Causal effects of plasma lipids on the risk of atrial fibrillation: A multivariable mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have suggested that plasma lipids contribute substantially to cardiovascular disease, but "cholesterol paradox" in atrial fibrillation (AF) remains. We sought to investigate the causal effects of lipid profiles on the risk of AF. METHODS AND RESULTS: Two-sample Mendelian randomization (MR) framework was implemented to examine the causality of association. Summary estimations of genetic variants associated with low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total cholesterol, triglycerides, lipoprotein-a [Lp(a)], apolipoprotein A1 (ApoA 1), and apolipoprotein B (ApoB) were 81, 99, 96, 61, 30, 10, and 23 single nucleotide polymorphisms, respectively. Genetic association with AF were retrieved from a genome-wide association study that included 1,030,836 individuals. The complications for AF were predefined as cardioembolic stroke (CES) and heart failure (HF). In the multivariable MR, the odds ratios for AF per standard deviation (SD) increase were 1.030 (95% confidence interval (CI) 0.979-1.083; P = 0.257) for LDL-cholesterol, 0.986 (95% CI 0.931-1.044; P = 0.622) for HDL-cholesterol, 0.965 (95% CI 0.896-1.041; P = 0.359) for triglycerides, 1.001 (95% CI 1.000-1.003; P = 0.023) for Lp(a), 1.017 (95% CI 0.966-1.070; P = 0.518) for ApoA1, and 1.002 (95% CI 0.963-1.043; P = 0.923) for ApoB. There was no evidence that other lipid components were causally associated with AF, CES, or HF, other than for a marginal association between triglycerides and HF. CONCLUSIONS: This MR study provides robust evidence that high Lp(a) increases the risk of AF, suggesting that interventions targeting Lp(a) may contribute to the primary prevention of AF.

Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury.

Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1ß, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 µM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI.

Effect of rainwater-borne hydrogen peroxide on manure-derived Cu and Zn speciation distribution and bioavailability in rice-soil system.

Pot experiment was conducted to examine the effects of rainwater-borne hydrogen peroxide (H2O2) on transformation of Cu, Zn from pig manure in soils and its resulting impacts on the growth of Cu and Zn uptake by a rice plant. Results showed that the exogenous application of H2O2 significantly improved the rice biomass and yield. Addition of H2O2 into the soils led to reduced uptake of soil-borne Cu and Zn by the rice plants and this had a significant effect on reducing the accumulation of Zn in rice grains. It was indicated that the increased pH in soil might play important role in reducing Cu and Zn content in rice. Furthermore, Cu and Zn content in exchangeable form and carbonate bounded form dramatically decreased in soil, on the contrary, the organic combination state increased significantly in H2O2 treatment. The findings point to a potential research direction that rainwater-borne H2O2 in nature may help to change morphology of heavy metals in natural soil environments, but further study is still needed to explore the related mechanisms in Cu and Zn in manures and paddy rice field receiving rainwater-borne H2O2.

[Buyang Huanwu decoction promotes neuroblast migration from subventricular zone via inducing angiogenesis after ischemia].

OBJECTIVE: To study the effect of Buyang Huanwu decoction (BYHWD) inducing angiogenesis on the neuroblast migration from the subventricular zone and its mechanisms after focal cerebral ischemia. METHOD: The middle cerebral artery occlusion (MCAO) was performed to mice for 30 minutes to establish the model. The rats were divided into sham group, model group, BYHWD group and endostatin group. BYHWD (20 g x kg(-1), ig) and endostatin (10 µg, sc) were administered 24 h after ischemia once a day for consecutively 14 days. At 14 d after ischemia, the density of micro-vessel and the number of neuroblasts in the ischemia border zone were determined by immunofluorescence staining. The mRNA and protein expression of cell-derived factor-1 (SDF-1) and brain-derived neurotrophic (BDNF) were examined by real-time PCR and Western blot. RESULT: Compared with the model group, BYHWD significantly increased the density of micro-vessel and the number of DCX positive cells in the ischemia border zone (P < 0.01), and significantly increased the SDF-1 and BDNF mRNA and protein expression (P < 0.01). Compared with BYHWD group, endostatin significantly reduced the density of micro-vessel and the number of DCX positive cells in the ischemia border zone (P < 0.01), as well as the SDF-1, BDNF mRNA and protein expression (P < 0.01). CONCLUSION: BYHWD could promote the neuroblast migration from the subventricular zone via inducing angiogenesis after cerebral ischemia, the mechanism may be correlated with up-regulating the expression of SDF-1 and BDNF.

