Efficacy and underlying mechanisms of berberine against lipid metabolic diseases: a review.

Lipid-lowering therapy is an important tool for the treatment of lipid metabolic diseases, which are increasing in prevalence. However, the failure of conventional lipid-lowering drugs to achieve the desired efficacy in some patients, and the side-effects of these drug regimens, highlight the urgent need for novel lipid-lowering drugs. The liver and intestine are important in the production and removal of endogenous and exogenous lipids, respectively, and have an important impact on circulating lipid levels. Elevated circulating lipids predisposes an individual to lipid deposition in the vascular wall, affecting vascular function. Berberine (BBR) modulates liver lipid production and clearance by regulating cellular targets such as cluster of differentiation 36 (CD36), acetyl-CoA carboxylase (ACC), microsomal triglyceride transfer protein (MTTP), scavenger receptor class B type 1 (SR-BI), low-density lipoprotein receptor (LDLR), and ATP-binding cassette transporter A1 (ABCA1). It influences intestinal lipid synthesis and metabolism by modulating gut microbiota composition and metabolism. Finally, BBR maintains vascular function by targeting proteins such as endothelial nitric oxide synthase (eNOS) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). This paper elucidates and summarizes the pharmacological mechanisms of berberine in lipid metabolic diseases from a multi-organ (liver, intestine, and vascular system) and multi-target perspective.

P2y12 inhibitor monotherapy after 1-3 months dual antiplatelet therapy in patients with coronary artery disease and chronic kidney disease undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials.

Introduction: In patients with coronary artery disease (CAD) and chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI), whether short-term dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitors confers benefits compared with standard DAPT remains unclear. This study aimed to assess the efficacy and safety of 1-3 months of DAPT followed by P2Y12 monotherapy in patients with CAD and CKD undergoing PCI. Methods: PubMed, Embase, and the Cochrane Library were searched to identify randomized controlled trials (RCTs) comparing the P2Y12 inhibitor monotherapy after a 1-3 months DAPT vs. DAPT in patients with CAD and CKD after PCI. The primary outcome was the incidence of major adverse cardiovascular events (MACEs), defined as a composite of all-cause mortality, myocardial infarction, stent thrombosis, target-vessel revascularization, and stroke. The safety outcome was the major bleeding events, defined as a composite of TIMI major bleeding or Bleeding Academic Research and Consortium (BARC) type 2, 3, or 5 bleeding. The pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated with a fixed- or random-effects model depending on the heterogeneity among studies. Results: Four RCTs including 20,468 patients (2,833 patients with CKD and 17,635 without CKD) comparing P2Y12 inhibitor monotherapy with DAPT were included in our meta-analysis. Patients with CAD and CKD had higher risk of ischemic and bleeding events. P2Y12 inhibitor monotherapy after 1-3 months of DAPT significantly reduced the risk of major bleeding compared to DAPT in CKD patients (RR: 0.69, 95% CI: 0.51-0.95, P = 0.02) and non-CKD patients (RR: 0.66, 95% CI: 0.49-0.89, P = 0.01). No significant difference regarding MACEs between P2Y12 inhibitor monotherapy and DAPT was found in CKD patients (RR: 0.88, 95% CI: 0.59-1.31, P = 0.53) and non-CKD (RR: 0.91, 95% CI: 0.79-1.04, P = 0.17). Conclusion: P2Y12 inhibitor monotherapy after 1-3 months of DAPT was an effective strategy for lowering major bleeding complications without increasing the risk of cardiovascular events in patients with CAD and CKD undergoing PCI as compared with DAPT. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, CRD42022355228.

Bibliometric evaluation of publications on inflammasomes in atherosclerosis from 2002 to 2022.

