Akkermansia Muciniphila supplementation improves hyperlipidemia, cardiac function, and gut microbiota in high fat fed apolipoprotein E-deficient mice.

Hyperlipidemia, obesity and gut dysbiosis are pivotal risk factors for atherosclerotic cardiovascular disease (ACVD). Supplementation of Akkermansia muciniphila (AKK) has also been proven to be effective in the prevention and treatment of obesity and other metabolic disorders. Here we found that AKK was more abundant in healthy control than ACVD patients via metagenomic sequencing on fecal samples. Subsequently, we investigated the role and underlying mechanism of AKK on obesity-associated atherosclerosis. AKK intervention partially reversed the exacerbation of atherosclerotic lesion formation in ApoE-/- mice by improving dyslipidemia. Interestingly, replenishment with AKK significantly enhanced cardiac function and reduced the body weight. It also reduced pro-inflammatory cytokine IL-6 and increased anti-inflammatory IL-10 in the circulation. Additionally, AKK colonization dramatically regulated gut microbiota and increased the abundance of Lactobacillaceae. Our findings have provided novel insights into the therapeutic potential of AKK as a beneficial microbe for treating atherosclerotic-associated cardiovascular diseases.

Interfacial Wrinkling Structures Based on a Double Cross-Linking Strategy Enable a Dual-Mode Optical Information Encryption.

Surface wrinkling structures based on a bilayer system are widely employed in storing and encrypting specific optical information. However, constructing a stable wrinkling structure with high-level security remains an extensive challenge due to the delamination issue between the skin layer and the substrate. Herein, a double cross-linking strategy is introduced between a hydrogel layer doped with fluorescent molecules and polydimethylsiloxane to establish a stable interfacial wrinkling structure with dual-mode functionality, in which the light reflection of the wrinkles and fluorescence intensity of fluorescent molecules can be simultaneously regulated by the modulus ratio between the two layers. The spontaneous wrinkling structures with a physically unclonable function can enhance the photoluminescence emission intensity of the wrinkling area under ultraviolet radiation. Meanwhile, the skin layer constructed of acrylamide and acrylic acid copolymer protects the interfacial wrinkling patterns from the loss of a detailed structure for authentication due to external damage. The stable interfacial wrinkling structures with fluorescence can find potential applications in the fields of information storage and encryption.

Designed wrinkles for optical encryption and flexible integrated circuit carrier board.

Patterns on polymers usually have different mechanical properties as those of the substrates, causing deformation or distortion and even detachment of the patterns from the polymer substrates. Herein, we present a wrinkling strategy, which utilizes photolithography to define the area of stress distribution by light-induced physical crosslinking of polymers and controls diffusion of residual solvent to redistribute the stress and then offers the same material for patterns as substrate by thermal polymerization, providing uniform wrinkles without worrying about force relaxation. The strategy allows the recording and hiding of up to eight switchable images in one place that can be read by the naked eye without crosstalk, applying the wrinkled polymer for optical anti-counterfeiting. The wrinkled polyimide film was also utilized to act as a substrate for the creation of fine copper circuit by a full-additive process. It generates flexible integrated circuit (IC) carrier board with copper wire density of 400% higher than that of the state-of-the-art in industry while fulfilling the standards for industrialization.

Association between oxidative balance score, systemic inflammatory response index, and cardiovascular disease risk: a cross-sectional analysis based on NHANES 2007-2018 data.

