Identification and verification of circRNA biomarkers for coronary artery disease based on WGCNA and the LASSO algorithm.

BACKGROUND: The role of circular RNAs (circRNAs) as biomarkers of coronary artery disease (CAD) remains poorly explored. This study aimed to identify and validate potential circulating circRNAs as biomarkers for the diagnosis of CAD. METHODS: The expression profile of circRNAs associated with CAD was obtained from Gene Expression Omnibus (GEO) database. Differential expression analysis, weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operation (LASSO) were employed to identify CAD-related hub circRNAs. The expression levels of these hub circRNAs were validated using qRT-PCR in blood samples from 100 CAD patients and 100 controls. The diagnostic performance of these circRNAs was evaluated through logistic regression analysis, receiver operator characteristic (ROC) analysis, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). Functional enrichment analyses were performed to predict the possible mechanisms of circRNAs in CAD. RESULTS: A total of ten CAD-related hub circRNAs were identified through WGCNA and LASSO analysis. Among them, hsa_circ_0069972 and hsa_circ_0021509 were highly expressed in blood samples of CAD patients, and they were identified as independent predictors after adjustment for relevant confounders. The area under the ROC curve for hsa_circ_0069972 and hsa_circ_0021509 was 0.760 and 0.717, respectively. The classification of patients was improved with the incorporation of circRNAs into the clinical model composed of conventional cardiovascular risk factors, showing an IDI of 0.131 and NRI of 0.170 for hsa_circ_0069972, and an IDI of 0.111 and NRI of 0.150 for hsa_circ_0021509. Functional enrichment analyses revealed that the hsa_circ_0069972-miRNA-mRNA network was enriched in TGF-ß、FoxO and Hippo signaling pathways, while the hsa_circ_0021509-miRNA-mRNA network was enriched in PI3K/Akt and MAPK signaling pathways. CONCLUSION: Hsa_circ_0069972 and hsa_circ_0021509 were identified by integrated analysis, and they are highly expressed in CAD patients. They may serve as novel biomarkers for CAD.

Association between living alone and all-cause mortality of young and middle-aged patients with acute myocardial infarction: analysis of the China Acute Myocardial Infarction (CAMI) registry.

BACKGROUND: Lack of social support is a known predictor of the prognosis after acute myocardial infarction (AMI). Although as a common factor associated with social support, there are limited data on long-term prognostic impact of living status in young and middle-aged patients with AMI. METHODS: We analyzed data from the China Acute Myocardial Infarction (CAMI) Registry, consecutive AMI young and middle-aged patients admitted at 108 hospitals in China between January 2013 and September 2014 were included. Eligible patients were assigned to living alone and not living alone groups based on their living status. The primary endpoint was 2-year all-cause mortality. The secondary endpoints included in-hospital mortality and 2-year major adverse cardiac and cerebrovascular events (MACCEs; a composite of all-cause mortality, MI, or stroke). Multilevel logistic and multilevel Cox regression models were used to evaluate the effect of living status on short-term and long-term outcomes. RESULTS: A total of 8307 consecutive AMI young and middle-aged patients were included, 192 (2.3%) patients were living alone. Of the analyzed patients, living alone was associated with 2-year all-cause mortality and MACCEs among all analyzed patients after multivariate adjustment (adjusted hazard ratio [HR] = 2.171 [1.210-3.895], P = 0.009; adjusted HR = 2.169 [1.395-3.370], P = 0.001), but not with poorer in-hospital mortality. CONCLUSIONS: The analysis suggested that living alone was associated with both 2-year all-cause mortality and MACCEs in AMI young and middle-aged patients but did not show an extra effect on the in-hospital mortality after covariate adjustment. TRIAL REGISTRATION: Trial registration number: NCT01874691; Registered 31 October 2012.

Transcription factors: key regulatory targets of vascular smooth muscle cell in atherosclerosis.

