Brain-Derived Exosomal miRNA Profiles upon Experimental SAE Rats and Their Comparison with Peripheral Exosomes.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction secondary to body infection without overt central nervous system infection. Dysregulation of miRNA expression in the transcriptome can spread through RNA transfer in exosomes, providing an early signal of impending neuropathological changes in the brain. Here, we comprehensively analyzed brain-derived exosomal miRNA profiles in SAE rats (n = 3) and controls (n = 3). We further verified the differential expression and correlation of brain tissue, cerebrospinal fluid, and plasma exosomal miRNAs in SAE rats. High-throughput sequencing of brain-derived exosomal miRNAs identified 101 differentially expressed miRNAs, of which 16 were downregulated and 85 were upregulated. Four exosomal miRNAs (miR-127-3p, miR-423-3p, mR-378b, and miR-106-3p) were differentially expressed and correlated in the brain tissue, cerebrospinal fluid, and plasma, revealing the potential use of miRNAs as SAE liquid brain biopsies. Understanding exosomal miRNA profiles in SAE brain tissue and exploring the correlation with peripheral exosomal miRNA can contribute to a comprehensive understanding of miRNA changes in the SAE pathological process and provide the possibility of establishing early diagnostic assays.

Lifestyle effects on aging and CVD: A spotlight on the nutrient-sensing network.

Aging is widespread worldwide and a significant risk factor for cardiovascular disease (CVD). Mechanisms underlying aging have attracted considerable attention in recent years. Remarkably, aging and CVD overlap in numerous ways, with deregulated nutrient sensing as a common mechanism and lifestyle as a communal modifier. Interestingly, lifestyle triggers or suppresses multiple nutrient-related signaling pathways. In this review, we first present the composition of the nutrient-sensing network (NSN) and its metabolic impact on aging and CVD. Secondly, we review how risk factors closely associated with CVD, including adverse life states such as sedentary behavior, sleep disorders, high-fat diet, and psychosocial stress, contribute to aging and CVD, with a focus on the bridging role of the NSN. Finally, we focus on the positive effects of beneficial dietary interventions, specifically dietary restriction and the Mediterranean diet, on the regulation of nutrient metabolism and the delayed effects of aging and CVD that depend on the balance of the NSN. In summary, we expound on the interaction between lifestyle, NSN, aging, and CVD.

Macrophage metabolic reprogramming and atherosclerotic plaque microenvironment: Fostering each other?

Macrophages are the central immune cells in atherosclerosis (AS) and play a critical role in the initiation, progression and invasion of atherosclerotic plaques. Metabolic reprogramming is a crucial feature that determines macrophage function and is driven by a combination of intrinsic alterations in macrophages and extrinsic factors such as cytokines acting in the plaque microenvironment. Intrinsic macrophage mechanisms activate signal transduction pathways that change metabolic enzyme activity, and the expression of metabolic regulators. Extrinsic signalling mechanisms involve lipids and cytokines in the microenvironment, promoting and amplifying macrophage metabolic reprogramming. This review describes the intrinsic and extrinsic mechanisms driving macrophage metabolic reprogramming in the AS microenvironment and the interplay of these metabolic rewires in the microenvironment. Moreover, we discuss whether targeting these different pathways to treat macrophage microenvironmental changes can alter the fate of the vulnerable plaques.

Emerging healthy lifestyle factors and all-cause mortality among people with metabolic syndrome and metabolic syndrome-like characteristics in NHANES.

