Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases.

BACKGROUND: Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. METHODS: A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. RESULTS: Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aß deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. CONCLUSIONS: In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.

An early prediction model for type 2 diabetes mellitus based on genetic variants and nongenetic risk factors in a Han Chinese cohort.

Aims: We aimed to construct a prediction model of type 2 diabetes mellitus (T2DM) in a Han Chinese cohort using a genetic risk score (GRS) and a nongenetic risk score (NGRS). Methods: A total of 297 Han Chinese subjects who were free from type 2 diabetes mellitus were selected from the Tianjin Medical University Chronic Disease Cohort for a prospective cohort study. Clinical characteristics were collected at baseline and subsequently tracked for a duration of 9 years. Genome-wide association studies (GWASs) were performed for T2DM-related phenotypes. The GRS was constructed using 13 T2DM-related quantitative trait single nucleotide polymorphisms (SNPs) loci derived from GWASs, and NGRS was calculated from 4 biochemical indicators of independent risk that screened by multifactorial Cox regressions. Results: We found that HOMA-IR, uric acid, and low HDL were independent risk factors for T2DM (HR >1; P<0.05), and the NGRS model was created using these three nongenetic risk factors, with an area under the ROC curve (AUC) of 0.678; high fasting glucose (FPG >5 mmol/L) was a key risk factor for T2DM (HR = 7.174, P< 0.001), and its addition to the NGRS model caused a significant improvement in AUC (from 0.678 to 0.764). By adding 13 SNPs associated with T2DM to the GRS prediction model, the AUC increased to 0.892. The final combined prediction model was created by taking the arithmetic sum of the two models, which had an AUC of 0.908, a sensitivity of 0.845, and a specificity of 0.839. Conclusions: We constructed a comprehensive prediction model for type 2 diabetes out of a Han Chinese cohort. Along with independent risk factors, GRS is a crucial element to predicting the risk of type 2 diabetes mellitus.

PGF2α facilitates pathological retinal angiogenesis by modulating endothelial FOS-driven ELR+ CXC chemokine expression.

The pathological retinal angiogenesis often causes blindness. Current anti-angiogenic therapy for proliferative retinopathy targets the vascular endothelial growth factor (VEGF), but many patients do not radically benefit from this therapy. Herein, we report that circulating prostaglandin (PG) F2α metabolites were increased in type 2 diabetic patients with proliferative retinopathy, and the PGF2α receptor (Ptgfr) was upregulated in retinal endothelial cells (ECs) from a mouse model of oxygen-induced retinopathy (OIR). Further, disruption of the PTGFR receptor in ECs attenuated OIR in mice. PGF2α promoted the proliferation and tube formation of human retinal microvascular endothelial cells (HRMECs) via the release of ELR+ CXC chemokines, such as CXCL8 and CXCL2. Mechanistically, the PGF2α /PTGFR axis potentiated ELR+ CXC chemokine expression in HRMECs through the Gq /CAMK2G/p38/ELK-1/FOS pathway. Upregulated FOS-mediated ELR+ CXC chemokine expression was observed in retinal ECs from PDR patients. Moreover, treatment with PTGFR inhibitor lessened the development of OIR in mice in a CXCR2-dependent manner. Therefore, inhibition of PTGFR may represent a new avenue for the treatment of retinal neovascularization, particularly in PDR.

An early prediction model for chronic kidney disease.

Based on the high incidence of chronic kidney disease (CKD) in recent years, a better early prediction model for identifying high-risk individuals before end-stage renal failure (ESRD) occurs is needed. We conducted a nested case-control study in 348 subjects (116 cases and 232 controls) from the "Tianjin Medical University Chronic Diseases Cohort". All subjects did not have CKD at baseline, and they were followed up for 5 years until August 2018. Using multivariate Cox regression analysis, we found five nongenetic risk factors associated with CKD risks. Logistic regression was performed to select single nucleotide polymorphisms (SNPs) from which we obtained from GWAS analysis of the UK Biobank and other databases. We used a logistic regression model and natural logarithm OR value weighting to establish CKD genetic/nongenetic risk prediction models. In addition, the final comprehensive prediction model is the arithmetic sum of the two optimal models. The AUC of the prediction model reached 0.894, while the sensitivity was 0.827, and the specificity was 0.801. We found that age, diabetes, and normal high values of urea nitrogen, TGF-ß, and ADMA were independent risk factors for CKD. A comprehensive prediction model was also established, which may help identify individuals who are most likely to develop CKD early.

Association of hypertension and hypertriglyceridemia on incident hyperuricemia: an 8-year prospective cohort study.

