Targeted delivery of MerTK protein via cell membrane engineered nanoparticle enhances efferocytosis and attenuates atherosclerosis in diabetic ApoE-/- Mice.

BACKGROUND: Clearance of apoptotic cells by efferocytosis is crucial for prevention of atherosclerosis progress, and impaired efferocytosis contributes to the aggravated atherosclerosis. RESULTS: In this study, we found that diabetic ApoE-/- mice showed aggravated atherosclerosis as hyperglycemia damaged the efferocytosis capacity at least partially due to decreased expression of Mer tyrosine kinase (MerTK) on macrophages. To locally restore MerTK in the macrophages in the plaque, hybrid membrane nanovesicles (HMNVs) were thus developed. Briefly, cell membrane from MerTK overexpressing RAW264.7 cell and transferrin receptor (TfR) overexpressing HEK293T cell were mixed with DOPE polymers to produce nanovesicles designated as HMNVs. HMNVs could fuse with the recipient cell membrane and thus increased MerTK in diabetic macrophages, which in turn restored the efferocytosis capacity. Upon intravenous administration into diabetic ApoE-/- mice, superparamagnetic iron oxide nanoparticles (SMN) decorated HMNVs accumulated at the aorta site significantly under magnetic navigation, where the recipient macrophages cleared the apoptotic cells efficiently and thus decreased the inflammation. CONCLUSIONS:  Our study indicates that MerTK decrease in macrophages contributes to the aggravated atherosclerosis in diabetic ApoE-/- mice and regional restoration of MerTK in macrophages of the plaque via HMNVs could be a promising therapeutic approach.

Dose-response associations of triglyceride to high-density lipoprotein cholesterol ratio and triglyceride-glucose index with arterial stiffness risk.

BACKGROUND: The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and triglyceride-glucose (TyG) index are novel indexes for insulin resistance (IR). We aimed to evaluate associations of TG/HDL-C and TyG with arterial stiffness risk. METHODS: We enrolled 1979 participants from the Rural Chinese Cohort Study, examining arterial stiffness by brachial-ankle pulse wave velocity (baPWV). Logistic and linear regression models were employed to calculate effect estimates. For meta-analysis, we searched relevant articles from PubMed, Embase and Web of Science up to August 26, 2023. The fixed-effects or random-effects models were used to calculate the pooled estimates. We evaluated dose-response associations using restricted cubic splines. RESULTS: For cross-sectional studies, the adjusted ORs (95%CIs) for arterial stiffness were 1.12 (1.01-1.23) and 1.78 (1.38-2.30) for per 1 unit increment in TG/HDL-C and TyG. In the meta-analysis, the pooled ORs (95% CIs) were 1.26 (1.14-1.39) and 1.57 (1.36-1.82) for per 1 unit increment of TG/HDL-C and TyG. Additionally, both TG/HDL-C and TyG were positively related to PWV, with ß of 0.09 (95% CI 0.04-0.14) and 0.57 (95% CI 0.35-0.78) m/s. We also found linear associations of TG/HDL-C and TyG with arterial stiffness risk. CONCLUSIONS: High TG/HDL-C and TyG were related to increased arterial stiffness risk, indicating TG/HDL-C and TyG may be convincing predictors of arterial stiffness.

Right ventricular volume and function by three-dimensional echocardiography: results of the echocardiographic measurements in normal Chinese adults (EMINCA) II.

Three-dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D-RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D-RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D-RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor-dependent and vendor-independent software platforms were used to analyze the 3D-RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D-RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D-RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D-RV values should be stratified by sex, age, race, and vendor.

Miscarriage and stillbirth in relation to risk of cardiovascular diseases: A systematic review and meta-analysis.