Atherosclerosis (AS), leading to gradual occlusion of the arterial lumen, refers to the accumulation of lipids and inflammatory debris in the arterial wall. Despite therapeutic advances over past decades including intervention or surgery, atherosclerosis is still the most common cause of cardiovascular diseases and the main mechanism of death and disability worldwide. Vascular smooth muscle cells (VSMCs) play an imperative role in the occurrence of atherosclerosis and throughout the whole stages. In the past, there was a lack of comprehensive understanding of VSMCs, but the development of identification technology, including in vivo single-cell sequencing technology and lineage tracing with the CreERT2-loxP system, suggests that VSMCs have remarkable plasticity and reevaluates well-established concepts about the contribution of VSMCs. Transcription factors, a kind of protein molecule that specifically recognizes and binds DNA upstream promoter regions or distal enhancer DNA elements, play a key role in the transcription initiation of the coding genes and are necessary for RNA polymerase to bind gene promoters. In this review, we highlight that, except for environmental factors, VSMC genes are transcriptionally regulated through complex interactions of multiple conserved cis-regulatory elements and transcription factors. In addition, through a series of transcription-related regulatory processes, VSMCs could undergo phenotypic transformation, proliferation, migration, calcification and apoptosis. Finally, enhancing or inhibiting transcription factors can regulate the development of atherosclerotic lesions, and the downstream molecular mechanism of transcriptional regulation has also been widely studied.

Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.

BACKGROUND: Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. METHODS: MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. RESULTS: MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. CONCLUSIONS: We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Association of Circular RNAs levels in blood and Essential Hypertension with Carotid Plaque.

BACKGROUND: As one of the essential hypertension (EH)-mediated target organ damage, carotid plaque is a crucial subclinical precursor for cardiovascular events. Therefore, it is vital to identify the risk factors and pathogenesis for EH with carotid plaque. METHODS: Based on our previous microarray analysis, we selected four circRNAs as the candidate circRNAs and detected their expression levels in blood of 192 subjects (64 healthy controls, 64 EH patients, and 64 EH patients with carotid plaque) by qRT-PCR analysis. The regulatory mechanism of circRNAs involved in carotid plaque was predicted by bioinformatics analysis. RESULTS: The level of hsa_circ_0124782 increased significantly and the levels of hsa_circ_0131618 and hsa_circ_0127342 decreased significantly in the EH group and EH with carotid plaque group compared with the control group (P < .05). Functional enrichment analysis showed that three circRNAs might be implicated in pathogenesis for carotid plaque. CONCLUSION: Our study revealed the relationship between three circRNAs and carotid plaque, suggesting that they may serve as potential biomarkers for EH with carotid plaque.

Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update.

Myocardial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reportedly related to disease severity and mortality, attracting attention to exploring relevant pathogenic mechanisms. Limited by insufficient evidence, myocardial injury caused by direct viral invasion of cardiomyocytes (CMs) is not fully understood. Based on recent studies, endosomal dependence can compensate for S protein priming to mediate SARS-CoV-2 infection of CMs, damage the contractile function of CMs, trigger electrical dysfunction, and tip the balance of the renin-angiotensin-aldosterone system to exert a myocardial injury effect. In this review, we shed light on the direct injury caused by SARS-CoV-2 to provide a comprehensive understanding of the cardiac manifestations of coronavirus disease 2019 (COVID-19).

Circulating circular RNAs as biomarkers for the diagnosis of essential hypertension with carotid plaque.

BACKGROUND: At present, no early diagnostic markers for essential hypertension (EH)-induced subclinical target organs damage (such as carotid plaque) are available. This study aimed to identify the circular RNAs (circRNAs) in EH with carotid plaques, and assess their utility as biomarkers. METHODS: First, circRNAs were identified through microarry analysis and database prediction. Second, a case-control study of EH patients with carotid plaque (n = 100) and healthy controls (n = 100) was performed to evaluate circRNAs expression in peripheral blood. Finally, receiver operating characteristic (ROC) curve was established to evaluate the diagnostic value. RESULTS: Five circRNAs (hsa_circ_0105130, hsa_circ_0109569, hsa_circ_0072659, hsa_circ_0079586 and hsa_circ_0064684) were identified as the candidate circRNAs. We found that circRNAs were increased in case group compared with controls (P < .05). The results of ROC shown that these five circRNAs, especially hsa_circ_0109569 (AUC = 0.741), all had the moderate predictive value. CONCLUSIONS: Our study revealed circulating circRNAs may act as promising noninvasive biomarkers for early detection and population screening of EH-induced subclinical target organ injury.

The influence of pre-existing hypertension on coronavirus disease 2019 patients.

Hypertension represents one of the most common pre-existing conditions and comorbidities in Coronavirus disease 2019 (COVID-19) patients. To explore whether hypertension serves as a risk factor for disease severity, a multi-centre, retrospective study was conducted in COVID-19 patients. A total of 498 consecutively hospitalised patients with lab-confirmed COVID-19 in China were enrolled in this cohort. Using logistic regression, we assessed the association between hypertension and the likelihood of severe illness with adjustment for confounders. We observed that more than 16% of the enrolled patients exhibited pre-existing hypertension on admission. More severe COVID-19 cases occurred in individuals with hypertension than those without hypertension (21% vs. 10%, P = 0.007). Hypertension associated with the increased risk of severe illness, which was not modified by other demographic factors, such as age, sex, hospital geological location and blood pressure levels on admission. More attention and treatment should be offered to patients with underlying hypertension, who usually are older, have more comorbidities and more susceptible to cardiac complications.

Malignant transformation of craniofacial fibrous dysplasia: a systematic review of overall survival.

The incidence of malignant transformation of fibrous dysplasia (FD) is very rare. Thus, the available knowledge of its characteristics, management, and survival is scarce. Here, we present a systemic review of fibrous dysplasia that had undergone malignant transformation. A comprehensive search was performed on PubMed electronic database. The survival rates and hazard ratios of age, gender, past history of previous radiotherapy, type of FD, and treatment were collected from the published articles and analyzed. Forty-eight cases were eligible for inclusion in the study. Patient's age, gender, past history radiotherapy, and type of FD did not influence the overall survival (OS). The Kaplan Meier analysis showed that the patients who had not received any treatment had poor prognosis with a median survival of 4 months. The patients that received surgery had significantly longer OS than that in the biopsy group. The prognosis of malignant transformation of FD is relatively poor, and surgery is the optimal treatment of choice. Nevertheless, the efficacy of postoperative adjuvant therapy to patient OS is still undefined.

The interval between carotid artery stenting and open heart surgery is related to perioperative complications.

OBJECTIVES: To assess 30-day outcomes and the optimal interval between carotid artery stenting (CAS) and open heart surgery (OHS). BACKGROUND: Whether or not they show symptoms of carotid atherosclerosis, patients with significant carotid stenosis who underwent OHS face a high risk of perioperative stroke. Planning appropriate treatment for carotid stenosis before OHS has become an important clinical issue. METHODS: From January 2005 to June 2010, 154 inpatients scheduled for CAS and OHS were recruited and followed up for 30 days after OHS. The primary end point was a composite of major stroke or neurological death. The secondary end points included a composite of major stroke, myocardial infarction (MI) or any death, minor stroke, and acute kidney injury (AKI). RESULTS: The incidence of the primary end point, the composite of major stroke, MI or any death, minor stroke and AKI was 3.2%, 5.8%, 2.6%, and 4.5%, respectively. Only an interval between CAS and OHS of ≤5 days could independently predict the incidence of the primary end point (OR, 14.06, 95% CI, 1.52-130.13; P=0.020). Moreover, congestive heart failure (OR, 7.07, 95% CI, 1.55-21.27; P=0.012) and an interval between CAS and OHS of ≤5 days (OR, 7.05, 95% CI, 1.58-31.40; P=0.010) were identified as independent risk factors for the composite of major stroke, MI, or any death. CONCLUSIONS: Our findings indicate that CAS followed by OHS is safe and feasible. More importantly, an interval between CAS and OHS of >5 days may decrease periprocedural complications, especially major stroke and neurological death.

Stenting for left subclavian artery stenosis in patients scheduled for left internal mammary artery-coronary artery bypass grafting.

