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Si-Yu Chen,1,* Xiang-Quan Kong,1,2,* Ke-Fan Zhang,3,* Shuai Luo,1 Feng Wang,1 Jun-Jie Zhang1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Cardiology, Nanjing Heart Centre, Nanjing, People’s Republic of China; 3Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun-Jie Zhang, Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, People’s Republic of China, Tel/Fax +86-25-52208048, Email jameszll@163.comAbstract: The rising prevalence of cardiovascular disease has become a global health concern. The occurrence of cardiovascular disease is the result of long-term interaction of many risk factors, one of which is diabetes. As a novel anti-diabetic drug, DPP4 inhibitor has been proven to be cardiovascular safe in five recently completed cardiovascular outcome trials. Accumulating studies suggest that DPP4 inhibitor has potential benefits in a variety of cardiovascular diseases, including hypertension, calcified aortic valve disease, coronary atherosclerosis, and heart failure. On the one hand, in addition to improving blood glucose control, DPP4 inhibitor is involved in controlling cardiovascular risk factors. On the other hand, DPP4 inhibitor directly regulates the occurrence and progression of cardiovascular diseases through a variety of mechanisms. In this review, we summarize the recent advances of DPP4 in cardiovascular disease, aiming to discuss DPP4 inhibitor as a potential option for cardiovascular therapy.Keywords: DPP4, DDP4 inhibitor, GLP-1, inflammation, cardiovascular disease

Xiangquan Kong,* Xueqing Zhang,* Yunxia Huang, Lirui Tang, Qingqin Peng, Jinluan Li Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China *These authors contributed equally to this work. Background: Colorectal signet ring cell (SRC) carcinoma occurs rarely with a poor prognosis. The present study assessed the prognostic factors and predictive value of SRC ratio in colorectal mucinous adenocarcinoma (MAC) with SRCs (MAC-SRC).Patients and methods: A total of 95 consecutive colorectal MAC-SRC patients, confirmed pathologically from February 1987 to December 2015, were analyzed retrospectively in our institute. Clinical characteristics, pathological grade, TNM staging, and SRC ratio were assessed to identify the prognostic factors related to progression-free survival (PFS) and overall survival (OS). SPSS 22.0 was used for statistical analyses.Results: The median follow-up time was 29.7 months (range 0.8–165). Meanwhile, 5-year PFS and OS rates were 25.6% (95% confidence interval [CI] 16.192–35.008%) and 40.5% (95% CI 29.524–51.476%), respectively. Among the 81 patients who underwent surgery, 78 (96.3%) were diagnosed as stage T3 or T4; 74 (91.4%) showed lymph node involvement, and 27 (29.3%) presented distant metastasis. Metastases of the peritoneal cavity and ovaries were observed commonly in colorectal MAC-SRC. In the multivariate Cox regression model, SRC ratio ≥35%, absence of preoperative radiotherapy, and distant metastasis were independent predictors of PFS. Furthermore, SRC ratio ≥35%, absence of preoperative chemotherapy (pre-CT), and distant metastasis were independent risk factors for poor prognosis.Conclusion: A long-term follow-up of colorectal MAC-SRC reveals that it is a rare subtype of colorectal MAC with a dismal prognosis. Furthermore, SRC ratio, pre-CT, and M stage seem to affect OS independently. Keywords: colorectal mucinous adenocarcinoma, signet ring cell, progression-free survival, overall survival, prognostic factors

Jianqi Feng,1,2 Xiangqing Kong,1 Yanhui Sheng,1 Rong Yang1 1Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 2Department of Cardiology, the Second Affiliated Hospital of XuZhou Medical University, XuZhou, Jiangsu, People’s Republic of China Objectives: To observe the change in pulmonary artery systolic pressure (PASP) of patients with persistent pulmonary arterial hypertension (PAH) after patent ductus arteriosus (PDA) occlusion.Background: After occlusion of PDA in patients with PAH, some patients still tend to suffer from persistent PAH.Methods: A chest X-ray, an electrocardiogram, and an echocardiogram were performed on nine patients at 24 hours, 1 and 6 months, and 1 year serially.Results: There was a significant fall (P0.05). During the follow up, there was a further fall in the PASP in five patients (No 1, 5, 6, 7, and 8). Four patients (No 2, 3, 4, and 8) showed the evidence of worsening PAH and were treated with sildenafil. Patient 2 died from acute right heart failure after a period of 11 months from the time of transcatheter closure, triggered by pulmonary infection.Conclusion: Some patients with borderline hemodynamic data with PDA and PAH can deteriorate or keep sustained PAH after PDA closure. The treatment of permanent closure to these patients must be cautious. Keywords: patent ductus arteriosus (PDA), transcatheter closure (TCC), pulmonary artery hypertension, follow-up

Aims: This study aims to ascertain whether abdominal fat accumulation evaluated by waist circumference increases the risk of hypertension using the nationwide population., Methods: We enrolled 47,037 participants from the China Health and Nutrition Survey (CHNS), China Health and Retirement Longitudinal Study (CHARLS), and National Health, and Nutrition Examination Survey (NHANES). The adjusted logistic regression model was used to examine the relationship between waist circumference and prevalent hypertension. 9445 participants without baseline hypertension from the CHNS and CHARLS were followed up to investigate the association between waist circumference and onset hypertension. The association was evaluated using a Cox regression model and restricted cubic spline. Furthermore, Mendelian randomization was employed to explore causal inferences., Results: In the baseline survey, waist circumference demonstrated a notable correlation with hypertension, presenting an odds ratio (with 95% confidence intervals) of 1.34 (1.28 ~ 1.40). After a mean follow-up of 3.8 years for participants without baseline hypertension, 2,592 (27.5%) developed hypertension. In the pooled analysis, the Cox regression showed that every 10 cm increase in waist circumference was associated with 20% (95% CI: 13% ~ 27%) elevated risk of new-onset hypertension. Restricted cubic splines indicated a pronounced linear dose-response relationship. A subgroup analysis affirmed the persisting association between waist circumference and hypertension onset even in those with normal BMI. The Mendelian randomization method revealed a significant causative association between waist circumference and hypertension., Conclusion: Elevated waist circumference stands as an independent risk factor for hypertension, even in those with normal BMI. Our results provide evidence supporting the routine measure for waist circumference., Competing Interests: Declarations. Ethics approval and consent to participate: The China Health and Nutrition Survey was approved by the institutional review committees of the University of North Carolina at Chapel Hill and National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention. The China Health and Retirement Longitudinal Study was approved by the Ethics Review Committee of Peking University. National Health and Nutrition Examination Survey was approved by the National Center for Health Statistics Research Ethics Review Board. Written informed consent was obtained from all participants. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia., Methods: Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia., Results: Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1 SMC-IKO (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1 SMC-IKO mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N 6 -methyladenosine methyltransferase) and YTHDF3 (YTH N6-methyladenosine RNA binding protein F3; N 6 -methyladenosine-specific reader) enhance PFN1 translation efficiency in an N 6 -methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src (SRC proto-oncogene, nonreceptor tyrosine kinase), promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), a typical transcription factor known to induce VSMC phenotype switching., Conclusions: This study unveils the significance of PFN1 N 6 -methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway., Competing Interests: None.

