BACKGROUND:Conventional obesity definitions overlook heterogeneity related to metabolic health and muscle strength. This study examined the associations between dynapenic-metabolic obesity (DMO) and incident stroke among middle-aged and older Chinese adults. METHODS:Our study included 11,770 participants aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018) with 2011 as baseline. Dynapenia was defined by handgrip strength (<28 kg for men, <18 kg for women); metabolic dysfunction by ≥2 of 4 criteria (hypertension, dyslipidemia, impaired glycemia, or low HDL-C); and obesity by BMI ≥25 kg/m2 (general obesity) or waist circumference ≥ 90 cm for men and ≥ 85 cm for women (abdominal obesity). Cox models estimated hazard ratios (HRs) for stroke, adjusting for covariates. Mediation analysis evaluated the roles of C-reactive protein (CRP) and intrinsic capacity (IC). RESULTS:During follow-up, 787 participants (6.7%) experienced stroke. Obesity alone, without dynapenia or metabolic dysfunction, was associated with elevated stroke risk (general obesity: HR 1.50, 95% CI 1.15-1.95; abdominal obesity: HR 1.55, 95% CI 1.21-1.98). The highest risk was observed in participants with combined dynapenia and metabolic dysfunction (DMGO: HR 2.97, 95% CI 2.01-4.37; DMAO: HR 2.96, 95% CI 2.08-4.21). Mediation analyses indicated that systemic inflammation and reduced intrinsic capacity partially explained these associations. Findings were consistent across subgroups and sensitivity analyses. CONCLUSIONS:Dynapenic-metabolic obesity is strongly associated with incident stroke, but even obesity alone increases risk. Systemic inflammation and impaired intrinsic capacity partially mediate these effects, highlighting the importance of integrated strategies targeting adiposity, metabolic health, and muscle function to prevent stroke in aging populations.

BackgroundThe results of population-based studies show a diverse association between the triglyceride-glucose (TyG) index and hypertension. The present study aimed to investigate this association based on a cross-sectional study on Chinese adults and meta-analysis of epidemiology studies.MethodsThe cross-sectional analysis used the baseline data from the on-going REACTION study in China. The TyG index was calculated as Ln [triglyceride(mg/dl)×fasting plasma glucose(mg/dl)/2]. A multivariate-adjusted logistic regression model was used to calculate the odds ratio (OR) with a 95% confidence interval (CIs) for the prevalence of hypertension, with the lowest TyG quartile as a reference.ResultsA total of 4,177 participants aged 58.62 ± 8.40 years were included. TyG was significantly associated with higher odds of hypertension (OR:1.273, 95% CI:1.171-1.384), and the association remained pronounced with isolated systolic hypertension (OR:1.161, 95% CI:1.045-1.289) and systolic-diastolic hypertension (OR:1.313, 95% CI:1.163-1.483) but not with isolated diastolic hypertension (OR:1.164, 95% CI:0.929-1.460). In the present meta-analysis, 34 relevant studies were included through systematic searches of PUBMED, Embase, and the Cochrane Library. A positive association between the TyG index and hypertension was revealed in the meta-analysis of cohort studies (HR:1.57, 95% CI:1.25-1.96) and cross-sectional studies (OR:2.01, 95% CI:1.47-2.76).ConclusionElevated TyG index levels were significantly associated with a higher risk of clinical hypertension, which may provide new insights into the clinical management of hypertension.

