Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis.

Psoriasis is a common chronic inflammatory skin disease with a complex pathogenesis involving immune system dysregulation and inflammation. Previous studies have indicated that metabolic abnormalities are closely related to the development and occurrence of psoriasis. However, the specific involvement of amino acid metabolism in the pathogenesis of psoriasis remains unclear. In this study, we conducted a comprehensive analysis of amino acid metabolism pathway changes in psoriasis patients using transcriptome data, genome-wide association studies (GWASs) data, and single-cell data. Our findings revealed 11 significant alterations in amino acid metabolism pathways within psoriatic lesions, with notable restorative changes observed after biological therapy. Branched-chain amino acids, tyrosine and arginine metabolism have a causal relationship with the occurrence of psoriasis and may play a crucial role by promoting the proliferation and differentiation of the keratinocytes or immune-related pathways. Activation of phenylalanine, tyrosine and tryptophan biosynthesis suggests a favourable prognosis of psoriasis after treatment. Additionally, we identified the abnormal metabolic pathways in specific cell types and key gene sets that contribute to amino acid metabolic disorders in psoriasis. Overall, our study enhances understanding of the role of metabolism in the pathogenesis of psoriasis and provides potential targets for developing new therapeutic strategies for the disease.

Assessment of relationships between bullous pemphigoid and neurological diseases: A bidirectional two-sample Mendelian randomization study.

Bullous pemphigoid (BP) is the most prevalent autoimmune vesiculobullous skin illness that tends to affect the elderly. Growing evidence has hinted a correlation between BP and neurological diseases. However, existing observational studies contained inconsistent results, and the causality and direction of their relationship remain poorly understood. To assess the causal relationship between BP and neurological disorders, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and stroke. A bidirectional two-sample Mendelian randomization (MR) adopted independent top genetic variants as instruments from the largest accessible genome-wide association studies (GWASs), with BP (n = 218 348), PD (n = 482 730), AD (n = 63 926), stroke (n = 446 696), and MS (n = 115 803). Inverse variance weighted (IVW), MR-Egger, weighted mode methods, weighted median, and simple mode were performed to explore the causal association. Multiple sensitivity analyses, MR-Pleiotropy Residual Sum and Outlier (PRESSO) was used to evaluate horizontal pleiotropy and remove outliers. With close-to-zero effect estimates, no causal impact of BP on the risk of the four neurological diseases was discovered. However, we found that MS was positively correlated with higher odds of BP (OR = 1.220, 95% CI: 1.058-1.408, p = 0.006), while no causal associations were observed between PD (OR = 0.821, 95% CI: 0.616-1.093, p = 0.176), AD (OR = 1.066, 95% CI: 0.873-1.358, p = 0.603), stroke (OR = 0.911, 95% CI: 0.485-1.713, p = 0.773) and odds of BP. In summary, no causal impact of BP on the risk of PD, AD, MS and stroke was detected in our MR analysis. However, reverse MR analysis identified that only MS was positively correlated with higher odds of BP, but not PD, AD and stroke.

Associations of serum DNA methylation levels of chemokine signaling pathway genes with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

OBJECTIVE: To investigate the associations of serum DNA methylation levels of chemokine signaling pathway genes with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in elderly people in Xinjiang, China, and to screen out genes whose DNA methylation could distinguish AD and MCI. MATERIALS AND METHODS: 37 AD, 40 MCI and 80 controls were included in the present study. DNA methylation assay was done using quantitative methylation-specific polymerase chain reaction (qMSP). Genotyping was done using Sanger sequencing. RESULTS: DNA methylation levels of ADCY2, MAP2K1 and AKT1 were significantly different among AD, MCI and controls. In the comparisons of each two groups, AKT1 and MAP2K1's methylation was both significantly different between AD and MCI (p < 0.05), whereas MAP2K1's methylation was also significantly different between MCI and controls. Therefore, AKT1's methylation was considered as the candidate serum marker to distinguish AD from MCI, and its association with AD was independent of APOE ε4 allele (p < 0.05). AKT1 hypermethylation was an independent risk factor for AD and MAP2K1 hypomethylation was an independent risk factor for MCI in logistic regression analysis (p < 0.05). CONCLUSION: This study found that the serum of AKT1 hypermethylation is related to AD independently of APOE ε4, which was differentially expressed in the Entorhinal Cortex of the brain and was an independent risk factor for AD. It could be used as one of the candidate serum markers to distinguish AD and MCI. Serum of MAP2K1 hypomethylation is an independent risk factor for MCI.

