Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.

BACKGROUND: Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA). METHODS: We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10-16, as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors. RESULTS: Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10-7) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10-5), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects. CONCLUSIONS: We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis.

Common Genetic Variants of Response to Hepatitis B Vaccines Correlate with Risks of Chronic Infection of Hepatitis B Virus: A Community-Based Case-Control Study.

Hepatitis B (HB) vaccination effectively reduces the risks of chronic infection with the hepatitis B virus (HBV). It is unknown whether there is a common genetic determinant for response to the HB vaccine and susceptibility to chronic HBV infection. This case-control study, which included 193 chronic HBV carriers and 495 non-carriers, aimed to explore the effects of the most significant single nucleotide polymorphisms (SNPs) in response to the HB vaccine on the risks of chronic HBV infection. Out of 13 tested SNPs, the genotype distributions of four SNPs at the human leukocyte antigen (HLA) class II region, including rs34039593, rs614348, rs7770370, and rs9277535, were significantly different between HBV carriers and non-carriers. The age-sex-adjusted odds ratios (OR) of chronic HBV infection for rs34039593 TG, rs614348 TC, rs7770370 AA, and rs9277535 AA genotypes were 0.51 (95% confidence interval [CI], 0.33-0.79; p = 0.0028), 0.49 (95% CI, 0.32-0.75; p = 6.5 × 10-4), 0.33 (95% CI, 0.18-0.63; p = 7.4 × 10-4), and 0.31 (95% CI, 0.14-0.70; p = 0.0043), respectively. Multivariable analyses showed that rs614348 TC and rs7770370 AA genotypes were significantly independent protectors against chronic HBV infection. The multivariable-adjusted ORs for subjects with none, either one, or both of the protective genotypes were 1.00 (referent), 0.47 (95% CI: 0.32-0.71; p = 3.0 × 10-4), and 0.16 (95% CI: 0.05-0.54; p = 0.0032), respectively. Among eight HBeAg-positive carriers, only one of them carried a protective genotype. This study shows that response to the HB vaccine and susceptibility to chronic HBV infection share common genetic determinants and indicates that HLA class II members are the main responsible host genetic factors.

Effects of a 12-week walking intervention on circulating lipid profiles and adipokines in normal weight and abdominal obese female college students.

Background/objectives: Regular exercise such as aerobic exercise has been shown to reduce the risk of some diseases such as cardiovascular disease (CVD). However, only few studies have investigated the impact of regular aerobic exercise on non-obese and overweight/obese persons. Therefore, this study was designed to compare the effect of a 12-week 10,000 steps a day walking intervention on the body composition, serum lipids, adipose tissue function, and obesity-associated cardiometabolic risk between normal weight and overweight/obese female college students. Methods: Ten normal weight (NWCG) and 10 overweight/obese (AOG) individuals were recruited in this study. Both groups performed a regular 10,000 steps a day walk for 12 weeks. Their blood pressure, body mass index, waist-to-hip ratio, and blood lipid profiles were evaluated. Moreover, serum leptin and adiponectin levels were measured using an enzyme-linked immunosorbent assay. Results: Our results revealed that triglyceride (TG), TG/high-density lipoprotein cholesterol (HDL-C) ratio and leptin were significantly reduced in the AOG group after the 12-week walking intervention. However, total cholesterol, HDL-C, and adiponectin/leptin ratio were significantly increased in the AOG group. There was little or no change in these variables in the NWCG group after the 12-week walking intervention. Conclusions: Our study demonstrated that a 12-week walking intervention may help improve cardiorespiratory fitness and obesity-associated cardiometabolic risk by decrease resting heart rate, modulating blood lipid profiles, and inducing adipokine alterations in obese individuals. Therefore, our research encourages obese young adults to improve their physical health by participating in a 12-week walking program of 10,000 steps a day.

Prevalences of diabetes mellitus and carotid atherosclerosis and their relationships in middle-aged adults and elders: a community-based study.