BACKGROUND: The impact of integrated lifestyles on health has attracted a lot of attention. It remains unclear whether adherence to low-risk healthy lifestyle factors is protective in individuals with metabolic syndrome and metabolic syndrome-like characteristics. We aimed to explore whether and to what extent overall lifestyle scores mitigate the risk of all-cause mortality in individuals with metabolic syndrome and metabolic syndrome-like characteristics. METHODS: In total, 6934 participants from the 2007 to 2014 National Health and Nutrition Examination Survey (NHANES) were included. The weighted healthy lifestyle score was constructed based on smoking, alcohol consumption, physical activity, diet, sleep duration, and sedentary behavior information. Generalized linear regression models and restricted cubic splines were used to analyze the association between healthy lifestyle scores and all-cause mortality. ​ RESULTS: Compared to participants with relatively low healthy lifestyle scores, the risk ratio (RR) in the middle healthy lifestyle score group was 0.51 (RR = 0.51, 95% CI 0.30-0.88), and the high score group was 0.26 (RR = 0.26, 95% CI 0.15-0.48) in the population with metabolic syndrome. The difference in gender persists. In females, the RRs of the middle and high score groups were 0.47 (RR = 0.47, 95% CI 0.23-0.96) and 0.21 (RR = 0.21, 95% CI 0.09-0.46), respectively. In males, by contrast, the protective effect of a healthy lifestyle was more pronounced in the high score group (RR = 0.33, 95% CI 0.13-0.83) and in females, the protective effects were found to be more likely. The protective effect of a healthy lifestyle on mortality was more pronounced in those aged < 65 years. Higher lifestyle scores were associated with more prominent protective effects, regardless of the presence of one metabolic syndrome factor or a combination of several factors in 15 groups. What's more, the protective effect of an emerging healthy lifestyle was more pronounced than that of a conventional lifestyle. CONCLUSIONS: Adherence to an emerging healthy lifestyle can reduce the risk of all-cause mortality in people with metabolic syndrome and metabolic syndrome-like characteristics; the higher the score, the more obvious the protective effect. Our study highlights lifestyle modification as a highly effective nonpharmacological approach that deserves further generalization.

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy.

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.

Circulating Exosomal circRNAs Contribute to Potential Diagnostic Value of Large Artery Atherosclerotic Stroke.

Large artery atherosclerotic (LAA) stroke is closely associated with atherosclerosis, characterized by the accumulation of immune cells. Early recognition of LAA stroke is crucial. Circulating exosomal circRNAs profiling represents a promising, noninvasive approach for the detection of LAA stroke. Exosomal circRNA sequencing was used to identify differentially expressed circRNAs between LAA stroke and normal controls. From a further validation stage, the results were validated using RT-qPCR. We then built logistic regression models of exosomal circRNAs based on a large replication stage, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic efficacy. Using exosomal circRNA sequencing, large sample validation, and diagnostic model construction revealed that exosomal circ_0043837 and circ_ 0001801were independent predictive factors for LAA stroke, and had better diagnostic efficacy than plasma circRNAs. In the atherosclerotic group (AS), we developed a nomogram for clinical use that integrated the two-circRNA-based risk factors to predict which patients might have the risk of plaque rupture. Circulating exosomal circRNAs profiling identifies novel predictive biomarkers for the LAA stroke and plaque rupture, with superior diagnostic value than plasma circRNAs. It might facilitate the prevention and better management of this disease.

Associations of miR-146a, miR-149, miR-196a2, and miR-499 Polymorphisms with Ischemic Stroke in the Northern Chinese Han Population.

BACKGROUND Recently, miR-146a C>G, miR- 149 T>C, miR-196a2 T>C and miR-499 A>G polymorphisms have been associated with susceptibility to many diseases, including ischemic stroke (IS). However, results have been reported inconsistency in IS, especially in the Chinese population. This study aimed to investigate the polymorphisms of the 4 miRNAs and IS risk in the Chinese population. MATERIAL AND METHODS We used a case-control study to explore these associations in 396 patients with IS and 378 healthy controls. According to TOAST standards, the selected patients were divided into subgroups: the large artery atherosclerosis (LAA) subgroup and the small artery occlusion (SAO) subgroup. The method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotypes. RESULTS The miR-146a C>G polymorphism was remarkably different (CC vs. CG+GG: P=0.027; CC+CG vs. GG: P=0.020; C vs. G: P=0.006). The miR-149 T>C polymorphism was also remarkably different (TT vs. TC+CC: P=0.017; TT+TC vs. CC: P=0.020; T vs. C: P=0.004). The miR-146a and miR-149 polymorphisms were also remarkably different in the LAA subgroup (P<0.05). However, we did not find an association of miR-196a2 T>C or miR-499 A>G polymorphisms with IS (P>0.05); we did not find any association in the LAA subgroup or the SAO subgroup (P>0.05). CONCLUSIONS Our study suggested that miR-146a C>G and miR-149 T>C polymorphisms might remarkably increase the risk of IS, which might be mainly associated with an increased risk in LAA stroke; however, the miR-196a2 T>C and miR-499 A>G polymorphisms might not be associated with IS risk in the northern Chinese Han population.

Atorvastatin Upregulates the Expression of miR-126 in Apolipoprotein E-knockout Mice with Carotid Atherosclerotic Plaque.

Carotid atherosclerosis (AS) is a chronic inflammatory disease of the carotid arterial wall, which is very important in terms of the occurrence of cerebral vascular accidents. Studies have demonstrated that microRNAs (miRNAs) and their target genes are involved in the formation of atherosclerosis and that atorvastatin might reduce atherosclerotic plaques by regulating the expression of miRNAs. However, the related mechanism is not yet known. In this study, we first investigated the effects of atorvastatin on miR-126 and its target gene, i.e., vascular cell adhesion molecule-1 (VCAM-1) in apolipoprotein E-knockout (ApoE-/-) mice with carotid atherosclerotic plaque in vivo. We compared the expressions of miR-126 and VCAM-1 between the control, atherosclerotic model and atorvastatin treatment groups of ApoE-/- mice using RT-PCR and Western blot. We found the miR-126 expression was significantly down-regulated, and the VCAM-1 expression was significantly up-regulated in the atherosclerotic model group, which accelerated the progression of atherosclerosis in the ApoE-/- mice. These results following atorvastatin treatment indicated that miR-126 expression was significantly up-regulated, VCAM-1 expression was significantly down-regulated and atherosclerotic lesions were reduced. The present results might explain the mechanism by which miR-126 is involved in the formation of atherosclerosis in vivo. Our study first indicated that atorvastatin might exert its anti-inflammatory effects in atherosclerosis by regulating the expressions of miR-126 and VCAM-1 in vivo.

Association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and ischemic stroke in the Chinese population: a meta-analysis.

PURPOSE: The association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and ischemic stroke (IS) has been extensively studied; however, the results from genetic association studies have been inconsistent even in the Chinese population. As far as we know, there was no previous meta-analysis concerning this association in the Chinese population. Therefore, the aim of our meta-analysis was to further evaluate the association in the Chinese population. METHODS: We collected all of the relevant studies from Pubmed, OVID, Embase, Chinese Wan Fang database, CNKI, Chongqing VIP database and CBM up to August 2014. The available data was analyzed by Stata (version 12.0). We used odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to present the strength of the association. Heterogeneity was evaluated by the Q-test and I(2) statistic. Different genetic models, subgroup analysis, publication bias and sensitivity analysis were used to improve the comprehensive understanding. RESULTS: The results showed a significant association between the MTHFR gene C677T polymorphism and IS in six genetic models (additive model: OR = 1.34, 95%CI: 1.17 ∼ 1.54, p < 0.001; dominant model: OR = 1.44, 95% CI:1.26 ∼ 1.64, p < 0.001; recessive model: OR = 1.45, 95% CI: 1.15 ∼ 1.83, p = 0.001; heterozygote model: OR = 1.35, 95% CI: 1.18 ∼ 1.55, p < 0.001; homozygote model: OR = 1.80, 95% CI: 1.34 ∼ 2.41, p < 0.001; and allelic model: OR = 1.34, 95% CI: 1.17 ∼ 1.53, p < 0.001) based on the overall population, as well as subgroup analysis. In addition, the similar results were obtained in the sensitivity analysis based on studies with the high quality. CONCLUSIONS: This meta-analysis presented a significant association between the MTHFR gene C677T polymorphism and IS, the T allele might be a risk factor for IS in the Chinese population.