Significant association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) rs3846662 and sirtuin 1 (SIRT1) rs7895833 and apolipoprotein E (APOE) hypermethylation with mild cognitive impairment (MCI).

Our study investigated the association of five genes with MCI in the Xinjiang Uygur population in China. In addition, we also analyzed the association between APOE methylation and MCI.Forty-three MCI and 125 controls were included in the present study. Genotyping was done by Sanger sequencing. DNA methylation assay was done using quantitative methylation-specific polymerase chain reaction (qMSP).The distribution of HMGCR rs3846662 allele frequencies was significantly different between the MCI group and the control group (P = .04), especially in women (P = .032). Subgroup analysis showed that there was a statistically significant association of HMGCR rs3846662 with MCI in the non-APOE ε4 group (P = .024), especially in the females with non-APOE ε4. Similarly, HMGCR rs3846662 genotype and allele frequency in the ApoE E2 protein group were significantly different in the MCI group and the control group (genotype P = .021; allele P = .007). In addition, SIRT1 rs7895833 genotype frequency in the APOE ε4 group was found to be significantly different between the MCI and the control group (P = .005). We also observed a significant association of SIRT1 rs7895833 with MCI in the ApoE E4 protein subgroup (P = .005). In addition, APOE methylation levels were significantly different between the MCI group and the control group (P = .021), especially in men (P = .006). Subgroup analysis showed that APOE methylation levels were significantly associated with MCI in the non-APOE ε4 group (P = .009), especially in men (P = .015).This study found a significant association of HMGCR rs3846662 with MCI in females independent of APOE ε4. In contrast, we revealed that the association of SIRT1 rs7895833 with MCI was dependent on with APOE ε4. We also showed that hypermethylation of APOE in MCI was independent of APOE ε4.

Association of multiple candidate genes with mild cognitive impairment in an elderly Chinese Uygur population in Xinjiang.

BACKGROUND: Mild cognitive impairment (MCI) is a high-risk factor for Alzheimer's disease (AD). In the present study, we investigated the association of genetic polymorphisms of five genes (8-oxoguanine DNA glycosylase 1 (OGG1), bridging integrator 1 (BIN1), sortilin-related receptor 1 (SORL1), presenilin 2 (PSEN2) and nerve growth factor (NGF)) with MCI risk in a Xinjiang Uygur population. We also tested the relationship between the promoter methylation of genes OGG1 and dihydrolipoamide S-succinyltransferase (DLST) with MCI. METHODS: This study involved 43 MCI patients and 125 controls. Genotyping was done by Sanger sequencing. DNA methylation assays used quantitative methylation-specific polymerase chain reaction. RESULTS: We found that polymorphisms of five genes and the methylation of DLST and OGG1 genes were not associated with MCI (P > 0.05). Further subgroup analysis found that DLST hypomethylation was significantly associated with MCI in the carriers of apolipoprotein E (APOE) ε4 (P = 0.042). In the carriers of non-APOE ε4, DLST methylation levels were significantly lower in the male control group than in the female control group (p = 0.04). Meanwhile, among the non-APOE ε4 carriers younger than 75, OGG1 hypermethylation levels were significantly associated with MCI (P = 0.049). DLST methylation in female controls was significantly lower than that in male controls (P = 0.003). According to gender stratification, there was a significant positive correlation of fasting plasma glucose (FBG) and high-density lipoprotein (HDL) with OGG1 methylation in the female controls (FBG: P = 0.024; HDL: P = 0.033). There was a significant inverse correlation between low-density lipoprotein and DLST methylation in male MCI (P = 0.033). There was a significant positive correlation between HDL and DLST methylation levels in the female controls (P = 0.000). CONCLUSIONS: This study was the first to discover that DLST promoter methylation interacted with APOE ε4 and thus affected the pathogenesis of MCI. In addition, OGG1 promoter methylation interacted with several other factors to increase the risk of MCI.