Aims: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) for the treatment of aortic regurgitation (AR)., Methods: From September 2019 to February 2022, 62 patients who underwent transfemoral TAVI procedure for pure, symptomatic severe AR with the VitaFlow system were enrolled in the current study. The outcomes were assessed according to the Valve Academic Research Consortium 3 criteria. Procedural results and clinical outcomes for 1 year were analyzed., Results: The mean age was 71.56 ± 7.34 years and 58.1% were male. The mean Society of Thoracic Surgeons score was 5.44 ± 3.22%. The device success rate was 79.0%. Only one patient was converted to open surgery. The in-hospital mortality rate was 1.6%. The 1-year all-cause mortality rate was 6.5%. The new permanent pacemaker implantation rate was 29.0% in-hospital and 30.7% at 1-year follow-up. The second valve implantation rate was 14.5%. No patient developed more than moderate paravalvular leakage during follow-up. The mean ejection fraction improved from 54.05 ± 10.83% at baseline to 59.32 ± 8.70% (p < 0.001 compared with baseline) at 12 months. Left ventricular end-diastolic diameter decreased from 61.62 ± 5.58 mm at baseline to 55.20 ± 4.51 mm (p < 0.001 compared with the baseline) at 12 months., Conclusions: Transfemoral TAVI procedure shows efficacy in treating patients with severe pure native AR. The safety is improved with the development of the VitaFlow system., (© 2024 Wiley Periodicals LLC.)

Objective: To compare the prognostic values of different classification by using transpulmonary pressure gradient (TPG), diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) in patients with pulmonary hypertension due to left heart disease (PH-LHD), and investigated hemodynamic and clinical factors associated with mortality in patients with PH-LHD. Methods: This was a single-center prospective cohort study. In-hospital patients diagnosed with PH-LHD via right heart catheterization at the Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, from September 2013 to December 2019 were enrolled. Patients were divided according to TPG (cutoff value 12 mmHg; 1 mmHg=0.133 kPa), DPG (cutoff value 7 mmHg), PVR (cutoff value 3 Wood Units), and the combination of TPG and PVR. Baseline characteristic was recorded. All patients were followed up until the occurrence of endpoint event, defined as all-cause death that occurred during the follow-up period, or until April 18, 2022. Receiver operating characteristic curves were used to compare the predictive value of 3 classification methods for all-cause death in PH-LHD patients. The optimal cutoff values were calculated using Jorden index. Survival analysis was performed using Kaplan-Meier analysis, and log-rank test was used to compare the predictive efficacy of classification methods based on optimal cutoff values or guidance-recommended thresholds for the survival of PH-LHD patients. Variables showing statistical significance in the univariate analysis were incorporated into multivariate Cox regression model to analyze the independent risk factors for all-cause mortality. Results: A total of 243 patients were enrolled, aged (54.9±12.7) years old, including 169 (69.5%) males. During a median follow-up of 57 months, there were 101 (41.6%) deaths occurred. Grouping results were as follows: (1) TPG: TPG≤12 mmHg group 115 patients, TPG>12 mmHg group 128 patients; (2) DPG: DPG<7 mmHg group 193 patients, DPG≥7 mmHg group 50 patients; (3) PVR: PVR≤3 Wood Units group 108 patients, PVR>3 Wood Units group 135 patients; (4) TPG and PVR: TPG≤12 mmHg and PVR≤3 Wood Units group 89 patients, TPG>12 mmHg and PVR>3 Wood Units group 109 patients. PVR ( AUC =0. 698,95% CI :0.631-0.766) had better predictive value for all-cause mortality than TPG ( AUC =0.596, 95% CI : 0.523-0.669) and DPG ( AUC =0.526, 95% CI : 0.452-0.601) (all P <0.05). The optimal cutoff values for TPG, DPG, and PVR were13.9 mmHg, 2.8 mmHg, and 3.8 Wood Units, respectively. Kaplan-Meier analysis based on the optimal cutoff values or guidance-recommended thresholds showed that PVR and TPG were the predictors of survival ( P <0.05), while DPG did not showed significance ( P >0.05). Multivariate Cox regression analysis showed that age, PVR and log 2 N-terminal pro-B-type natriuretic peptide were independent risk factors for all-cause mortality in PH-LHD patients (all P <0.05). Conclusion: Classification according to PVR was most valuable in predicting all-cause death in PH-LHD patients, while TPG showed moderate predictive ability and DPG had no predictive value.

Background: We explore the association between leucocyte telomere length (LTL) and all-cause and cardiovascular disease (CVD)-specific death in CVD patients., Methods: We acquired 1599 CVD patients from a nationally representative US population survey for this study. We applied Kaplan-Meier curves, adjusted weighted Cox regression models, and restricted cubic spline to investigate the association between LTL and all-cause death. Additionally, we employed competing risk regression to assess the impact of LTL on cardiovascular-specific death, setting non-cardiovascular death as a competing event., Results: The overall mortality rate was 31.0% after a median follow-up of 13.9 years. Patients with shorter LTL exhibited a higher risk of all-cause death, with an adjusted hazard ratio (HR) of 1.25 (95% confidence interval (CI): 1.05-1.48). Restricted cubic spline illustrated a linear dose-response relationship. In gender-specific analyses, female patients with shorter LTL showed a higher risk of death (weighted HR, 1.79; 95% CI, 1.29-2.48), whereas this association was not observed in males (weighted HR, 0.90; 95% CI, 0.61-1.32). The Fine-Gray competing risk model revealed no significant relationship between LTL and cardiovascular-specific mortality but a significant association with non-cardiovascular death (adjusted HR, 1.24; 95% CI, 1.02-1.51)., Conclusions: LTL is inversely associated with all-cause death in female CVD patients. The significant correlation between reduced LTL and increased all-cause mortality emphasizes LTL as a potential marker for tertiary prevention against cardiovascular disease., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Background: Drug-coated balloon (DCB) angioplasty seems a safe and effective option for specific de novo coronary lesions. However, the beneficial effect of intravascular ultrasound (IVUS)-guided DCB angioplasty in de novo lesions remains uncertain., Objectives: This study aimed to assess the benefits of IVUS guidance over angiography guidance during DCB angioplasty in de novo coronary lesions., Methods: A total of 260 patients with high bleeding risk who had a de novo coronary lesion (reference vessel diameter 2.0-4.0 mm, and lesion length ≤15 mm) were randomly assigned to either an IVUS-guided or an angioplasty-guided DCB angioplasty group. The primary endpoint was in-segment late lumen loss (LLL) at 7 months after procedure. The secondary endpoint was target vessel failure at 6 months., Results: A total of 2 patients in the angiography-guided group and 7 patients in the IVUS-guided group underwent bailout stent implantation (P = 0.172). The primary endpoint of 7-month LLL was 0.03 ± 0.52 mm with angiography guidance vs -0.10 ± 0.34 mm with IVUS guidance (mean difference 0.14 mm; 95% CI: 0.02-0.26; P = 0.025). IVUS guidance was also associated with a larger 7-month minimal lumen diameter (2.06 ± 0.62 mm vs 1.75 ± 0.63 mm; P < 0.001) and a smaller diameter stenosis (28.15% ± 13.88% vs 35.83% ± 17.69%; P = 0.001) compared with angiography guidance. Five target vessel failures occurred at 6 months, with 4 (3.1%) in the angiography-guided group and 1 (0.8%) in the IVUS-guided group (P = 0.370)., Conclusions: This study demonstrated that IVUS-guided DCB angioplasty is associated with a lower LLL in patients with a de novo coronary lesion compared with angiography guidance. (Intravascular Ultrasound Versus Angiography Guided Drug-Coated Balloon [ULTIMATE-III]; NCT04255043)., Competing Interests: Funding Support and Author Disclosures This study was supported by the National Natural Science Foundation of China (NSFC 81970307, NSFC 82100357, NSFC 82270344, and NSFC 82200385), and was jointly supported by Jiangsu Natural Science Foundation (BK20221173), Six Talent Peaks Project of Jiangsu Province (2019-WSN-156), Jiangsu Health Committee (H2019077), and Nanjing Health Committee (JQX22007 and ZKX23030), and Social development project of Jiangsu province (BE2019615). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine., Methods and Results: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming., Conclusions: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Calcified aortic stenosis (AS) is one of the most common valvular heart diseases worldwide, characterized by progressive fibrocalcific remodeling and thickening of the leaflets, which ultimately leads to obstruction of blood flow. Its pathobiology is an active and complicated process, involving endothelial cell dysfunction, lipoprotein deposition and oxidation, chronic inflammation, phenotypic transformation of valve interstitial cells, neovascularization, and intravalvular hemorrhage. To date, no targeted drug has been proven to slow down or prevent disease progression. Aortic valve replacement is still the optimal treatment of AS. This article reviews the etiology, diagnosis, and management of calcified aortic stenosis and proposes novel potential therapeutic targets., Competing Interests: Disclosure: All authors have no conflicts of interest to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study aims to conduct a cost-effectiveness analysis of three different anesthesia strategies, namely chatting while under local anesthesia (Chat-LA), total intravenous anesthesia (TIVA), and general anesthesia with laryngeal mask airway (GA-LMA), employed in transperineal magnetic resonance imaging (MRI)/ultrasound (US) fusion prostate biopsy (TP-MUF-PB). A retrospective study was conducted involving 1202 patients who underwent TP-MUF-PB from June 2016 to April 2023 at The First Affiliated Hospital of Soochow University (Suzhou, China). Clinical data and outcomes, including total costs, complications, and quality-adjusted life years (QALYs), were compared. Probability sensitivity and subgroup analyses were also performed. Chat-LA was found to be the most cost-effective option, outperforming both TIVA and GA-LMA. However, subgroup analyses revealed that in younger patients (under 65 years old) and those with smaller prostate volumes (<40 ml), TIVA emerged as a more cost-effective strategy. While Chat-LA may generally be the most cost-effective and safer anesthesia method for TP-MUF-PB, personalization of anesthesia strategies is crucial, considering specific patient demographics such as age and prostate volume., (Copyright © 2024 Copyright: ©The Author(s)(2024).)