INTRODUCTION: The relationship between pregnancy loss and the risk of cardiovascular diseases (CVDs) remains a matter of debate. Our intention in conducting this meta-analysis was to analyze the relationship between miscarriage and stillbirth and risk of CVDs. METHODS: PubMed, Embase, and Web of Science were systematically searched up to May 30, 2023 for all relevant studies. The random-effects model was applied to estimate the pooled relative risks (RRs) and 95% confidence intervals (95% CIs). We evaluated RR estimates for the risk of CVDs with each additional miscarriage and stillbirth through generalized least squares regression. RESULTS: Twenty-three articles were incorporated into the meta-analysis. For women with a history of miscarriage, the pooled RRs for the risk of total CVDs, coronary heart disease (CHD), stroke, and total CVD deaths were 1.16 (95 % CI 1.10-1.22), 1.26 (1.12-1.41), 1.13 (1.03-1.24), and 1.20 (1.01-1.42), respectively. For women with a history of stillbirth, the pooled RRs for the risk of total CVDs, CHD, stroke, and total CVD deaths were 1.60 (1.34-1.89), 1.30 (1.12-1.50), 1.37 (1.06-1.78), and 1.95 (1.05-3.63), respectively. With each additional miscarriage, the risk increased for total CVDs (1.08, 1.04-1.13), CHD (1.08, 1.04-1.13), and stroke (1.05, 1.00-1.10). With each additional stillbirth, the risk increased for total CVDs (1.11, 1.03-1.21) and CHD (1.13, 1.07-1.19). CONCLUSION: This meta-analysis indicates that both miscarriages and stillbirths are related to a higher risk of total CVDs, CHD, stroke, and total CVD deaths. The risk of total CVDs and CHD increased with the number of miscarriages or stillbirths.

Toward Ultrasound Molecular Imaging of Endothelial Dysfunction in Diabetes: Targets, Strategies, and Challenges.

Diabetes vasculopathy is a significant complication of diabetes mellitus (DM), and early identification and timely intervention can effectively slow the progression. Accumulating studies have shown that diabetes causes vascular complications directly or indirectly through a variety of mechanisms. Direct imaging of the endothelial molecular changes not only identifies the early stage of diabetes vasculopathy but also sheds light on the precise treatment. Targeted ultrasound contrast agent (UCA)-based ultrasound molecular imaging (UMI) can noninvasively detect the expression status of molecular biomarkers overexpressed in the vasculature, thereby being a potential strategy for the diagnosis and treatment response evaluation of DM. Amounts of efforts have been focused on identification of the molecular targets expressed in the vasculature, manufacturing strategies of the targeted UCA, and the clinical translation for the diagnosis and evaluation of therapeutic efficacy in both micro- and macrovasculopathy in DM. This review summarizes the latest research progress on endothelium-targeted UCA and discusses their promising future and challenges in diabetes vasculopathy theranostics.

Obesity and risk of depressive disorder in children and adolescents: A meta-analysis of observational studies.

PURPOSE: This meta-analysis evaluated the relationship between overweight/obesity and depressive disorders in children and adolescents. METHODS: We examined the databases of PubMed, Embase and Web of Science for pertinent observational studies released up until 20 February 2022. The pooled relative risks (RRs) and 95% confidence intervals (CIs) of obesity and overweight with depressive disorder were calculated by means of random-effects models. The Newcastle-Ottawa Quality Assessment Scale and Agency for Healthcare Research and Quality scale were adopted to evaluate the study quality. RESULTS: Finally, for this meta-analysis, we evaluated 22 observational publications covering 175 135 participants (5 cohort study articles, 1 case-control study article and 16 cross-sectional study articles). A significant positive association was found between obesity and the risk of depression (RR 1.32, 95% CI 1.09-1.60, I2 = 79.90%, Pheterogeneity < 0.001) and in the association between obesity and depressive symptoms (RR 1.16, 95% CI: 1.00-1.35, I2 = 25.0%, Pheterogeneity = 0.247). On sensitivity analysis, the pooled RRs remained robust. Subgroup analysis indicated that obese children and teenagers in western countries were more prone to depression. CONCLUSION: Evidence from this meta-analysis, based on observational studies, supported the idea that obese children and adolescents are more likely to experience depression and depressive symptoms.

Ultra-processed food consumption and risk of cardiovascular events: a systematic review and dose-response meta-analysis.