Comparison of LC-MS/MS vs chemiluminescent microparticle immunoassay in measuring the valproic acid concentration in plasma of epilepsy patients in a new perspective.

OBJECTIVES: This study was designed to compare the performance of LC-MS/MS with chemiluminescent microparticle immunoassay (CMIA) for determination of VPA in epilepsy patients in the perspective of metabolites' hepatotoxicity. METHOD: Samples were collected and then analyzed using both LC-MS/MS and CMIA. A LO2 cells (normal human hepatic cells) experiment was carried out to confirm VPA metabolites' hepatotoxicity using AST(Aspertate Aminotransferase, AST), ALT(Alanine aminotransferase, ALT) and LDH(lactate dehydrogenase, LDH) in supernate as index. RESULTS: The regression equation analysis showed as LC-MS/MS=1.0094CMIA-1.8937, with the concordance correlation coefficient of 0.9700, and the CUSUM test proved no significant deviation from linearity (P>.05). CMIA compared to LC-MS/MS gave a positive bias of 1.2 µg/mL. In LO2 experiment, VPA and its metabolites groups showed an obvious increment of AST, ALT, and LDH in supernate. CONCLUSION: The LC-MS/MS is largely consistent with the CMIA in analytical time and quantification ability for VPA, but the LC-MS/MS can simultaneously determinate VPA and its metabolites in plasma, and is also a higher cost-efficiency method in consideration of toxic metabolites monitoring. The overestimation of VPA by CMIA showed no clinical significance. The metabolites 3-OH-VPA and 5-OH-VPA damage the LO2 cells and the results presented a statistical significance (P<.05). It is vital to monitor the metabolites' concentrations for VAP's clinical safety application, and now is the occasion that laboratory and clinic consider the LC-MS/MS method as a more advantageous alternative to CMIA method in therapeutic monitoring of VPA.

[Association of KCNE1 and KCNE4 gene polymorphisms with atrial fibrillation among Uygur and Han Chinese populations in Xinjiang].

OBJECTIVE: To assess the association of KCNE1 (rs1805127) and KCNE4 (rs12621643) polymorphisms with atrial fibrillation (AF) among ethnic Uygur and Han Chinese in Xinjiang. METHODS: A case-control study was carried out. The patients and controls were selected based on ethnicity, gender and age with an 1:1 ratio. DNA was extracted from peripheral blood samples. Genotypes of KCNE1 (rs1805127) and KCNE4 (rs12621643) were determined with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Multivariate Logistic regression analysis showed KCNE1 (rs1805127) to be an independent risk factor for AF among Uygurs, while KCNE4 (rs12621643) was a risk factor for both Uygur and Han patients with AF (P < 0.05). The population attributable risk percentage (PARc%) of obstructive sleep apnea hpoventilation syndrome, obesity, hypertension, cholesterol, Hcy, hs-CRP, IL-6, KCNE1 (rs1805127) and KCNE4 (rs12621643) were 9.68%, 12.06%, 15.76%, 6.91%, 11.37%, 17.78%, 9.31%, 11.27% and 6.46% among the Uygurs, respectively. The PARc% of drinking, hypertension, cholesterol, Hcy, hs-CRP, IL-6, and KCNE4 (rs12621643) were 12.94%, 14.48%, 7.24%, 8.49%, 17.29%, 9.49% and 7.41% among Hans. CONCLUSION: The KCNE1 (rs1805127) appears to an independent risk factor for AF in the Uygur population. And the KCNE4 (rs12621643) was an independent risk factor for AF among both Uygurs and Hans. Management of the risk factors of AF based on testing of "risk genes" may have an impact on the prevention and treatment of AF.