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3β signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury., (© 2024. The Author(s).)

Picrachinentins A-F ( 1 - 6 , respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis . Structurally, compounds 1 - 6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the β-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5 ) or hexanoyl (Hexa, 1 , 2 , 4 , and 6 ) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H 2 O 2 -damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H 2 O 2 -induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 μM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Previous studies primarily demonstrated that transfemoral transcatheter aortic valve replacement (TAVR) with self-expanding valve appeared to be a safe and feasible treatment for patients with pure native aortic regurgitation (AR). However, the routine application of transfemoral TAVR for pure AR patients lacks support from randomized trials., Trial Design: SEASON-AR trial is a prospective, multicenter, randomized, controlled, parallel-group, open-label trial, involving at least 20 sites in China, aiming to enroll 210 patients with pure native severe AR and high surgical risk. All enrolled patients are randomly assigned in a 1:1 fashion to undergo transfemoral TAVR with VitaFlow TM valve and receive guideline-directed medical therapy (GDMT) or to receive GDMT alone. The primary endpoint is the rate of major adverse cardiac events (MACE) at 12 months after the procedure, defined by the composite of all-cause mortality, disabling stroke, and rehospitalization for heart failure. The major secondary endpoints encompass various measures, including procedure-related complications, device success, 6-minute walk distance, and the occurrence of each individual component of the primary endpoint. After hospital discharge, follow-up was conducted through clinical visits or telephone contact at 1, 6, and 12 months. The follow-up will continue annually until 5 years after the index procedure to assess the long-term outcomes., Conclusion: SEASON-AR trial is the first study designed to investigate the clinical efficacy and safety of transfemoral TAVR with a self-expanding valve in patients with pure native severe AR with inoperable or high-risk, as compared to medical treatment only., Competing Interests: Conflict of interest There is nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To explore the long-term effects of intravascular ultrasound (IVUS) guidance on patients with acute coronary syndrome (ACS) undergoing drug-eluting stents (DES) implantation. Methods: Data used in this study derived from ULTIMATE trial, which was a prospective, multicenter, randomized study. A total of 1 448 all-comer patients were enrolled between 2014 August and 2017 May. Primary endpoint of this study was target vessel failure (TVF) at 3 years, including cardiac death, target-vessel-related myocardial infarction, and clinically-driven target vessel revascularization. Results: ACS was present in 1 136 (78.5%) patients, and 3-year clinical follow-up was available in 1 423 patients (98.3%). TVF in the ACS group was 9.6% (109/1 136), which was significantly higher than 4.5% (14/312) in the non-ACS group (log-rank P =0.005). There were 109 TVFs in the ACS patients, with 7.6% (43/569) TVFs in the IVUS group and 11.6% (66/567) TVFs in the angiography group (log-rank P =0.019). Moreover, patients with optimal IVUS guidance were associated with a lower risk of 3-year TVF compared to those with suboptimal IVUS results (5.4% (16/296) vs. 9.9% (27/273),log-rank P =0.041). Conclusions: This ULTIMATE-ACS subgroup analysis showed that ACS patients undergoing DES implantation were associated with a higher risk of 3-year TVF. More importantly, the risk of TVF could be significantly decreased through IVUS guidance in patients with ACS, especially in those who had an IVUS-defined optimal procedure.