OBJECTIVES: To evaluate the early and long-term outcomes of stent placement for left subclavian artery stenosis (LSAS) in patients scheduled for left internal mammary artery-coronary artery bypass grafting (LIMA-CABG). BACKGROUND: Few studies have demonstrated the safety and effectiveness of endovascular therapy for the treatment of LSAS before LIMA-CABG; therefore, use of this therapy requires further exploration and evaluation. METHODS: Between February 2000 and April 2014, the clinical data of 167 consecutive patients (mean age 64 ± 9 years, 141 males) scheduled for LIMA-CABG with LSAS who were treated by stenting at the Fuwai Hospital were collected and analyzed retrospectively. RESULTS: The technical success rate of the procedure was 97.6% (163/167). The mean stenosis of target lesions decreased from 86.5 ± 9.9% to 7.6 ± 4.6% (P < 0.001). The incidences of death, stroke, and myocardial infarction, as well as the combined incidence of death, stroke, and myocardial infarction from the time of stenting to 30 days after the stenting procedure were 0.6% (n = 1), 1.8% (n = 3), 0% (n = 0), and 1.8% (n = 3), respectively. The 10-year rate of follow-up was 94.6%. The overall survival rate was 98.8% at 1 year, 97.5% at 2 years, 93.9% at 5 years, and 86.2% at 10 years. A total of 14.1% (23/163) of patients developed in-stent restenosis. Stent restenosis-related angina and myocardial infarction were observed in 13 and 3 patients, respectively. The patency rates of the left subclavian artery were 95.7, 93.8, 86.5, and 75.2% at 1, 2, 5, and 10 years, respectively. The target vessel reconstruction rate was 8.0% (13/163). CONCLUSIONS: Stenting of LSAS at experienced medical centers for patients scheduled for LIMA-CABG was safe and effective with a low incidence of complication and in-stent restenosis.

Molecular Modeling Studies of 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11ß-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11ß-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11ß-HSD1 inhibitors.

Attenuating Hypoxia-Induced Apoptosis and Autophagy of Mesenchymal Stem Cells: the Potential of Sitagliptin in Stem Cell-Based Therapy.

BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleiotropic effects on cardiovascular protection beyond the antidiabetic property. However, it remains unknown that the impact of one DPP-4 inhibitor sitagliptin on the survival of mesenchymal stem cells (MSCs) in hypoxia and serum deprivation (H/SD) environment. METHODS: The apoptosis and autophagy of MSCs were analyzed in different concentrations of sitagliptin under H/SD condition. For later studies, we tested the relationship between anti-apoptotic and anti-autophagic effects of sitagliptin. The level of cell apoptosis was analyzed by Annexin V-FITC/PI staining, western blot of Bcl-2 and Bax proteins. Autophagy flux was assessed by multiple autophagy related proteins and substrates. Cell autophagy was identified by acridine orange staining, western blot of Beclin 1 and light chain 3 protein, and transmission electron microscopy. RESULTS: We demonstrated that sitagliptin attenuated hypoxia-induced apoptosis and autophagy of MSCs. Furthermore, sitagliptin regulated cell autophagy by Bcl-2/ Beclin 1 pathway in H/SD condition. CONCLUSIONS: This study provides insight into the utility of the DPP-4 inhibitor sitagliptin for MSCs transplantation in the ischemic microenvironment that extends its antidiabetic property.

Tongxinluo decreases apoptosis of mesenchymal stem cells concentration-dependently under hypoxia and serum deprivation conditions through the AMPK/eNOS pathway.

Tongxinluo (TXL), a traditional Chinese medicine, is widely used to treat cardiovascular diseases in China. Our previous study has demonstrated the pro-survival role of TXL on mesenchymal stem cells (MSCs) in vivo. But whether TXL could decrease apoptosis of MSCs in vitro, and the underlying mechanism are still unknown. Moreover, AMPK/eNOS pathway is crucial in regulating cell apoptosis. Therefore, we designed the study to investigate whether TXL could decrease MSCs apoptosis under hypoxia and serum deprivation (H/SD) conditions and to determine the role of AMPK/eNOS pathway. To test the hypothesis, MSCs were treated with TXL (50-400 µg/mL) under H/SD for 6 hours. For inhibitor studies, the cells were preincubated with AMPK inhibitor compound C. Results indicated that TXL decreased MSCs apoptosis concentration-dependently evidenced by reduced Annexin V+/PI- cells and increased red/green ratio of JC-1. Further, TXL enhanced the phosphorylation of AMPK and eNOS. Whereas, treatment with compound C decreased the phosphorylation of AMPK and eNOS and was accompanied by attenuated anti-apoptotic effect of TXL. In conclusion, TXL protected MSCs against H/SD-induced injury at least in part through the AMPK/eNOS pathway, which provides a novel explanation for the multi-effect of TXL on cardiovascular system.

Comparison of different interventions for the reduction of labor pain: A systematic review and network meta-analysis.