Bioequivalence of two oseltamivir formulations in healthy Chinese volunteers
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BACKGROUND: The aim of this study was to compare the bioavailability of a new generic formulation of oseltamivir 75-mg capsule (test) and a branded formulation Tamiflu® (reference) to meet regulatory criteria for marketing the test product in healthy Chinese male volunteers. METHODS: This single-dose, randomized-sequence, open-label, two-period crossover study was conducted in fasted healthy Chinese male volunteers, who first received a single oral dose of the test or reference formulation with a 7-day washout period, and then the alternative formulation. The study drug was administered after a 10-hour overnight fast. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 24, and 36 hours after administration of the study drug. Plasma concentrations of the parent oseltamivir and its metabolite oseltamivir carboxylate were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for the log-transformed values were within the predetermined equivalence range (70 - 143% for Cmax, 80 - 125% for AUC) according to the guidelines of the State Food and Drug Administration of China. Adverse events (AEs) were monitored throughout the study based on clinical parameters and patient reports. RESULTS: Characteristics of the 20 male volunteers included were as follows: mean age 23 (± 0.7, SD) years (range 21 - 24 years); weight 69 (± 7.1) kg (range 60 - 88 kg); height 177 (± 5.9) cm (range 168 - 192 cm). All included subjects completed the study. The mean geometric ratio between the test and reference formulations of oseltamivir was 99.5% (90% CI), 86.3 - 114.8%) for Cmax, 104.4% (95.7 - 113.9%) for AUC0-t, and 104.4% (95.6 - 113.9%) for AUC0-∞. That of oseltamivir carboxylate was 103.7% (90% CI, 95.3 - 112.8%) for Cmax, 101.7% (96.6 - 107.1%) for AUC0-t, and 101.4% (96.5 - 106.5%) for AUC0-∞. There was no significant difference in pharmacokinetic parameters between the two groups. Only 1 AE (nausea) occurred in 1 subject who received the test formulation; the AE resolved without any treatment. CONCLUSIONS: The result of this single-dose study indicated that the test formulation of oseltamivir capsule met the Chinese regulatory criteria for bioequivalence vs. the reference formulation in fasted healthy Chinese male volunteers.
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[Association of vitamin D receptor gene polymorphisms with mild cognitive impairment among elderly ethnic Uygurs].

OBJECTIVE: To assess the association of vitamin D receptor gene (VDR) Apa I, Bsm I genotypes and allele frequencies and mild cognitive impairment (MCI) among elderly ethnic Uygurs from Xinjiang, China. METHODS: The polymorphisms of the VDR genotypes (Apa I and Bsm I) were analyzed by the SNaPshot method in 124 MCI patients and 124 controls. RESULTS: Factors which can increase the risk for MCI have included the A allele of the Apa I polymorphism [OR=1.62, 95%CI(1.13-2.31)] and the AA genotype [OR=3.49, 95% CI(1.57-7.74)], the T allele of the Bsm I polymorphism [OR=1.94, 95%CI(1.24-3.05)], higher triglyceride and systolic blood pressure levels. CONCLUSION: Polymorphisms of the VDR gene including the A allele and AA genotype of Apa I, and the T allele of Bsm I are probably associated with MCI among elderly ethnic Uygurs, and so are higher levels of triglyceride and systolic blood pressure.

Mild cognitive impairment risk factor survey of the Xinjiang Uyghur and Han elderly.