Background: Ultra-processed food (UPF) consumption continues to increase worldwide. However, evidences from meta-analyses are limited regarding the effects on cardiovascular events (CVEs). Methods: A meta-analysis was performed to assess the dose-response relationship of UPF consumption and CVEs risk (including the morbidity and mortality of cardiovascular causes, and myocardial infarction, stroke, transient ischemic attack, coronary intervention). Databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched for observational studies published in English language up to October 24, 2023. Generalized least squares regression and restricted cubic splines were used to estimate the linear/nonlinear relationship. PROSPERO CRD 42023391122. Findings: Twenty studies with 1,101,073 participants and 58,201 CVEs cases with a median follow-up of 12.2 years were included. A positive linear relationship between UPF intake and CVEs risk was identified. In addition, positive correlation between coronary heart disease and UPF consumption in terms of daily serving and daily energy proportion. No significant association of UPF consumption with the risk of cerebrovascular disease was observed. Briefly, 10% increase of UPF by daily weight proportion was associated with a 1.9% increase of CVEs risk (RR = 1.019; 95% CI, 1.007-1.031; P = 0.002), an additional daily serving corresponding to 2.2% CVEs risk increase (RR = 1.022; 95% CI, 1.013-1.031; P < 0.001), and 10% increase by daily energy proportion corresponding to 1.6% CVEs risk increase (RR = 1.016; 95% CI, 1.002-1.030; P = 0.022). Interpretation: UPF consumption were associated with a higher risk of CVEs in the positive linear relationship. Our findings highlight the importance of minimizing UPF consumption for cardiovascular health and might be help to pursue public health policies in control of UPF consumption. Funding: This work was supported by the Key Research and Development Program of Shaanxi Province (2023-ZDLSF-22), the Innovative Talent Support Program of Shaanxi Province (2022KJXX-106), and the Key Research and Development Program of Shaanxi Province (2023-YBSF-424).

Supplementation of Clostridium butyricum Alleviates Vascular Inflammation in Diabetic Mice.

Background: Gut microbiota is closely related to the occurrence and development of diabetes and affects the prognosis of diabetic complications, and the underlying mechanisms are only partially understood. We aimed to explore the possible link between the gut microbiota and vascular inflammation of diabetic mice. Methods: The db/db diabetic and wild-type (WT) mice were used in this study. We profiled gut microbiota and examined the and vascular function in both db/db group and WT group. Gut microbiota was analyzed by 16s rRNA sequencing. Vascular function was examined by ultrasonographic hemodynamics and histological staining. Clostridium butyricum (CB) was orally administered to diabetic mice by intragastric gavage every 2 days for 2 consecutive months. Reactive oxygen species (ROS) and expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by fluorescence microscopy. The mRNA expression of inflammatory cytokines was tested by quantitative polymerase chain reaction. Results: Compared with WT mice, CB abundance was significantly decreased in the gut of db/db mice, together with compromised vascular function and activated inflammation in the arterial tissue. Meanwhile, ROS in the vascular tissue of db/db mice was also significantly increased. Oral administration of CB restored the protective microbiota, and protected the vascular function in the db/db mice via activating the Nrf2/HO-1 pathway. Conclusion: This study identified the potential link between decreased CB abundance in gut microbiota and vascular inflammation in diabetes. Therapeutic delivery of CB by gut transplantation alleviates the vascular lesions of diabetes mellitus by activating the Nrf2/HO-1 pathway.

Truncated PD1 Engineered Gas-Producing Extracellular Vesicles for Ultrasound Imaging and Subsequent Degradation of PDL1 in Tumor Cells.

PDL1 blockade therapy holds great promise in cancer immunotherapy. Ultrasound imaging of PDL1 expression in the tumor is of great importance in predicting the therapeutic efficacy. As a proof-of-concept study, a novel ultrasound contrast agent has been innovated here to image and block PDL1 in the tumor tissue. Briefly, extracellular vesicles (EVs) are engineered to display truncated PD1 (tPD1) on the surface to bind PDL1 with high affinity by fusion to EV-abundant transmembrane protein PTGFRN. The engineered EVs are then encapsulated with Ca(HCO3)2 via electroporation and designated as Gp-EVtPD1, which would recognize PDL1 highly expressed cells and produce gas in the endosomes and lysosomes. On the one hand, the echogenic signal intensity correlates well with the PDL1 expression and immune response inhibition in the tumor. On the other hand, during the trajectory of Gp-EVtPD1 in the recipient cells, tPD1 on the EV binds PDL1 and triggers the PDL1 endocytosis and degradation in endosomes/lysosomes in a sequential manner, and thus boosts the anti-tumor immunity of cytotoxic T cells. In summary, Gp-EVtPD1 serves as a novel ultrasound contrast agent and blocker of PDL1, which might be of great advantage in imaging PDL1 expression and conquering immune checkpoint blocker resistance.