Moyamoya disease, characterized by basal cerebral artery obstruction, was studied for differential protein expression to elucidate its pathogenesis. Proteomic analysis of cerebrospinal fluid from 10 patients, categorized by postoperative angiography into good and poor prognosis groups, revealed 46 differentially expressed proteins. Notably, cadherin 18 (CDH18) was the most significantly upregulated in the good prognosis group. In addition, the expression of cadherin 18 (CDH18) and phenotypic transformation-related proteins were measured by qRT-PCR and western blot. The effects of CDH18 in vascular smooth muscle cells were detected by CCK-8, EdU, transwell and wound healing assays. The overexpression of CDH18 in vascular smooth muscle cells (VSMCs) was found to inhibit proliferation, migration, and phenotypic transformation. These findings suggest CDH18 as a potential therapeutic target in moyamoya disease.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal clinical subtype and lacks effective targeted therapies at present. Isobavachalcone (IBC), the main active component of Psoralea corylifolia L., has potential anticancer effects. Herein, we identified IBC as a natural sirtuin 2 (SIRT2) inhibitor and characterized the potential mechanisms underlying the inhibition of TNBC. Molecular dynamics analysis, enzyme activity assay, and cellular thermal shift assay were performed to evaluate the combination of IBC and SIRT2. The therapeutic effects, mechanism, and safety of IBC were analyzed in vitro and in vivo using cellular and xenograft models. IBC effectively inhibited SIRT2 enzyme activity with an IC50 value of 0.84 ± 0.22 μM by forming hydrogen bonds with VAL233 and ALA135 within its catalytic domain. In the cellular environment, IBC bound to and stabilized SIRT2, consequently inhibiting cellular proliferation and migration, and inducing apoptosis and cell cycle arrest by disrupting the SIRT2/α-tubulin interaction and inhibiting the downstream Snail/MMP and STAT3/c-Myc pathways. In the in vivo model, 30 mg/kg IBC markedly inhibited tumor growth by targeting the SIRT2/α-tubulin interaction. Furthermore, IBC exerted its effects by inducing apoptosis in tumor tissues and was well-tolerated. IBC alleviated TNBC by targeting SIRT2 and triggering the reactive oxygen species ROS/β-catenin/CDK2 axis. It is a promising natural lead compound for future development of SIRT2-targeting drugs.

BACKGROUND:Analyzing distance-dependent functional connectivity density (FCD) yields valuable insights into patterns of brain activity. Nevertheless, whether alterations of FCD in non-acute stroke patients are associated with the anatomical distance between brain regions remains unclear. This study aimed to explore the distance-related functional reorganization in non-acute stroke patients following left and right hemisphere subcortical lesions, and its relationship with clinical assessments. METHODS:In this study, we used resting-state fMRI to calculate distance-dependent (i.e., short- and long-range) FCD in 25 left subcortical stroke (LSS) patients, 22 right subcortical stroke (RSS) patients, and 39 well-matched healthy controls (HCs). Then, we compared FCD differences among the three groups and assessed the correlation between FCD alterations and paralyzed motor function using linear regression analysis. RESULTS:Our findings demonstrated that the left inferior frontal gyrus displayed distance-independent FCD changes, while the bilateral supplementary motor area, cerebellum, and left middle occipital gyrus exhibited distance-dependent FCD alterations in two patient subgroups compared with HCs. Furthermore, we observed a positive correlation between increased FCD in the bilateral supplementary motor area and the motor function of lower limbs, and a negative correlation between increased FCD in the left inferior frontal gyrus and the motor function of both upper and lower limbs across all stroke patients. These associations were validated by using a longitudinal dataset. CONCLUSIONS:The FCD in the cerebral and cerebellar cortices shows distance-related changes in non-acute stroke patients with motor dysfunction, which may serve as potential biomarkers for predicting motor outcomes after stroke. These findings enhance our comprehension of the neurobiological mechanisms driving non-acute stroke. TRIAL REGISTRATION:All data used in the present study were obtained from a research trial registered with the ClinicalTrials.gov database (NCT05648552, registered 05 December 2022, starting from 01 January 2022).

