 (T residue) were determined from an analysis of 80 individuals with an overall PIC value of 0.39. The identification of these three polymorphisms in the PDC gene will be useful for future genetic linkage studies of chromosome 1q in inherited retinopathies.« less

D2-Thr92Ala, thyroid hormone levels and biochemical hypothyroidism in preeclampsia.

PubMed

Procopciuc, Lucia Maria; Caracostea, Gabriela; Hazi, Georgeta; Nemeti, Georgiana; Stamatian, Florin

2017-02-01

To identify if there is a relationship between the deiodinase D2-Thr92Ala genetic variant, thyroid hormone levels and biochemical hypothyroidism in preeclampsia. We genotyped 125 women with preeclampsia and 131 normal pregnant women using PCR-RFLP. Serum thyroid hormone levels were determined using ELISA. Our study showed higher TSH and FT4 levels and lower FT3 levels in women with preeclampsia compared to normal pregnant women, with statistical significance for women with mild and severe preeclampsia. The risk to develop pregnancy-induced hypertension (PIH), mild or severe preeclampsia was increased in carriers of at least one D2-Ala92 allele. TSH and FT4 levels were significantly higher and FT3 levels were significantly lower in preeclamptic women with severe preeclampsia if they carried the D2-Ala92 allele compared to non-carriers. Pregnant women with PIH and mild preeclampsia, carriers of at least one D2-Ala92 allele, delivered at lower gestational age neonates with a lower birth weight compared to non-carriers, but the results were statistically significant only in severe preeclampsia. The D2-Thr92Ala genetic variant is associated with the severity and the obstetric outcome of preeclampsia, and it also influences thyroid hormone levels. The study demonstrates non-thyroidal biochemical hypothyroidism - as a result of deiodination effects due to D2 genotypes.

Shark island pedicle flap for repair of combined nasal ala-perialar defects.

PubMed

Cvancara, Joseph L; Wentzell, J Michael

2006-05-01

The combined nasal ala-perialar defect involving the concave intersection of the lateral nasal ala, nasal sidewall, cheek, and upper cutaneous lip is a problem for reconstructive surgery. During repair of combined cheek and nose defects, it is important not to blunt the alar facial sulcus. Defects involving these adjacent cosmetic units can be repaired by using combination procedures such as a flap/graft. Our purpose is to introduce, describe, and illustrate a one-stage flap repair descriptively named the "shark" island pedicle flap (SIPF). The SIPF was developed for a specific combined nasal ala-perialar defect. This reconstruction restores the natural contours, preserves cosmetic boundaries, and eliminates the need for pexing sutures and graft/flap combinations. The SIPF is an island pedicle flap with a superior arm that rotates 90 degrees into the wound. This arm repairs the alar portion of the defect. The advancing island pedicle flap repairs the alar facial sulcus. The 90 degrees rotation of the superior arm forces the alar portion of the flap to tilt 90 degrees relative to the remaining body of the flap, forming an inverted cone of redundancy. Natural re-creation of the lateral ala and the alar facial sulcus results. Illustrative examples with a descriptive technique are provided for the SIPF. A well-planned SIPF reconstruction can provide exceptional cosmetic and functional results. Cutaneous reconstructive surgeons will find the SIPF useful and reproducible in their armamentarium for single-stage aesthetic and functional repair of a specific combined lateral ala-adjacent perialar tissue defect.

Cytokine gene polymorphisms in bullous pemphigoid in a Chinese population.

PubMed

Chang, Y T; Liu, H N; Yu, C W; Lin, M W; Huang, C H; Chen, C C; Liu, M T; Lee, D D; Wang, W J; Tsai, S F

2006-01-01

Bullous pemphigoid (BP) is an autoimmune bullous disease mostly associated with autoantibodies to the hemidesmosomal BP autoantigens BP180 and BP230. High levels of interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma have been detected in skin lesions or sera of patients with BP. Cytokine gene polymorphisms may affect cytokine production and contribute to susceptibility to autoimmune diseases. Until now, no cytokine gene polymorphism study has been conducted on patients with BP. We aimed to determine whether the genetic polymorphisms of the cytokine genes might influence the development of BP. DNA samples were obtained from 96 BP patients and 174 control subjects. Using direct sequencing and microsatellite genotyping, we examined 23 polymorphisms in 11 cytokine genes including the IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, IL-13, IL-4 receptor, TNF-alpha and IFN-gamma genes. Although the BP patients were more likely to carry the -511T and -31C alleles of the IL-1beta gene (P = 0.04), the significance disappeared after correction for multiple testing (Pc). There was complete linkage disequilibrium between the -511T and -31C alleles of the IL-1beta gene. In female patients with BP, the associations with IL-1beta (-511T) and (-31C) alleles were much stronger (68% vs. 40.6%, odds ratio = 3.11, Pc = 0.006). No significantly different allelic and genotypic distributions of other cytokine gene polymorphisms could be found between the patients with BP and controls. Moreover, no association with the extent of disease involvement (localized or generalized) was observed. The IL-1beta (-511) and (-31) polymorphisms were significantly associated with BP in women. The other genetic polymorphisms of cytokine genes that we analysed do not appear to be associated with BP susceptibility in our Chinese population.

Impact of gamma rays on the Phaffia rhodozyma genome revealed by RAPD-PCR.