To understand risk factors of the Xinjiang Uyghur, Han two ethnic elderly with mild cognitive impairment (mild cognitive impairment, MCI), and provide evidence for in-depth study of the causes and prevention of MCI. The MCI epidemiological survey was based on Xinjiang Uyghur and Han residents with 60 years of age or older. The total number of participants is 5398, including 3931 Uyghur residents, and 1467 Han residents. There are 456 participants with MMSE score 2 points above the demarcation points, excluded from the survey for dementia, cerebrovascular disease and other central nervous system disorders, according to case-control study method of random selection in epidemiological survey. In accordance with the clinical diagnostic criteria of MCI, which is from Disorder Diagnostic and Statistical Manual (the revised version of the fourth edition (DSM-IV) from of the American Psychiatric Association, there are 305 cases of MCI, including 159 cases of Han, 146 cases of Uyghur. In the Han groups: univariate analysis showed a correlation (P < 0.05) between sex, age, blood pressure, triglyceride (TG), low density lipoprotein (LDL-ch) and MCI. Multivariate Logistic regression analysis showed: age, hypertension, TG, LDL-ch (increased) may increase the risk of MCI (OR values were: 1.115, 1.981, 1.315, 1.495, with P < 0.05). In the Uyghur groups: univariate analysis showed a correlation (P < 0.05) between age, gender, hypertension, abnormal glucose metabolism, TG, TC, LDL-ch and MCI. Multivariate Logistic regression analysis showed: age, hypertension, abnormal glucose metabolism, TG, TC, LDL-ch (increased), women have a higher risk of MCI (OR values were: 1.063, 2.145, 2.879, 2.078, 1.429, 1.485, 0.462, P < 0.05). Age, hypertension, TG and LDL-ch are risk factors of MCI for Han population, while age, hypertension, abnormal glucose metabolism, TG, TC and LDL-ch are risk factors of MCI for Uyghur population.

The effect of SIRT1 gene polymorphisms on ambulatory blood pressure of hypertensive patients in the Kazakh population.

OBJECTIVE: To investigate the effect of silent information regulator 1 (SIRT1) gene polymorphisms on ambulatory blood pressure in hypertensive patients. METHODS: Three hundred forty hypertensive patients were recruited from January 2013 to January 2015. SIRT1 Tag single-nucleotide polymorphisms (SNPs; rs2273773, rs4746720, and rs7896005) were genotyped using a PCR-direct sequencing method, and the association between the SIRT1 gene SNPs and ambulatory blood pressure was analyzed. RESULTS: After adjusting for confounding factors, patients with the rs2273773/CT+CC genotypes had lower 24-h systolic and diastolic blood pressures; there were no associations between rs4746720 and rs7896005 genotypes and blood pressure. CONCLUSION: The SIRT1 gene polymorphism (rs2273773) is significantly associated with ambulatory blood pressure level in Han Chinese patients with hypertension.

[Epidemiological survey of atrial fibrillation among Uygur and Han elderly people in Xinjiang Uygur autonomous region].

OBJECTIVE: To investigate prevalence of atrial fibrillation (AF) in Uygur and Han elderly populations in Xinjiang Uygur autonomous region (Xinjiang). METHODS: Epidemiological survey was conducted among the residents selected through stratified random cluster sampling in the southern, northern and eastern Xinjiang. RESULTS: The overall AF prevalence among Uygur and Han elderly people was 3.56%. The crude prevalence of AF was 2.91% among Uygur elderly people and 4.13% among Han elderly people. The sex specific prevalence of AF were 3.19% and 2.61% among Uygur males and females respectively, and 5.01% and 3.31% among Han males and females respectively. The prevalence of valvular AF among Uygur ethnic group was higher than that in Han ethnic group; the prevalence of non-valvular and isolated AF in Han ethnic group were higher than those in Uygur ethnic group. The compliance of aspirin and ß-blocker medication among Han ethnic group was better than that in Uygur ethnic group. The compliance of warfarin medication was poor in both Uygur ethnic group and Han ethnic group. The prevalence of ischemic stroke were 8.82% and 0.98% in Uygur elderly people with or without AF. The prevalence of ischemic stroke were 6.08% and 0.70% in Han elderly people with or without AF. CONCLUSION: The prevalence of AF in elderly people in Xinjiang is similar to the results from other domestic studies, the prevalence of AF in Han elderly people was higher than that in Uygur elderly peoples.