Ultrasound Imaging of Tumor Vascular CD93 with MMRN2 Modified Microbubbles for Immune Microenvironment Prediction.

Vascular microenvironment is found to be closely related to immunotherapy efficacy. Identification and ultrasound imaging of the unique vascular characteristics, able to predict immune microenvironment, is important for immunotherapy decision-making. Herein, it is proved that high CD93 expression in the tumor vessels is closely related to the poor immune response of prostate cancer. For ultrasound molecular imaging of CD93, CD93-targeted microbubbles (MBs) consist a gaseous core and the MMRN2 (Multimerin-2) containing cell membrane (CM) /lipid hybrid membrane is then synthesized. In vitro and in vivo assays demonstrate that these MBs can recognize CD93 efficiently and then accumulate within tumor regions highly expressing CD93. Contrast-enhanced ultrasound (CEUS) imaging with CD93-targeted MBs demonstrates that targeted ultrasound intensity is negatively related to inflammatory tumor immune microenvironment (TIME) and cytotoxic T cell infiltration. Together, endothelial expression of CD93 in tumor is a unique predictor of immunosuppressive microenvironment and CD93-targeted MBs have a great potential to evaluate tumor immune status.

Association of methylation risk score with incident type 2 diabetes mellitus: A nested case-control study.

AIMS: To investigate the association of methylation risk score (MRS) and its interactions with environmental factors with type 2 diabetes mellitus (T2DM) risk. METHODS: We conducted a nested case-control study with 241 onset cases and 241 matched controls. Conditional logistic regression models were employed to identify risk CpG sites. Simple and weighted MRSs were constructed based on the methylation levels of ATP-binding cassette G1 gene, fat mass and obesity associated gene, potassium voltage-gated channel member 1 gene, and thioredoxin-interacting protein gene previously associated with T2DM to estimate the association of MRS with T2DM risk. Stratified analyses were used to investigate interactions between MRS and environmental factors. RESULTS: A total of 10 CpG loci were identified from the aforementioned genes to calculate MRS. After controlling for potential confounding factors, taking tertile 1 as reference, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM of tertile 3 was 2.39 (1.36-4.20) for simple MRS and 2.59 (1.45-4.63) for weighted MRS. With per SD score increment in MRS, the OR (95% CI) was 1.66 (1.29-2.14) and 1.60 (1.24-2.08) for simple and weighted MRSs, respectively. J-curved associations were observed between both simple and weighted MRSs and T2DM risks. Additionally, multiplication interactions for smoking and hypertension with simple MRS on the risk of T2DM were found, similarly for smoking and obesity with weighted MRS on the risk of T2DM (all Pinteraction < .05). CONCLUSION: Elevated simple and weighted MRSs were associated with increased risk of T2DM. Environmental risk factors may influence the association between MRS and T2DM.

Profibrogenic macrophage-targeted delivery of mitochondrial protector via exosome formula for alleviating pulmonary fibrosis.

Pulmonary fibrosis (PF) is a devastating lung disease with limited treatment options. During this pathological process, the profibrogenic macrophage subpopulation plays a crucial role, making the characterization of this subpopulation fundamentally important. The present study revealed a positive correlation between pulmonary macrophages with higher mitochondrial mass (Mømitohigh) and fibrosis. Among the Mømitohigh subpopulation of CD206+ M2, characterized by higher expression of dynamin 1-like (Drp1), as determined by flow cytometry and RNA-seq analysis, a therapeutic intervention was developed using an exosome-based formula composed of pathfinder and therapeutics. A pathfinder exosome called "exosomeMMP19 (ExoMMP19)", was constructed to display matrix metalloproteinase-19 (MMP19) on the surface to locally break down the excessive extracellular matrix (ECM) in the fibrotic lung. A therapeutic exosome called "exosome therapeutics (ExoTx)", was engineered to display D-mannose on the surface while encapsulating siDrp1 inside. Prior delivery of ExoMMP19 degraded excessive ECM and thus paved the way for ExoTx to be delivered into Mømitohigh, where ExoTx inhibited mitochondrial fission and alleviated PF. This study has not only identified Mømitohigh as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.

Targeted elimination of senescent cells by engineered extracellular vesicles attenuates atherosclerosis in ApoE-/- mice with minimal side effects.