Individual and joint toxicity of three chloroacetanilide herbicides to freshwater cladoceran Daphnia carinata.

Individual and joint toxicity of three chloroacetanilide herbicides to a freshwater cladoceran were studied. The 48 h-LC50 values of alachlor, acetochlor and butachlor to Daphnia carinata Dc42 were 11.1, 11.8 and 3.45 mg L(-1), respectively. The toxicity was significantly (p < 0.05) related to hydrophobicity. The additive indexes of binary mixtures of three herbicides were less than zero and it showed antagonism. The body length of D. carinata treated with high concentration of herbicides was shorter than that of control group significantly (p < 0.05). It suggests that joint actions must be considered when assessing the acute toxicity of chloroacetanilide herbicides to D. carinata.

C Deletion at the re74650330 Locus of the SLC39A8 Gene (rs74650330) Increases the Risk of Coronary Artery Disease in Individuals with Low-Density Lipoprotein Cholesterol Levels.

Background: Genetic variants of the SLC39A8 gene are associated with several cardiovascular disease risk factors, including body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-density lipoprotein cholesterol (HDL-C) levels. The present study aimed to investigate the association between the SLC39A8 SNPs rs13107325 and rs74650330 and CAD in the Han population in Jiangsu (China). Methods: Genotyping of these SNPs was performed in 258 patients with CAD and 170 healthy controls using the base-quenched probe technique. The association between the alleles of the rs74650330 locus and blood lipid and glucose profiles was investigated. Receiver operating characteristic (ROC) curve analysis was used to quantify the optimal thresholds for lipid and FBG levels and the risk factors for CAD were estimated by logistic regression analysis. Results: The rs13107325 polymorphism was not found in the 428 Chinese individuals enrolled in the current study. For rs74650330, individuals harboring the C allele had significantly higher HDL levels than those without this allele in the control group (p = 0.039), while the opposite was true for low-density lipoprotein cholesterol (LDL-C) levels (p = 0.046). Further analysis indicated that when LDL-C levels were lower than 2.365 mmol/L, subjects with C/del and del/del had a 7.293-fold increased risk of CAD compared with that of controls without the mutation (odds ratio: 7.293; 95% confidence interval: 0.953-55.79). Conclusions: The susceptibility of SLC39A8 polymorphisms to CAD were studied and revealed a possible role for the deletion variant of rs74650330 in increasing the risk of CAD among the Chinese Han population.

MicroRNA-489 suppresses isoproterenol-induced cardiac fibrosis by downregulating histone deacetylase 2.

Cardiac fibrosis is a hallmark of cardiovascular diseases. Several studies have indicated that microRNAs (miRs) are associated with the development of cardiac fibrosis. However, to date, the underlying molecular mechanisms of miR-489 in cardiac fibrosis have not been studied. The present study investigated the biological function of miR-489 in isoproterenol (ISO)-induced cardiac fibrosis. It was observed that miR-489 was downregulated in the heart tissue and cardiac fibroblasts (CFs) obtained from rats with ISO-induced cardiac fibrosis, as compared with the levels in the control group. By contrast, the expression levels of histone deacetylase 2 (HDAC2), collagen I (Col1A1) and α-smooth muscle actin (α-SMA) were increased in the heart tissue and CFs obtained from ISO-treated rats compared with the control group. Furthermore, ISO-treated CFs were transfected with a miR-489 mimic, which resulted in decreased viability and differentiation of CFs compared with the control group. Bioinformatics analysis and a dual-luciferase reporter assay further revealed that HDAC2 is a downstream target of miR-489. Subsequently, a loss-of-function experiment demonstrated that depletion of HDAC2 decreased the expression levels of Col1A1 and α-SMA in CFs. Taken together, the results obtained in the present study revealed that the miR-489/HDAC2 signaling pathway may serve as a novel regulatory mechanism in ISO-induced cardiac fibrosis and may increase the understanding on cardiac fibrosis.

Salidroside protects against homocysteine-induced injury in human umbilical vein endothelial cells via the regulation of endoplasmic reticulum stress.