Twenty-six clerodane diterpenoids have been isolated from T. sagittata, a plant species of traditional Chinese medicine Radix Tinosporae, also named as "Jin Guo Lan". Among them, there are eight previously undescribed clerodane diterpenoids (tinotanoids A-H: 1-8), and 18 known diterpenoids (9-26). The absolute configurations of compounds 1, 2, 5, 8, 13, 17 and 20 were determined by single-crystal X-ray diffraction. Compound 1 is the first example of rotameric clerodane diterpenoid with a γ-lactone ring which is constructed between C-11 and C-17; meanwhile, compounds 3 and 4 are two pairs of inseparable epimers. Compounds 2, 12 and 17 demonstrated excellent inhibitory activity on NO production against LPS-stimulated BV-2 cells with IC 50 values of 9.56 ± 0.69, 9.11 ± 0.53 and 11.12 ± 0.70 μM, respectively. These activities were significantly higher than that of the positive control minocycline (IC 50  = 23.57 ± 0.92 μM). Moreover, compounds 2, 12 and 17 dramatically reduced the LPS-induced upregulation of iNOS and COX-2 expression. Compounds 2 and 12 significantly inhibited the levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 that were increased by LPS stimulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A total of 17 structurally diverse clerodane diterpenoids, including ten undescribed clerodane diterpenoids (tinopanoids K-T, 1-10) and seven known compounds (11-17), were isolated from the vines and leaves of Tinospora crispa. Compound 3 has not only bear the dominant substituents of γ-hydroxy-α, β-unsaturated-γ-lactone with anti-inflammatory activity, but also a ternary epoxy structure at C-3/C-4. The planar structures and relative configurations of the clerodane diterpenoids were elucidated by spectroscopic data interpretation. The absolute configurations of compounds 1, 4, 8 and 13 were determined by single-crystal X-ray crystallographic, while that of compound 3 was determined using computed ECD data and single crystal X-ray diffraction of related p-bromobenzoate ester (3a). Subsequently, all compounds were evaluated for their inhibitory effect on nitric oxide (NO) production of LPS-activated BV-2 cells, and compounds 3 and 8 exhibited better NO inhibitory potency, with IC 50 values of 5.6 and 13.8 μM than the positive control minocycline (Mino, IC 50  = 22.9 μM). The corresponding results of western blot analysis and qRT-PCR revealed that compound 3 can significantly inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expressions, mRNA levels of pro-inflammatory cytokins of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). The underlying mechanism by which compound 3 exerted anti-neuroinflammatory effects was investigated by western blot and immunofluorescence assay, which suggested compound 3 inhibited LPS induced neuroinflammation via the suppression of toll-like receptor 4 (TLR4) dependent Signal Transducer and Activator of Transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways, and the activation of Heme Oxygenase-1 (HO-1) mediated signals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Interleukin-6 (IL-6) is a multi-effective cytokine involved in multiple immune responses. Whether fibroblasts also turn out to be a cytokine IL-6 factory during interaction with Treponema pallidum is not yet understood. To explore whether fibroblasts participate in inflammation due to syphilis, a series of experiments were performed to explore the role of T. pallidum lipoprotein Tp47 in IL-6 production in human dermal fibroblasts. The Toll-like receptor 2 (TLR2) and participating signalling pathways in this process were also evaluated. The results showed that the expressions of IL-6 and the protein levels of TLR2 in fibroblasts were upregulated after stimulation with Tp47, and this effect was impeded by the TLR2 inhibitor C29. In addition, Tp47 promoted the phosphorylation of p38, PI3K/Akt, and nuclear factor-kappaB (NF-κB), and the translocation of NF-κB in fibroblasts. Moreover, p38, PI3K, and NF-κB inhibitors significantly reduced IL-6 production in fibroblasts stimulated with Tp47. Furthermore, the TLR2 inhibitor C29 inhibited the phosphorylation of p38, Akt, and NF-κB, and the translocation of NF-κB in fibroblasts. In conclusion, our results showed that Tp47 enhanced IL-6 secretion in human dermal fibroblasts through TLR2 via p38, PI3K/Akt, and NF-κB signalling pathways. These findings contribute to our understanding of syphilis inflammation., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: The association between vitamin D levels and atherosclerotic cardiovascular disease (ASCVD) risk remains unclear. In this study, the association between serum 25(OH)D and 10-year ASCVD risk was examined in a national sample of middle-aged and older adults., Methods: Cross-sectional data from the 2009-2014 National Health and Nutrition Examination Survey were analyzed. The Pooled Cohort Equations were used to estimate the risk of a first ASCVD event in 10 years. An adjusted multiple linear regression model was used to investigate the association between serum 25(OH)D and ASCVD risk. In addition, we performed sensitivity analysis and interactive analysis to assess the robustness of associations across different subgroups., Results: A total of 3354 participants were included in this study. The linear regression model indicated that the risk of ASCVD decreased with the increase in serum 25(OH)D. When analyzed as a continuous variable, serum 25(OH)D was significantly associated with the estimated 10-year risk of ASCVD. In the fully adjusted model, each 10-nmol/L increase in serum 25(OH)D reduced the estimated 10-year ASCVD risk by 0.172% ( P < .001). Individuals in the moderate, insufficient, and sufficient vitamin D deficiency groups had a 0.449% ( P = .362), 0.957% ( P = .046), 1.475% ( P = .003) decrease in ASCVD risk, respectively, when a severe vitamin D deficiency group was set as a reference in the fully adjusted model., Conclusion: Our data suggest a negative association between vitamin D levels and the predicted 10-year risk of ASCVD. Further studies are required to investigate whether vitamin D supplements could reduce the risk of ASCVD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Evidence suggests that selenium supplementation could be useful in the treatment of Hashimoto thyroiditis (HT), but the available trials are heterogeneous. This study investigates clinically relevant effects of selenium supplementation in patients with HT., Methods: A systematic search was performed in PubMed, Web of Science, EMBASE, Scopus, and the Cochrane Library. The latest update was performed on December 3, 2022. We investigated the changes in thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb) after selenium supplementation. The effect sizes were expressed as weighted mean difference (WMD) with 95% confidence intervals (CIs)., Results: After screening and full-text assessment, 7 controlled trials comprising 342 patients were included in the systematic review. The results showed that there was no significant change in TPOAb levels (WMD = -124.28 [95% CI: -631.08 to 382.52], P = .631, I2 = 94.5%) after 3 months of treatment. But there was a significant decrease in TPOAb levels (WMD = -284.00 [95% CI: -553.41 to -14.60], P < .05, I2 = 93.9%) and TgAb levels (WMD = -159.86 [95% CI: -293.48 to -26.24], P < .05, I2 = 85.3%) after 6 months of treatment., Conclusions: Selenium supplementation reduces serum TPOAb and TgAb levels after 6 months of treatment in patients with HT, but future studies are warranted to evaluate health-related quality or disease progression., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Systemic chronic inflammation (SCI) is closely involved in the pathogenesis of many diseases. This study aims to investigate the association between MLR with mortality and cardiovascular disease (CVD) mortality in US adults., Methods: 35,813 adults were enrolled from the 1999-2014 National Health and Nutrition Examination Survey (NHANES) cycle. Individuals were categorized according to MLR tertiles and followed until 31 December 2019. Kaplan-Meier plots and log-rank tests were utilized to explore survival differences among the MLR tertiles. Adjusted multivariable Cox analysis was employed to investigate the relationship of MLR with mortality and CVD mortality. Restricted cubic spline and subgroup analysis were further used to discern non-linear relationship and the relationship in categories., Results: During a median follow-up of 134 months, 5865 (16.4%) all-cause deaths and 1602 (4.5%) cardiovascular deaths occurred. Kaplan-Meier plots revealed significant differences in all-cause and cardiovascular mortality among the MLR tertiles. In the fully-adjusted Cox regression model, individuals in the highest tertile of MLR had higher risk of mortality (HR = 1.26, 95% CI: 1.17-1.35) and CVD mortality (HR = 1.41, HR, 95% CI: 1.23-1.62) than those in the lowest tertile. The restricted cubic spline exhibited a J-shaped relationship between MLR with mortality and CVD mortality (P for non-linearity <0.001). The further subgroup analysis demonstrated a robust trend across categories., Conclusion: Our study demonstrated that increased baseline MLR was positively associated with a higher risk of death in US adults. MLR was a strong independent predictor of mortality and CVD mortality in the general population., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Neuropathic pain is a complex condition that seriously affects human quality of life. This study aimed to investigate the therapeutic mechanism of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and try to discover new targets for alleviating neuropathic pain. Extracellular vesicles were isolated and identified via ultracentrifugation. BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) in the presence or absence of MSC-EVs. Further, microglial activation and neuroinflammation were evaluated by flow cytometry, RT-qPCR, and ELISA. High-throughput sequencing analysis was performed to reveal the differentially expressed (DE) miRNAs in BV-2 microglia. Autophagy-related regulators were assessed by Western blotting and Immunofluorescence staining. Chronic constriction injury (CCI) model was used to induce neuropathic pain in rats, and the mechanical withdrawal threshold (MWT) was measured. High-throughput sequencing analysis identified 17 DE miRNAs, which were mainly enriched in PI3K-AKT and mTOR signaling pathways. MSC-EVs inhibited the activation of PI3K/AKT/mTOR signaling pathway in LPS-stimulated microglia. Moreover, MSC-EVs treatment enhanced the autophagy level in activated microglia, whereas autophagy inhibitor 3-MA reversed the suppressing effects of MSC-EVs on microglial activation and neuroinflammation. The MSC-EV-mediated transfer of miR-99b-3p was verified to promote microglial autophagy, and miR-99b-3p overexpression suppressed the expression of pro-inflammatory factors in activated microglia. During in vivo studies, intrathecal injection of MSC-EVs significantly up-regulated the expression of miR-99b-3p, and alleviated mechanical allodynia caused by activated microglia in the spinal cord dorsal horn of CCI rats. Moreover, MSC-EVs treatment repaired CCI-induced autophagic impairment by stimulating autophagy in the spinal cord. Collectively, our findings demonstrated that MSC-EVs had an analgesic effect on neuropathic pain via promoting autophagy, and these antinociceptive effects were at least in part caused by MSC-EV-mediated transfer of miR-99b-3p, thereby inhibiting microglial activation and pro-inflammatory cytokines expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Mesenchymal stem cells (MSCs)-derived exosomes have shown promise as a cell-free therapeutic strategy for neuropathic pain. This study was conducted to explore the potential mechanisms underlying the analgesic effects of MSC-derived exosomes in treating neuropathic pain., Methods: Human umbilical cord MSCs (huc-MSCs)-derived exosomes were isolated and identified. BV-2 microglia were stimulated with lipopolysaccharide (LPS) in the presence or absence of exosomes. Differentially expressed proteins were identified by tandem mass tag (TMT)-based proteomic analysis. The analgesic effects of huc-MSCs-derived exosomes were evaluated in a rat model of chronic constriction injury (CCI). The underlying mechanism was investigated by flow cytometry, RT-qPCR, Western blotting, immunofluorescent staining, and small interfering RNA transfection., Results: In vitro, huc-MSCs-derived exosomes suppressed LPS-induced microglial activation and inhibited activation of the TLR2/MyD88/NF-κB signaling pathway. Based on the proteomic analysis, Rsad2 was identified and confirmed to be down-regulated by huc-MSCs-derived exosomes. Importantly, knockdown of Rsad2 also inhibited microglial activation and restrained activation of the TLR2/MyD88/NF-κB signaling pathway. In vivo, intrathecal injection of exosomes ameliorated CCI-induced mechanical allodynia, down-regulated Rsad2 expression and restrained TLR2/MyD88/NF-κB signaling activation in the spinal microglia., Conclusion: Huc-MSCs-derived exosomes exerted analgesic effects on neuropathic pain by inhibiting activation of the TLR2/MyD88/NF-κB signaling pathway in the spinal microglia. The mechanism underlying these antinociceptive effects involved exosome-mediated interference with Rsad2 expression, thereby inhibiting microglial activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Vascular smooth muscle cells (VSMCs), the major cell type in the arterial vessel wall, have a contractile phenotype that maintains the normal vessel structure and function under physiological conditions. In response to stress or vascular injury, contractile VSMCs can switch to a less differentiated state (synthetic phenotype) to acquire the proliferative, migratory, and synthetic capabilities for tissue reparation. Imbalances in VSMCs phenotypic switching can result in a variety of cardiovascular diseases, including atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification. It is very important to identify the molecular mechanisms regulating VSMCs phenotypic switching to prevent and treat cardiovascular diseases with high morbidity and mortality. However, the key molecular mechanisms and signaling pathways participating in VSMCs phenotypic switching have still not been fully elucidated despite long-term efforts by cardiovascular researchers. In this review, we provide an updated summary of the recent studies and systematic knowledge of VSMCs phenotypic switching in atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification, which may help guide future research and provide novel insights into the prevention and treatment of related diseases.