BACKGROUND/PURPOSE: Atherosclerosis and diabetes mellitus (DM) are both severe chronic diseases that cause huge burdens on patients' families and societies. Connections between the two diseases have brought high attention recently, however, population-based study with large sample size was few. The study aimed to explore the relationship between carotid atherosclerosis and DM. METHODS: We enrolled 3908 adults aged 40-74 years from communities and measured their cardio-metabolic profiles and scanned their carotid arteries bilaterally. RESULTS: The overall prevalence rates of carotid plaque and DM were 34.4 and 10.7%, respectively. The age-specific prevalence rates of DM and carotid plaque were nearly linearly correlated in both sexes (both Pearson's correlation coefficient r > 0.97). The prevalence rates of carotid plaque, total plaque number ≥3, maximum diameter stenosis ≥30%, and plaque score ≥3 were 53.6, 24.8, 19.1, and 28.6%, respectively, in DM patients and were 32.1, 9.4, 9.8, and 11.2%, respectively, in non-DM controls. After adjustment for other conventional risk factors, the multivariable-adjusted OR of having carotid plaque was 1.60 (95% CI 1.27-2.01) and were 2.06 (95% CI 1.55-2.75), 1.33 (95% CI 0.99-1.78), and 2.03 (95% CI 1.55-2.65) for total plaque number ≥3, maximum diameter stenosis ≥30%, and plaque score ≥3, respectively. CONCLUSION: We demonstrated that prevalences of DM were linearly correlated with prevalences of carotid plaque and DM patients had higher prevalence rates of carotid plaque and more advanced carotid atherosclerosis than non-DM controls. Our results indicated the need to address the role of DM in atherosclerosis development.

The Anti-Proliferative and Apoptotic Effects of Rutaecarpine on Human Esophageal Squamous Cell Carcinoma Cell Line CE81T/VGH In Vitro and In Vivo.

The overall five-year survival rate for patients with esophageal cancer is low (15 to 25%) because of the poor prognosis at earlier stages. Rutaecarpine (RTP) is a bioalkaloid found in the traditional Chinese herb Evodia rutaecarpa and has been shown to exhibit anti-proliferative effect on tumor cells. However, the mechanisms by which RTP confer these effects and its importance in esophageal squamous cell carcinoma treatment remain unclear. Thus, in the present study, we first incubated human esophageal squamous cell carcinoma cell line, CE81T/VGH, with RTP to evaluate RTP's effects on tumor cell growth and apoptosis. We also performed a xenograft study to confirm the in vitro findings. Furthermore, we determined the expression of p53, Bax, bcl-2, caspase-3, caspase-9, and PCNA in CE81T/VGH cells or the tumor tissues to investigate the possible mechanisms. All the effects of TRP were compared with that of cisplatin. The results showed that RTP significantly inhibits CE81T/VGH cell growth, promotes arrest of cells in the G2/M phase, and induces apoptosis. Consistently, the in vivo study showed that tumor size, tumor weight, and proliferating cell nuclear antigen protein expression in tumor tissue are significantly reduced in the high-dose RTP treatment group. Furthermore, the in vitro and in vivo studies showed that RTP increases the expression of p53 and Bax proteins, while inhibiting the expression of Bcl-2 in cancer cells. In addition, RTP significantly increases the expression of cleaved caspase-9 and cleaved caspase-3 proteins in tumor tissues in mice. These results suggest that RTP may trigger the apoptosis and inhibit growth in CE81T/VGH cells by the mechanisms associated with the regulation of the expression of p53, Bax, Bcl-2, as well as caspase-9 and caspase-3.

Association of Common Variants in OLA1 Gene with Preclinical Atherosclerosis.

Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in OLA1 genes on preclinical atherosclerosis. A total of 564 and 746 subjects who had thicker and normal carotid intima-media thickness (cIMT), respectively, were enrolled. Among 55 screened SNPs, rs35145102, rs201641962, rs12466587, rs4131583, and rs16862482 in OLA1 showed significant associations with cIMT. SNP rs35145102 is a 3'-utr variant and correlates with the differential expression of OLA1 in immune cells. These five genetic markers form a single closely linked block and H1-ATTGT and H2-GCCTC were the top two most prevalent 5-locus haplotypes. The H1 + H1 genotype negatively and H1 + H2 genotype positively correlated with thicker cIMT. The five identified SNPs in the OLA1 gene showed significant correlations with cIMT. Furthermore, we found that OLA1 was required for migration and proliferation of human aortic endothelial and smooth muscle cells and regulated vascular tube formation by human aortic endothelial cells. Therefore, these genetic variants in the OLA1 gene may serve as markers for risk prediction of atherosclerotic diseases.