Validation of an LC-MS/MS method for quantitative analysis of the 5 bioactive components of Wuzhi capsule in human plasma samples.

BACKGROUND: Wuzhi capsule (WZC) is an ethanol extract from the ripe fruit of Schisandra sphenanthera in traditional Chinese medicine that has long been used to treat viral and drug-induced hepatitis in China. The principal active components in WZC are Schisandra lignans. The clinical pharmacokinetics of these components in the form of an oral WZC preparation is unknown. To optimize the WZC dosage and develop WZC-related combination therapies, it is necessary to conduct a comprehensive pharmacokinetic study of the Schisandra lignans. METHODS: A method was developed for simultaneous quantification of multiple bioactive lignans in WZC in human plasma through liquid-liquid extraction followed by multiple reaction monitoring liquid chromatography/tandem mass spectrometry with positive-mode electrospray ionization. The 5 bioactive constituents were separated by isocratic elution using a mobile phase consisting of acetonitrile, methanol, and 0.1% aqueous formic acid at a flow rate of 0.3 mL/min. The total run time was 3.5 minutes. RESULTS: All analytes showed good linearity over a wide concentration range with a lower limit of quantification at 0.5 ng/mL. Using this method, we determined the 5 bioactive lignans in WZC from human plasma simultaneously and performed a pharmacokinetic study on the Schisandra lignans in healthy volunteers. CONCLUSIONS: Owing to simplicity, quickness, high sensitivity, and selectivity, and a sufficient lower limit of detection of the new liquid chromatography/tandem mass spectrometry method, it may be used as a routine technique for clinical monitoring of WZC, and for understanding interactions between herbal and conventional drug therapies.

Rapid and sensitive liquid chromatography coupled with electrospray ionization tandem mass spectrometry method for the analysis of paclitaxel, docetaxel, vinblastine, and vinorelbine in human plasma.

BACKGROUND: A rapid and sensitive analytical method using liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-MS/MS) was developed for the determination of paclitaxel, docetaxel, vinblastine, and vinorelbine in human plasma. METHODS: A simple liquid-liquid extraction procedure was applied using only 100-µL plasma. Chromatographic separation of these anticancer drugs was achieved with an isocratic mobile phase consisting of acetonitrile/aqueous buffer (10 mmol/L ammonium acetate and 0.1% formic acid in 70:30, vol/vol) at a flow rate of 0.25 mL/min in a short time (4.5 minutes). RESULTS: The calibration curves for paclitaxel, docetaxel, vinblastine, and vinorelbine in spiked human plasma ranged from 25 to 2500, 10 to 1000, 10 to 1000, and 10 to 1000 ng/mL, respectively. The squares of the linear correlation coefficients were all more than 0.99. The intraday and interday relative standard deviations across 3 validation runs over the entire concentration range were less than 9.2%. CONCLUSIONS: The established method should be helpful for the pharmacokinetic monitoring of paclitaxel, docetaxel, vinblastine, and vinorelbine in the human plasma of non-small cell lung cancer patients.

Relationship between vitamin D receptor gene polymorphism and mild cognitive impairment in elderly Uygur people.

To explore the relationship between vitamin D receptor gene (ApaI, BsmI) genotypes and allele frequency and mild cognitive impairment in Xinjiang Uygur population. The polymorphisms of the VDR genotypes (ApaI and BsmI) were analyzed by Snapshot method in 124 MCI patients and 124 controls. A allele of ApaI gene increased the risk of MCI [OR = 1.62, 95% CI (1.13-2.31)]; AA genotype increased the risk of MCI [OR = 3.49, 95% CI (1.57-7.74)]. T allele of BsmI gene increased the risk of MCI [OR = 1.94, 95% CI (1.24-3.05)]. The risk of MCI increased accompanied with higher TG and SBP level. VDR (ApaI) AA genotype, a allele and VDR (BsmI) T allele probably associated with elderly MCI patients in Uygur ethnicity, higher level of TG and SBP were risk factors to elderly people with MCI among Uygurs.

[Association of single nucleotide polymorphism of KCNE1 and KCNE4 gene with atrial fibrillation in Xinjiang Uygur and Han population].

OBJECTIVE: To investigate the association between the KCNE1 gene G38S and the KCNE4 gene E145D and atrial fibrillation in Uygur and Han populations living in Xinjiang. METHODS: KCNE1 gene G38S and the KCNE4 gene E145D genotype and frequency were determined using PCR restriction fragment length polymorphism (PCR-RFLP) in 488 atrial fibrillation patients (237 Uygur and 251 Han residents) and 488 age-and-gender matched controls (237 Uygur and 251 Han residents). RESULTS: Genotype and allele frequency of KCNE1 gene G38S were similar between atrial fibrillation group and control group in the Han population (P = 0.556, P = 0.946). In the Uygur population, there was a statistical difference between atrial fibrillation group and control group (P = 0.018, P = 0.003). Logistic regression analysis revealed the KCNE1 38 G was one of the independent risk factors for atrial fibrillation in the Uygur population (OR = 1.634, 95%CI: 1.192-2.240, P = 0.002). The KCNE4 gene E145D, genotype and allele frequency were significantly different between atrial fibrillation group and control group in the Uygur population and Han population (P = 0.041, P = 0.015;P = 0.032, P = 0.013) . Logistic regression analysis revealed the KCNE4 145D was one of the independent risk factors for atrial fibrillation in the Uygur population and Han population (OR = 1.636, 95%CI:1.173-2.281, P = 0.004; OR = 1.491, 95%CI:1.076-2.065, P = 0.016) . CONCLUSIONS: KCNE1 G38S is not associated with atrial fibrillation in the Han population while the KCNE1 G38S is associated with atrial fibrillation in the Uygur population. KCNE4 gene E145D is associated with atrial fibrillation in both Uygur population and Han population.

Changes in microRNAs expression are involved in age-related atrial structural remodeling and atrial fibrillation.

BACKGROUND: Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of extracellular matrix proteins. However, their role in age-related cardiac remodeling and atrial fibrillation (AF) was not well understood. The present study was designed to decipher molecular mechanisms underlying age-related atrial structural remodeling and AF. METHODS: Three groups of dogs were studied: adult and aged dogs in sinus rhythm and with persistent AF induced by rapid atrial pacing. The expressions of microRNAs were measured by quantitative real-time polymerase chain reaction. Pathohistological and ultrastructural changes were tested by light and electron microscopy. Apoptosis index of myocytes was detected by TUNEL. RESULTS: Samples of atrial tissue showed the abnormal pathohistological and ultrastructural changes, the accelerated fibrosis, and apoptosis with aging and/or in AF dogs. Compared to the adult group, the expressions of microRNAs-21 and -29 were significantly increased, whereas the expressions of microRNAs-1 and -133 showed obvious downregulation tendency in the aged group. Compared to the aged group, the expressions of microRNAs-1, -21, and -29 was significantly increased in the old group in AF; contrastingly, the expressions of microRNA-133 showed obvious downregulation tendency. CONCLUSION: These multiple aberrantly expressed microRNAs may be responsible for modulating the transition from adaptation to pathological atrial remodeling with aging and/or in AF.

Accelerated fibrosis and apoptosis with ageing and in atrial fibrillation: Adaptive responses with maladaptive consequences.