Senescent cells in plaques emerge as a detrimental factor for atherosclerosis (AS), for which targeted senolysis might be a promising therapeutic strategy. The development of safe and efficient senolytics for senescent cell eradication by targeted delivery is greatly needed. Methods: Pro-apoptotic intelligent Bax (iBax)-overexpressing plasmid was constructed by molecular cloning, in which Bax CDS was fused to miR-122 recognition sites. Extracellular vesicle-based senolytics (EViTx) were developed to be conjugated with magnetic nanoparticles on the surface, iBax mRNA encapsulated inside, and BAX activator BTSA1 incorporated into the membrane. EViTx was characterized, and in vivo distribution was tracked via fluorescence imaging. The therapeutic effects of EViTx on AS and its systemic side effects were analyzed in ApoE-/- mice. Results: Magnetic nanoparticles, iBax mRNA and BAX activator BTSA1 were efficiently loaded into/onto EViTx. With external magnetic field navigation, EViTx was delivered into atherosclerotic plaques and induced significant apoptosis in senescent cells regardless of origins. Repeated delivery of EViTx via tail vein injection has achieved high therapeutic efficacy in ApoE-/- mice. Notably, EViTx is inevitably accumulated in liver cells, while the iBax mRNA was translationally repressed by miR-122, an endogenous miRNA highly expressed in hepatocytes, and thus the liver cells are protected from the potential toxicity of Bax mRNA. Conclusion: Our work demonstrated that magnetic EV-based delivery of iBax mRNA and the BAX activator BTSA1, efficiently induced apoptosis in recipient senescent cells in atherosclerotic plaques. This strategy represents a promising treatment approach for AS and other age-related diseases.

Long-Term Exposure to Traffic Noise and Risk of Incident Cardiovascular Diseases: a Systematic Review and Dose-Response Meta-Analysis.

While noise pollution from transportation has become an important public health problem, the relationships between different sources of traffic noise and cardiovascular diseases (CVDs) remain inconclusive. A comprehensive meta-analysis was therefore conducted to quantitatively assess the effects of long-term exposure to road traffic, railway, and aircraft noise on CVDs and relevant subtypes. We systematically retrieved PubMed, Embase, and Web of Science for articles published before April 4, 2022. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated by the fixed- or random-effects models. In total, 23 articles were included in our meta-analysis. The risk of CVDs increased by 2% (RR 1.020, 95% CI 1.006-1.035) and 1.6% (RR 1.016, 95% CI 1.000-1.032) for every 10 dB increment of road traffic and aircraft noise. For CVD subtypes, the risk increased by 3.4% (1.034, 1.026-1.043) for stroke and 5% (1.050, 1.006-1.096) for heart failure with each 10 dB increment of road traffic noise; the risk of atrial fibrillation increased by 1.1% (1.011, 1.002-1.021) with each 10 dB increment of railway noise; and the risk increased by 1% (1.010, 1.003-1.017) for myocardial infarction, 2.7% (1.027, 1.004-1.050) for atrial fibrillation, and 2.3% (1.023, 1.016-1.030) for heart failure with each 10 dB increment in aircraft noise. Further, effects from road traffic, railway, and aircraft noise all followed positive linear trends with CVDs. Long-term exposure to traffic noise is positively related to the incidence risk of cardiovascular events, especially road traffic noise which significantly increases the risk of CVDs, stroke, and heart failure.

Correlation of heavy metals' exposure with the prevalence of coronary heart disease among US adults: findings of the US NHANES from 2003 to 2018.

We sought to explore the association between heavy metal exposure and coronary heart disease (CHD) based on data from the US National Health and Nutrition Examination Survey (NHANES, 2003-2018). In the analyses, participants were all aged > 20 and had participated in heavy metal sub-tests with valid CHD status. The Mann-Kendall test was employed to assess the trends in heavy metals' exposure and the trends in CHD prevalence over 16 years. Spearman's rank correlation coefficient and a logistics regression (LR) model were used to estimate the association between heavy metals and CHD prevalence. 42,749 participants were included in our analyses, 1802 of whom had a CHD diagnosis. Total arsenic, dimethylarsonic acid, monomethylarsonic acid, barium, cadmium, lead, and antimony in urine, and cadmium, lead, and total mercury in blood all showed a substantial decreasing exposure level tendency over the 16 years (all Pfor trend < 0.05). CHD prevalence varied from 3.53 to 5.23% between 2003 and 2018. The correlation between 15 heavy metals and CHD ranges from - 0.238 to 0.910. There was also a significant positive correlation between total arsenic, monomethylarsonic acid, and thallium in urine and CHD by data release cycles (all P < 0.05). The cesium in urine showed a negative correlation with CHD (P < 0.05). We found that exposure trends of total arsenic, dimethylarsonic acid, monomethylarsonic acid, barium, cadmium, lead, and antimony in urine and blood decreased. CHD prevalence fluctuated, however. Moreover, total arsenic, monomethylarsonic acid, and thallium in urine all showed positive relationships with CHD, while cesium in urine showed a negative relationship with CHD.