Aim: This study investigates the trend in general obesity and abdominal obesity in US adults from 2001 to 2018., Methods: We included 44,184 adults from the nine cycles of the continuous NHANES (2001-2002, 2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012, 2013-2014, 2015-2016, and 2017-2018). The age-adjusted mean body mass index and waist circumference were calculated, and the sex-specific annual change was estimated by the survey cycle. We used the weighted sex-specific logistic regression models to analyze the prevalence of general obesity and abdominal obesity from 2001 to 2018. The weighted adjusted odds ratio (OR) with a 95% confidence interval (CI) was calculated., Results: Our study showed that general obesity and abdominal obesity account for about 35.48 and 53.13% of the US population. From 2001-2002 to 2017-2018, the age-adjusted prevalence of general obesity increased from 33.09 to 41.36% in females and from 26.88 to 42.43% in males. During 2001-2018, the age-adjusted prevalence of abdominal obesity increased from 57.58 to 67.33% in females and from 39.07 to 49.73% in males. A significant time-dependent increase was observed in the prevalence of general obesity (adjusted OR, 1.007; 95% CI 1.005-1.009, P < 0.001) and abdominal obesity (adjusted OR, 1.006; 95% CI, 1.004-1.008; P < 0.001)., Conclusion: General obesity and abdominal obesity are a heavy health burden among US adults, and the increasing trend remains in both males and females from 2001 to 2018., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Huang, Hua, Qu, Cheng, Liu, Kong, Ma and Sun.)

This study aims to investigate the relationship between waist circumference and hypertension risk in normal-weight/overweight individuals with normal cardiometabolic profiles. The authors included 7217 normal-weight and overweight individuals with normal cardiometabolic profiles from the 2001 to 2014 US National Health and Nutrition Examination Survey. The authors summarized demographic characteristics, cardiometabolic profiles, and behavioral factors across waist circumference quartiles. Then, in the logistic regression analysis, the authors observed a positive and significant association between waist circumference (as a continuous variable) and the prevalence of hypertension in all three models (nonadjusted, minimally adjusted, and fully adjusted), with odds ratios (95% confidence intervals) of 1.76 (1.65-1.86), 1.29 (1.20-1.39), and 1.24 (1.09-1.40), respectively. When analyzed as a categorical variable, individuals in the highest waist circumference group had a 1.48-fold increased risk of hypertension than the lowest group in the fully adjusted model. Moreover, the Cox regression analysis revealed a positive and significant association between waist circumference and all-cause mortality in individuals with hypertension in the nonadjusted model (HR, 1.27; 95% CI, 1.10-1.47) and the fully adjusted model (HR, 1.59; 95% CI, 1.22-2.06). In conclusions, our results showed that, even in those with normal metabolic profiles, high waist circumference was significantly associated with the increased prevalence of hypertension. And once hypertension has been established, patients with high waist circumference showed elevated all-cause mortality. Therefore, waist circumference should be routinely measured and controlled regardless of metabolic profiles., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Real-time reverse transcription-polymerase chain reaction (RT-PCR) is the gold standard for diagnosing coronavirus disease 2019 (COVID-19). However, RT-PCR may yield false-positive results, leading to unnecessary countermeasures. Here, we report a "positive" nucleic acid test on a 10-pooled sample during the routine screening that caused many adverse societal effects, and financial and resource losses. However, they were subsequently determined to be a case of vaccine contamination. This case study increases awareness of false-positive RT-PCR results for SARS-CoV-2, especially when participants are vaccinators. Moreover, it could provide relevant suggestions to prevent the recurrence of such incidents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kong, Wang, Fang, Yang and Tong.)

Purpose: To compare the consistency of one-dimensional Response Evaluation Criteria in Solid Tumors (1D-RECIST), two-dimensional WHO criteria (2D-WHO), and three-dimensional (3D) measurement for therapeutic response assessment of nasopharyngeal carcinoma (NPC)., Materials and Methods: Retrospective data of 288 newly diagnosed NPC patients were reviewed. Tumor size was assessed on magnetic resonance imaging (MRI) according to the 1D-RECIST, 2D-WHO, and 3D measurement criteria. Agreement between tumor responses was assessed using unweighted k statistics. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off point of the PTV. The Kaplan-Meier method and Cox regression were used for the survival analysis., Results: The optimal cut-off point of the PTV for progression-free survival (PFS) was 29.6%. Agreement with PTV measurement was better for 1D measurement than for 2D and 3D measurements (kappa values of 0.646, 0.537, and 0.577 for 1D, 2D, and 3D measurements, respectively; P < 0.05). The area under the curve of the 1D measurement (AUC=0.596) was similar to that of the PTV measurement (AUC=0.621). Compared with 2D and 3D measurements, 1D measurement is superior for predicting prognosis in NPC (C-index of 0.672, 0.663, and 0.646 were for 1D, 2D, and 3D measurements, respectively; P < 0.005). Survival analysis showed that patients with non-responders had worse prognosis (P < 0.05)., Conclusions: The 1D measurement more closely agreed with the PTV measurement than the 2D and 3D measurements for predicting therapeutic responses in NPC. Therefore, we recommend using the less time-consuming 1D-RECIST criteria in routine clinical practice., (Copyright © 2022. Published by Elsevier Inc.)

Five undescribed triterpenoids, two unusual omphalane-type sesquiterpenoids together with twenty-five known compounds were isolated from the leaves and stems of Rhododendron minutiflorum Hu. The absolute configurations of 1-3 and 6 were established by single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD). Compounds 6-7 feature the rare omphalane-type sesquiterpene skeleton and are verified by single-crystal X-ray diffraction analysis for the first time. In the biological activity assay, most of the triterpenoids have different degrees of inhibitory effects on α-glucosidase, with IC 50 values ranging from 6.97 to 229.3 μM (the positive control drug acarbose has an IC 50 value of 3.07 × 10 -3  μM). Structure and activity relationship (SAR) study reveals that the oxidation degrees of C-3, C-8, or C-11 to C-13 of the ursane-type triterpenoid influence the inhibitory activity dramatically., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Provisional stenting using drug-eluting stent is effective for simple coronary bifurcation lesions. Kissing balloon inflation using conventional non-compliant balloon is the primary treatment of side branch (SB) after main vessel (MV) stenting. Drug-coating balloon (DCB) is reported to be associated with less frequent clinical events in in-stent restenosis and small vessel disease. The importance of DCB in bifurcation treatment is understudied. Accordingly, this trial is designed to investigate the superiority of DCB to non-compliant balloon angioplasty for SB after provisional stenting in patients with true coronary bifurcation lesions., Methods and Analysis: The DCB-BIF trial is a prospective, multicentre, randomised, superiority trial including 784 patients with true coronary bifurcation lesions. Patients will be randomised in a 1:1 fashion to receive either DCB or non-compliant balloon angioplasty if SB diameter stenosis >70% after MV stenting. The primary endpoint is the composite of major adverse cardiac event at the 1-year follow-up, including cardiac death, myocardial infarction (MI) or clinically driven target lesion revascularisation. The major secondary endpoints include all-cause death, periprocedural MI, spontaneous MI, clinically driven target vessel revascularisation, in-stent restenosis, stroke and individual component of the primary endpoint. The safety endpoint is the risk of stent thrombosis., Ethics and Dissemination: The study protocol and informed consent have been reviewed and approved by the Institutional Review Board of all participating centres. The written informed consent for participation in the trial will be obtained from all participants. The results of this study will be published in a peer-reviewed journal and disseminated at conferences., Trial Registration Number: NCT04242134., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aims to investigate the association between waist circumference and the development of hypertension based on a nationwide cohort Chinese population. A total of 5330 individuals free of hypertension at baseline were collected from the China Health and Retirement Longitudinal Study. The association between waist circumference and the development of hypertension was analyzed by an adjusted cox regression model and visualized by restricted cubic splines. Further, we applied the supervised machine learning methods to evaluate the importance of multiple variates for new-onset hypertension. Additionally, the robustness of the association was assessed by a subgroup analysis. A total of 1490 individuals (28.0%) developed hypertension during a mean follow-up of 3.32 years. The new-onset hypertension was more observed in those with increased waist circumference (P for trend < .001). In the fully adjusted Cox regression, each 10 cm increase of waist circumference would result in an 18% elevated risk of hypertension. The random forest method and the Extreme Gradient Boosting method revealed waist circumference as an important feature to predict the development of hypertension. The sensitivity analysis indicated a consistent trend between waist circumference and new-onset hypertension in all BMI categories. This study suggested high waist circumference as an independent risk factor for new-onset hypertension based on a nationwide cohort of Chinese adults aged ≥45 years old. Our results supported that waist circumference should be routinely measured., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Obesity has grown to become a major health problem over the past few decades. Obesity-related comorbidities, such as diabetes mellitus, hypertension, obstructive sleep apnea, and dyslipidemia, are inextricably linked with increased adverse clinical consequences and mortality. Compared with other strategies for obesity, bariatric surgery is efficient in weight loss and has been proved to exert positive effects on obesity-related risk factors. This broad improvement in risk factors has resulted in substantial remission or reductions of comorbidities and better performance on clinical outcomes, including cardiovascular diseases, cancer, and mortality. With the development of surgical procedures, the safety of bariatric surgery has been validated and the rate of peri-operative death is low all over the world. Nonetheless, surgeons ought to be careful about potential complications, such as nutrition deficiencies, psychological disorders, or new digestive tract tumors after surgery. For patients with obesity, bariatric surgery might be a precious and crucial tool to bring additional benefits including comorbidities protection and life span extension. All patients with obesity should be engaged in a union consultation group to select a suitable treatment., (Copyright © 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Aims: In-stent restenosis (ISR) remains an Achilles heel of drug-eluting stents despite technical advances in devices and procedural techniques. Neointimal hyperplasia (NIH) is the most important pathophysiological process of ISR. The present study mapped normal arteries and stenotic arteries to uncover potential cellular targets of neointimal hyperplasia. Methods and Results: By comparing the left (control) and right (balloon injury) carotid arteries of rats, we mapped 11 clusters in normal arteries and 11 mutual clusters in both the control and experimental groups. Different clusters were categorized into 6 cell types, including vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), macrophages, unknown cells and others. An abnormal cell type expressing both VSMC and fibroblast markers at the same time was termed a transitional cell via pseudotime analysis. Due to the high proportion of VSMCs, we divided them into 6 clusters and analyzed their relationship with VSMC phenotype switching. Moreover, N-myristoyltransferase 1 (NMT1) was verified as a credible VSMC synthetic phenotype marker. Finally, we proposed several novel target genes by disease susceptibility gene analysis, such as Cyp7a1 and Cdk4, which should be validated in future studies. Conclusion: Maps of the heterogeneous cellular landscape in the carotid artery were defined by single-cell RNA sequencing and revealed several cell types with their internal relations in the ISR model. This study highlights the crucial role of VSMC phenotype switching in the progression of neointimal hyperplasia and provides clues regarding the underlying mechanism of NIH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Chen, Wang, Wang, Luo, Chen, Gu, Kong, Zuo, Chen, Ge, Zhang and Chen.)