BACKGROUND:New targeted drugs about angiogenesis could develop the treatment of glioma. We aimed to explore the role of phosducin like 3 (PDCL3) in angiogenesis of glioma. MATERIALS AND METHODS:RNA sequencing data and matched clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. To screen for the reliable genes with the filtering analyses, survival, multivariate Cox, receiver operating characteristic (ROC) curve filtration, and clinical correlation analyses were performed. The PDCL3 gene was validated by immunohistochemistry as a reliable gene for further analysis. Then we used the combined data of TCGA and Genotype-Tissue Expression from UCSC to detect the differential gene expression of PDCL3. Related signal pathways in glioma were explored by the gene set enrichment analysis and co-expression analysis. Lastly, we performed in vitro experiments to verify the gene functions and related mechanisms. RESULTS:The three filtering analyses and immunostaining indicated that the expression of PDCL3 in glioma tissues was higher than the normal tissues. Gene function analysis showed that PDCL3 activated the vascular endothelial growth factor (VEGF) signal pathway, and its mechanism was related to pathways in cancer, like NOD like receptor signaling pathway, the RIG-I like receptor signaling pathway and the P53 signaling pathway by MAPK/AKT in gliomas. This suggested that the proliferation, migration and invasion of glioma cells might be inhibited by the downregulation of PDCL3 in vitro, which may be related to the activation of VEGF signaling pathway. CONCLUSION:We demonstrated that PDCL3 could function as an independent adverse prognostic marker in glioma. Its pro-oncogenic mechanism may be related to the VEGF signaling pathway.

According to the limited molecular information reflected by single spectroscopy, and the complementarity of FTIR spectroscopy and Raman spectroscopy, we propose a novel diagnostic technology combining multispectral fusion and deep learning. We used serum samples from 45 healthy controls, 44 non-small cell lung cancer (NSCLC), 38 glioma and 37 esophageal cancer patients, and the Raman spectra and FTIR spectra were collected respectively. Then we performed low-level fusion and feature fusion on the spectral, and used SVM, Convolutional Neural Network-Long-Short Term Memory (CNN-LSTM) and the multi-scale convolutional fusion neural network (MFCNN). The accuracy of low-level fusion and feature fusion models are improved by about 10% compared with single spectral models.

Objective: This study aimed to identify immune infiltration characteristics and new immunological diagnostic biomarkers in the cerebrovascular tissue of moyamoya disease (MMD) using bioinformatics analysis.Methods: GSE189993 and GSE141022 were downloaded from the GEO database. Differentially expressed gene and PPI analysis were performed. After performing WGCNA, the most significant module associated with MMD was obtained. Next, functional pathways according to GSEA, GO, and KEGG were enriched for the aforementioned core genes obtained from PPI and WGCNA. Additionally, immune infiltration, using the CIBERSORT deconvolution algorithm, immune-related biomarkers, and the relationship between these genes, was further explored. Finally, diagnostic accuracy was verified with ROC curves in the validation dataset GSE157628.Results: A total of 348 DEGs were screened, including 89 downregulated and 259 upregulated genes. The thistlel module was detected as the most significant module associated with MMD. Functional analysis of the core genes was chiefly involved in the immune response, immune system process, protein tyrosine kinase activity, secretory granule, and so on. Among 13 immune-related overlapping genes, 4 genes (BTK, FGR, PTPN11, and SYK) were identified as potential diagnostic biomarkers, where PTPN11 showed the highest specificity and sensitivity. Meanwhile, a higher proportion of eosinophils, not T cells or B cells, was demonstrated in the specific immune infiltration landscape of MMD.Conclusion: Immune activities and immune cells were actively involved in the progression of MMD. BTK, FGR, PTPN11, and SYK were identified as potential immune diagnostic biomarkers. These immune-related genes and cells may provide novel insights for immunotherapy in the future.