INTRODUCTION: Previous studies showed that homocysteine (Hcy) could injure vascular endothelial cells via several mechanisms, including its promotion of oxidative stress pathway and endoplasmic reticulum stress (ER stress) pathway. Salidroside (SAL) is an active component of Rhodiola rosea with documented antioxidative properties. Emerging evidence conformed that SAL attenuated Hcy-induced endothelial dysfunction by reducing oxidative stress. However, its role in ER stress pathway remains unclarified. AIMS: The purpose of this study was to explore the mechanism of the protective effect of SAL on Hcy-induced endothelial dysfunction. RESULTS: Pretreatment of the human umbilical vein endothelial cells (HUVECs) with SAL significantly reduced the cell damage effects brought by Hcy in a dose-dependent manner. Functional studies on the HUVECs found that SAL rescued the endoplasmic reticulum stress induced by Hcy. The underlying mechanisms involve the inhibition of Hcy-induced activation of binding protein (Bip) and C/EBP homologous protein (CHOP), as well as the phosphorylation of protein kinase RNA-like ER kinase (PERK) or inositol-requiring enzyme 1 alpha (IRE1α). CONCLUSIONS: Taken together, these findings implicate that SAL could regulate ER stress pathway on the viability of endotheliocyte induced by Hcy in vitro. Our findings provide the first evidence that SAL plays an important role in endotheliocyte protection via suppressing ER stress pathway in HUVEC cells and that it may be a promising therapeutic target for atherosclerosis and cardiovascular disease.

Inhibition of long noncoding RNA BDNF-AS rescues cell death and apoptosis in hypoxia/reoxygenation damaged murine cardiomyocyte.

BACKGROUND: Hypoxia/reoxygenation (H/R)-induced cardiomyocyte damage in vitro bears many similarities to myocardial infraction in vivo. In this study, we investigated whether long noncoding RNA (lncRNA) BDNF-AS has functional role in rescuing H/R-induced damage in cardiomyocyte in vitro. METHOD: Murine neonatal cardiomyocytes were cultured in vitro, and treated with either long (Hypoxia (L)) or short (Hypoxia (S)) H/R conditions. Viability and TUNEL assays were conducted to assess cardiomyocyte death or apoptosis. QRT-PCR was used to examine BDNF-AS mRNA expression. Endogenous BDNF-AS was downregulated by siRNA in cardiomyocyte. Its effect on H/R-induced cardiomyocyte damage was then examined. In addition, survival-associated proteins, including BDNF, VEGF and Akt were examined by western blot in siRNA-transfected cardiomyocytes. RESULTS: Hypoxia (S) induced apoptosis whereas Hypoxia (L) induced cell death in murine neonatal cardiomyocyte in vitro. Under both conditions, endogenous cardiomyocyte BDNF-AS was significantly upregulated. SiRNA-mediated BDNF-AS downregulation rescued cardiomyocyte death under Hypoxia (L) condition, and reduced cardiomyocyte apoptosis under Hypoxia (L) condition. Moreover, BDNF-AS downregulation activated BDNF and VEGF through upregulation, and activated Akt through phosphorylation in H/R-damaged cardiomyocyte. CONCLUSION: Inhibition of lncRNA BDNF-AS may be an efficient way to rescue cardiomyocyte from H/R-induced apoptosis or cell death.

Inhibition effects of tanshinone on the aggregation of α-synuclein.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Lewy bodies that are formed by the aggregated α-synuclein are a major pathological feature of PD. Salvia miltiorrhiza has been used as food and as a traditional medicine for centuries in China, with tanshinone I (TAN I) and tanshinone IIA (TAN IIA) as its major bioactive ingredients. Here, we investigated the effects of TAN I and TAN IIA on α-synuclein aggregation both in vitro and in a transgenic Caenorhabditis elegans PD model (NL5901). We demonstrated that TAN I and TAN IIA inhibited the aggregation of α-synuclein as demonstrated by the prolonged lag time and the reduced thioflavin-T fluorescence intensity; TAN I and TAN IIA also disaggregated preformed mature fibrils in vitro. Moreover, the presence of TAN I or TAN IIA affected the secondary structural transformation of α-synuclein from unstructured coils to ß-sheets, and alleviated the membrane disruption caused by aggregated α-synuclein in vitro. Besides, the immuno-dot-blot assay indicated that TAN I and TAN IIA reduce the formation of oligomers and fibrils. We further found that TAN I and TAN IIA extended the life span of NL5901, a strain of transgenic C. elegans that expresses human α-synuclein, possibly by attenuating the aggregation of α-synuclein. Taken together, our results suggested that TAN I and TAN IIA may be explored further as potential candidates for the prevention and treatment of PD.