Immune-checkpoint inhibitors (ICIs), a unique antibody-based therapeutic strategy, have revolutionized the treatment landscape of solid and hematological cancers. Despite the proven benefits of ICIs, the cardiotoxicity from unspecific immune activation (uncommon but potentially fatal) is a continuing concern. Accumulating preclinical research has demonstrated that ICIs initiate inflammation in the myocardium, while clinically significant cardiotoxicity were reported in few patients receiving ICI therapy, probably due to the low incidence and unspecific symptoms. The subtle signs and symptoms (e.g., chest pain, dizziness, and dyspnea) were likely attributed to cancer and/or non-cardiac events by previous studies, thus limiting the understanding of the incidence, outcomes, risk factors, and management of ICI-related cardiotoxicity. The heterogeneous clinical presentation and complex diagnostic procedure further make it challenging to accurately identify ICI-related cardiac events in clinical trials. Therefore, ICI-related cardiotoxicity, whose incidence is probably underestimated, has not been well recognized. In this article, we provide an overview of potential mechanisms underlying ICI-related cardiotoxicity and review accumulating clinical evidence of ICI-related cardiotoxicity, with a focus on myocarditis. Moreover, we discuss possible strategies to manage ICI-related cardiotoxicity and highlight the importance of developing cardio-oncology., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression, and participates in cytokine secretion in many diseases. However, the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied. A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool. Some rats were first treated with JAK2/STAT3 small interfering RNA (Si-JAK2/Si-STAT3) or overexpression plasmids of JAK2/STAT3. In the brains of subarachnoid hemorrhage model rats, the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated, reaching a peak at 48 hours after injury. Simultaneously, the interactions between JAK2 and SOCS1 were reduced. In contrast, the interactions between JAK2 and STAT3 were markedly enhanced. Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis, destruction of the blood-brain barrier, brain edema, and cognitive functional impairment after subarachnoid hemorrhage. This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein, decreased total levels of JAK2 and STAT3 protein, and increased SOCS1 protein expression. However, overexpression of JAK2 and STAT3 exerted opposite effects, aggravating subarachnoid hemorrhage-induced early brain injury. Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors (inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α) and increased the release of anti-inflammatory factors (arginase-1, interleukin-10, and interleukin-4). Furthermore, primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro, and the JAK2 inhibitor AG490 was used as an intervention. The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression. Together, our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses. This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China (approval No. LLSC-20180202) on March 1, 2018., Competing Interests: None

Background: Hypertension is a significant risk factor of cardiovascular diseases, posing a serious threat to global health. Calcium plays an important role in regulating body homeostasis. The association of calcium with hypertension remains uncertain in the general population. Methods and Results: Cross-sectional data from the 2007-2018 National Health and Nutrition Examination Survey (NHANES) were analyzed. Adjusted multivariable logistic regression analysis and restricted cubic spline were used to investigate the association of serum calcium with the prevalence of hypertension. A total of 26,778 participants were included. The increase in calcium levels showed a positive association with the prevalence of hypertension in all three models with ORs of 1.347 (1.249-1.454), 1.522 (1.401-1.654), and 1.438 (1.306-1.583). The further subgroup analysis demonstrated a robust trend across all categories by sex, age, race, BMI, and eGFR. The restricted cubic spline plot exhibited an S-curve relationship between calcium and hypertension. Conclusion: Our cross-sectional study demonstrated a positive association between higher serum calcium level and the prevalence of hypertension. Our findings highlighted serum calcium level in hypertensive patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hua, Liu, Sun, Kong, Sun and Xiong.)

Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3β (glycogen synthase kinase-3β) activity and upregulating β-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

Background: The purpose of this study was to examine the correlation between fasting blood glucose and new-onset hypertension and examine any synergistically effect modification with multiple risk factors., Methods: We conducted post-hoc analyses of repeated-measures data in the original Dongzhi osteoporosis cohort study. In total, 3985 participants without hypertension aged 25-64 years were included in the current analyses. Generalized estimating equation models were used to assess the relationship between fasting blood glucose and risk of new-onset hypertension after adjusting for pertinent covariates and autocorrelations among siblings., Results: 393 men (19.4%) and 398 women (20.3%) without hypertension at the baseline developed hypertension by the end of the study period. Compared to lower baseline fasting blood glucose levels (Q1-Q3: < 5.74 mmol/L; clinical cut points: < 5.6 mmol/L), higher baseline fasting blood glucose levels (Q4: ≥ 5.74 mmol/L; clinical cut points: ≥ 5.6 mmol/L and < 7.0 mmol/L) increased the risk of new-onset hypertension significantly [(OR: 1.54, 95% CI 1.19-1.98, P < 0.001); (OR: 1.38, 95% CI 1.09-1.75, P = 0.008)] in women. Additionally, a stronger significant association was found in women with elevated fasting blood glucose on risk of new-onset of hypertension with higher total cholesterol (≥ 5.2 mmol/L) [(OR: 2.76; 95% CI: (1.54, 4.96), P < 0.001)]. However, no association was found between fasting blood glucose and risk of new-onset hypertension in men., Conclusions: High fasting blood glucose may be significantly associated with risk of new-onset hypertension in Chinese women, especially in women with higher total cholesterol. Further randomized studies are needed to confirm our findings., (© 2021. The Author(s).)