BACKGROUND: Hypertension and high triglyceride are two of the most important risk factors for hyperuricemia. Epidemiological records show that hypertension and dyslipidemia often coexist and may significantly increase the risk of target organ damage. However, their combined effect on incident hyperuricemia is poorly understood. Thus, we aimed to investigate the separate and combined effect of hypertension and hypertriglyceridemia on the incidence of hyperuricemia. METHODS: A prospective cohort study of 6424 hyperuricemia-free participants aged 20 to 94 years between August 2009 and October 2017 was performed at Tianjin General Hospital of China. Participants were categorized into four groups by combining hypertension and hypertriglyceridemia status at baseline. The restricted cubic spline fitting Cox regression model was used to evaluate the relationship between blood pressure and triglyceride and hyperuricemia. Cox regression models were performed to calculate hazard ratios (HRs) and 95% confident intervals (CIs) to estimate baseline factors and their association with the incidence of hyperuricemia. A Kaplan-Meier survival analysis was performed to compare the incidence of hyperuricemia among subjects in each separate and combined hypertension and hypertriglyceridemia group. RESULTS: During the 8-year follow-up period, 1259 subjects developed hyperuricemia (20.6%). There existed positive relationships between blood pressure and triglyceride levels and hyperuricemia. This risk factor arising from a combination of the two (HR, 3.02; 95% CI 2.60-3.50) is greater than that from hypertension (HR, 1.48; 95% CI 1.28-1.71) or hypertriglyceridemia (HR, 1.84; 95% CI 1.55-2.18) separately. The Kaplan-Meier survival analysis indicated that combined effect of hypertension and hypertriglyceridemia may predict higher onset of hyperuricemia. CONCLUSION: The combined effect of hypertension and hypertriglyceridemia on the risk of hyperuricemia is much stronger than that by hypertension or hypertriglyceridemia separately. Hypertension combined with hypertriglyceridemia may be an independent and powerful predictor for hyperuricemia.

Higher Serum Uric Acid Level Predicts Non-alcoholic Fatty Liver Disease: A 4-Year Prospective Cohort Study.

Background: Non-alcoholic fatty liver disease (NAFLD) has become a serious disease affecting people's health in the world. This article studies the causal relationship between NAFLD and serum uric acid (SUA) levels. Methods: During the 4 years of follow-up in a fixed cohort that was established in 2014, 2,832 follow-up subjects without NAFLD were finally included in this study. The study population was divided into four groups according to baseline SUA levels. Cox hazard regression model and Kaplan-Meier survival curves analysis were used to predict risk factors of NAFLD. The receiver operating characteristic curve analyses were used to determine SUA cutoffs for predicting NAFLD. Results: The cumulative prevalence rates of NAFLD were 33.97% (962/2,832), 38.93% (758/1,947) in males and 23.05% (204/885) in females. The results showed that males had a higher incidence of NAFLD (χ2 = 68.412, P = 0.000). The Cox regression analysis disclosed that the hazard ratios of NAFLD [95% confidence interval (CI)] were 1.431 (95% CI, 1.123~1.823), 1.610 (95% CI, 1.262-2.054), and 1.666 (95% CI, 1.287-2.157) across the second to the fourth quartile of SUA adjusted for other confounders. The SUA cutoffs, sensitivity, specificity, and area under the curve (AUC) (95% CI) were ≥288.5 µmol/L, 75.5, 46.5%, 0.637(0.616-0.658), respectively, for total; ≥319.5 µmol/L, 65.8%, 48.4%, 0.590 (0.564-0.615), respectively, for males; and ≥287.5 µmol/L, 51.0%, 75.6%, 0.662 (0.619-0.704), respectively, for females. Kaplan-Meier survival curves revealed that individuals with higher SUA level had an increased risk of NAFLD in comparison to lower SUA level (P = 0.000). Conclusion: Serum uric acid is positively correlated with NAFLD, and elevated SUA level can be used as an independent predictor for NAFLD.

Triglyceride is an independent predictor of type 2 diabetes among middle-aged and older adults: a prospective study with 8-year follow-ups in two cohorts.