Comprehensive analysis of a chemokine- and chemokine receptor family-based signature for patients with lung adenocarcinoma.

The clinical significance and comprehensive features of chemokines and their receptors in lung adenocarcinoma (LUAD) have not been clarified. We aimed to characterize the expression profiles of chemokine and chemokine receptor family members and construct a chemokine- and chemokine receptor-based prognosis signature. A total of 1511 patients with LUAD from seven independent cohorts were included in the study. The training set collected from The Cancer Genome Atlas (TCGA) database containing 468 cases. The validation was performed on the basis of six different cohorts downloaded from Gene Expression Omnibus (GEO) database. A five-chemokine- and chemokine receptor-(CXCL2, CXCL13, CCL26, CCL20, CX3CR1) based prognosis signature was constructed with TCGA dataset using LASSO Cox regression and Cox proportional hazards regression analysis. A multivariate analysis verified that this signature was an independent prognostic factor. The predictive value of this signature was further verified by other six independent cohorts and multiple clinical subtypes. We performed immune cell infiltration analysis and biological pathway analysis which provided more insight into this signature-related immune and inflammatory landscape and clarified the intrinsic molecular mechanism by which this signature could be used to predict clinical prognosis. Furthermore, we explored the close relationship between this signature and tumor mutation burden (TMB), neoantigen burden, PD-1, PD-L1, CTLA4, TIDE score, T cell-inflamed score. This signature provided a robust prognostic biomarker for LUAD and could serve as a predictor for immunotherapy response, which may be used as an important supplement to immunotherapy to achieve individualized tumor treatment by optimizing the prognostic management and immunotherapy for patients with LUAD.

Genetic variants associated with serum alanine aminotransferase levels among patients with hepatitis C virus infection: A genome-wide association study.

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10-5 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10-5 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.

Compound Cocktail Inhibits Influenza Viral Pneumonia via Phospholipase Cγ1 Phosphorylation-Related Necroptosis and Partial Autophagy in Natural Killer Cells.

Influenza viral infections are prone to global outbreaks and cause pneumonia in affected populations. High morbidity and mortality caused by pneumonia occur during an influenza pandemic. Antivirals or control of inflammation is the primary means of influenza treatment. A compound cocktail composed of arctiin, daidzein, glycyrrhizic acid, and liquiritin inhibited mouse pneumonia resulting from a PR8 viral infection and caused a weight gain after oral administration. Natural killer cell activating receptors, both Ly49D and Ly49H in the lungs, were increased in the treatment in mice. In H3N2 virus-infected natural killer-92MI cells, the cocktail treatment had different effects on phosphorylation sites of phospholipase Cγ1 (PLCγ1) and killed infected cells through necroptosis or late apoptosis, in which RIP3 was increased and both caspase-3 and phosphorylated-JNK in the cells were downregulated. Acid phosphatase activity in viral-infected natural killer-92MI cells was induced by the compound cocktail treatment, which could be related to the p62 decrease in natural killer-92MI cells. In addition, an autophagic flux induction was observed in alveolar basal epithelial cells (A549). Protein p65, but not phosphorylated-p65, was significantly decreased by the treatment. Our results indicate that the compound cocktail strengthened the phosphorylation of PLCγ1-related necroptosis and partial autophagy in natural killer cells, which could yield an inhibitory effect on viral pneumonia in influenza.

Adjuvant Chemotherapy with Chinese Herbal Medicine Formulas Versus Placebo in Patients with Lung Adenocarcinoma after Radical Surgery: a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: The toxicity and side effects caused by adjuvant chemotherapy (ACT) after radical surgery for lung adenocarcinoma (LAC) lead to early termination frequently. This study was conducted to provide an objective basis for the effect of Chinese herbal medicine formulas (CHMFs) combined with chemotherapy in reducing toxicity and enhancing efficacy of ACT. METHOD: From February 17th, 2012 to March 20th, 2015, 233 patients from 7 hospitals diagnosed with LAC in IB~IIIA stage were randomly assigned into ACT + CHMF group (116 patients) and ACT + placebo group (117 patients). CHMF was taken orally until the end of chemotherapy. Chemotherapy-related toxic, side effects were investigated as the primary outcome. Disease-free survival (DFS) and overall survival (OS) were used as the secondary outcome. RESULTS: At one week following chemotherapy, the incidence of dry mouth, diarrhea and thrombocytopenia significantly decreased in CHMF group (P = 0.017, P = 0.033, P = 0.019, respectively). At two weeks following chemotherapy, fatigue and diarrhea were more obvious in the placebo group (P = 0.028, P = 0.025, respectively). In addition, patients in the CHMF group showed an increase in median DFS from 37.1 to 51.5 months compared with placebo group although there was no statistical significance (P = 0.16). In the stage IB subgroup, the CHMF group had a significantly better DFS (HR (95% CI) = 0.53 (0.28-0.99), P = 0.046). There was no significant difference in OS between the groups (P = 0.72). CONCLUSION: For patients with LAC, ACT combined with CHMF after radical surgery can prolong the DFS time especially in the early stage, and reduces the chemotherapy-related toxic and side effects. TRIAL REGISTRATION: NCT01441752. Registered 14 July, 2011.

Intravenous sodium valproate for acute migraine in the emergency department: A meta-analysis.

The role of intravenous sodium valproate (iVPA) in acute migraine attack has not been completely established. The aim of this updated review was to evaluate the efficacy and safety of iVPA in patients with acute migraine in the emergency department. We searched the PubMed, Web of Science, and Cochrane Library databases for relevant randomized controlled trials (RCTs). The primary outcome was improvement of headache intensity and headache relief. The need for rescue therapy, recurrence of headache, and number of adverse events was also assessed. Seven double-blinded RCTs involving 682 patients were analyzed. Overall, patients receiving iVPA had less improvement of headache intensity (SMD: -0.39, 95% CI: -0.73 to -0.06, P = .02) and lower rate of headache relief (OR: 0.51, 95% CI: 0.33 to 0.77, P = .002) than those receiving other active comparators. In addition, iVPA increased the odds of rescue therapy compared with other active drugs (OR: 3.76; 95% CI: 1.96 to 7.20, P < .0001). Subgroup analysis showed that iVPA was comparable to dexamethasone, with similar improvement of headache intensity, and recurrence of headache. For migraine without aura, we found no significant difference in headache intensity improvement when iVPA was compared with active comparators (SMD: -0.00, 95% CI: -0.54 to 0.54, P = 1.00). iVPA was inferior to the studied comparators and was comparable to dexamethasone for aborting migraine attack. Based on the available evidence, iVPA may be a reasonable alternative or salvage therapy. In particular, iVPA might be a promising agent for migraine with aura and migraine status.

Level of Hepatitis B (HB) Core Antibody Associates With Seroclearance of HBV DNA and HB Surface Antigen in HB e Antigen-Seronegative Patients.

BACKGROUND & AIMS: Although a low level of hepatitis B surface antigen (HBsAg) is a marker of hepatitis B virus (HBV) seroclearance, additional biomarkers are needed for more accurate prediction. We investigated whether quantification of antibody against HBV core protein (anti-HBc) can identify patients with undetectable levels of HBV DNA and HBsAg seroclearance among those who were HBV e antigen (HBeAg)-seronegative. METHODS: We performed a retrospective analysis of data from a community-based cohort of individuals (30-65 years old) in Taiwan who were HBsAg seropositive, anti-HCV negative, and free of cirrhosis and/or liver cancer, recruited from 1991 through 1992, and evaluated every 6-12 months until June 30, 2004. We measured levels of anti-HBc in blood samples from 2500 participants who were seronegative for HBeAg. The first date at which a sample tested negative for HBV DNA or HBsAg, and remained negative in subsequent tests, was designated as the date of spontaneous HBV DNA undetectability or HBsAg seroclearance. We calculated cumulative incidences of HBV DNA undetectability and HBsAg seroclearance; associations between level of anti-HBc and undetectability of HBV DNA or HBsAg seroclearance were estimated by Cox proportional hazard regression. The effects of time on the associations between level of anti-HBc and HBsAg seroclearance was assessed by the area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: After a 12-year follow-up period, higher proportions of subjects with levels of anti-HBc <3 log IU/mL had undetectable levels of HBV DNA (58%) and HBsAg seroclearance (53%) than subjects with higher levels of anti-HBc (29.6% and 19.8%, respectively) (P < .001). For subjects with levels of HBsAg <102 IU/mL and anti-HBc <3 log IU/mL, the adjusted rate ratio of HBV DNA undetectability was 16.45 (95% CI, 11.15-24.28) and of HBsAg seroclearance was 17.95 (95% CI, 12.49-25.81), compared to subjects with higher levels of HBsAg and anti-HBc. A model that included level of anti-HBc as a parameter identified subjects with HBsAg seroclearance within 10 years with an AUROC of 82%; this value was significantly higher than that from models that include only level of HBV DNA and HBsAg (P < .0001). CONCLUSIONS: In a retrospective analysis of a large cohort of patients with chronic HBV infection in Taiwan, we associated levels of anti-HBc <3 log IU/mL with undetectable HBV DNA and HBsAg seroclearance occurred within 10 years; patients who also have levels of HBsAg <102 IU/mL have greater odds. Combining data on levels of HBsAg, HBV DNA, and anti-HBc is able to identify HBeAg-seronegative patients who can achieve HBsAg seroclearance with an AUROC value of 82%.

Association Between High Levels of Hepatitis B Core Antibody and Seroclearance of Hepatitis B e Antigen in Individuals With Chronic Hepatitis B Virus Infection.

For chronic hepatitis B patients, hepatitis B e antigen (HBeAg) seroclearance signals a transition from an immunologically active phase to an inactive carrier state with a reduction in hepatitis B virus (HBV) DNA levels and a reduced risk of hepatocellular carcinoma (HCC).1 Predictors of HBeAg seroclearance include lower HBV DNA levels, viral genotype, the precore mutation, and higher serum alanine aminotransferase (ALT) levels.2.

Regularized aggregation of statistical parametric maps.

Combining statistical parametric maps (SPM) from individual subjects is the goal in some types of group-level analyses of functional magnetic resonance imaging data. Brain maps are usually combined using a simple average across subjects, making them susceptible to subjects with outlying values. Furthermore, t tests are prone to false positives and false negatives when outlying values are observed. We propose a regularized unsupervised aggregation method for SPMs to find an optimal weight for aggregation, which aids in detecting and mitigating the effect of outlying subjects. We also present a bootstrap-based weighted t test using the optimal weights to construct an activation map robust to outlying subjects. We validate the performance of the proposed aggregation method and test using simulated and real data examples. Results show that the regularized aggregation approach can effectively detect outlying subjects, lower their weights, and produce robust SPMs.

Common Genetic Variants on Bone Morphogenetic Protein Receptor Type IB (BMPR1B) Gene Are Predictive for Carotid Intima-Media Thickness.

BACKGROUND: Bone morphogenetic proteins (BMP) 2 and 4 are implicated in the development of atherosclerosis. However, the relationships between the proteins, their main receptors and carotid intima-media thickness (cIMT), a predictive preclinical phenotype of atherosclerosis, have not been established. Methods and Results: We screened and validated the relationships of single-nucleotide polymorphisms (SNPs) on BMP2, BMP4, BMPR1A, BMPR1B, and BMPR2 with thicker cIMT by 2 independent case-control studies that used different subject selection methods. Among 200 screened SNPs, 12 on BMPR1B were regarded as candidate genetic markers (P-value <5.0×10-4). After combining the discovery and validation studies and adjusting for traditional cardiovascular risk factors, rs4456963*G, rs4235438*T, rs2522530*T, and rs3796433*C showed significant higher odds ratios (ORs) of having thicker cIMT (adjusted ORs: 1.50-1.56; all P-values <2.5×10-4). Multivariate analyses showed that rs4456963 and rs3796433 were significantly independent determinants of cIMT thickening. The corresponding multivariate-adjusted ORs for rs4456963*G and rs3796433*C alleles were 1.50 (95% confidence interval (CI): 1.22-1.84) and 1.50 (95% CI: 1.23-1.82), respectively. Interaction between rs4456963 and rs3796433 was evident by the significantly higher OR (8.16, 95% CI: 3.12-21.3) for subjects with the GG-CC genotype. The rs4456963*G and rs3796433*C showed positively linear trends with severity of carotid atherosclerosis. CONCLUSIONS: We identified 2 SNPs on BMPR1B showing significantly independent correlations with thicker cIMT. The study provides invaluable evidence supporting that BMPR1B is closely related to carotid atherosclerosis and a potential target for the development of therapeutic agents for atherosclerotic disease.

Segment-specific prevalence of carotid artery plaque and stenosis in middle-aged adults and elders in Taiwan: A community-based study.

BACKGROUND: Plaque in carotid arteries (CAs) is a major factor of systemic atherosclerosis and cardiovascular disease (CVD). The left and right CAs have different anatomic and geometric features and may influence the predictability of CVD. However, the site- and segment-specific prevalence of carotid plaques (CP) and study on severity of carotid atherosclerosis with CVD risks was very limited. METHODS: We enrolled 1539 healthy residents aged 40-to-74 years from two northern districts in Taiwan. All volunteers received high resolution B-mode carotid ultrasound scans and CVD risk factors evaluations. RESULTS: The prevalence rate of extracranial CP was 21.9% in females and 33.8% in males. Carotid bifurcation is the most affected segment. As compared with the right CAs, the age-sex-adjusted matched odds ratio of having plaques in the left CAs was 1.32 (95% confidence interval = 1.02-1.73). The proportions of subjects had a total plaque number≥2, maximum stenosis≥30%, and plaque score≥3 were 8.9, 10.3, and 7.2%, respectively, in females and were 17.7, 17.2, and 15.1%, respectively, in males. Among subjects with moderate and severe carotid atherosclerosis, the mean ± SD of estimated 10-year CVD risk was 19.1 ± 14.6% and more than 65% of them need intensive blood pressure, lipids, or sugar controls. CONCLUSION: We found that bifurcation was the most prevalent segment, and left CAs was more likely to form plaque than right CAs. The major CVD risk factors were highly prevalent and the estimated CVD risks were high in subjects with more advanced carotid atherosclerosis. The study provides further direction for CVD prevention and treatment.

Anti-Inflammatory Effect of Erinacine C on NO Production Through Down-Regulation of NF-κB and Activation of Nrf2-Mediated HO-1 in BV2 Microglial Cells Treated with LPS.

Previous studies have revealed the anti-inflammatory and neuroprotective properties of Hericium erinaceus extracts, including the fact that the active ingredient erinacine C (EC) can induce the synthesis of nerve growth factor. However, there is limited research on the use and mechanisms of action of EC in treating neuroinflammation. Hence, in this study, the inflammatory responses of human BV2 microglial cells induced by LPS were used to establish a model to assess the anti-neuroinflammatory efficacy of EC and to clarify its possible mechanisms of action. The results showed that EC was able to reduce the levels of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) proteins produced by LPS-induced BV2 cells, in addition to inhibiting the expression of NF-κB and phosphorylation of IκBα (p-IκBα) proteins. Moreover, EC was found to inhibit the Kelch-like ECH-associated protein 1 (Keap1) protein, and to enhance the nuclear transcription factor erythroid 2-related factor (Nrf2) and the expression of the heme oxygenase-1 (HO-1) protein. Taken together, these data suggest that the mechanism of action of EC involves the inhibition of IκB, p-IκBα, and iNOS expressions and the activation of the Nrf2/HO-1 pathway.

Autophagy induces transforming growth factor-ß-dependent epithelial-mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling.

Autophagy promotes invasion of hepatocarcinoma cells through transforming growth factor (TGF)-ß-dependent epithelial-mesenchymal transition (EMT). This study investigated the mechanism by which autophagy induces TGF-ß-triggered EMT and invasion of hepatocarcinoma cells. Autophagy was induced in HepG2 and BEL7402 cells by starvation in Hank's balanced salt solution. Induction of autophagy degraded phosphodiesterase (PDE) 4A and increased intracellular cAMP, PKA activity and PKA phosphorylation, resulting in increased cAMP response element binding (CREB) phosphorylation in hepatocarcinoma cells. Autophagy-induced activation of cAMP/PKA/CREB signalling further enhanced TGF-ß1 expression, downregulated the expression of epithelial markers and upregulated the expression of mesenchymal markers, accelerating invasion of hepatocarcinoma cells. Inhibition of autophagy by Atg3 and Atg7 knockdown or by chloroquine treatment prevented degradation of PDE4A and activation of cAMP/PKA/CREB signalling, suppressing TGF-ß1 expression, EMT and invasion in hepatocarcinoma cells. In addition, inhibition of cAMP/PKA/CREB signalling also blocked autophagy-induced TGF-ß1 expression and prevented EMT and invasion of hepatocarcinoma cells under starvation. Furthermore, exogenous inhibition of PDE4A or activation of cAMP/PKA/CREB signalling rescued TGF-ß1 expression, EMT and invasion in autophagy-deficient hepatocarcinoma cells. These findings suggest that autophagy induces TGF-ß1 expression and EMT in hepatocarcinoma cells via cAMP/PKA/CREB signalling, which is activated by autophagy-dependent PDE4A degradation.

Hepatitis C viral load, genotype, and increased risk of developing end-stage renal disease: REVEAL-HCV study.

The association between hepatitis C virus (HCV) infection and end-stage renal disease (ESRD) remains controversial without considering the role of HCV viral load and genotype. This study aimed to determine whether HCV RNA level and genotype affect the risk of developing ESRD. Between 1991 and 1992, 19,984 participants aged 30-65 years were enrolled in a community-based prospective cohort study in Taiwan. Chronic HCV infection was defined by detectable HCV viral load. ESRD was determined as the need for chronic dialysis or renal transplantation. Conventional Cox proportional hazard and competing risk models were used to determine the hazard ratio (HR) for ESRD. After a median follow-up of 16.8 years, 204 cases were detected during 319,474 person-years. The incidence rates of ESRD for nonchronically HCV-infected and chronically HCV-infected patients were 60.2 and 194.3 per 100,000 person-years, respectively. The multivariable HR was 2.33 (95% confidence interval [CI] 1.40-3.89) when comparing patients with and without chronic HCV infection. Patients with low and high HCV RNA levels were at higher risk of ESRD than those who were nonchronically HCV-infected (HR, 2.11, 95% CI 1.16-3.86, and HR, 3.06, 95% CI 1.23-7.58; Ptrend < 0.001). This association remained robust after taking pre-ESRD death as a competing event for ESRD. Patients with HCV genotype 1 tended to have a higher risk of developing ESRD (HR, 3.60 95% CI 1.83-7.07) compared with nonchronically HCV-infected subjects. CONCLUSIONS: This study reveals that chronic HCV infection is associated with an increased risk of developing ESRD and suggests that elevated serum levels of HCV RNA (>167,000 IU/mL) and HCV genotype 1 are strong predictors of ESRD, indicating clinical implications for the management of chronic HCV. (Hepatology 2017;66:784-793).

Effects of green tea extract on overweight and obese women with high levels of low density-lipoprotein-cholesterol (LDL-C): a randomised, double-blind, and cross-over placebo-controlled clinical trial.

BACKGROUND: This study aims to examine the effects of green tea extract (GTE) supplement on overweight and obese women with high levels of low density lipoprotein-cholesterol (LDL-C). METHODS: The randomized, double-blind, crossover and placebo-controlled clinical trial was conducted from August 2012 to December 2013. Seventy-three out of 90 subjects aged between 18 and 65 years, with body mass index (BMI) ≥ 27 kg/m2 and LDL-C ≥ 130 mg/dl were included in the analysis. The subjects were randomly divided into Groups A and B. Group A received GTE supplement treatment for the first 6 weeks, while Group B received placebo daily. After 6 weeks of treatment and 14 days of washout period, Group A switched to placebo and Group B switched to GTE treatment for 6 weeks. The reduction of LDL-C level between treatments was assessed as the outcome. Additionally, anthropometric measurements, plasma lipoproteins and hormone peptides of both groups were measure at the beginning of weeks 6, 8, and 14 after treatment. RESULTS: Subjects treated with GTE (n = 73) for 6 weeks showed significant differences, with 4.8% (p = 0.048) reduction in LDL-C and 25.7% (p = 0.046) increase in leptin. However, there was no statistical difference in the levels of total cholesterol, triglyceride and high density lipoprotein between the GTE and placebo groups after treatments. CONCLUSIONS: This study shows that green tea extract effectively increases leptin and reduces LDL in overweight and obese women after 6 weeks of treatment even though there were no significant changes in other biochemical markers related to overweight. TRIAL REGISTRATION: This clinical trial is registered with ClinicalTrials.gov: NCT02116517 on 17 April 2014. Retrospectively registered. The first patient enrolled in October 2012 and the study was completed December 2013.