Aims: This study aimed to investigate the association between waist circumference and the prevalence of (pre) hypertension. Methods: Cross-sectional data from the 2007-2018 National Health and Nutrition Examination Survey were analyzed. The historical trend of abdominal obesity was assessed by the Cochran-Armitage trend test. After preprocessed by the multiple imputation strategy, we used generalized additive models to assess the association of waist circumference with systolic/diastolic blood pressure and performed correlation analysis by the Spearman correlation coefficient. Moreover, we used multivariable logistic regression (non-adjusted, minimally adjusted, and fully adjusted models), restricted cubic spline, and sensitivity analysis to investigate the association between waist circumference and (pre) hypertension. Results: A total of 27,894 participants were included in this study. In the fully adjusted model, waist circumference was positively associated with (pre) hypertension with odds ratios (95% confidence intervals) of 1.28 (1.18-1.40) in the young group and 1.23 (1.15-1.33) in the old group. Restricted cubic spline showed a higher prevalence of (pre) hypertension with the increase of waist circumference. In the subgroup analysis, waist circumference showed a robust trend across all BMI categories with odds ratios (95% confidence intervals) of 3.33 (1.29-8.85), 1.35 (1.17-1.57), 1.27 (1.13-1.41), and 1.09 (1.01-1.17) in underweight, normal weight, overweight, and obese individuals, respectively. Conclusion: This study highlighted waist circumference as a significant biomarker to evaluate the risk of (pre) hypertension. Our results supported the measure of waist circumference regardless of BMI when evaluating the cardiometabolic risk related to fat distribution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Hua, Zou, Qu, Yuan, Sun, Sun and Kong.)

Electrocardiogram (ECG) is a commonly-used, non-invasive examination recording cardiac voltage versus time traces over a period. Deep learning technology, a robust artificial intelligence algorithm, can imitate the data processing patterns of the human brain, and it has experienced remarkable success in disease screening, diagnosis, and prediction. Compared with traditional machine learning, deep learning algorithms possess more powerful learning capabilities and can automatically extract features without extensive data pre-processing or hand-crafted feature extraction, which makes it a suitable tool to analyze complex structures of high-dimensional data. With the advances in computing power and digitized data availability, deep learning provides us an opportunity to improve ECG data interpretation with higher efficacy and accuracy and, more importantly, expand the original functions of ECG. The application of deep learning has led us to stand at the edge of ECG innovation and will potentially change the current clinical monitoring and management strategies. In this review, we introduce deep learning technology and summarize its advantages compared with traditional machine learning algorithms. Moreover, we provide an overview on the current application of deep learning in ECGs, with a focus on arrhythmia (especially atrial fibrillation during normal sinus rhythm), cardiac dysfunction, electrolyte imbalance, and sleep apnea. Last but not least, we discuss the current challenges and prospect directions for the following studies., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021. Published by Elsevier B.V.)

Many studies have verified the safety of combined radiotherapy and immune checkpoint blockades (ICBs) without the specific radiation dose or sequencing of combination. We aimed to evaluate the expression and response of PD-1, TIM-3, LAG-3 after neoadjuvant radiotherapy (NRT) and explore the possibility and optimal schedule of combining immunotherapy with radiotherapy in treating rectal cancer. Immunohistochemistry was performed to detect the expression of PD-1, TIM-3, LAG-3, CD8, and CD3. These molecules' expression was detected on the specimens of 76 rectal cancer patients following NRT and 13 of these patients before NRT. The expression of ICBs was assessed by the percentage of positive cells. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after NRT (0% vs. 3%, p=0.043 and 5% vs. 45%, p=0.039, respectively). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (80% vs. 50%, p=0.011, 90% vs. 0%, p=0.000, respectively). The LAG-3 expression was higher in patients treated with short-course RT than long-course RT (22.5% vs. 8.0%, p=0.0440 in ICs; 0% vs. 70%, p<0.001 in TCs). On the contrary, CD8 was higher after long-course RT (15% vs. 8%, p=0.0146). Interestingly, the level of ICs TIM-3 was low in > eight weeks after long-course RT (p=0.045). The expressions of PD-1, ICs TIM-3, ICs LAG-3, CD3, and CD8 were associated with the disease-free survival (DFS) in univariate analysis (p=0.036, 0.008, 0.018, 0.025, and 0.004, respectively). Adjusted by the relevant variables, PD-1 (HR 0.274; 95% CI 0.089-0.840; p=0.024) and ICs TIM-3 (HR 0.425; 95% CI 0.203-0.890; p=0.023) were independent prognostic factors of DFS in rectal cancer patients following NRT. In conclusion, we have identified that PD-1 and ICs LAG-3 presented a trend towards increased expression after NRT, supporting the ICBs and NRT combination as a potential treatment option for local advanced rectal cancer patients. The radiotherapeutic mode and timing of the treatment might significantly affect the expression of ICBs, which indicated that the sequencing and time window of ICBs immunotherapy utility might deserve a high value.

Background: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor., Methods: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population., Conclusion: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Calcific aortic valve disease (CAVD) is the most common subclass of valve heart disease in the elderly population and a primary cause of aortic valve stenosis. However, the underlying mechanisms remain unclear., Methods: The gene expression profiles of GSE83453, GSE51472, and GSE12644 were analyzed by 'limma' and 'weighted gene co-expression network analysis (WGCNA)' package in R to identify differentially expressed genes (DEGs) and key modules associated with CAVD, respectively. Then, enrichment analysis was performed based on Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, DisGeNET, and TRRUST database. Protein-protein interaction network was constructed using the overlapped genes of DEGs and key modules, and we identified the top 5 hub genes by mixed character calculation., Results: We identified the blue and yellow modules as the key modules. Enrichment analysis showed that leukocyte migration, extracellular matrix, and extracellular matrix structural constituent were significantly enriched. SPP1, TNC, SCG2, FAM20A, and CD52 were identified as hub genes, and their expression levels in calcified or normal aortic valve samples were illustrated, respectively., Conclusions: This study suggested that SPP1, TNC, SCG2, FAM20A, and CD52 might be hub genes associated with CAVD. Further studies are required to elucidate the underlying mechanisms and provide potential therapeutic targets.

Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in the occurrence and development of in-stent restenosis (ISR), the underlying mechanism of which remains a key issue needing to be urgently addressed. This study is designed to investigate the role of plasma small extracellular vesicles (sEV) in VSMC phenotypic modulation. sEV were isolated from the plasma of patients with ISR (ISR-sEV) or not (Ctl-sEV) 1 year after coronary stent implantation using differential ultracentrifugation. Plasma sEV in ISR patients are elevated markedly and decrease the expression of VSMC contractile markers α -SMA and calponin and increase VSMC proliferation. miRNA sequencing and qRT-PCR validation identified that miRNA-501-5p was the highest expressed miRNA in the plasma ISR-sEV compared with Ctl-sEV. Then, we found that sEV-carried miRNA-501-5p level was significantly higher in ISR patients, and the level of plasma sEV-carried miRNA-501-5p linearly correlated with the degree of restenosis ( R 2 = 0.62). Moreover, miRNA-501-5p inhibition significantly increased the expression of VSMC contractile markers α -SMA and calponin and suppressed VSMC proliferation and migration; in vivo inhibition of miRNA-501-5p could also blunt carotid artery balloon injury induced VSMC phenotypic modulation in rats. Mechanically, miRNA-501-5p promoted plasma sEV-induced VSMC proliferation by targeting Smad3. Notably, endothelial cells might be the major origins of miRNA-501-5p. Collectively, these findings showed that plasma sEV-carried miRNA-501-5p promotes VSMC phenotypic modulation-mediated ISR through targeting Smad3., Competing Interests: The authors declare that no conflict of interest exists., (Copyright © 2021 Xiao-Fei Gao et al.)