Background: It is unclear which cortical regions are specific to or commonly associated with the impairments of the upper/lower limbs and the activities of daily life (ADL) in stroke patients. Purpose: To investigate the relationships between MRI-assessed surface-based morphometry (SBM) features and motor function as well as ADL in participants with chronic stroke. Study Type: Prospective. Subjects: Thirty-five participants with subcortical stroke more than 3 months from the first-onset (age: 56.44 +/- 9.56 years; 32 male). Field Strength/Sequence: T-1-weighted images, 3.0 T, three-dimensional fast field-echo sequence. Assessment: FreeSurfer (6.0) was used to parcellate each hemisphere into 34 regions based on the Desikan-Killiany atlas and to extract the surface area, volume, thickness, and curvature. The motor function and ADL were assessed by the Fugl-Meyer Assessment for the Upper/Lower Extremity (FMA-UE/FMA-LE) and the Chinese version of the Modified Barthel Index (MBI-C), respectively. Statistical Tests: A linear mixed-effect model was applied to evaluate the relationship between the morphological features and the FMA-UE, FMA-LE, and MBI-C. A false discovery rate corrected P value < 0.05 was considered statistically significant. Results: Correlations between the size of stroke lesion and MRI measurements did not pass the FDR correction (adjusted P > 0.05). SBM features in motor-related and high-order cognitive cortical regions showed significant correlations with FMA-UE and FMA-LE, respectively. Moreover, the thickness in the prefrontal cortex significantly positively correlated, while the surface area in the right supramarginal gyrus significantly negatively correlated, with both FMA-UE, FMA-LE, and MBI-C. The thickness in the left frontal lobe significantly positively correlated with both FMA-UE and MBI-C. Data Conclusion: This study's findings suggest that different hemiparetic motor-related outcomes in participants with subcortical stroke which suffered a corticospinal tract-related injury show specific, but also share common, associations with several cortical regions.

Introduction: Gliomas, the most prevalent tumors of the central nervous system, are known for their aggressive nature and poor prognosis. The heterogeneity among gliomas leads to varying responses to the same treatments, even among similar glioma types. In our study, we efferocytosis-related subtypes and explored their characteristics in terms of immune landscape, intercellular communication, and metabolic processes, ultimately elucidating their potential clinical implications.Methods and Results: We first identified efferocytosis-related subtypes in Bulk RNA-seq using the NMF algorithm. We then preliminarily demonstrated the correlation of these subtypes with efferocytosis by examining enrichment scores of cell death pathways, macrophage infiltration, and the expression of immune ligands. Our analysis of single-cell RNA-seq data further supported the association of these subtypes with efferocytosis. Through enrichment analysis, we found that efferocytosis-related subtypes differ from other types of gliomas in terms of immune landscape, intercellular communication, and substance metabolism. Moreover, we found that the efferocytosis-related classification is a prognostic factor with robust predictive performance by calculating the AUC values. We also found that efferocytosis-related subtypes, when compared with other gliomas in drug sensitivity, survival, and TIDE scores, show a clear link to the effectiveness of chemotherapy, radiotherapy, and immunotherapy in glioma patients.Discussion: We identified efferocytosis-related subtypes in gliomas by analyzing the expression of 137 efferocytosis-associated genes, exploring their characteristics in immune landscape, intercellular communication, metabolic processes, and genomic variations. Moreover, we discovered that the classification of efferocytosis-related subtypes has a strong prognostic predictive power and holds potential significance in guiding clinical treatment.

Background:Tetramethylpyrazine (TMP), a potent anti-free radical and anti-inflammations substance, has been demonstrated to possess a direct vessel relaxation property. This study aimed to evaluate the effect of TMP treatment in pulmonary hypertension (PH) and test the hypothesis that TMP prevents or reverses the process of PH.Methods:Rats (n = 36) injected with 50 mg/kg of monocrotaline (MCT) subcutaneously 4 weeks to develop PH were then randomized to TMP (5 mg/kg per day) for another 4 weeks. Hemodynamics was evaluated via the right ventricle. Pulmonary vessels structural remodeling and inflammation were examined by histologic and transmission electron microscopy observation. The expression of inducible nitric oxide synthase (iNOS) and cGMP-dependent protein kinases 1 (PKG-1) was detected by immunohistochemical staining and Western blot. Generation of reactive oxygen species (ROS) and antioxidation species was measured by biochemical analyses.Results:MCT increased PH and right ventricle hypertrophy. TMP alleviated pulmonary arterial pressure elevation, leukocyte infiltration, and structural remodeling of pulmonary arterials induced by MCT successfully. TMP treatment significantly increased the PKG-1 expression and suppressed the iNOS expression. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT) was significantly higher than control group, while malondialdehyde (MDA) levels were lower compared with MCT group.Conclusion:TMP can suppress established MCT-induced PH through the ROS/iNOS/PKG axis. The underlying mechanisms may be associated with its anti-inflammatory, antioxidant, and antiproliferative properties in pulmonary arterial.