OBJECTIVE: This systematic review and network meta-analysis were performed to compare different interventions for the reduction of labor pain. METHODS: PubMed, Embase, Cochrane Library, Web of Science and ScienceDirect databases were searched for the randomized controlled trials (RCTs) meeting prespecified inclusion criteria up to January, 2023. Interventions including electrical acupoint stimulation (TEAS), epidural analgesia (EA) and control treatments. The primary outcomes included pain scores, failure rate of natural delivery, adverse events and Apgar scores. The methodological quality was assessed by the Cochrane risk of bias tool. Meta-analysis was performed by R software with gemtc package. Surfaces under the cumulative ranking curves (SUCRA) were used to rank the intervention. RESULTS: Twelve studies met the inclusion criteria and were included in the network meta-analysis. TEAS (WMD -3.1, 95% CrI -3.8, -2.5) and EA (WMD -2.1, 95% CrI -2.8, -1.3) was more effective than the control in decreasing VAS. TEAS ranked first (SUCRA, 90.9%), EA ranked second (SUCRA, 74.0%) and control ranked last (SUCRA, 35.0%) for reducing VAS. For patients with labor pain, with respect to the most effective treatment for reducing failure rate of natural delivery, TEAS ranked first (SUCRA, 96.6%), EA ranked second (SUCRA, 50.4%) and control ranked last (SUCRA, 3.0%). With regard to the Apgar scores, there was high probability that TEAS ranked first (SUCRA, 80.7%), compared to control (SUCRA, 41.4%) and EA (SUCRA 27.9%). With regard to the adverse events, there was high probability that TEAS ranked first (SUCRA, 99.9%), compared to control (SUCRA, 33.2%) and EA (SUCRA 17.6%). CONCLUSION: TEAS has the potential to serve as a viable alternative for women in labor, offering a simple, noninvasive, and non-pharmacological intervention that surpasses EA in terms of both analgesic effectiveness and safety for both mothers and neonates.

Platelet-inspired targeting delivery for coronary heart disease.

Platelets play a pivotal role in many physiological and pathological processes, with their special targeting/adhering properties towards infarcted myocardium, injured or dysfunctional endothelium, and growing thrombus. Leveraging the site-targeting/adhering property, a variety of platelet-inspired targeting delivery（PITD）designs have been developed, the majority of which are reached by hitchhiking live platelets, cloaking nanoparticles with platelet membranes and mimicking platelet functions. With PITD, drugs or regenerative cells can directly reach targeted sites with minimized systematical distribution thus being of great clinical benefits. Coronary heart disease (CHD) is a major health burden worldwide. Plenty of PITD designs have shown promising outcomes for the treatment of CHD in preclinical models, especially in thrombolysis and post-percutaneous coronary intervention (post-PCI) anti-restenosis. Besides, PITD applications in cardiac protection and atherosclerotic plaque imaging are also under investigation. What's more, the potential benefits of PITD in the field of cell-based therapy are also attracting growing attention since it may resolve the problem of low arriving and retention efficiency, which are also particularly discussed in this review. In brief, our focus is putting on PITD strategies designed for the treatment of CHD, which hopefully can facilitate further optimization of this direction.

Targeted Delivery of Mesenchymal Stem Cell-Derived Bioinspired Exosome-Mimetic Nanovesicles with Platelet Membrane Fusion for Atherosclerotic Treatment.

Purpose: Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis. Methods: To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs. Results: Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE-/- mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1. Conclusion: This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy.

The impacts of percutaneous coronary intervention to treat chronic total occlusion of right coronary artery on the 5-year prognosis: A single-centered retrospective study.