ATP-binding cassette transporter A1 R219K polymorphism and ischemic stroke risk in the Chinese population: a meta-analysis.

Recently, many studies have been focused on the association between the ATP-binding cassette transporter A1 (ABCA1) gene R219K polymorphism and ischemic stroke (IS). However, the study results have been inconsistent, especially in the Chinese population. Therefore, we performed a meta-analysis to better clarify the association between the ABCA1 gene and IS. All of the relevant studies used in our meta-analysis were identified using PubMed, OVID, Cochrane Library, Chinese Wan Fang database, Chinese VIP database, China National Knowledge Infrastructure (CNKI), and China Biological Medicine Database (CBM) up to May 2013. Statistical analysis was conducted with STATA software version 11.0. Odds ratios with 95% confidence intervals were applied to evaluate the strength of the association between ABCA1 gene R219K polymorphism and IS. Heterogeneity was evaluated using the Q-test and I(2) statistic. The funnel plots, Begg's and Egger's regression tests were used to assess the publication bias. Our meta-analysis showed the dominant genetic model (OR=0.92, 95% CI: 0.88-0.96), the recessive genetic model (OR=0.73, 95% CI: 0.51-1.05), the homozygote genetic model (OR=0.64, 95% CI: 0.44-0.94), the heterozygote genetic model (OR=0.81, 95% CI: 0.69-0.95), and the allelic genetic model (OR=0.83, 95% CI: 0.69-0.99). For R219K in IS, there were significant associations with these genetic models, but not with the recessive genetic model. Our meta-analysis indicated that the ABCA1 gene R219K polymorphism might be associated with IS and the K allele might be a protective factor in the Chinese population.

miR-137, a new target for post-stroke depression?

Expression of miR-137 is downregulated in brain tissue from patients with depression and suicidal behavior, and is also downregulated in peripheral blood from stroke patients. However, it is not yet known if miR-137 acts as a bridge between stroke and depression. To test this, we used middle cerebral artery occlusion and chronic mild stress to establish a post-stroke depression model in rats. Compared with controls, we found significantly lower miR-137 levels in the brain and peripheral blood from post-stroke depression rats. Injection of a miR-137 antagonist into the brain ventricles upregulated miR-137 levels, and improved behavioral changes in post-stroke depression rats. Luciferase assays showed miR-137 bound to the 3'UTR of Grin2A, regulating Grin2A expression in a neuronal cell line. Grin2A gene overexpression in the brain of post-stroke depression rats, noticeably suppressed the inhibitory effect of miR-137 on post-stroke depression. Overall, our results show that miR-137 suppresses Grin2A protein expression through binding to Grin2A mRNA, thereby exerting an inhibitory effect on post-stroke depression. Our results offer a new therapeutic direction for post-stroke depression.

[Lecithin-cholesterol acyltransferase gene 608C/T polymorphism associated with atherosclerotic cerebral infarction].

OBJECTIVE: To explore the distribution of lecithin-cholesterol acyltransferase gene (LCAT) 608C/T polymorphism in Chinese Han population and the relationship of the polymorphism association with the occurrence of atherosclerotic cerebral infarction. METHODS: The lecithin:cholesterol acyltransferase gene 608C/T polymorphism is identified by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP)and restriction fragment length polymorphism (RFLP) in 150 patients with ACI and 122 healthy controls matching age and sex. RESULTS: The distribution of LCAT 608C/T gene polymorphism was in accordance with Hardy-Weinberg equilibrium. The CT genotype frequency (14.0%) and T allele frequency (7.0%) in ACI group were significantly higher than those in control group (P<0.05). The concentration of high density lipoprotein cholesterol (HDL-C) in 608CC subgroups were significantly higher than those in 608CT subgroups both in ACI group and in control group (P<0.05). CONCLUSION: The LCAT 608C/T polymorphism is possibly a predisposing factor in ACI happening of Chinese Han population. T allele frequency is possibly concerned with the metabolism of HDL-C.