BACKGROUND: Although there is abundant evidence indicating the connection between triglyceride and type 2 diabetes mellitus (T2DM), few reports or cohort studies confirm that high TG concentration may predict the incidence of T2DM independently. Thus, we studied the association between triglyceride (TG) and T2DM in a male-dominated, middle and older aged cohort, Tianjin General Hospital Cohort. And we further verified our results in the China Health and Retirement Longitudinal Study (CHARLS). METHODS: We conducted an 8-year retrospective cohort study (2009-2017) with 7241 participants who were free from T2DM at baseline. Three groups were constructed based on baseline TG levels (normal, borderline-high, and high). We used a Cox proportional hazards model to evaluate the relationship between TG and T2DM after adjusting for possible risk factors. A Kaplan-Meier survival analysis was performed to compare the incidence of T2DM among subjects in each TG group. We also tested the association between TG and T2DM in the CHARLS cohort. RESULTS: In Tianjin General Hospital Cohort, 7241 participants (male 75.8%, female 24.2%) were included, mean age was 61.49 ± 13.85 years at baseline. The cumulative incidence of T2DM in our cohort study was 8.6% (9.2% in men and 6.6% in women). Compared with the normal TG group, the hazard ratios in the borderline and high group were 1.30 (95% CI 1.04-1.62) and 1.54 (95% CI 1.24-1.90). The Kaplan-Meier survival analysis indicated that higher TG levels may predict higher onset of T2DM. These results were verified in the CHARLS cohort, the hazard ratio with T2DM (95% CI) for logTG was 3.94 (2.64-5.87). CONCLUSIONS: Our findings suggest that the TG level may be an independent risk factor and predictor for T2DM.

Higher triglyceride level predicts hyperuricemia: A prospective study of 6-year follow-up.

BACKGROUND: Despite abundant evidence indicating that higher triglyceride (TG) levels are associated with increased risks of hyperuricemia (HUA), it is unclear whether TG levels can independently predict the incidence of HUA. OBJECTIVE: The aim of the study was to investigate whether TG is an independent risk factor of HUA in a cohort study. METHODS: We explored the relationship between TG levels and HUA in a dynamic cohort established in 2009. During the 6 years of follow-up, 5442 subjects without HUA were studied. We divided subjects into 4 groups based on baseline TG levels and used the Cox hazard regression model to estimate HUA risk by TG quartile, after adjustment for potential confounding factors. Kaplan-Meier survival analysis compared the risk of HUA incidence among individuals in each TG quartile. RESULTS: The incidence of HUA in this cohort was 25.9%. The hazard ratios (95% confidence intervals) for HUA in the second, third, and fourth TG quartiles, compared with the first quartile, were 1.19 (1.01-1.40), 1.33 (1.13-1.57), and 1.62 (1.37-1.92), respectively. The Kaplan-Meier survival analysis suggested that higher TG levels predicted higher incidences of HUA in a dose-dependent relationship. Stratification analyses showed that the association between TG levels and the presence of HUA was more pronounced in individuals aged <50 years, of obese, with normal estimated glomerular filtration rate, and with hypertension. CONCLUSION: Our findings suggest that TG level is a significant and independent risk factor for HUA.

Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis.

The prevalence of hyperuricemia and gout has been increasing, but the comparative effectiveness and safety of different treatments remain uncertain. We aimed to compare the effectiveness and safety of different treatments for hyperuricemia using network meta-analysis methodology. We systematically reviewed fifteen randomized controlled trials (involving 7,246 patients through January 2016) that compared the effects of different urate-lowering drugs (allopurinol, benzbromarone, febuxostat, pegloticase and probenecid) on hyperuricemia. Drug efficacy and safety, as outcomes, were measured by whether the target level of serum urate acid was achieved and whether any adverse events occurred, respectively. We derived pooled effect sizes expressed as odds ratios (ORs) and 95% confidence intervals (CIs). The efficacy and safety of the drugs were ranked by cumulative ranking probabilities. Our findings show that febuxostat, benzbromarone, probenecid, pegloticase, and allopurinol were all highly effective at reducing the risk of hyperuricemia compared to placebo. Febuxostat had the best efficacy and safety compared to the other drugs. Furthermore, febuxostat 120 mg QD was more effective at achieving urate-lowering targets (OR: 0.17, 95% CI: 0.12-0.24) and safer (OR: 0.72, 95% CI: 0.56-0.91) than allopurinol.

Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation.

Unlike genetic aberrations, epigenetic alterations do not modify the deoxyribonucleic acid (DNA) coding sequence and can be reversed pharmacologically. Identifying a particular epigenetic alteration such as abnormal DNA methylation may provide better understanding of cancers and improve current therapy. In a Chinese pedigree with colorectal carcinoma and acute myeloid leukemia, we examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. DNA methylation status in the four cases, which all harbor a MLL3 germline mutation, differed from that of the normal control, and hypermethylation was more prevalent. Also, more CpG sites were hypermethylated in the acute-phase AML patient than in the AML patient in remission. Fifty-nine hyper- or hypomethylated genes were identified as common to all four cases. Genome-wide DNA methylation analysis demonstrated that differentially methylated sites among acute myeloid leukemia and colorectal carcinoma cases and the control were in both promoters (CpG island) and gene body regions (shelf/shore areas). Hypermethylation was more prevalent in cancer cases. The study supports the suggestion that the level of DNA methylation changes in AML progression.

Serum Uric Acid Levels were Dynamically Coupled with Hemoglobin A1c in the Development of Type 2 Diabetes.