PubMed

Najafi, N; Hosseini, Ramin; Ahmadi, Ar

2011-12-01

Phaffia rhodozyma is a red yeast which produces astaxanthin as the major carotenoid pigment. Astaxanthin is thought to reduce the incidence of cancer and degenerative diseases in man. It also enhances the immune response and acts as a free-radical quencher, a precursor of vitamin A, or a pigment involved in the visual attraction of animals as mating partners. The impact of gamma irradiation was studied on the Phaffia rhodozyma genome. Ten mutant strains, designated Gam1-Gam10, were obtained using gamma irradiation. Ten decamer random amplified polymorphic DNA (RAPD) primers were employed to assess genetic changes. Nine primers revealed scorable polymorphisms and a total of 95 band positions were scored; amongst which 38 bands (37.5%) were polymorphic. Primer F with 3 bands and primer J20 with 13 bands produced the lowest and the highest number of bands, respectively. Primer A16 produced the highest number of polymorphic bands (70% polymorphism) and primer F showed the lowest number of polymorphic bands (0% polymorphism). Genetic distances were calculated using Jaccard's coefficient and the UPGMA method. A dendrogram was created using SPSS (version 11.5) and the strains were clustered into four groups. RAPD markers could distinguish between the parental and the mutant strains of P. rhodozyma. RAPD technique showed that some changes had occurred in the genome of the mutated strains. This technique demonstrated the capability to differentiate between the parental and the mutant strains.

Using the ALA's "Evaluating Library Instruction" (1996).

ERIC Educational Resources Information Center

Roselle, Ann

1997-01-01

Using a multi-method approach--student and faculty surveys and a comparison of bibliographies from senior nursing students--to evaluate the Information Literacy Skills Program at the University of Botswana, this study found that information about the impact of instruction can be discovered through more open-ended questions; the ALA's…

The complex filling of alae crater, Kilauea Volcano, Hawaii

USGS Publications Warehouse

Swanson, D.A.; Duffield, W.A.; Jackson, D.B.; Peterson, D.W.

1972-01-01

Since February 1969 Alae Crater, a 165-m-deep pit crater on the east rift of Kilauea Volcano, has been completely filled with about 18 million m3 of lava. The filling was episodic and complex. It involved 13 major periods of addition of lava to the crater, including spectacular lava falls as high as 100 m, and three major periods of draining of lava from the crater. Alae was nearly filled by August 3, 1969, largely drained during a violent ground-cracking event on August 4, 1969, and then filled to the low point on its rim on October 10, 1969. From August 1970 to May 1971, the crater acted as a reservoir for lava that entered through subsurface tubes leading from the vent fissure 150 m away. Another tube system drained the crater and carried lava as far as the sea, 11 km to the south. Much of the lava entered Alae by invading the lava lake beneath its crust and buoying the crust upward. This process, together with the overall complexity of the filling, results in a highly complicated lava lake that would doubtless be misinterpreted if found in the fossil record. ?? 1972 Stabilimento Tipografico Francesco Giannini & Figli.

Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium

PubMed Central

Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

2016-01-01

Objective Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). Materials and Methods In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Results Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. Conclusion ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions. PMID:27540524

Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium.

PubMed

Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

2016-01-01

Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions.

Conformational and chemical selection by a trans-acting editing domain

PubMed Central

Danhart, Eric M.; Bakhtina, Marina; Cantara, William A.; Kuzmishin, Alexandra B.; Ma, Xiao; Sanford, Brianne L.; Vargas-Rodriguez, Oscar; Košutić, Marija; Goto, Yuki; Suga, Hiroaki; Nakanishi, Kotaro; Micura, Ronald; Musier-Forsyth, Karin

2017-01-01

Molecular sieves ensure proper pairing of tRNAs and amino acids during aminoacyl-tRNA biosynthesis, thereby avoiding detrimental effects of mistranslation on cell growth and viability. Mischarging errors are often corrected through the activity of specialized editing domains present in some aminoacyl-tRNA synthetases or via single-domain trans-editing proteins. ProXp-ala is a ubiquitous trans-editing enzyme that edits Ala-tRNAPro, the product of Ala mischarging by prolyl-tRNA synthetase, although the structural basis for discrimination between correctly charged Pro-tRNAPro and mischarged Ala-tRNAAla is unclear. Deacylation assays using substrate analogs reveal that size discrimination is only one component of selectivity. We used NMR spectroscopy and sequence conservation to guide extensive site-directed mutagenesis of Caulobacter crescentus ProXp-ala, along with binding and deacylation assays to map specificity determinants. Chemical shift perturbations induced by an uncharged tRNAPro acceptor stem mimic, microhelixPro, or a nonhydrolyzable mischarged Ala-microhelixPro substrate analog identified residues important for binding and deacylation. Backbone 15N NMR relaxation experiments revealed dynamics for a helix flanking the substrate binding site in free ProXp-ala, likely reflecting sampling of open and closed conformations. Dynamics persist on binding to the uncharged microhelix, but are attenuated when the stably mischarged analog is bound. Computational docking and molecular dynamics simulations provide structural context for these findings and predict a role for the substrate primary α-amine group in substrate recognition. Overall, our results illuminate strategies used by a trans-editing domain to ensure acceptance of only mischarged Ala-tRNAPro, including conformational selection by a dynamic helix, size-based exclusion, and optimal positioning of substrate chemical groups. PMID:28768811

Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women.