For more than 20 years, researchers have isolated and identified postnatal dental pulp stem cells (DPSCs) from different teeth, including natal teeth, exfoliated deciduous teeth, healthy teeth, and diseased teeth. Their mesenchymal stem cell (MSC)-like immunophenotypic characteristics, high proliferation rate, potential for multidirectional differentiation and biological features were demonstrated to be superior to those of bone marrow MSCs. In addition, several main application forms of DPSCs and their derivatives have been investigated, including stem cell injections, modified stem cells, stem cell sheets and stem cell spheroids. In vitro and in vivo administration of DPSCs and their derivatives exhibited beneficial effects in various disease models of different tissues and organs. Therefore, DPSCs and their derivatives are regarded as excellent candidates for stem cell-based tissue regeneration. In this review, we aim to provide an overview of the potential application of DPSCs and their derivatives in the field of regenerative medicine. We describe the similarities and differences of DPSCs isolated from donors of different ages and health conditions. The methodologies for therapeutic administration of DPSCs and their derivatives are introduced, including single injections and the transplantation of the cells with a support, as cell sheets, or as cell spheroids. We also summarize the underlying mechanisms of the regenerative potential of DPSCs.

Introduction Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin. Areas covered Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins. Expert opinion The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms.

Objective To assess the effect of adding coagulation indices to the currently existing prognostic prediction models of traumatic brain injury (TBI) in the prediction of outcome. Methods A total of 210 TBI patients from 2017 to 2019 and 131 TBI patients in 2020 were selected for development and internal verification of the new model. The primary outcomes include death at 14 days and Glasgow Outcome Score (GOS) at 6 months. The performance of each model is evaluated by means of discrimination (area under the curve (AUC)), calibration (Hosmer-Lemeshow (H-L) goodness-of-fit test), and precision (Brier score). Results The IMPACT Core model showed better prediction ability than the CRASH Basic model. Adding one coagulation index at a time to the IMPACT Core model, the new combined models IMPACT Core+FIB and IMPACT Core+APTT are optimal for the 6-month unfavorable outcome and 6-month mortality, respectively (AUC, 0.830 and 0.878). The new models were built based on the regression coefficients of the models. Internal verification indicated that for the prediction of 6-month unfavorable outcome and 6-month mortality, both the IMPACT Core+FIB model and the IMPACT Core+APTT model show better discrimination (AUC, 0.823 vs. 0.818 and 0.853 vs. 0.837), better calibration (HL, p = 0.114 and p = 0.317) and higher precision (Brier score, 0.148 vs. 0.141 and 0.147 vs. 0.164), respectively, than the original models. Conclusion Our research shows that the combination of the traumatic brain injury prognostic models and coagulation indices can improve the 6-month outcome prediction of patients with TBI.