Improved extracellular vesicle-based mRNA delivery for familial hypercholesterolemia treatment.

Extracellular vesicle (EV)-based low-density lipoprotein receptor (Ldlr) mRNA delivery showed excellent therapeutic effects in treating familial hypercholesterolemia (FH). Nevertheless, the loading inefficiency of EV-based mRNA delivery presents a significant challenge. Recently, RNA-binding proteins (RBPs) have been fused to EV membrane proteins for selectively encapsulating targeted RNAs to promote loading efficiency. However, the strong interaction between therapeutic RNAs and RBPs prevents RNA release from endosomes to the cytosol in the recipient cells. In this study, an improved strategy was developed for efficient encapsulation of Ldlr mRNA into EVs in donor cells and controllable release in recipient cells. Methods: The MS2 bacteriophage coat protein (CD9-MCP) fusion protein, Ldlr mRNA, and a customized MS2 containing RNA aptamer base-pair matched with Ldlr mRNA were expressed in donor cells. Cells receiving the above therapeutic EVs were simultaneously treated with EVs containing "Ldlr releaser" with a sequence similar to the recognition sites in Ldlr mRNA. Therapeutic effects were analyzed in Ldlr-/- mice receiving EV treatments via the tail vein. Results: In vitro experiments demonstrated improved loading efficiency of Ldlr mRNA in EVs via MS2-MCP interaction. Treatment of "Ldlr releaser" competitively interacted with MS2 aptamer with higher affinity and released Ldlr mRNA from CD9-MCP for efficient translation. When the combinatory EVs were delivered into recipient hepatocytes, the robust LDLR expression afforded therapeutic benefits in Ldlr-/- mice. Conclusion: We proposed an EV-based mRNA delivery strategy for enhanced encapsulation of therapeutic mRNAs in EVs and RNA release into the cytosol for translation in recipient cells with great potential for gene therapy.

Exercise Improves Metabolism and Alleviates Atherosclerosis via Muscle-Derived Extracellular Vesicles.

Regular exercise maintains a healthy metabolic profile, while the underlying mechanisms have not been fully elucidated. Extracellular vesicles serve as an important mediator in intercellular communication. In this study, we aimed to explore whether exercise-induced extracellular vesicles (EVs) of skeletal muscle origins contribute to exercise-related protective effects on metabolism. We found that the twelve weeks of swimming training improved glucose tolerance, reduced visceral lipid accumulation, alleviated liver damage, and inhibited atherosclerosis progression in both obese WT mice and ApoE-/- mice, which could be partially blocked by EV biogenesis repression. Injection of skeletal muscle-derived EVs from exercised C57BL/6J mice (twice a week for 12 weeks) had similar protective effects on both obese WT mice and ApoE-/- mice as exercise itself. Mechanistically, these exe-EVs could be endocytosed by major metabolic organs, especially the liver and adipose tissue. With the protein cargos rich in mitochondrial and fatty acid oxidation-related components, exe-EVs remodeled metabolism towards beneficial cardiovascular outcomes. Our study here has shown that exercise remodels metabolism towards beneficial cardiovascular outcomes at least partially via the skeletal muscle secreted EVs. Therapeutic delivery of exe-EVs or the analogues could be promising for prevention of certain cardiovascular and metabolic diseases.

Ultrasound Responsive Nanovaccine Armed with Engineered Cancer Cell Membrane and RNA to Prevent Foreseeable Metastasis.