Background: There is limited research on the relationship between Systemic Oxidative Stress (SOS) status and inflammatory indices. Adding onto existing literature, this study aimed to examine the association between dietary Oxidative Balance Score (OBS) and lifestyle OBS (which make up the overall OBS), and Cardiovascular Disease (CVD) prevalence at different Systemic Immune Inflammation Index (SII) and Systemic Inflammatory Response Index (SIRI) levels. Methods: This study involved 9,451 subjects selected from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. The OBS comprised 20 dietary and lifestyle factors. Statistical methods included Weighted Linear Regression Analysis (WLRA), Logistic Regression Analysis (LRA), Sensitivity Analysis (SA), and Restricted Cubic Spline (RCS) analysis. Results: The multivariate WLRA revealed that OBS was significantly negatively correlated with both SII (ß = -5.36, p < 0.001) and SIRI (ß = -0.013, p < 0.001) levels. In SA, removing any single OBS component had no significant effect on the WLRA results of SII and SIRI. Further subgroup analyses revealed that OBS was more impactful in lowering SII in women than in men. Additionally, OBS was more significantly negatively correlated with SII and SIRI in the low-age group than in the high-age group. Moreover, RCS analysis confirmed this linear relationship. Compared to dietary OBS, lifestyle OBS exerted a more significant effect on Coronary Artery Disease (CAD) (OR: 0.794, p = 0.002), hypertension (OR: 0.738, p < 0.001), Congestive Heart Failure (CHF) (OR: 0.736, p = 0.005), Myocardial Infarction (MI) (OR: 0.785, p = 0.002), and stroke (OR: 0.807, p = 0.029) prevalence. Furthermore, SIRI exhibited a significant interaction in the relationship between overall OBS, dietary OBS, and CHF (P for interaction < 0.001). On the other hand, SII had a significant interaction in the relationship between overall OBS, dietary OBS, and MI (P for interaction < 0.05). Conclusion: OBS, including lifestyle and dietary OBS, were significantly negatively associated with SII and SIRI. Higher lifestyle OBS was associated with reduced risks of CAD, hypertension, CHF, MI, and stroke.

Effects of antidiabetic agents on platelet characteristics with implications in Alzheimer's disease: Mendelian randomization and colocalization study.

Background: Observational studies have found a potential link between the use of thiazolidinediones (TZDs) and a lower risk of Alzheimer's disease (AD) development. Platelets were the great source of amyloid-ß (Aß) and involved in the development of AD. This study aimed to assess the correlation between antidiabetic agents and platelet characteristics, hoping to provide a potential mechanism of TZDs neuroprotection in AD. Method: Drug-targeted Mendelian randomization (MR) was performed to systematically illustrate the long-term effects of antidiabetic agents on platelet characteristics. Four antidiabetic agent targets were considered. Positive control analysis for type 2 diabetes (T2D) was conducted to validate the selection of instrumental variables (IVs). Colocalization analysis was used to further strengthen the robustness of the results. Result: Positive control analysis showed an association of four antidiabetic agents with lower risk of T2D, which was consistent with their mechanisms of action and previous evidence from clinical trials. Genetically proxied TZDs were associated with lower platelet count (ß[IRNT] = -0.410 [95 % CI -0.533 to -0.288], P = 5.32E-11) and a lower plateletcrit (ß[IRNT] = -0.344 [95 % CI -0.481 to -0.206], P = 1.04E-6). Colocalization suggested the posterior probability of hypothesis 4 (PPH4) > 0.8, which further strengthened the MR results. Conclusion: Genetically proxied TZDs were causally associated with lower platelet characteristics, particularly platelet count and plateletcrit, providing insight into the involvement of platelet-related pathways in the neuroprotection of TZDs against AD. Future studies are warranted to reveal the underlying molecular mechanism of TZDs' neuroprotective effects through platelet pathways.

Causal associations of genetically predicted gut microbiota and blood metabolites with inflammatory states and risk of infections: a Mendelian randomization analysis.

Background: Inflammation serves as a key pathologic mediator in the progression of infections and various diseases, involving significant alterations in the gut microbiome and metabolism. This study aims to probe into the potential causal relationships between gut microbial taxa and human blood metabolites with various serum inflammatory markers (CRP, SAA1, IL-6, TNF-α, WBC, and GlycA) and the risks of seven common infections (gastrointestinal infections, dysentery, pneumonia, bacterial pneumonia, bronchopneumonia and lung abscess, pneumococcal pneumonia, and urinary tract infections). Methods: Two-sample Mendelian randomization (MR) analysis was performed using inverse variance weighted (IVW), maximum likelihood, MR-Egger, weighted median, and MR-PRESSO. Results: After adding other MR models and sensitivity analyses, genus Roseburia was simultaneously associated adversely with CRP (Beta IVW = -0.040) and SAA1 (Beta IVW = -0.280), and family Bifidobacteriaceae was negatively associated with both CRP (Beta IVW = -0.034) and pneumonia risk (Beta IVW = -0.391). After correction by FDR, only glutaroyl carnitine remained significantly associated with elevated CRP levels (Beta IVW = 0.112). Additionally, threonine (Beta IVW = 0.200) and 1-heptadecanoylglycerophosphocholine (Beta IVW = -0.246) were found to be significantly associated with WBC levels. Three metabolites showed similar causal effects on different inflammatory markers or infectious phenotypes, stearidonate (18:4n3) was negatively related to SAA1 and urinary tract infections, and 5-oxoproline contributed to elevated IL-6 and SAA1 levels. In addition, 7-methylguanine showed a positive correlation with dysentery and bacterial pneumonia. Conclusion: This study provides novel evidence confirming the causal effects of the gut microbiome and the plasma metabolite profile on inflammation and the risk of infection. These potential molecular alterations may aid in the development of new targets for the intervention and management of disorders associated with inflammation and infections.

Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage ( P  < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P  = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications ( P  < 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.

Polygenic risk score predicts all-cause death in East Asian patients with prior coronary artery disease.

Introduction: Coronary artery disease (CAD) is a highly heritable and multifactorial disease. Numerous genome-wide association studies (GWAS) facilitated the construction of polygenic risk scores (PRS) for predicting future incidence of CAD, however, exclusively in European populations. Furthermore, identifying CAD patients with elevated risks of all-cause death presents a critical challenge in secondary prevention, which will contribute largely to reducing the burden for public healthcare. Methods: We recruited a cohort of 1,776 Chinese CAD patients and performed medical follow-up for up to 11 years. A pruning and thresholding method was used to calculate PRS of CAD and its 14 risk factors. Their correlations with all-cause death were computed via Cox regression. Results and discussion: We found that the PRS for CAD and its seven risk factors, namely myocardial infarction, ischemic stroke, angina, heart failure, low-density lipoprotein cholesterol, total cholesterol and C-reaction protein, were significantly associated with death (P ≤ 0.05), whereas the PRS of body mass index displayed moderate association (P < 0.1). Elastic-net Cox regression with 5-fold cross-validation was used to integrate these nine PRS models into a meta score, metaPRS, which performed well in stratifying patients at different risks for death (P < 0.0001). Combining metaPRS with clinical risk factors further increased the discerning power and a 4% increase in sensitivity. The metaPRS generated from the genetic susceptibility to CAD and its risk factors can well stratify CAD patients by their risks of death. Integrating metaPRS and clinical risk factors may contribute to identifying patients at higher risk of poor prognosis.

Characterizing the metabolic divide: distinctive metabolites differentiating CAD-T2DM from CAD patients.

OBJECTIVE: To delineate the metabolomic differences in plasma samples between patients with coronary artery disease (CAD) and those with concomitant CAD and type 2 diabetes mellitus (T2DM), and to pinpoint distinctive metabolites indicative of T2DM risk. METHOD: Plasma samples from CAD and CAD-T2DM patients across three centers underwent comprehensive metabolomic and lipidomic analyses. Multivariate logistic regression was employed to discern the relationship between the identified metabolites and T2DM risk. Characteristic metabolites' metabolic impacts were further probed through hepatocyte cellular experiments. Subsequent transcriptomic analyses elucidated the potential target sites explaining the metabolic actions of these metabolites. RESULTS: Metabolomic analysis revealed 192 and 95 significantly altered profiles in the discovery (FDR < 0.05) and validation (P < 0.05) cohorts, respectively, that were associated with T2DM risk in univariate logistic regression. Further multivariate regression analyses identified 22 characteristic metabolites consistently associated with T2DM risk in both cohorts. Notably, pipecolinic acid and L-pipecolic acid, lysine derivatives, exhibited negative association with CAD-T2DM and influenced cellular glucose metabolism in hepatocytes. Transcriptomic insights shed light on potential metabolic action sites of these metabolites. CONCLUSIONS: This research underscores the metabolic disparities between CAD and CAD-T2DM patients, spotlighting the protective attributes of pipecolinic acid and L-pipecolic acid. The comprehensive metabolomic and transcriptomic findings provide novel insights into the mechanism research, prophylaxis and treatment of comorbidity of CAD and T2DM.

Characteristics of the gut microbiome and metabolic profile in elderly patients with sarcopenia.