Background: Venous thrombosis (VTE) is a common adverse event among inpatients, which can cause pulmonary embolism, and greatly increases mortality. The effects of rivaroxaban in patients undergoing brain glioma surgery have still not been explored. This single-center study of 94 patients undergoing surgery for cerebral glioma aimed to compare postoperative thromboprophylaxis with and without rivaroxaban. Material/Methods: We designed a randomized, controlled, double-blind study to evaluate the effect of rivaroxaban on 94 patients undergoing brain glioma surgery. These patients were divided into a rivaroxaban group (administered at 10 mg per day from admission to discharge) and a placebo group. The primary study endpoint was incidence of VTE at discharge. The secondary endpoints included safety outcomes of major bleeding, allergy, or VTE-related death. Results: A total of 94 patients were enrolled in the study: 47 in the rivaroxaban group and 47 in the placebo group. Baseline characteristics of participants were well-matched in both groups. A significant reduction was found in the incidence of VTE in the rivaroxaban treatment group versus the placebo group (1/47 vs 10/47 patients, P=0.008). The rate of major bleeding events was quite low in both group (1/47 vs 1/47 patients). One patient in the placebo group died due to a pulmonary embolism and intractable concomitant underlying diseases. Conclusions: Our results indicate that treatment with rivaroxaban is a safe and effective thromboprophylaxis treatment in patients undergoing surgery for malignant cerebral glioma.

We aimed to examine whether prognostic nutritional index (PNI) could serve as an auxiliary predictor for major cardiovascular events (MCEs) in patients undergoing invasive coronary angiography (ICA). A total of 485 participants were enrolled, divided into low-PNI (≥47.40) and high-PNI (<47.40) groups. ICA determined the stenotic vessels of coronary artery disease. The primary outcome was incidental MCEs, a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or rehospitalization of in-stent restenosis. There were 47 (9.69%) MCEs during the 3.78-years follow-up. The cumulative incidence of MCEs was significantly higher in the low-PNI patients compared with the high-PNI patients (17.07% vs. 7.18%, p = 0.001). Malnutrition risk (low PNI) was significantly and independently associated with a higher risk of MCEs (hazard ratios: 2.593, 95% confidence intervals [CI]: 1.418–4.742). Combined use of the number of stenotic vessels with malnutrition risk showed a higher capacity to predict the MCEs than the presence of stenotic vessels alone (areas under the receiver operator characteristic curve: 0.696 [95% CI, 0.618–0.775] vs. 0.550 [95% CI, 0.466–0.633], p = 0.013). In conclusion, lower PNI levels may predict a higher risk of cardiovascular events in patients undergoing ICA, which supports the necessity of the risk assessment of nutrition status and guide the clinical treatment on strengthening nutritional support before ICA is performed, as well as nutritional intervention after ICA.

Cervical cancer is a malignant tumor that threatens women's health and life.Cervical pathology examination, as the gold standard for cervical cancer diagnosis, provides an important basis for the surgical plan and postoperative follow-up strategy for cervical cancer.Cervical biopsy diagnosis includes normal, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC).At present, cervical pathology examination still relies on the doctor's personal clinical experience and subjective judgment, which is time-consuming and may cause misdiagnosis or missed diagnosis.In addition, the current intelligent classification of cervical pathological images still has disadvantages such as imperfect classification system and low classification accuracy.Therefore, this experiment uses the ResNet50 model of the convolutional neural network as the feature extractor, and selects the K-Nearest Neighbour (KNN), Random Forest (RF), Support Vector Machine (SVM) classifiers in Machine Learning to perform cervical tissue pathological images Discrimination, the accuracy of the classification results were 85.83%, 80.33%, and 86.67%.In order to further improve the accuracy of the model and enhance the applicability and stability of the model, this experiment proposes the Stacked Generalization (SK) classification model.The first-layer base learner of the SK classification model selects CNN-KNN, CNN-RF, CNN-SVM, and the second-layer classifier selects Multilayer Perceptron (MLP).Among them, MLP makes the final result by learning the classification performance of the base learner for label discrimination, the accuracy of the classification model after ensemble learning is 90.00%.In addition, this experiment uses the Synthetic Minority Oversampling Technique (SMOTE) algorithm to amplify the training samples, and the amplified data set has a classification accuracy of 89.17% under the training of the SK classification model.The results show that the SK classification model in this experiment has a high classification ability for cervical histopathological images, and has good generalization ability and robustness.