Background: Inflammasomes have emerged as an important and promising area of investigation in atherosclerosis. This field, however, lacks bibliometric studies. To help understand how basic and clinical research on inflammasomes in atherosclerosis will develop in the future, we used bibliometric analysis to visualize hotspots and trends. Methods: Studies related to inflammasomes in atherosclerosis were collected from the Web of Science Core Collection database. Each study was analyzed bibliometrically and visually. CiteSpace and VOSviewer software were used to generate knowledge maps. Results: A total of 894 articles were identified. Sixty-two countries and 338 institutions led by China and the United States contributed to these publications. The leading research institutions were Harvard Medical School and Columbia University. Circulation was the most frequently cited journal in this field. Among the 475 authors determined, Eicke Latz authored the most studies, and Peter Duewell has been cocited the most. NLRP3 inflammasome, NF-kappa B, macrophage and oxidative stress are the most commonly used keywords. Conclusion: There has been a blooming of research on inflammasomes in atherosclerosis during the last two decades. Future studies will likely explore the molecular mechanism of inflammasomes in cell death. More compellingly, researchers may further delve into the potential clinical value of affecting pathological changes in atherosclerosis by modulating the initial transcription immune response and intracellular multiprotein assembly process of the NLRP3 inflammasome. Our research will be helpful to scholars focusing on inflammation-a much-needed breakthrough in the pathophysiological alterations of atherosclerosis-with a novel perspective.

Association Between Lipoprotein(a) and Calcific Aortic Valve Disease: A Systematic Review and Meta-Analysis.

Background: Preliminary studies indicated that enhanced plasma levels of lipoprotein(a) [lp(a)] might link with the risk of calcific aortic valve disease (CAVD), but the clinical association between them remained inconclusive. This systematic review and meta-analysis were aimed to determine this association. Methods: We comprehensively searched PubMed, Embase, Web of Science, and Scopus databases for studies reporting the incidence of CAVD and their plasma lp(a) concentrations. Pooled risk ratio (RR) and 95% confidence interval (95% CI) were calculated to evaluate the effect of lp(a) on CAVD using the random-effects model. Subgroup analyses by study types, countries, and the level of adjustment were also conducted. Funnel plots, Egger's test and Begg's test were conducted to evaluate the publication bias. Results: Eight eligible studies with 52,931 participants were included in this systematic review and meta-analysis. Of these, four were cohort studies and four were case-control studies. Five studies were rated as high quality, three as moderate quality. The pooled results showed that plasma lp(a) levels ≥50 mg/dL were associated with a 1.76-fold increased risk of CAVD (RR, 1.76; 95% CI, 1.47-2.11), but lp(a) levels ≥30 mg/dL were not observed to be significantly related with CAVD (RR, 1.28; 95% CI, 0.98-1.68). We performed subgroup analyses by study type, the RRs of cohort studies revealed lp(a) levels ≥50 mg/dL and lp(a) levels ≥30 mg/dL have positive association with CAVD (RR, 1.70; 95% CI, 1.39-2.07; RR 1.38; 95% CI, 1.19-1.61). Conclusion: High plasma lp(a) levels (≥50 mg/dL) are significantly associated with increased risk of CAVD.

Role and Mechanism of PKC-δ for Cardiovascular Disease: Current Status and Perspective.

Protein kinase C (PKC) is a protein kinase with important cellular functions. PKC-δ, a member of the novel PKC subfamily, has been well-documented over the years. Activation of PKC-δ plays an important regulatory role in myocardial ischemia/reperfusion (IRI) injury and myocardial fibrosis, and its activity and expression levels can regulate pathological cardiovascular diseases such as atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. This article aims to review the structure and function of PKC-δ, summarize the current research regarding its activation mechanism and its role in cardiovascular disease, and provide novel insight into further research on the role of PKC-δ in cardiovascular diseases.

Lingbao Huxin Pill Alleviates Apoptosis and Inflammation at Infarct Border Zone through SIRT1-Mediated FOXO1 and NF- κ B Pathways in Rat Model of Acute Myocardial Infarction.