PubMed

Bustamante, M; Nogués, X; Mellibovsky, L; Agueda, L; Jurado, S; Cáceres, E; Blanch, J; Carreras, R; Díez-Pérez, A; Grinberg, D; Balcells, S

2007-11-01

Osteoporosis and obesity are complex diseases with a strong genetic component. Bone mineral density (BMD) and body mass index (BMI) linkage studies identified a locus at 1q21-23, where the interleukin-6 receptor (IL6R) gene is located. The IL6R and the gp130 receptors are the mediators of IL6 action. Serum levels of IL6 and sIL6R (the soluble form of IL6R) are higher in several diseases such as osteoporosis or obesity. Variants at IL6R have been associated with BMI and obesity. However, IL6R is an as-yet-unexplored osteoporosis candidate gene. In the present study we analysed two polymorphisms in the IL6R promoter, -1435 C/T (rs3887104) and -208 G/A (rs4845617), and the Asp358Ala polymorphism (rs8192284), in relation to both BMD and BMI in a cohort of 559 postmenopausal Spanish women. The promoter polymorphisms, -1435 C/T and -208 G/A were associated with femoral neck (FN) BMD (P=0.011 and P=0.025 respectively). The C-A and T-G promoter haplotypes were also associated with FN BMD. Additionally, the Asp358Ala variant was associated with lumbar spine BMD (P=0.038). Finally, the -208 G/A polymorphism and the C-G and C-A haplotypes were associated with BMI and obesity, where GG was the risk genotype (P=0.033 for BMI; P=0.010 for obesity). These data suggest that variants in the IL6R gene are not only involved in the determination of BMI but also relevant for the determination of BMD. The IL6R gene may belong to the growing list of genes known to be involved in both phenotypes.

The Arg72 variant of the p53 functional polymorphism (rs1042522) is associated with coronary artery disease in young South Africans of Indian ancestry.

PubMed

Khan, Sajidah; Phulukdaree, Alisa; Ramkaran, Prithiksha; Moodley, Devapregasan; Chuturgoon, Anil A

2016-11-30

Tumor protein p53 (p53), classically referred to as a tumor suppressor gene, is involved in cell cycle regulation and may be related to atherosclerosis by affecting smooth muscle cell proliferation, a feature of atherogenesis. A polymorphism at codon 72 (rs1042522) results in functional variability and hence plays a role in the pathophysiology of coronary artery disease (CAD). This polymorphism has been well established for its role in cancer and has only recently been investigated in CAD. Limited data is available on South Africans (SA) of Indian ancestry. We examined associations of this polymorphism and clinical markers in a cohort of young SA Indian CAD patients. A total of 284 subjects were recruited into this study which included 100 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45years), 100 age- and sex-matched Indian controls and 84 age- and sex-matched Black controls. Polymorphic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for clinical markers were obtained from pathology reports. Genotype distribution differed significantly between CAD patients and Indian controls (Pro/Pro, Pro/Arg, Arg/Arg: 24%, 48%, 28% vs. 30%, 61%, 9% respectively, p=0.0025). There was a significant genotype distribution between Indian and Black controls (Pro/Pro, Pro/Arg, Arg/Arg: 30%, 61%, 9% vs. 45.2% 40.5%, 14.3% respectively, p=0.0212). A significantly higher frequency of the p53 Arg72 allele was found in CAD patients compared to controls (52% vs. 39.5% respectively, p=0.0159). The variant allele was slightly higher in Indian controls (39.5%) compared to Black controls (34.5%), but this did not reach statistical significance (p=0.3324). The levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin and %HbA1c were not significantly influenced by the p53 genotypic variants. Although the p53 codon 72 SNP is not associated with clinical markers of disease in CAD, the

ALA 2010: Where to Eat in DC

ERIC Educational Resources Information Center

Library Journal, 2010

2010-01-01

As host to visitors and transplants from around the world, Washington, DC, benefits from the constant infusion of different cultures. Although most neighborhoods lack a unified culinary flavor, make no mistake: DC is a city of distinctive areas, each with its own style, ensuring that hungry American Library Association (ALA) 2010 conference…

A Prospective Open-label Pilot Study of Fluvastatin on Pro-inflammatory and Pro-thrombotic Biomarkers in Antiphospholipid Antibody Positive Patients

PubMed Central

Erkan, Doruk; Willis, Rohan; Murthy, Vijaya L.; Basra, Gurjot; Vega, JoAnn; Ruiz Limón, Patricia; Carrera, Ana Laura; Papalardo, Elizabeth; Martínez-Martínez, Laura Aline; González, Emilio B.; Pierangeli, Silvia S.

2014-01-01

Objective: To determine if pro-inflammatory and pro-thrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL)-positive patients, and to examine the effects of fluvastatin on these biomarkers. Methods: Four groups of patients (age 18-65) were recruited: a) Primary Antiphospholipid Syndrome (PAPS); b) Systemic Lupus Erythematosus (SLE) with APS (SLE/APS); c) Persistent aPL positivity without SLE or APS (Primary aPL); and d) Persistent aPL positivity with SLE but no APS (SLE/aPL). The frequency-matched control group, used for baseline data comparison, was identified from a databank of healthy persons. Patients received fluvastatin 40 mg daily for three months. At three months, patients stopped the study medication and they were followed for another three months. Blood samples for 12 pro-inflammatory and pro-thrombotic biomarkers were collected monthly for six months. Results: Based on the comparison of the baseline samples of 41 aPL-positive patients with 30 healthy controls, 9/12 (75%) biomarkers (interleukin [IL]-6, IL1β, vascular endothelial growth factor [VEGF], tumor necrosis factor [TNF]-□α, interferon [IFN]-α, inducible protein-10 [IP10], soluble CD40 ligand [sCD40L], soluble tissue factor [sTF], and intracellular cellular adhesion molecule [ICAM]-1) were significantly elevated. Twenty-four patients completed the study; fluvastatin significantly and reversibly reduced the levels of 6/12 (50%) biomarkers (IL1β, VEGF, TNFα, IP10, sCD40L, and sTF). Conclusion: Our prospective mechanistic study demonstrates that pro-inflammatory and pro-thrombotic biomarkers, which are differentially upregulated in persistently aPL-positive patients, can be reversibly reduced by fluvastatin. Thus, statin-induced modulation of the aPL effects on target cells can be a valuable future approach in the management of aPL-positive patients. PMID:23933625

Recombinant Brucella abortus gene expressing immunogenic protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayfield, J.E.; Tabatabai, L.B.

This patent describes a synthetic recombinant DNA molecule containing a DNA sequence. It comprises a gene of Brucella abortus encoding an immunogenic protein having a molecular weight of approximately 31,000 daltons as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis under denaturing conditions, the protein having an isoelectric point around 4.9, and containing a twenty-five amino acid sequence from its amino terminal end consisting of Gln-Ala-Pro-Thr-Phe-Phe-Arg-Ile-Gly-Thr-Gly-Gly-Thr-Ala-Gly-Thr-Tyr-Tyr-Pro-Ile-Gly-Gly-Leu-Ile-Ala, wherein Gln, Ala, Pro, Thr, Phe, Arg, Ile, Gly, Tyr, and Leu, respectively, represent glutamine, alanine, proline, threonine, phenylalanine, arginine, isolecuine, glycine, tyrosine, and leucine.

Furosemide loading test in a case of homozygous solute carrier family 12, member 1 (SLC12A1) mutation (g.62382825G>A, p.Pro372Leu) in Japanese Black cattle.

PubMed

Hasegawa, Kiyotoshi; Sasaki, Shinji; Sakamoto, Yoichi; Takano, Akifumi; Takayama, Megumi; Higashi, Tomoko; Sugimoto, Yoshikazu; Yasuda, Yasuaki

2017-10-01

Hydrallantois is the excessive accumulation of fluid in the allantoic cavity in a pregnant animal and is associated with fetal death. We recently identified a recessive missense mutation in the solute carrier family 12, member 1 (SLC12A1) gene (g.62382825G>A, p.Pro372Leu) that is associated with hydrallantois in Japanese Black cattle. Unexpectedly, we found a case of the homozygous risk-allele for SLC12A1 in a calf, using a PCR-based direct DNA sequencing test. The homozygote was outwardly healthy up to 3 months of age and the mother did not exhibit any clinical symptoms of hydrallantois. In order to validate these observations, we performed confirmation tests for the genotype and a diuretic loading test using furosemide, which inhibits the transporter activity of the SLC12A1 protein. The results showed that the calf was really homozygous for the risk-allele. In the homozygous calf, administration of furosemide did not alter urinary Na + or Cl - levels, in contrast to the heterozygote and wild-type calves in which these were significantly increased. These results demonstrate that the SLC12A1 (g.62382825G>A, p.Pro372Leu) is a hypomorphic or loss-of-function mutation and the hydrallantois with this mutation shows incomplete penetrance in Japanese Black cattle. © 2017 Japanese Society of Animal Science.

Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection.

PubMed

Bartolomé, Javier; Castillo, Inmaculada; Quiroga, Juan Antonio; Carreño, Vicente

2016-02-01

Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5)  ± 5.8 × 10(4) vs. 4.1 × 10(5)  ± 5.9 × 10(4)  copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C. © 2015 Wiley Periodicals, Inc.

Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): current clinical and development status

NASA Astrophysics Data System (ADS)

Marcus, Stuart L.; Sobel, Russel S.; Golub, Allyn L.; Carroll, Ronald L.; Lundahl, Scott L.; Shulman, D. Geoffrey

1996-04-01

Exogenous provision of ALA to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX, (PpIX), to produce a photodynamic effect. Therefore, ALA may be considered the only current PDT agent in clinical development which is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous T-cell lymphoma, superficial basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses, and is also being examined for treatment of acne and hirsutism. PpIX induced by ALA application also may serve as a fluorescence detection marker for photodiagnosis (PD) of malignant and pre- malignant conditions of the urinary bladder and other organs. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and is beginning to be examined in human clinical studies. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This brief paper reviews the current clinical and development status of ALA PDT.

Potentiation of ALA-PDT antitumor activity in mice using topical DMXAA

NASA Astrophysics Data System (ADS)

Marrero, Allison; Sunar, Ulas; Sands, Theresa; Oseroff, Allan; Bellnier, David

2009-06-01

Photodynamic treatment of subcutaneously implanted Colon 26 tumors in BALB/c mice using the aminolevulinic acid (ALA)-induced photosensitizer protoporphyrin IX (PpIX) was shown to be enhanced by the addition of the vascular disrupting agent 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA; Novartis ASA404). DMXAA increases vascular permeability and decreases blood flow in both murine and human tumors. Sufficiently high parenteral DMXAA doses can lead to tumor collapse and necrosis. We have previously reported marked enhancement of antitumor activity when PDT, using either Photofrin or HPPH, is combined with low-dose intraperitoneal DMXAA. We now describe the first attempt to combine topically-applied DMXAA with PDT. For this, DMXAA was applied two hours before PpIX-activating light delivery. PDT with ALA-PDT alone (ALA 20%; 80 J/cm2 delivered at 75 mW/cm2) caused a 39% decrease in tumor volume compared to unirradiated controls. Addition of topical DMXAA to ALA-PDT resulted in a 74% reduction in tumor volume. Diffuse correlation spectroscopy (DCS), a non-invasive blood flow imaging method, is being used to understand the mechanism of this effect and to aid in the proper design of the therapy. For instance, our most recent DCS data suggests that the 2-hour interval between the DMXAA and light applications may not be optimum. This preliminary study suggests a potential role for topical DMXAA in combination with PDT for dermatologic tumors.

Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients.

PubMed

Adlbrecht, Christopher; Hülsmann, Martin; Strunk, Guido; Berger, Rudolf; Mörtl, Deddo; Struck, Joachim; Morgenthaler, Nils G; Bergmann, Andreas; Jakowitsch, Johannes; Maurer, Gerald; Lang, Irene M; Pacher, Richard

2009-04-01

The identification of chronic heart failure (CHF) patients at high risk of adverse outcome remains a challenge. New peptides are emerging that may give additional information. In CHF patients, endothelin (ET) levels predict mortality risk. Adrenomedullin has been shown to predict mortality in ischaemic heart failure, but not in unselected or non-ischaemic CHF patients. Moreover, ADM and ET have never been assessed in one model. The aim of the present study was to assess the prognostic value of midregional-pro-adrenomedullin (MR-proADM) and C-terminal-pro-endothelin-1 (CT-proET-1) in outpatients with CHF. We measured plasma MR-proADM and CT-proET-1 levels in 786 consecutive CHF outpatients and compared them with B-type natriuretic peptide (BNP) levels. At 24-month follow-up, 233 patients had died. A stepwise forward Cox regression model with age, sex, estimated glomerular filtration rate, NYHA > II, left ventricular ejection fraction (LVEF), MR-proADM, CT-proET-1, and BNP as possible predictors revealed that MR-proADM levels [hazard ratio (HR) = 1.77, P < 0.001] in addition to age (HR = 1.02, P = 0.004), ejection fraction (HR = 0.98, P = 0.004), and NYHA > II (HR = 1.86, P < 0.001) were predictors of death at 24 months. When the analysis was repeated dependent on NYHA-stage, MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers, but only in patients with mild/moderate CHF. Our data suggest that MR-proADM may be an important prognostic humoral marker, especially in mild/moderately symptomatic and non-ischaemic CHF patients.

Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya.

PubMed

Zhang, Lyna; Prather, Donald; Vanden Eng, Jodi; Crawford, Sara; Kariuki, Simon; ter Kuile, Feiko; Terlouw, Dianne; Nahlen, Bernard; Lal, Altaf A; Slutsker, Laurence; Udhayakumar, Venkatachalam; Shi, Ya Ping

2010-03-29

Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined. Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya. An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21). This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.

Fluorescence spectroscopy of gastrointestinal tumors using δ-ALA

NASA Astrophysics Data System (ADS)

Borisova, E. G.; Vladimirov, B. G.; Angelov, I. G.; Avramov, L. A.

2007-03-01

In the recent study delta-aminolevulinic acid/Protoporphyrin IX (δ-ALA/PpIX) is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The δ-ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built to use the light guide of standard video-endoscopic system (Olimpus Corp.). Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer (USB4000, OceanOptics Inc.). The fluorescence detected from tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Mucosa autofluorescence lies at 450-600 nm region. The fluorescence of PpIX is clearly pronounced at the 630-710 nm region. Deep minima in the tumor fluorescence signals are observed in the region 540-575 nm, related to hemoglobin re-absorption. Such high hemoglobin content is an indication of the tumors neovascularisation and it is clearly pronounced in all dysplastic and tumor sites investigated. The lack of fluorescence peaks in the red spectral area for normal mucosa is an indication for selective accumulation of δ-ALA/PpIX only in abnormal sites and gives high contrast when lesion borders are determined from clinicians during video observation in the process of diagnostic procedure. Very good correlation between fluorescence signals and histology examination results of the lesions investigated is achieved.

PPARγ2 C1431T genotype increases metabolic syndrome risk in young men with low cardiorespiratory fitness.