It has been widely reported that exosomes derived from mesenchymal stem cells (MSCs) have a protective effect on myocardial infarction (MI). However, the specific molecules which play a damaging role in MSCs shuttled miRNAs are much less explored. MiRNA-153-3p (miR-153-3p) is a vital miRNA which has been proved to modulate cell proliferation, apoptosis, angiogenesis, peritoneal fibrosis and aortic calcification. Here, we aim to study the effect and mechanism of miR-153-3p in MSC-derived exosomes on hypoxia-induced myocardial and microvascular damage. The exosomes of MSCs were isolated and identified, and the MSCs-exosomes with low expression of miR-153-3p (exo-miR-153-3p(-)) were constructed to interfere with the endothelial cells and cardiomyocytes in the oxygen-glucose deprivation (OGD) model. The viability, apoptosis, angiogenesis of endothelial cells and cardiomyocytes were determined. Additionally, ANGPT1/VEGF/VEGFR2/PI3K/Akt/eNOS pathway was detected by ELISA and/or western blot. The results illustrated that exo-miR-153-3p(-) significantly reduced the apoptosis of endothelial cells and cardiomyocytes and promoted their viability. Meanwhile, exomiR-153-3p(-) can promote the angiogenesis of endothelial cells. Mechanistically, miR-153-3p regulates the VEGF/VEGFR2/PI3K/Akt/eNOS pathways by targeting ANGPT1. Intervention with VEGFR2 inhibitor (SU1498, 1 mu M) remarkably reversed the protective effect of exo-miR-153-3p(-) in vascular endothelial cells and cardiomyocytes treated by OGD. Collectively, MSCs-derived exosomes with low-expressed miR-153-3p notably promotes the activation of ANGPT1 and the VEGF/VEGFR2 /PI3K/Akt/eNOS pathways, thereby preventing the damages endothelial cells and cardiomyocytes against hypoxia.

Background Ischemic stroke is a serious cardiovascular disease with high morbidity and mortality rates that affects millions of people worldwide.Currently, the only therapy with proven efficacy for acute ischemic stroke is alteplase, however, it still has many shortcomings and limitations. Therefore,we screen new compounds from traditional Chinese medicine to explore their efficacy against ischemic reperfusion injury. Procyanidins, a natural productextracted from grapes seed, which have been shown can ameliorate cerebral ischemic injury. However, the underlying mechanism is still not very clear. Theaim of this study was to investigate the effect of procyanidins on middle cerebral artery occlusion/reperfusion (MCAO/R)-mediated cerebral ischemic injuryand its underlying possible mechanisms. Methods SD rats were used to evaluate the effect of procyanidins on MCAO/R induced cerebral ischemic injury in vivo. Histological analysis was used toassess neuronal apoptosis. Cell signaling was assayed by Western blot. Results In this study, we found that procyanidins can significantly ameliorate the middle cerebral artery occlusion/reperfusion (MCAO/R)-mediatedneurological deficits, and relieved brain edema, cerebral infarction volume, histopathological damage and apoptosis in rats. In addition, procyanidins canalso markedly inhibit MCAO/R and oxygen-glucose deprivation/reoxygenation (OGD/R)-mediated activation of TLR4-p38-NF-κB-NLRP3 signalingpathway in vitro and in vivo. Moreover, procyanidins can inhibit MCAO/R and OGD/R-induced the production of inflammatory cytokines such asinterleukin-1β (IL-1β) in vitro and in vivo. Besides, treatment with TLR4 inhibitor (Cli-095) in BV2 cell also shows the same effect. Conclusion Altogether, these data suggested that procyanidins exerted a potential neuroprotective effect may by inhibit the TLR4-p38-NF-κB-NLRP3signaling pathway in the brain in MCAO/R rats.