Introduction: There is growing evidence of research indicating that the gut microbiota is involved in the development of sarcopenia. Nevertheless, there exists a notable deficiency in comprehension concerning the connection between irregularities in the intestinal microbiome and metabolic processes in older individuals suffering from sarcopenia. Methods: To analyze fecal samples obtained from a cohort of 30 older patients diagnosed with sarcopenia as well as 30 older patients without sarcopenia, this study employed 16S rDNA sequencing and liquid chromatography-mass spectrometry (LC-MS)-based non-targeted metabolomics profiling techniques. Results: As a result, we found that 29 genera and 172 metabolites were significantly altered in the sarcopenic patients. Among them, Blautia, Lachnospiraceae_unclassified, and Subdoligranulum were the bacteria with a potential diagnostic value for sarcopenia diagnosis. Correlation analysis between clinical indices and these gut bacteria suggested that the IL-6 level was negatively correlated with Blautia. Function prediction analysis demonstrated that 17 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways differ significantly between sarcopenic and non-sarcopenic patients. The primary classes of metabolites identified in the study included lipids and lipid-like molecules, organic acids and derivatives, and organoheterocyclic compounds. KEGG enrichment analysis showed that purine metabolism, arginine and proline metabolism, alanine, aspartate, and glutamate metabolism, butanoate metabolism, and histidine metabolism may contribute to the development of sarcopenia. The correlation study on gut microbiota and metabolites found that Lachnospiraceae_unclassified was positively associated with seven metabolites that were more abundant in the non-sarcopenia group and negatively correlated with three metabolites that were more abundant in the sarcopenia group. In addition, Subdoligranulum was positively correlated with seven metabolites that were lacking in sarcopenia and negatively correlated with two metabolites that were enriching in sarcopenia. Moreover, Blautia was positively associated with xanthosine. Discussion: We conducted a study on the intestinal microbiota and metabolic profile of elderly individuals with sarcopenia, offering a comprehensive analysis of the overall ecosystem. Through this investigation, we were able to validate existing research on the gut-muscle axis and further investigate potential pathogenic processes and treatment options for sarcopenia.

A consortium of three-bacteria isolated from human feces inhibits formation of atherosclerotic deposits and lowers lipid levels in a mouse model.

By a survey of metagenome-wide association studies (MWAS), we found a robust depletion of Bacteroides cellulosilyticus, Faecalibacterium prausnitzii, and Roseburia intestinalis in individuals with atherosclerotic cardiovascular disease (ACVD). From an established collection of bacteria isolated from healthy Chinese individuals, we selected B. cellulosilyticus, R. intestinalis, and Faecalibacterium longum, a bacterium related to F. prausnitzii, and tested the effects of these bacteria in an Apoe/- atherosclerosis mouse model. We show that administration of these three bacterial species to Apoe-/- mice robustly improves cardiac function, reduces plasma lipid levels, and attenuates the formation of atherosclerotic plaques. Comprehensive analysis of gut microbiota, plasma metabolome, and liver transcriptome revealed that the beneficial effects are associated with a modulation of the gut microbiota linked to a 7α-dehydroxylation-lithocholic acid (LCA)-farnesoid X receptor (FXR) pathway. Our study provides insights into transcriptional and metabolic impact whereby specific bacteria may hold promises for prevention/treatment of ACVD.

Stepwise Stimuli-Responsive, Multicolor-Chromic Perylene Bisimide/Polyvinyl Alcohol Co-assembly System for Information Encryption.

The issue of information security has become a concern in all aspects of daily life, prompting the development of encryption technologies. Therein, optical encryption using color/graphical patterns holds great potential. However, current approaches generally rely on monochromic change upon one or more stimuli, limiting their further application in advanced confidential encryption. Herein, we propose a delicate strategy based on a co-assembly system of perylene bisimides (PBI)/polyvinyl alcohol (PVA) that demonstrates stepwise stimuli response and multicolor changes. The color of the supramolecular system changes from red to purple under the stimulus of UV light, and to orange when exposed to water. The multidimensional chromic response is achieved by an evolution process including the generation, packing rearrangement and quenching of PBI radical anions/dianions. With the virtues of photo- and hydrochromism, this novel co-assembly system was successfully employed for advanced anticounterfeiting and versatile information encryption applications.

Exploring the causal effects of the gut microbiome on serum lipid levels: A two-sample Mendelian randomization analysis.

Background: The gut microbiome was reported to be associated with dyslipidemia in previous observational studies. However, whether the composition of the gut microbiome has a causal effect on serum lipid levels remains unclear. Objective: A two-sample Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationships between gut microbial taxa and serum lipid levels, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and log-transformed triglyceride (TG) levels. Materials and methods: Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and four blood lipid traits were obtained from public datasets. Five recognized MR methods were applied to assess the causal estimates, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates. Results: The combined results from the five MR methods and sensitivity analysis showed 59 suggestive causal associations and four significant causal associations. In particular, genus Terrisporobacter was associated with higher LDL-C (P IVW = 3.01 × 10-6) and TC levels (P IVW = 2.11 × 10-4), phylum Actinobacteria was correlated with higher LDL-C level (P IVW = 4.10 × 10-4), and genus Oscillospira was associated with lower TG level (P IVW = 2.19 × 10-6). Conclusion: This research may provide novel insights into the causal relationships of the gut microbiome on serum lipid levels and new therapeutic or prevention strategies for dyslipidemia.

Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis.

Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha (LXRα) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.

Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner.

Hepatosteatosis is characterized by abnormal accumulation of triglycerides (TG), leading to prolonged and chronic inflammatory infiltration. To date, there is still a lack of effective and economical therapies for hepatosteatosis. Oridonin (ORI) is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens. In this paper, we showed that ORI exerted significant protective effects against hepatic steatosis, inflammation and fibrosis, which was dependent on LXRα signaling. It is reported that LXRα regulated lipid homeostasis between triglyceride (TG) and phosphatidylethanolamine (PE) by promoting ATGL and EPT1 expression. Therefore, we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα-dependent manner, and the results showed the TG reduction and PE elevation. In detail, hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes, respectively. Taken together, the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.

Tryptophan was metabolized into beneficial metabolites against coronary heart disease or prevented from producing harmful metabolites by the in vitro drug screening model based on Clostridium sporogenes.

In our previous study of 2,130 Chinese patients with coronary heart disease (CHD), we found that tryptophan (TRP) metabolites contributed to elevated risks of death. Many TRP-derived metabolites require the participation of intestinal bacteria to produce, and they play an important role in the pathogenesis of metabolic diseases such as CHD. So it is necessary to metabolize TRP into beneficial metabolites against CHD or prevent the production of harmful metabolites through external intervention. Indole-3-butyric acid (IBA) may be a key point of gut microbiota that causes TRP metabolism disorder and affects major adverse cardiovascular events in CHD. Therefore, this study aimed to develop a method based on in vitro culture bacteria to evaluate the effects of IBA on specific microbial metabolites quickly. We detected the concentrations of TRP and its metabolites in 11 bacterial strains isolated from feces using liquid chromatography-mass spectrometry, and selected Clostridium sporogenes as the model strain. Then, IBA was used in our model to explore its effect on TRP metabolism. Results demonstrated that the optimal culture conditions of C. sporogenes were as follows: initial pH, 6.8; culture temperature, 37°C; and inoculum amount, 2%. Furthermore, we found that IBA increases the production of TRP and 5-HIAA by intervening TRP metabolism, and inhibits the production of KYNA. This new bacteria-specific in vitro model provides a flexible, reproducible, and cost-effective tool for identifying harmful agents that can decrease the levels of beneficial TRP metabolites. It will be helpful for researchers when developing innovative strategies for studying gut microbiota.

Tumor-derived extracellular vesicles confer 5-fluorouracil resistance in esophageal cancer via long noncoding RNA AC116025.2 delivery.

5-Fluorouracil (5-FU) resistance is one of the main causes for treatment failure in esophageal cancer (EC). Here, we intended to elucidate the mechanism of tumor-derived extracellular vesicles (TEVs)-encapsulated long noncoding RNAs (lncRNAs) AC116025.2 in 5-FU resistance in EC. EVs were isolated from the serum samples of EC patients and HEEC, TE-1, and TE-1/5-FU cells, followed by RT-qPCR detection of AC116025.2 expression in EVs. The relationship among AC116025.2, microRNA (miR)-4496, and SEMA5A was evaluated. Next, EC cells were cocultured with EVs, followed by lentivirus transduction and plasmid transfection for studying the role of TEVs-AC116025.2 in EC cells in relation to miR-4496 and SEMA5A. Tumor formation in nude mice was applied for in vivo confirmation. Elevated AC116025.2 expression was seen in the EVs from the serum of 5-FU insensitive patients and from 5-FU-resistant EC cells. Mechanistically, AC116025.2 bound to miR-4496 that inversely targeted SEMA5A in EC cells. EVs-oe-AC116025.2 augmented EC cell viability, colony formation, and 5-FU resistance, but diminished their apoptosis through miR-4496-mediated SEMA5A. Furthermore, EVs-oe-AC116025.2 augmented tumor formation and 5-FU resistance of EC cells in vivo. Conclusively, our data offered evidence of the promoting mechanism of TEVs in the 5-FU resistance of EC by delivering AC116025.2.

Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a metabolically perturbed pathological condition. However, the knowledge of metabolic signatures on outcomes of CAD and their potential causal effects and impacts on left ventricular remodeling remains limited. We aim to assess the contribution of plasma metabolites to the risk of death and major adverse cardiovascular events (MACE) as well as left ventricular remodeling. RESULTS: In a prospective study with 1606 Chinese patients with CAD, we have identified and validated several independent metabolic signatures through widely-targeted metabolomics. The predictive model respectively integrating four metabolic signatures (dulcitol, ß-pseudouridine, 3,3',5-Triiodo-L-thyronine, and kynurenine) for death (AUC of 83.7% vs. 76.6%, positive IDI of 0.096) and metabolic signatures (kynurenine, lysoPC 20:2, 5-methyluridine, and L-tryptophan) for MACE (AUC of 67.4% vs. 59.8%, IDI of 0.068) yielded better predictive value than trimethylamine N-oxide plus clinical model, which were successfully applied to predict patients with high risks of death (P = 0.0014) and MACE (P = 0.0008) in the multicenter validation cohort. Mendelian randomisation analysis showed that 11 genetically inferred metabolic signatures were significantly associated with risks of death or MACE, such as 4-acetamidobutyric acid, phenylacetyl-L-glutamine, tryptophan metabolites (kynurenine, kynurenic acid), and modified nucleosides (ß-pseudouridine, 2-(dimethylamino) guanosine). Mediation analyses show that the association of these metabolites with the outcomes could be partly explained by their roles in promoting left ventricular dysfunction. CONCLUSIONS: This study provided new insights into the relationship between plasma metabolites and clinical outcomes and its intermediate pathological process left ventricular dysfunction in CAD. The predictive model integrating metabolites can help to improve the risk stratification for death and MACE in CAD. The metabolic signatures appear to increase death or MACE risks partly by promoting adverse left ventricular dysfunction, supporting potential therapeutic targets of CAD for further investigation.

Bacteroides fragilis Supplementation Deteriorated Metabolic Dysfunction, Inflammation, and Aorta Atherosclerosis by Inducing Gut Microbiota Dysbiosis in Animal Model.

BACKGROUND: The gut microbial ecosystem is an important factor that regulates host health and the onset of chronic diseases, such as inflammatory bowel diseases, obesity, hyperlipidemia, and diabetes mellitus, which are important risk factors for atherosclerosis. However, the links among diet, microbiota composition, and atherosclerotic progression are unclear. METHODS AND RESULTS: Four-week-old mice (-/- mice, C57Bl/6) were randomly divided into two groups, namely, supplementation with culture medium (control, CTR) and Bacteroides fragilis (BFS), and were fed a high-fat diet. The gut microbiota abundance in feces was evaluated using the 16S rDNA cloning library construction, sequencing, and bioinformatics analysis. The atherosclerotic lesion was estimated using Oil Red O staining. Levels of CD36, a scavenger receptor implicated in atherosclerosis, and F4/80, a macrophage marker in small intestine, were quantified by quantitative real-time PCR. Compared with the CTR group, the BFS group showed increased food intake, fasting blood glucose level, body weight, low-density lipoprotein level, and aortic atherosclerotic lesions. BFS dramatically reduced Lactobacillaceae (LAC) abundance and increased Desulfovibrionaceae (DSV) abundance. The mRNA expression levels of CD36 and F4/80 in small intestine and aorta tissue in the BFS group were significantly higher than those in the CTR group. CONCLUSIONS: gut microbiota dysbiosis was induced by BFS. It was characterized by reduced LAC and increased DSV abundance and led to the deterioration of glucose/lipid metabolic dysfunction and inflammatory response, which likely promoted aorta plaque formation and the progression of atherosclerosis.