PubMed

Sanada, Kiyoshi; Iemitsu, Motoyuki; Murakami, Haruka; Tabata, Izumi; Yamamoto, Kenta; Gando, Yuko; Suzuki, Katsuhiko; Higuchi, Mitsuru; Miyachi, Motohiko

2011-02-11

The peroxisome proliferator-activated receptor gamma 2 (PPARγ2) genotypes are related to obesity and the metabolic syndrome (MetS). A low level of cardiorespiratory fitness is also a strong determining factor in the development of MetS. This cross-sectional study was performed to investigate the influence of the interaction between the PPARγ2 genotype and cardiorespiratory fitness on the risk of MetS. Healthy Japanese men (n = 211) and women (n = 505) participated in this study. All subjects were divided into 8 groups according to sex, fitness level (high and low fitness groups), and age (younger, age < 40 yr; middle-aged/older, age ≥ 40 yr). The PPARγ2 genotypes (Pro12Ala and C1431T) were analyzed by real-time PCR with Taq-Man probes. Two-way ANCOVA with adjustment for age as a covariate indicated that fitness and the CC genotype of C1431T in the PPARγ2 gene interacted to produce a significant effect on MetS risk in younger men and that the risk of MetS in the CC genotype group with low cardiorespiratory fitness was significantly higher than that in the corresponding CT+TT genotypes or in the high fitness groups. There was no significant interaction between fitness and genotype in determining MetS risk in middle-aged/older men or in women in any group. With regard to the Pro12Ala genotype of the PPARγ2 gene, there were no significant differences in fitness or genotype effects nor were there any interactions between measurement variables. We concluded that the CC genotype of C1431T in the PPARγ2 gene together with low cardiorespiratory fitness may increase the risk of MetS in younger men (age < 40 yr), even with adjustment for age.

Resonance strengths in the {sup 14}N(p,gamma){sup 15}O and {sup 15}N(p,alphagamma){sup 12}C reactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marta, Michele; Trompler, Erik; Bemmerer, Daniel

2010-05-15

The {sup 14}N(p,gamma){sup 15}O reaction is the slowest reaction of the carbon-nitrogen-oxygen cycle of hydrogen burning in stars. As a consequence, it determines the rate of the cycle. The {sup 15}N(p,alphagamma){sup 12}C reaction is frequently used in inverse kinematics for hydrogen depth profiling in materials. The {sup 14}N(p,gamma){sup 15}O and {sup 15}N(p,alphagamma){sup 12}C reactions have been studied simultaneously, using titanium nitride targets of natural isotopic composition and a proton beam. The strengths of the resonances at E{sub p} = 1058 keV in {sup 14}N(p,gamma){sup 15}O and at E{sub p} = 897 and 430 keV in {sup 15}N(p,alphagamma){sup 12}C have beenmore » determined with improved precision, relative to the well-known resonance at E{sub p} = 278 keV in {sup 14}N(p,gamma){sup 15}O. The new recommended values are omegagamma=0.353+-0.018, 362+-20, and 21.9+-1.0 eV for their respective strengths. In addition, the branching ratios for the decay of the E{sub p} = 1058 keV resonance in {sup 14}N(p,gamma){sup 15}O have been redetermined. The data reported here should facilitate future studies of off-resonant capture in the {sup 14}N(p,gamma){sup 15}O reaction that are needed for an improved R-matrix extrapolation of the cross section. In addition, the data on the 430 keV resonance in {sup 15}N(p,alphagamma){sup 12}C may be useful for hydrogen depth profiling.« less

Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation.

PubMed

Ahn, H J; Tomura, M; Yu, W G; Iwasaki, M; Park, W R; Hamaoka, T; Fujiwara, H

1998-12-01

While IL-12 is known to activate JAK2 and TYK2 and induce the phosphorylation of STAT4 and STAT3, little is known regarding how the activation of these signaling molecules is related to the biologic effects of IL-12. Using an IL-12-responsive T cell clone (2D6), we investigated their requirements for proliferation and IFN-gamma production of 2D6 cells. 2D6 cells could be maintained with either IL-12 or IL-2. 2D6 lines maintained with IL-12 (2D6(IL-12)) or IL-2 (2D6(IL-2)) exhibited comparable levels of proliferation, but produced large or only small amounts of IFN-gamma, respectively, when restimulated with IL-12 after starvation of either cytokine. 2D6(IL-12) induced TYK2 and STAT4 phosphorylation. In contrast, their phosphorylation was marginally induced in 2D6(IL-2). The reduced STAT4 phosphorylation was due to a progressive decrease in the amount of STAT4 protein along with the passages in IL-2-containing medium. 2D6(IL-12) and 2D6(IL-2) similarly proliferating in response to IL-12 induced comparable levels of JAK2 activation and STAT5 phosphorylation. JAK2 was associated with STAT5, and IL-12-induced STAT5 phosphorylation was elicited in the absence of JAK3 activation. These results indicate that IL-12 has the capacity to induce/maintain STAT4 and STAT5 proteins, and that TYK2 and JAK2 activation correlate with STAT4 phosphorylation/IFN-gamma induction and STAT5 phosphorylation/cellular proliferation, respectively.

A periplasmic D-alanyl-D-alanine dipeptidase in the gram-negative bacterium Salmonella enterica.

PubMed

Hilbert, F; García-del Portillo, F; Groisman, E A

1999-04-01

The VanX protein is a D-alanyl-D-alanine (D-Ala-D-Ala) dipeptidase essential for resistance to the glycopeptide antibiotic vancomycin. While this enzymatic activity has been typically associated with vancomycin- and teicoplainin-resistant enterococci, we now report the identification of a D-Ala-D-Ala dipeptidase in the gram-negative species Salmonella enterica. The Salmonella enzyme is only 36% identical to VanX but exhibits a similar substrate specificity: it hydrolyzes D-Ala-D-Ala, DL-Ala-DL-Phe, and D-Ala-Gly but not the tripeptides D-Ala-D-Ala-D-Ala and DL-Ala-DL-Lys-Gly or the dipeptides L-Ala-L-Ala, N-acetyl-D-Ala-D-Ala, and L-Leu-Pro. The Salmonella dipeptidase gene, designated pcgL, appears to have been acquired by horizontal gene transfer because pcgL-hybridizing sequences were not detected in related bacterial species and the G+C content of the pcgL-containing region (41%) is much lower than the overall G+C content of the Salmonella chromosome (52%). In contrast to wild-type Salmonella, a pcgL mutant was unable to use D-Ala-D-Ala as a sole carbon source. The pcgL gene conferred D-Ala-D-Ala dipeptidase activity upon Escherichia coli K-12 but did not allow growth on D-Ala-D-Ala. The PcgL protein localizes to the periplasmic space of Salmonella, suggesting that this dipeptidase participates in peptidoglycan metabolism.

The RTEL1 rs6010620 polymorphism and glioma risk: a meta-analysis based on 12 case-control studies.

PubMed

Du, Shu-Li; Geng, Ting-Ting; Feng, Tian; Chen, Cui-Ping; Jin, Tian-Bo; Chen, Chao

2014-01-01

The association between the RTEL1 rs6010620 single nucleotide polymorphism (SNP) and glioma risk has been extensively studied. However, the results remain inconclusive. To further examine this association, we performed a meta-analysis. A computerized search of the PubMed and Embase databases for publications regarding the RTEL1 rs6010620 polymorphism and glioma cancer risk was performed. Genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analyses, tests of heterogeneity, cumulative meta-analyses, and assessments of bias were performed in our meta-analysis. Our meta-analysis confirmed that risk with allele A is lower than with allele G for glioma. The A allele of rs6010620 in RTEL1 decreased the risk of developing glioma in the 12 case-control studies for all genetic models: the allele model (OR=0.752, 95%CI: 0.715-0.792), the dominant model (OR=0.729, 95%CI: 0.685-0.776), the recessive model (OR=0.647, 95%CI: 0.569-0.734), the homozygote comparison (OR=0.528, 95%CI: 0.456-0.612), and the heterozygote comparison (OR=0.761, 95%CI: 0.713-0.812). In all genetic models, the association between the RTEL1 rs6010620 polymorphism and glioma risk was significant. This meta-analysis suggests that the RTEL1 rs6010620 polymorphism may be a risk factor for glioma. Further functional studies evaluating this polymorphism and glioma risk are warranted.

Population description and its role in the interpretation of genetic association

PubMed Central

Yu, Joon-Ho; Crouch, Julia; Fryer-Edwards, Kelly; Burke, Wylie

2010-01-01

Despite calls for greater clarity and precision of population description, studies have documented persistent ambiguity in the use of race/ethnicity terms in genetic research. It is unclear why investigators tolerate such ambiguity, or what effect these practices have on the evaluation of reported associations. To explore the way that population description is used to replicate and/or extend previously reported genetic observations, we examined articles describing the association of the peroxisome proliferator-activated receptor-gamma-γ Pro12Ala polymorphism with type 2 diabetes mellitus and related phenotypes, published between 1997 and 2005. The 80 articles identified were subjected to a detailed content analysis to determine (1) how sampled populations were described, (2) whether and how the choice of sample was explained, and (3) how the allele frequency and genetic association findings identified were contextualized and interpreted. In common with previous reports, we observed a variety of sample descriptions and little explanation for the choice of population investigated. Samples of European origin were typically described with greater specificity than samples of other origin. However, findings from European samples were nearly always compared to samples described as “Caucasian” and sometimes generalized to all Caucasians or to all humans. These findings suggest that care with population description, while important, may not fully address analytical concerns regarding the interpretation of variable study outcomes or ethical concerns regarding the attribution of genetic observations to broad social groups. Instead, criteria which help investigators better distinguish justified and unjustified forms of population generalization may be required. PMID:20157827

5-ALA-induced fluorescence as a marker for diagnostic tissue in stereotactic biopsies of intracranial lymphomas: experience in 41 patients.

PubMed

Kiesel, Barbara; Millesi, Matthias; Woehrer, Adelheid; Furtner, Julia; Bavand, Anahita; Roetzer, Thomas; Mischkulnig, Mario; Wolfsberger, Stefan; Preusser, Matthias; Knosp, Engelbert; Widhalm, Georg

2018-06-01

(57%) and inhomogeneous intratumoral fluorescence in 12 (43%). According to histopathological analysis, all samples with strong or vague fluorescence contained diagnostic lymphoma tissue, resulting in a positive predictive value of 100%. Analysis showed no influence of preoperative corticosteroids or immunosuppression on fluorescence. CONCLUSIONS The data obtained in this study demonstrate the technical and clinical utility of 5-ALA-induced fluorescence in stereotactic biopsies of intracranial lymphomas. Thus, 5-ALA can serve as a useful tool to select patients not requiring intraoperative histopathology, and its application should markedly reduce operation time and related costs in the future.