Cancer vaccine has been considered as a promising immunotherapy by inducing specific anti-tumor immune response. Rational vaccination at suitable time to efficiently present tumor associated antigen will boost tumor immunity and is badly needed. Here, a poly (lactic-co-glycolic acid) (PLGA)-based cancer vaccine of nanoscale is designed, in which engineered tumor cell membrane proteins, mRNAs, and sonosensitizer chlorin e6 (Ce6) are encapsulated at high efficiency. The nanosized vaccine can be efficiently delivered into antigen presentation cells (APCs) in lymph nodes after subcutaneous injection. In the APCs, the encapsulated cell membrane and RNA from engineered cells, which have disturbed splicing resembling the metastatic cells, provide neoantigens of metastatic cancer in advance. Moreover, the sonosensitizer Ce6 together with ultrasound irradiation promotes mRNA escape from endosome, and augments antigen presentation. Through 4T1 syngeneic mouse model, it has been proved that the proposed nanovaccine is efficient to elicit antitumor immunity and thus prevent cancer metastasis.

Dose-response meta-analysis of ultra-processed food with the risk of cardiovascular events and all-cause mortality: evidence from prospective cohort studies.

Background: Previous meta-analyses included abundant cross-sectional studies, and/or only assessed high versus low categories of UPF consumption. We conducted this meta-analysis based on prospective cohort studies to estimate the dose-response associations of UPF consumption with the risk of cardiovascular events (CVEs) and all-cause mortality among general adults. Methods: PubMed, Embase, and Web of Science were searched for relevant articles published up to August 17, 2021, and newly published articles between August 17, 2021 and July 21, 2022 were re-searched. Random-effects models were used to estimate the summary relative risks (RRs) and confidence intervals (CIs). Generalized least squares regression was used to estimate the linear dose-response associations of each additional serving of UPF. Restricted cubic splines were used to model the possible nonlinear trends. Results: Eleven eligible papers (17 analyses) were finally identified. The pooled effect size for the highest versus lowest category of UPF consumption showed positive associations with the risk of CVEs (RR = 1.35, 95% CI, 1.18-1.54) and all-cause mortality (RR = 1.21, 95% CI, 1.15-1.27). For each additional daily serving of UPF, the risk increased by 4% (RR = 1.04, 95% CI, 1.02-1.06) for CVEs and 2% (RR = 1.02, 95% CI, 1.01-1.03) for all-cause mortality. With increasing UPF intake, the risk of CVEs reflected a linear upward trend (Pnonlinearity = 0.095), while all-cause mortality reflected a nonlinear upward trend (Pnonlinearity = 0.039). Conclusion: Our findings based on prospective cohorts suggested that any increased level of UPF consumption was linked to higher CVEs and mortality risk. Thus, the recommendation is to control the intake of UPF in daily diet.

Alcohol Consumption and Risk of Fractures: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

Alcohol consumption remains inconsistently correlated with fracture risk, and a dose-response meta-analysis for specific outcomes is lacking. The objective of this study was to quantitatively integrate the data on the relationship between alcohol consumption and fracture risk. Pertinent articles were identified in PubMed, Web of Science, and Embase databases up to 20 February 2022. Combined RRs and 95% CIs were estimated by random- or fixed-effects models. Restricted cubic splines were used to model linear or nonlinear relationships. Forty-four articles covering 6,069,770 participants and 205,284 cases of fracture were included. The combined RRs and 95% CIs for highest compared with lowest alcohol consumption were 1.26 (1.17-1.37), 1.24 (1.13-1.35), and 1.20 (1.03-1.40) for total, osteoporotic, and hip fractures, respectively. A linear positive relationship between alcohol consumption and total fracture risk was detected (Pnonlinearity = 0.057); the risk was correlated with a 6% increase (RR, 1.06; 95% CI: 1.02, 1.10) per 14 g/d increment of alcohol consumption. J-shaped relationships of alcohol consumption with risk of osteoporotic fractures (Pnonlinearity < 0.001) and hip fractures (Pnonlinearity < 0.001) were found. Alcohol consumption of 0 to 22 g/d was linked to a reduced risk of osteoporotic fractures and hip fractures. Our findings show that any level of alcohol consumption is a risk factor for total fractures. Moreover, this dose-response meta-analysis shows that an alcohol consumption level of 0 to 22 g/d is related to a reduction in the risk of osteoporotic and hip fractures. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42022320623).