The aim of the study was to decipher the relationship between serum uric acid (SUA) and glycated hemoglobin A1c (HbA1c) or fasting plasma glucose (FPG) in both type 2 diabetes mellitus (T2DM) patients and normal subjects. A total of 2,250 unrelated T2DM patients and 4,420 Han Chinese subjects from a physical examination population were recruited for this study. In T2DM patients SUA levels were negatively correlated with HbA1c (rs = -0.109, P = 0.000) and 2 h plasma glucose levels (rs = -0.178, P = 0.000). In the physical examination population, SUA levels were inversely correlated with HbA1c (rs = -0.175, P = 0.000) and FPG (rs = -0.131, P = 0.009) in T2DM patients but positively correlated with HbA1c (rs = 0.040, P = 0.012) and FPG (rs = 0.084, P = 0.000) in normal-glucose subjects. Multivariate analyses showed that HbA1c was significantly negatively associated with HUA both in T2DM patients (OR = 0.872, 95% CI: 0.790~0.963) and in the physical examination T2DM patients (OR = 0.722, 95% CI: 0.539~0.968). Genetic association studies in T2DM patients showed that alleles of two glucose-uric acid transporter genes, ABCG2 and SLC2A9 were significantly associated with SUA levels (P < 0.05). SUA level is inversely correlated with HbA1c in T2DM patients but positively correlated with HbA1c in normal-glucose subjects. The reverse transporting of uric acid and glucose in renal tubules might be accounted for these associations.

Associations between serum uric acid and the incidence of hypertension: a Chinese senior dynamic cohort study.

BACKGROUND: The prevalence of hyperuricemia has increased dramatically during the past several decades. Studies indicating uric acid is an independent risk factor for hypertension did not sufficiently control for other known risk factors. We explored this relationship in a comprehensive Chinese senior dynamic cohort. METHODS: To investigate the relationship between serum uric acid (SUA) levels and hypertension, we carried out a 6-year retrospective study (2006-2011) in a dynamic cohort with 3591 subjects free of hypertension. The first occasion of documented hypertension per subject was the index event. A Cox proportional hazards model assessed the relationship between SUA and hypertension. Kaplan-Meier survival analysis compared incidence of hypertension among individuals with each SUA quartile. Receiver operating characteristic curves were generated to obtain the area under the curve as a prediction of hypertension from SUA levels. RESULTS: The cumulative prevalence of hypertension in our cohort was 20.7 %. The prevalence of hyperuricemia was 17.5 %. Cox regression analysis showed that, compared with the lowest SUA quartile (<4.69 mg/dl), the 4.69-5.58, 5.58-6.52, and ≥6.52 mg/dl quartiles yielded hazard ratios (95 % confidence intervals) for hypertension of 1.652 (1.265-2.156), 2.195 (1.705-2.825), and 3.058 (2.399-3.899), respectively. Cumulative incidence of hypertension was consistently higher among individuals with hyperuricemia than among those with normal SUA levels. A Kaplan-Meier survival analysis showed that hyperuricemia predicted higher incidences of hypertension in a dose-dependent manner: hypertension onset significantly differed across SUA quartiles. SUA levels were significantly and independently associated with incidence of hypertension in our cohort. CONCLUSIONS: Our results, controlling for known risk factors, suggest that SUA level is an independent risk factor for hypertension and could be a useful indicator of hypertension.

TOX and CDKN2A/B Gene Polymorphisms Are Associated with Type 2 Diabetes in Han Chinese.

To study associations between type 2 diabetes (T2DM) candidate genes and microvascular complications of diabetes (MVCDs), we performed case-control association studies for both T2DM and MVCDs in Han Chinese subjects. We recruited 1,939 unrelated Han Chinese T2DM patients and 918 individuals with normal blood glucose levels as nondiabetic controls. Among T2DM patients, 1116 have MVCDs, 266 have a history of T2DM of >10 years but never developed MVCDs. Eighty-two single-nucleotide polymorphisms (SNPs) in 54 candidate genes were genotyped. Discrete association studies were performed by the PLINK program for T2DM and MVCDs. Significant associations were found among candidate gene SNPs and T2DM, including rs1526167 of the TOX gene (allele A, P = 2.85 × 10(-9), OR = 1.44). The SNP rs10811661 of the CDKN2A/B gene was also associated with T2DM (allele T, P = 4.09 × 10(-7), OR = 1.36). When we used control patients with >10 years of T2DM history without MVCD, we found that the G allele of SNP rs1526167 of the TOX gene was associated with MVCD (nominal P = 4.33 × 10(-4)). In our study, significant associations were found between TOX and CDKN2A/B gene SNPs and T2DM. The TOX polymorphism might account for the higher risk of T2DM and the lower risk of MVCDs in the Han Chinese population.