Association of Gene Polymorphisms in Interleukin 6 in Infantile Bronchial Asthma.

PubMed

Babusikova, Eva; Jurecekova, Jana; Jesenak, Milos; Evinova, Andrea

2017-07-01

The genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene-gene interactions. Cytokines contribute to different aspects of asthma, as they determine the type, severity and outcomes of asthma pathogenesis. Allergic asthmatics undergoing an asthmatic attack exhibit significantly higher levels of pro-inflammatory cytokines, such as interleukins and chemokines. In recent years, cytokines and their receptors have been shown to be highly polymorphic, and this prompted us to investigate interleukin 6 promoter polymorphisms at position -174G/C (rs1800795) and at -572G/C (rs1800796) in relation to asthma in children. Interleukin 6 promoter polymorphisms were analyzed in bronchial asthma patients and healthy children using polymerase chain reaction-restriction fragment length polymorphism analysis. We observed a significant association between polymorphism at -174G/C and bronchial asthma (OR=3.4, 95% CI: 2.045-5.638, P<.001). Higher associations between polymorphism at IL-6 -174G/C and bronchial asthma were observed in atopic patients (OR=4.1, 95% CI: 2.308-7.280, P<8.10 -7 ). Interleukin 6 polymorphism is associated with bronchial asthma, particularly its atopic phenotype. Expression and secretion of interleukins in asthmatic patients may be affected by genetic polymorphisms, and could have a disease-modifying effect in the asthmatic airway and modify the therapeutic response. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

A determination of occlusal plane comparing different levels of the tragus to form ala-tragal line or Camper's line: A photographic study.

PubMed

Kumar, Sandeep; Garg, Sandeep; Gupta, Seema

2013-02-01

The purpose of this study was to determine accurately the part of the tragus to be used to form the Ala-Tragal line or Camper's line in orthognathic profile patients. 150 dentate subjects with age of 18-40 years with orthognathic profile were sampled. Life-size lateral digital photographs of the face with fox plane were taken in natural head position. Different angles between Eye-Ear plane and occlusal plane (OT1-OP), Eye-Ear plane and ala-superior border of tragus (OT1-AT1), Eye-Ear plane and ala-middle border of tragus (OT1-AT2) and Eye-Ear plane and ala-inferior border of tragus (OT1-AT3) were calculated using computer software package, AutoCAD 2004. From the three angles formed by the Eye-ear plane (OT1 or FH plane) and the ala-tragal lines, the one closest to the angle formed between Eye-Ear plane (OT1) and occlusal plane (OP) was used to determine the occlusal plane of orientation. The obtained results were subjected to ANOVA F test, Tukey's Honestly significant difference test, followed by Karl Pearson coefficient of correlation test. P values of less than 0.05 were taken as statistically significant. The mean of base line angle i.e. OT1-OP angle (11.96 ± 4.36) was found to be close to OT1-AT2 angle (13.67 ± 1.93) and OT1-AT3 angle (10.31 ± 2.03), but OT1-OP angle was found to be more closer to OT1-AT3 angle. Comparison of mean angles showed that OT1-OP angle in both males (11.68) and females (12.51) is close to OT1-AT3 angle (males- 11.01, females- 11.95). The line joining from ala to the lower border of the tragus was parallel to the occlusal plane in 53.3% of the subjects. There was no influence of the sex on the level of occlusal plane.

A determination of occlusal plane comparing different levels of the tragus to form ala-tragal line or Camper's line: A photographic study

PubMed Central

Garg, Sandeep; Gupta, Seema

2013-01-01

PURPOSE The purpose of this study was to determine accurately the part of the tragus to be used to form the Ala-Tragal line or Camper's line in orthognathic profile patients. MATERIALS AND METHODS 150 dentate subjects with age of 18-40 years with orthognathic profile were sampled. Life-size lateral digital photographs of the face with fox plane were taken in natural head position. Different angles between Eye-Ear plane and occlusal plane (OT1-OP), Eye-Ear plane and ala-superior border of tragus (OT1-AT1), Eye-Ear plane and ala-middle border of tragus (OT1-AT2) and Eye-Ear plane and ala-inferior border of tragus (OT1-AT3) were calculated using computer software package, AutoCAD 2004. From the three angles formed by the Eye-ear plane (OT1 or FH plane) and the ala-tragal lines, the one closest to the angle formed between Eye-Ear plane (OT1) and occlusal plane (OP) was used to determine the occlusal plane of orientation. The obtained results were subjected to ANOVA F test, Tukey's Honestly significant difference test, followed by Karl Pearson coefficient of correlation test. P values of less than 0.05 were taken as statistically significant. RESULTS The mean of base line angle i.e. OT1-OP angle (11.96 ± 4.36) was found to be close to OT1-AT2 angle (13.67 ± 1.93) and OT1-AT3 angle (10.31 ± 2.03), but OT1-OP angle was found to be more closer to OT1-AT3 angle. Comparison of mean angles showed that OT1-OP angle in both males (11.68) and females (12.51) is close to OT1-AT3 angle (males- 11.01, females- 11.95). CONCLUSION The line joining from ala to the lower border of the tragus was parallel to the occlusal plane in 53.3% of the subjects. There was no influence of the sex on the level of occlusal plane. PMID:23508203