OBJECTIVE: To investigate whether Lingbao Huxin Pill (LBHX) protects against acute myocardial infarction (AMI) at the infarct border zone (IBZ) of myocardial tissue by regulating apoptosis and inflammation through the sirtuin 1 (SIRT1)-mediated forkhead box protein O1 (FOXO1) and nuclear factor-κ B (NF-κ B) signaling pathways. METHODS: Six-week-old Wistar rats with normal diet were randomized into the sham, the model, Betaloc (0.9 mg/kg daily), LBHX-L (0.45 mg/kg daily), LBHX-M (0.9 mg/kg daily), LBHX-H (1.8 mg/kg daily), and LBHX+EX527 (0.9 mg/kg daily) groups according to the method of random number table, 13 in each group. In this study, left anterior descending coronary artery (LADCA) ligation was performed to induce an AMI model in rats. The myocardial infarction area was examined using a 2,3,5-triphenyltetrazolium chloride solution staining assay. A TdT-mediated dUTP nick-end labeling (TUNEL) assay was conducted to assess cardiomyocyte apoptosis in the IBZ. The histopathology of myocardial tissue at the IBZ was assessed with Heidenhain, Masson and hematoxylineosin (HE) staining assays. The expression levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1 ß, and intercellular adhesion molecule-1 were measured using enzyme-linked immunosorbent assays (ELISAs). The mRNA expressions of SIRT1 and FOXO1 were detected by real-time qPCR (RT-qPCR). The protein expressions of SIRT1, FOXO1, SOD2, BAX and NF- κ B p65 were detected by Western blot analysis. RESULTS: The ligation of the LADCA successfully induced an AMI model. The LBHX pretreatment reduced the infarct size in the AMI rats (P<0.01). The TUNEL assay revealed that LBHX inhibited cardiomyocyte apoptosis at the IBZ. Further, the histological examination showed that the LBHX pretreatment decreased the ischemic area of myocardial tissue (P<0.05), myocardial interstitial collagen deposition (P<0.05) and inflammation at the IBZ. The ELISA results indicated that LBHX decreased the serum levels of inflammatory cytokines in the AMI rats (P<0.05 or P<0.01). Furthermore, Western blot analysis revealed that the LBHX pretreatment upregulated the protein levels of SIRT1, FOXO1 and SOD2 (P<0.05) and downregulated NF- κ B p65 and BAX expressions (P<0.05). The RT-qPCR results showed that LBHX increased the SIRT1 mRNA and FOXO1 mRNA levels (P<0.05). These protective effects, including inhibiting apoptosis and alleviating inflammation in the IBZ, were partially abolished by EX527, an inhibitor of SIRT1. CONCLUSION: LBHX could protect against AMI by suppressing apoptosis and inflammation in AMI rats and the SIRT1-mediated FOXO1 and NF- κ B signaling pathways were involved in the cardioprotection effect of LBHX.

Prognostic Significance of Triglyceride-Glucose Index for Adverse Cardiovascular Events in Patients With Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Background: Insulin resistance (IR) represents a critical regulator in the development and progress of coronary artery disease (CAD). Triglyceride-glucose (TyG) index, a novel surrogate biomarker of IR, has been implicated in several cardiovascular diseases. Accordingly, we conduct a meta-analysis to elucidate the relationship between TyG index and adverse cardiovascular events in patients with CAD. Methods: To identify the studies examining the predictive capacity of the TyG index for adverse cardiovascular events in the setting of CAD, we performed a comprehensive literature retrieval of Scopus, PubMed, EMBASE, and Web of Science, from the inception of databases to October 5, 2021. We pooled the adjusted hazard ratio (HR) along with 95% CI using a random-effects model. The primary outcome was a composite of major adverse cardiovascular events (MACEs), including all-cause death, cardiovascular death (CV death), myocardial infarction (MI), stroke, hospitalization for unstable angina or heart failure, and revascularization. The secondary outcomes were all-cause death, CV death, MI, stroke, and revascularization. Additionally, we conducted subgroup analyses stratified by diabetes status, age, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), category of TyG index, sample size, follow-up duration, and study design. Results: About 12 studies involving 28,795 patients with CAD were finally taken into the quantitative analysis. Our findings showed that there was a 2.14-fold higher risk of MACEs among CAD populations in the highest TyG group compared with those in the lowest TyG group (HR: 2.14, 95% CI: 1.69-2.71, P < 0.001). A greater risk of MACEs was observed in participants with higher BMI than those with lower BMI (P = 0.03 for interaction). In the analysis of secondary outcomes, we also observed a markedly increased risk of MI, stroke, and revascularization in the highest TyG group compared with the lowest TyG group. No evidence of a significant association between TyG index and CV mortality or all-cause mortality in patients with CAD was identified. Conclusions: The elevated TyG index is a promising predictive factor of adverse cardiovascular events in patients with CAD. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42021228521.