The aim of this study was to investigate whether abnormal expression of matrix metalloproteinase (MMP)-9/tissue inhibitors of MMPs (TIMP)-1 and B cell lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) are correlated with the characteristic accelerated fibrosis and apoptosis during ageing and in atrial fibrillation (AF). Four groups of dogs were studied: adult dogs in sinus rhythm (SR), aged dogs in SR, adult dogs with AF induced by rapid atrial pacing and aged dogs with AF induced by rapid atrial pacing. The mRNA and protein expression levels of the target gene in the left atrium were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. Pathohistological and ultrastructural changes were assessed by light and electron microscopy. The apoptotic indices of myocytes were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). The mRNA and protein expression levels of MMP-9 and BAX and those of TIMP-1 and BCL-2 were significantly upregulated and down-regulated, respectively, in the aged groups compared with the adult groups. Compared with the control groups, the adult and aged groups with AF exhibited significantly increased mRNA and protein expression levels of MMP-9 and BAX and decreased expression levels of TIMP-1 and BCL-2. Samples of atrial tissue demonstrated abnormal pathohistological and ultrastructural changes, accelerated fibrosis and apoptosis. MMP-9/TIMP-1 and BCL-2/BAX hold potential for use as substrates conducive to AF and their abnormal expression plays a major role in structural remodeling of the atrium.

Association between apolipoprotein E gene polymorphism and Alzheimer's disease in Uighur and Han populations.

AIM: Currently, there are almost 100 genes related to Alzheimer's disease (AD), and studies have indicated that apolipoprotein E (APO E) ε4 allele is a genetic risk factor of AD. However, there have been no reports of the distributions of APO E genotypes and allele frequencies in Uighur and Han AD patients. METHODS: We analyzed APO E gene polymorphism in 209 AD cases diagnosed based on National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association and 220 non-dementia controls. We used polymerase chain reaction-restriction fragment length polymorphism methods as the basis of this epidemiological survey. RESULTS: In the AD and control groups, there are no statistically significant differences in APO E genotypes and allele frequency between the Uighur and Han ethnicities (P < 0.05). In the AD group, the ε3/4 genotype (28.2%) and ε4 allele frequency (14.8%) occurred at a higher rate than in the control (13.2% and 8.0%, respectively; P < 0.05). This distinction remained true within each ethnicity; the ε3/4 genotype and ε4 allele frequency are higher in the AD groups (Uighur, 30.6% and 15.8%, respectively; Han, 25.5% and 13.8%, respectively) than in the control groups (Uighur, 14.5% and 9.4%, respectively; Han, 11.7% and 6.3%, respectively; P < 0.05). CONCLUSIONS: The distribution of APO E genotype and allele frequency does not differ between the Uighur and Han ethnicities. The APO E ε4 allele is a risk factor of AD for both populations.

LC-MS/MS method for simultaneous determination of valproic acid and major metabolites in human plasma.

A rapid and sensitive method using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was developed and validated for simultaneous quantitative determination of valproic acid and three major metabolites (3-OH-valproic acid, 4-ene-valproic acid and 5-OH-valproic acid) in human plasma. The analytes and internal standard were isolated from 200 µL samples by solid phase extraction using a ZORBAX SB-C8 column (3.5 µm, 2.1×100 mm) with an isocratic mobile phase consisting of methanol-10mM ammonium acetate (80:20, v/v) containing 0.1% formic acid at a flow rate of 0.3 mL/min. The method had a chromatographic total run time of 2.0 min. The lower limit of quantification of valproic acid, 3-OH-valproic acid, 4-ene-valproic acid and 5-OH-valproic acid of the method was 2030, 51.5, 50.15 and 51.25 ng/mL, respectively. The method was linear for valproic acid and the three metabolites with correlation coefficients >0.995 for all analytes. The intra-day and inter-day accuracy and precision of the assay were less than 15.0%. This analytical method was successfully used to assay plasma concentrations of valproic acid and the three metabolites in human plasma from epileptic patients.