BACKGROUND: Chronic total occlusions (CTO) occur in about 20% of patients referred for coronary angiography, and right coronary artery (RCA) CTO has been reported in 38-50% of the entire CTO population. Limited data on angiographic and procedural characteristics of RCA-CTO and the risk of adverse cardiac events asks for a detailed study. METHODS: From 2010 to 2013, patients with attempted revascularization of at least one CTO lesion were included and followed up to 5 years after PCI. Eligible patients are assigned to RCA-CTO and non-RCA-CTO groups based on their target vessels. The primary endpoint was major adverse cardiovascular events (MACEs; a composite of all-cause death, myocardial infarction (MI) or rehospitalization for heart failure), and secondary endpoints were cardiac death, target lesion revascularization (TLR) and target vessel revascularization (TVR). RESULTS: The present study included 2659 eligible patients, among which 1285 patients were assigned to the RCA-CTO group, whereas 1374 patients were assigned to the non-RCA-CTO group. Lesions in RCA had longer lesion length, higher J-CTO score, higher rates of severe vessel tortuosity, a higher percentage of Rentrop grade 2-3, and more likely to be re-try lesion than those in LAD or LCX (all P < 0.01). CTO lesions in RCA reached less successful recanalization and post-procedural TIMI 3 flow (all <0.01). Multivariate Cox analysis revealed that RCA-CTO was not associated with primary outcome MACEs. Besides MACEs, RCA-CTO was also not associated with cardiac death, but was significantly associated with TLR and TVR (adjusted HR: 1.37 [95% CI:1.07-1.76], P = 0.01; adjusted HR: 1.43 [95% CI:1.13-1.82], P = 0.003). CONCLUSION: RCA-CTO lesions, which had more complex angiographic features, independently contributed to TLR and TVR but not to MACEs or cardiac death in the 5 years of follow-up.

Gomisin N in the herbal drug gomishi (Schisandra chinensis) suppresses inducible nitric oxide synthase gene via C/EBPß and NF-κB in rat hepatocytes.

Gomishi is the dried fruit of Schisandra chinensis Baillon (Fructus Schisandrae chinensis, FSC) and has been used in Japanese Kampo medicine to treat inflammatory and liver diseases. However, it is unclear which constituent of FSC is primarily responsible for its pharmacological effects. FSC was extracted with methanol, fractionated by hydrophobicity, and further purified. We measured the effects of each fraction or constituent thereof on the induction of the inflammatory mediator nitric oxide (NO), which was induced by interleukin 1ß in primary cultured rat hepatocytes. The hydrophobic fraction markedly suppressed NO induction and reduced the expression of inducible nitric oxide syntheses (iNOS) in interleukin 1ß-treated hepatocytes. Gomisin N and γ-schizandrin, two major constituents of the hydrophobic fraction, significantly reduced NO production and the levels of the iNOS protein, mRNA, and antisense transcript. Gomisin N and γ-schizandrin also decreased the transcription of interleukin 1ß and inflammatory chemokines. The overexpression of the p65 subunit of nuclear factor κB or CCAAT/enhancer-binding protein ß increased the promoter activity of the iNOS gene in the firefly luciferase assay, whereas gomisin N decreased the promoter activity. The anti-inflammatory activity of FSC and its constituents were analysed, and we demonstrated that gomisin N and γ-schizandrin are involved in the hepatoprotective effect of the FSC extract, which has therapeutic potential for liver disease.

Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR4/NF-κB system in high-fat-fed rabbits.

Vascular endothelial dysfunction (VED) and inflammation contribute to the initiation and progression of atherosclerosis. Melatonin (MLT) normalizes lipid profile, improves endothelial function, and possesses anti-inflammatory properties. However, the precise mechanisms are still unclear. This study investigated whether MLT could ameliorate VED, inflammation, and atherosclerosis by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) system in high-fat-fed rabbits. Rabbits were randomly divided into three groups that received a standard diet (control group), high-cholesterol diet (atherosclerosis group), or high-cholesterol diet plus 10 mg/kg/day MLT (MLT group) for 12 wk. After treatment, high-fat diet significantly increased serum lipid and inflammatory markers in rabbits in atherosclerosis group compared with that in control group. In addition, high-fat diet also induced VED and typical atherosclerotic plaque formation and increased intima/media thickness ratio, which were significantly improved by MLT therapy as demonstrated in MLT group. Histological and immunoblot analysis further showed that high-fat diet enhanced the expressions of TLR4, myeloid differentiation primary response protein (MyD88), and NF-κB p65, but decreased inhibitor of NF-κB (IκB) expression. By contrast, MLT therapy decreased the expressions of TLR4, MyD88, and NF-κB p65 and increased IκB expression. This study has demonstrated that MLT ameliorates lipid metabolism, VED, and inflammation and inhibits the progression of atherosclerosis in high-fat-fed rabbits. Moreover, our study indicates for the first time that suppression of the TLR4/NF-κB system in local vasculature with atherosclerotic damage is important for the protective effects of MLT.