A Meta-Analysis of Growth Differentiation Factor-15 and Prognosis in Chronic Heart Failure.

Background: Previous studies had reported increased circulating concentrations of growth differentiation factor-15 (GDF-15) in chronic heart failure (CHF), suggesting the potential prognostic significance of GDF-15 in this setting. To verify the relationship between the circulating GDF-15 levels and prognosis of CHF patients, we conducted an updated evidence-based meta-analysis. Methods: A comprehensive literature retrieval of PubMed, EMBASE, and Cochrane library was performed to collect the qualified studies that analyzed the prognostic value of GDF-15 in CHF from the inception of these online databases to September 25, 2021. The hazard ratio (HR) calculated for logGDF-15 of all-cause death and the related 95% confidence interval (CI) in multivariate analysis were used to measure the effect size. Additionally, subgroup analyses stratified by characteristics of the study participants were conducted for incremental evidence of GDF-15 in CHF with different clinical status. Results: A total of ten eligible studies involving 6,244 CHF patients were finally taken into the quantitative analysis. Results in the random-effects model indicated that there was an increased risk of 6% in all-cause mortality with a per 1LnU increase in baseline GDF-15 concentration (HR: 1.06, 95% CI: 1.03-1.10, P < 0.001). In stratified analyses, the association of GDF-15 with risk of all-cause mortality was found among chronic ischemic HF patients (HR:1.75, 95%CI: 1.24-2.48, P = 0.002), while the association was not found among chronic nonischemic HF patients (HR:1.01, 95%CI: 1.00-1.02, P = 0.219). Conclusion: The elevated GDF-15 is associated with an increased risk of all-cause mortality in CHF, especially, among CHF patients with ischemic etiology. The circulating GDF-15 might be a prognostic indicator in CHF patients. Registration Number: https://www.crd.york.ac.uk/PROSPERO; CRD42020210796.

Serum Uric Acid and Risk of Chronic Heart Failure: A Systematic Review and Meta-Analysis.

Objectives: A systematic review and meta-analysis was performed to evaluate the potential prognostic role of serum uric acid (SUA) in patients with chronic heart failure (CHF). Methods: The Embase, PubMed, Web of Science and Cochrane Library databases were searched up to 5 April 2021 for relevant publications. Random effects model was used to pool data. STATA15.0 software was used to perform meta-analysis. Heterogeneity was assessed using the Cochran Q statistic (significance level of P < 0.10) and I 2 statistics (significance level of 50%). Results: Ultimately, 18 publications reporting adverse events in CHF patients were included. The results indicate reveal associations between a high level of SUA and the risk of all-cause mortality (HR 2.24, 95% CI 1.49-3.37), cardiovascular mortality (HR 1.14, 95% CI 1.06-1.23), and the composite of death or cardiac events (HR 1.26, 95% CI 1.01-1.56) in CHF patients. A 1 mg/dL increase in serum uric acid led to 4% (HR 1.04, 95% CI 1.02-1.05) and 9% (HR 1.09, 95% CI 1.03-1.17) increases in the risk of all-cause mortality and the composite endpoint of death or cardiac events in CHF patients, respectively. Conclusion: Serum uric acid is positively associated with the risk of adverse events in CHF patients. This study protocol has been registered at PROSPERO as CRD42021247084 (https://www.crd.york.ac.uk/PROSPERO). Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO.