Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: A meta-analysis.

BACKGROUND AND AIM: The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. METHODS AND RESULTS: PubMed, Embase, and the Cochrane Library were searched for cohort and case-control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1,186,861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, -0.04 to 0.19; P = 0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, -0.08 to 0.13; P = 0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558,263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P = 0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744,466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P < 0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P = 0.004 and 0.033, respectively). CONCLUSIONS: PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD.

Relationship between triglyceride-glucose index and new-onset hypertension in general population-a systemic review and meta-analysis of cohort studies.

BACKGROUND: The triglyceride-glucose (TyG) index is an alternative biomarker for insulin resistance that may be connected to incident hypertension. We performed the meta-analysis to clarify the connection between TyG index and new-onset hypertension in the general population. METHODS: We recruited cohort studies that assessed the association between TyG index and the risk of hypertension in the general population by searching the databases of PubMed, EMBASE, and Web of Science (SCI) from their inception dates until July 18, 2023. The primary focus of the study was on the hazard ratio (HR) of hypertension in relation to the TyG index. The adjusted HR and 95% confidence interval (CI) were pooled by the random-effects model. Subgroup analyzes stratified by age, sex, follow-up duration, body mass index (BMI), and ethnicity were performed. RESULTS: Our analysis comprised 35 848 participants from a total of 7 cohort studies. The highest TyG index category showed a 1.51-fold greater risk of hypertension in the general population than the lowest category (HR = 1.51, 95%CI 1.26-1.80, p < .001). Consistent results were obtained using sensitivity analysis by eliminating one trial at a time (p values all <0.001). Subgroup analysis showed that the relationship between TyG index and hypertension was not substantially influenced by age, sex, BMI, participant ethnicity, and follow-up times (P for interaction all >0.05). CONCLUSIONS: Elevated TyG index significantly increased the risk of new-onset hypertension in the general population. It is necessary to conduct the research to clarify the probable pathogenic processes underpinning the link between the TyG index and hypertension.

Function of miR-21-5p derived from ADSCs-exos on the neuroinflammation after cerebral ischemia.

INTRODUCTION: Cerebral ischemia (CI) induces a profound neuroinflammatory response, but the underlying molecular mechanism remains unclear. Exosomes from adipose-derived stem cells (ADSC-exos) have been found to play a crucial role in cell communication by transferring molecules including microRNAs (miRNAs), which have been shown to modulate the inflammatory response after CI and are viable molecular targets for altering brain function. The current study aimed to explore the contribution of ADSC-exosomal miR-21-5p to the neuroinflammation after CI. METHODS: The differentially expressed miR-21-5p in CI was screened based on literature search. The target mRNAs of miR-21-5p were predicted using online databases and verified by luciferase reporter assay. Then, BV2 cells were treated with hemin to simulate the inflammatory response after CI, and its animal model was induced using the MCAO method. Ischemia was evaluated in rats using 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining. ADSCs-exos were further isolated and identified by western blot analysis and transmission electron microscope. RESULTS: MiR-21-5p was significantly down-regulated in CI and alleviated neuropathic damage after CI by the PIK3R1/PI3K/AKT signaling axis. And miR-21-5p derived from ADSCs-exos alleviated neuroinflammation after CI via promoting microglial M2 polarization. CONCLUSION: We demonstrated that ADSC-exosomal miR-21-5p mitigated post-CI inflammatory response through the PIK3R1/PI3K/AKT signaling axis and could offer neuroprotection after CI through promoting polarization of M2 microglia.

Effect of Intensive Lipid-Lowering Therapy on Coronary Plaque Stabilization Derived from Optical Coherence Tomography: a Meta-analysis and Meta-regression.

PURPOSE: The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD). METHODS: Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines. RESULTS: A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (ß, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (ß, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (ß, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (ß, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (ß, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (ß, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc. CONCLUSIONS: Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Procyanidin B2 improves endothelial progenitor cell function and promotes wound healing in diabetic mice via activating Nrf2.

One of the major reasons for the delayed wound healing in diabetes is the dysfunction of endothelial progenitor cells (EPCs) induced by hyperglycaemia. Improvement of EPC function may be a potential strategy for accelerating wound healing in diabetes. Procyanidin B2 (PCB2) is one of the major components of procyanidins, which exhibits a variety of potent pharmacological activities. However, the effects of PCB2 on EPC function and diabetic wound repair remain elusive. We evaluated the protective effects of PCB2 in EPCs with high glucose (HG) treatment and in a diabetic wound healing model. EPCs derived from human umbilical cord blood were treated with HG. The results showed that PCB2 significantly preserved the angiogenic function, survival and migration abilities of EPCs with HG treatment, and attenuated HG-induced oxidative stress of EPCs by scavenging excessive reactive oxygen species (ROS). A mechanistic study found the protective role of PCB2 is dependent on activating nuclear factor erythroid 2-related factor 2 (Nrf2). PCB2 increased the expression of Nrf2 and its downstream antioxidant genes to attenuate the oxidative stress induced by HG in EPCs, which were abolished by knockdown of Nrf2 expression. An in vivo study showed that intraperitoneal administration of PCB2 promoted wound healing and angiogenesis in diabetic mice, which was accompanied by a significant reduction in ROS level and an increase in circulating EPC number. Taken together, our results indicate that PCB2 treatment accelerates wound healing and increases angiogenesis in diabetic mice, which may be mediated by improving the mobilization and function of EPCs.

Feasibility and effectiveness of a single-catheter approach for adrenal vein sampling in patients with primary aldosteronism.

BACKGROUND: Adrenal vein sampling (AVS) is the preferred method for subtyping patients with primary aldosteronism, while the procedure is technically challenging. This study evaluated the feasibility and effectiveness of a single-catheter approach for AVS. METHODS: A retrospective analysis of 106 consecutive patients who underwent AVS was performed to determine the procedural success and complication rates. Bilateral AVS procedures were performed using a single 5-Fr Tiger catheter with repeated manual reshaping. RESULTS: We successfully advanced the catheter into the bilateral adrenal veins of all patients and reached a 90.6% procedural success rate of AVS. The procedural period was 33.0 ± 8.2 min, the fluoroscopy period was 5.8 ± 1.7 min, and the diagnostic contrast used was 17.3 ± 5.5 ml. Only one patient (0.9%) had a hematoma at the femoral puncture site. No other complications were observed. The operation period gradually shortened as the cumulative number of operations increased. The number of procedures required to overcome the learning curve was about 33 cases. CONCLUSIONS: The single-catheter approach is feasible and effective for AVS. Moreover, this approach required a relatively short learning curve for an inexperienced trainee.

Roles of arterial pressure volume index and arterial velocity pulse index trajectories in risk prediction in hypertensive patients with heart failure with preserved ejection fraction.

Background: Arterial pressure volume index (API) and arterial velocity pulse index (AVI) contribute to the development of vascular damage and cardiovascular disease. However, the relationship between common API/AVI trajectories and cardiovascular outcomes in hypertensive patients with heart failure with preserved ejection fraction (HFpEF) is unknown.Methods: A total of 488 consecutive hypertensive patients with HFpEF who repeatedly underwent API/AVI measurements were prospectively examined. We then applied API/AVI measurements into actual clinical practice. Latent mixture modeling was performed to identify API/AVI trajectories. Hazards ratios (HRs) were measured using Cox proportional hazard models.Results: We identified four distinct API/AVI trajectory patterns: low (7.6%), moderate (43.8%), high (28.9%), and very high (19.7%). Compared with the low group, higher API trajectories were associated with increased risk of total cardiovascular events (high group, adjusted HR: 2.91, 95% confidence interval [CI]: 1.97-4.26; very high group, adjusted HR: 2.46, 95%CI: 1.18-3.79). Consistently, higher AVI trajectories were also associated with a higher risk of total cardiovascular events (high group, adjusted HR: 2.58, 95%CI: 1.23-5.47; very high group, adjusted HR: 3.12, 95%CI: 1.83-6.08), compared with the low trajectory group.Conclusion: High API/AVI trajectories are strong predictors of cardiovascular risk in hypertensive patients with HFpEF. Among these patients, measuring API/AVI may improve risk stratification and provide additional information to tailor treatment strategies.

Tiaopi huxin recipe improved endothelial dysfunction and attenuated atherosclerosis by decreasing the expression of caveolin-1 in ApoE-deficient mice.

The Tiaopi Huxin recipe (TPHXR) is widely used in traditional Chinese medicine for the clinical treatment of coronary heart disease. However, the mechanism of TPHXR treatment of atherosclerosis (AS) has not been fully elucidated. In this study, we have aimed to explore the potential antiatherosclerotic effect of TPHXR and its underlying mechanisms. Male ApoE knockout (ApoE-/- ) mice were fed a high-fat diet for 12 weeks and were randomly divided into four groups: the control group, and the low-dose, medium-dose, and high-dose TPHXR groups. The nitric oxide (NO) levels in arterial tissue and human umbilical vein endothelial cells (HUVECs) were measured by diaminofluorescein-2 diacetate staining. Vasorelaxation of mice aorta was performed by wire myograph. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), hs-CRP, IL-6, and IL-1ß, in mice plasma were analyzed by enzyme-linked immunosorbent assay. Western blot analysis was applied to observe protein expression. Oil Red O staining was utilized for the quantification of atherosclerotic plaques. Results showed that 4 weeks of high- and medium-dose TPHXR treatment by oral gavage reduced atheromatous lesions in ApoE -/- mice. The high- and medium-dose TPHXR treatment, but not the low-dose treatment, promoted eNOS phosphorylation, increased NO levels and improved endothelium-dependent vasorelaxation in ApoE -/- mice. High- and medium-dose TPHXR, but not low-dose TPHXR, decreased the expression of cav-1, NF-κB p50, NF-κB p65, ICAM1, VCAM-1, TNF-α, IL-6, and IL-1ß in the vasculature of ApoE -/- mice. Enzyme-linked immunosorbent assay analysis indicated that high- and medium-dose TPHXR decreased the levels of TNF-α, IL-6, hs-CRP, and IL-1ß. In conclusion, our findings show that TPHXR improved the endothelial function and reduced atheromatous lesions in ApoE -/- mice. This result may be due to the decreased expression of caveolin-1 and NF-κB and, hence, the attenuated inflammatory response in AS mice vasculature. TPHXR may represent a promising intervention in patients with AS.

Knockout of TRPA1 exacerbates angiotensin II-induced kidney injury.

Macrophage-mediated inflammation plays a critical role in hypertensive kidney disease. Here, we investigated the role of transient receptor potential ankyrin 1 (TRPA1), a sensor of inflammation, in angiotensin II (ANG II)-induced renal injury. Subcutaneous infusion of ANG II (600 ng·min-1·kg-1) for 28 days was used to induce hypertension and renal injury in mice. The results showed that ANG II-induced hypertensive mice have decreased renal Trpa1 expression (P < 0.01), whereas ANG II receptor type 1a-deficient hypotensive mice have increased renal Trpa1 expression (P < 0.05) compared with their normotensive counterparts. ANG II induced similar elevations of systolic blood pressure in Trpa1-/- and wild-type (WT) mice but led to higher levels of blood urea nitrogen (P < 0.05), serum creatinine (P < 0.05), and renal fibrosis (P < 0.01) in Trpa1-/- mice than WT mice. Similarly, ANG II increased both CD68+/inducible nitric oxide synthase+ M1 and CD68+/arginase 1+ M2 macrophages in the kidneys of both Trpa1-/- and WT mice (all P < 0.01), with higher extents in Trpa1-/- mice (both P < 0.01). Compared with WT mice, Trpa1-/- mice had significantly increased expression levels of inflammatory cytokines and their receptors in the kidney. Cultured murine macrophages were stimulated with phorbol 12-myristate 13-acetate, which downregulated gene expression of TRPA1 (P < 0.01). A TRPA1 agonist, cinnamaldehyde, significantly inhibited phorbol 12-myristate 13-acetate-stimulated expression of IL-1ß and chemokine (C-C motif) ligand 2 in macrophages, which were attenuated by pretreatment with a TRPA1 antagonist, HC030031. Furthermore, activation of TRPA1 with cinnamaldehyde induced apoptosis of macrophages. These findings suggest that TRPA1 may play a protective role in ANG II-induced renal injury, likely through inhibiting macrophage-mediated inflammation.

Cinnamaldehyde Ameliorates High-Glucose-Induced Oxidative Stress and Cardiomyocyte Injury Through Transient Receptor Potential Ankyrin 1.

Oxidative stress plays a critical role in diabetic cardiomyopathy. Transient receptor potential ankyrin subtype 1 (TRPA1) has antioxidative property. In this study, we tested whether activation of TRPA1 with cinnamaldehyde protects against high-glucose-induced cardiomyocyte injury. Cinnamaldehyde remarkably decreased high-glucose-induced mitochondrial superoxide overproduction, upregulation of nitrotyrosine, P22, and P47, and apoptosis in cultured H9C2 cardiomyocytes (P < 0.01), which were abolished by a TRPA1 antagonist HC030031 (P < 0.01). Nrf2 and its induced genes heme oxygenase-1 (HO-1), glutathione peroxidase-1 (GPx-1), and quinone oxidoreductase-1 (NQO-1) were slightly increased by high glucose (P < 0.01) and further upregulated by cinnamaldehyde (P < 0.05 or P < 0.01). Feeding with cinnamaldehyde (0.02%)-containing diet for 12 weeks significantly decreased cardiac nitrotyrosine levels (P < 0.01), fibrosis, and cardiomyocyte hypertrophy (P < 0.05), while increased expression of antioxidative enzymes (HO-1, GPx-1, NQO-1, and catalase) (P < 0.01) in the myocardial tissue of db/db diabetic mice. These results suggest that cinnamaldehyde protects against high-glucose-induced oxidative damage of cardiomyocytes likely through the TRPA1/Nrf2 pathway.

Predictors and Management of Antiplatelet-Related Bleeding Complications for Acute Coronary Syndrome in Chinese Elderly Patients.

BACKGROUND/AIMS: Bleeding complications after percutaneous coronary intervention (PCI) are strongly associated with adverse patient outcomes. However, there are no specific guidelines for the predictors and management of antiplatelet-related bleeding complications in Chinese elderly patients with acute coronary syndrome (ACS). METHODS: A retrospective analysis of 237 consecutive patients (aged ≥ 75 years) with ACS who had undergone successful PCI from January 2010 to December 2016 was performed to identify predictors and management of antiplatelet-related bleeding complications. Multivariate logistic regression analysis was conducted to investigate independent predictors of antiplatelet-related bleeding complications. We defined antiplatelet-related bleeding complications as first hospitalization received long-term oral antiplatelet therapy and required hospitalization, including gastrointestinal and intracranial bleedings. RESULTS: After multivariable adjustment, independent risk predictors of antiplatelet-related bleeding complications included female gender (odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.98 to 4.15; P = 0.011), body mass index (OR: 1.54; 95% CI: 1.06 to 1.94; P = 0.034), previous history of bleeding (OR: 4.03; 95% CI: 1.84 to 6.12; P = 0.004), fasting blood glucose (OR: 2.79; 95% CI: 1.23 to 4.46; P = 0.025), and chronic total occlusion lesion (OR: 4.69; 95% CI: 2.19 to 7.93; P = 0.007). Of 46 patients with antiplatelet-related bleeding complications, 54.3% were treated short-term dual antiplatelet therapy (DAPT) cessation (0-7 days) and 45.7% underwent long-term DAPT cessation (> 7 days). Among these, 14 patients presented major adverse cardiac and cerebrovascular events (MACCE), whereas no re-bleeding happened over all available follow-up. The incidence of MACCE was not significantly different between the two groups one year after PCI (36.0% for short-term DAPT cessation versus 23.8% for long-term DAPT cessation, P = 0.522). CONCLUSION: For elderly patients with ACS, multiple factors were likely to contribute to antiplatelet-related bleeding complications, especially previous history of bleeding and chronic total occlusion lesion. Better individualized, tailored and risk-adjusted antiplatelet therapy after PCI is urgently needed in this high-risk population.

Disentangling "Bright" and "Dark" Interactions in Ordered Assemblies of Organic Semiconductors.

We report on spatially correlated wavelength-resolved photoluminescence and Kelvin probe force microscopy to probe ground state charge-transfer coupling and its correlation with pi-stacking order in nanoscale assemblies of a small molecule n-type organic semiconductor, tetraazaterrylene (TAT). We find a distinct upshift in surface potential contrast (SPC) corresponding to a decrease in work function in TAT in the transition from disordered spun-cast films to ordered crystalline nanowire assemblies, accompanied by a nanowire size dependence in the SPC shift suggesting that the shift depends on both ground state charge transfer interaction and a size (volume)-dependent intrinsic doping associated with the nitrogen substitutions. For the smallest nanowires studied (surface height ≈ 10-15 nm), the SPC shift with respect to disordered films is +110 meV, in close agreement with recent theoretical calculations. These results illustrate how "dark" (ground-state) interactions in organic semiconductors can be distinguished from "bright" (excited-state) exciton coupling typically assessed by spectral measurements alone.

Salvianolic Acid B Ameliorates Hyperglycemia and Dyslipidemia in db/db Mice through the AMPK Pathway.

BACKGROUND/AIMS: Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism. METHODS: Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks. RESULTS: Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver. CONCLUSION: Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.

Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2.

BACKGROUND/AIMS: It is well documented that hyperglycemia-induced oxidative stress is an important causative factor of endothelial dysfunction. Cinnamaldehyde (CA) is a key flavor compound in cinnamon essential oil that can enhance the antioxidant defense against reactive oxygen species (ROS) by activating NF-E2-related factor 2 (Nrf2), which has been shown to have a cardiovascular protective effect, but its role in endothelial dysfunction induced by high glucose is unknown. METHODS: Dissected male C57BL/6J mouse aortic rings and HUVECs were cultured in normal glucose(NG 5.5 mM) or high glucose(HG 30.0 mM) DMEM treatment with or without CA (10 µM). RESULTS: Treatment with CA protected the endothelium relaxation, inhibited ROS generation and preserved nitric oxide (NO) levels in the endothelium of mouse aortas treated with high glucose . CA up-regulated Nrf2 expression, promoted its translocation to the nucleus'and increased HO-1, NQO1, Catalase and Gpx1 expression under high glucose condition. The increased level of nitrotyrosine in HUVECs under high glucose was also attenuated by treatment with CA. Dihydroethidium (DHE) and DAF-2DA staining indicated that CA inhibited the ROS generation and preserved the NO levels in HUVECs, but these effects were reversed by Nrf2-siRNA in high glucose conditions. CONCLUSION: Our results indicated that CA protected endothelial dysfunction under high glucose conditions and this effect was mediated by Nrf2 activation and the up-regulation of downstream target proteins. CA administration may represent a promising intervention in diabetic patients who are at risk for vascular complications.

Biological activities of salvianolic acid B from Salvia miltiorrhiza on type 2 diabetes induced by high-fat diet and streptozotocin.

CONTEXT: Salvia miltiorrhiza Bge. (Labiatae) has been widely used for treating diabetes for centuries. Salvianolic acid B (SalB) is the main bioactive component in Salvia miltiorrhiza; however, its antidiabetic activity and possible mechanism are not yet clear. OBJECTIVE: To investigate the effects of SalB on glycometabolism, lipid metabolism, insulin resistance, oxidative stress, and glycogen synthesis in type 2 diabetic rat model. MATERIALS AND METHODS: High-fat diet (HFD) and streptozotocin-induced diabetic rats were randomly divided into model group, SalB subgroups (50, 100, and 200 mg/kg), and rosiglitazone group. RESULTS: Compared with the model group, SalB (100 and 200 mg/kg) significantly decreased blood glucose (by 23.8 and 21.7%; p < 0.05 and p < 0.01) and insulin (by 31.3 and 26.6%; p < 0.05), and increased insulin sensitivity index (by 10.9 and 9.3%; p < 0.05). They also significantly decreased total cholesterol (by 24.9 and 27.9%; p < 0.01), low-density lipoprotein cholesterol (by 56.2 and 64.6%; p < 0.01), non-esterified fatty acids (by 32.1 and 37.9%; p < 0.01), hepatic glycogen (by 41.3 and 60.5%; p < 0.01), and muscle glycogen (by 33.2 and 38.6%; p < 0.05), and increased high-density lipoprotein cholesterol (by 50.0 and 61.4%; p < 0.05 and p < 0.01), which were originally altered by HFD and streptozotocin. In addition, SalB (200 mg/kg) markedly decreased triglyceride and malondialdehyde (by 31.5 and 29.0%; p < 0.05 and p < 0.01), and increased superoxide dismutase (by 56.6%; p < 0.01), which were originally altered by HFD and streptozotocin. DISCUSSION AND CONCLUSION: The results indicate that SalB can inhibit symptoms of diabetes mellitus in rats and these effects may partially be correlated with its insulin sensitivity, glycogen synthesis and antioxidant activities.

Salvianolic acid B inhibited PPARγ expression and attenuated weight gain in mice with high-fat diet-induced obesity.

BACKGROUND/AIMS: Obesity contributes to the development of cardiometabolic disorders such as type 2 diabetes, fatty liver disease and cardiovascular disease. Salvianolic acid B (Sal B) is a molecule derived from the root of Salvia miltiorrhiza (Danshen), which is a traditional Chinese medicine that is widely used to treat cardiovascular diseases. However, the role of Sal B in obesity and obesity-related metabolic disorders is unknown. In this study, we aimed to investigate the effects of Sal B on high-fat diet-induced obesity and determine the possible mechanisms involved. METHODS: Male C57BL/6J mice fed a high-fat diet for 12 weeks received a supplement of Sal B (100 mg/kg/day) by gavage for a further 8 weeks. These mice were compared to control mice fed an un-supplemented high-fat diet. 3T3-L1 preadipocytes were used in vitro studies. RESULTS: Sal B administration significantly decreased body weight, white adipose tissue weight, adipocyte size and lipid (triglyceride and total cholesterol) levels in obese mice. Eight weeks of Sal B administration also improved the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) scores in high-fat diet-induced obese mice. In 3T3-L1 preadipocytes that were cultured in vitro and induced to differentiate, Sal B reduced the accumulation of lipid droplets and lipid content in a dose-dependent manner. Immunoblotting indicated that Sal B decreased peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) expression but increased the expression of GATA binding protein 2 and 3 (GATA 2, GATA 3) both in vivo and in vitro. CONCLUSION: Our data suggest that Sal B may reduce obesity and obesity-related metabolic disorders by suppressing adipogenesis. The effects of Sal B in adipose tissue may be related to its action on PPARγ, C/EBPα, GATA-2 and GATA-3.

Telmisartan attenuates monocrotaline-induced pulmonary artery endothelial dysfunction through a PPAR gamma-dependent PI3K/Akt/eNOS pathway.

BACKGROUND: Pulmonary artery endothelial dysfunction has been demonstrated in pulmonary arterial hypertension (PAH). Telmisartan has beneficial effects in endothelial function in PAH patients; however, the underlying mechanisms for these effects remain unknown. AIMS: In this study, we observed the effects of telmisartan on monocrotaline (MCT)-induced Sprague Dawley (SD) rat model of PAH. METHODS: After a single-dose injection of MCT (60 mg/kg), oral administration of telmisartan (10 mg/kg/d) was started from day 1 to day 28 or with saline as MCT control. The vasorelaxation and remodelling of pulmonary arteries; the expression of peroxisome proliferator-activated receptor γ (PPARγ), Akt, eNOS; levels of phosphorylation of Akt (p-Akt) and phosphorylation of eNOS (p-eNOS) were analysed in isolated rat pulmonary arteries and cultured human pulmonary artery endothelial cells (HPAECs). RESULTS: Compared to MCT control group, telmisartan treatment ameliorated pulmonary artery endothelial dysfunction and remodelling, prevented the elevation of right ventricular systolic pressure (RVSP) induced by MCT. Immunoblotting results indicated lower levels of PPARγ, p-Akt and p-eNOS in pulmonary arteries treated with MCT alone and levels were significantly restored by co-treatment with telmisartan. In isolated pulmonary arteries, the impaired endothelium-dependent vasorelaxation of pulmonary arteries was improved following incubation with telmisartan for 12 h, whereas this effect was blocked by the inhibition of either PPARγ or phosphoinositide 3-kinase (PI3K) signals transduction. In cultured HPAECs, treatment with telmisartan increased PPARγ expression and promoted the phosphorylation of Akt and eNOS, thereby increasing the production of NO. These effects were abolished by the inhibition of PPARγ or PI3K. CONCLUSION: Telmisartan protected against endothelial dysfunction in MCT-induced PAH through a PPARγ-dependent PI3K/Akt/eNOS pathway. Thus, telmisartan may be a promising therapeutic strategy for patients with a high risk of PAH.

Activation of PPAR-γ by pioglitazone attenuates oxidative stress in aging rat cerebral arteries through upregulating UCP2.

Increasing amounts of evidence implicate oxidative stress as having a pivotal role in age-related cerebrovascular dysfunction, which is an important risk factor for the development of cerebrovascular disease. Previous studies have shown that the activation of the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) in vascular endothelial cells results in an improvement of vascular function. Pioglitazone, a well-known PPAR-γ agonist, protects against oxidative stress in the rostral ventrolateral medulla by the upregulation of mitochondrial uncoupling protein 2 (UCP2). In this study, we sought to explore the effects and the underlying mechanisms of pioglitazone on age-related oxidative stress elevation and cerebrovascular dysfunction in aging rat cerebral arteries. A natural aging model was constructed and used in these experiments. One-month oral administration of pioglitazone (20 mg·kg·d) ameliorated the production of reactive oxygen species, promoted endothelial nitric oxide synthase phosphorylation and increased the nitric oxide available, thus improving endothelium-dependent relaxation in aging rat cerebral arteries. One-month pioglitazone administration also restored PPAR-γ expression and increased the levels of UCP2 in aging rat cerebral arteries. Using in vitro studies, we demonstrated that pioglitazone attenuated reactive oxygen species levels in aging human umbilical vein endothelial cells through PPAR-γ activation. Furthermore, we found that this occurs in an UCP2-dependent manner. Our study demonstrated that the activation of PPAR-γ by pioglitazone protected against oxidative stress damage in aging cerebral arteries by upregulating UCP2. PPAR-γ may be a new target in treating age-related cerebrovascular dysfunction.

Association between vacA genotypes and the risk of duodenal ulcer: a meta-analysis.

Epidemiological studies have reported the relationship between vacuolating cytotoxin A (vacA) s-/m- region genotypes and duodenal ulcer (DU), but the results remained inconclusive. We performed the present meta-analysis to investigate a more authentic association between vacA s-/m- region genotypes and DU. Literature search was performed by searching Embase, PubMed and ISI Web of Science databases as well as checking references from identified articles, reviews and the abstracts presented at related scientific societies meetings. The association was assessed by combined odds ratio (OR) with 95% confidence interval (CI). A total of 42 studies were included in our final meta-analysis. The combined ORs (95% CIs) showed that vacA s1 (OR = 2.96, 95% CI = 2.34-3.75), m1 (OR = 1.46, 95% CI = 1.05-2.04) and s1m1 (OR = 1.89, 95% CI = 1.47-2.42) were associated with increased DU risk significantly in the overall studied population. Subgroup analyses by ethnicity showed that vacA s1 increased the risk of DU in Asian countries (OR = 1.92, 95% CI = 1.30-2.83), European countries (OR = 3.58, 95% CI = 2.13-6.03) and Latin American countries (OR = 4.20, 95% CI = 2.21-7.98); vacA m1 increased the risk of DU in Latin American countries (OR = 2.98, 95% CI = 1.59-5.56); vacA s1m1 increased the risk of DU in Asian countries (OR = 2.04, 95% CI = 1.12-3.73) and Latin American countries (OR = 2.05, 95% CI = 1.20-3.48); vacA s2m1 increased the risk of DU in Latin American countries (OR = 2.30, 95% CI = 1.17-4.50). The data suggest that genotype testing of vacA s- and m- region will be useful in screening susceptible individuals for DU development.

A meta-analysis supporting the superiority of staged carotid artery stenting and coronary artery bypass grafting in patients with concurrent severe coronary and carotid artery stenosis.

BACKGROUND: This study sought to ascertain whether a staged approach involving carotid artery stenting (CAS) and coronary artery bypass grafting (CABG) holds superiority over the synchronous (Syn) strategy of CAS or carotid endarterectomy (CEA) and CABG in patients necessitating combined revascularization for concurrent carotid and coronary artery disease. METHOD: Studies were identified through 3 databases: PubMed, EMBASE, and the Cochrane Library. Statistical significance was defined as a P value of less than .05 for all analyses, conducted using STATA version 12.0. RESULTS: In the comparison between staged versus Syn CAS and CABG for patients with concomitant severe coronary and carotid stenosis, 4 studies were analyzed. The staged procedure was associated with a lower rate of 30-day stroke (OR = 8.329, 95% CI = 1.017-69.229, P = .048) compared to Syn CAS and CABG. In the comparison between staged CAS and CABG versus Syn CEA and CABG for patients with concomitant severe coronary and carotid stenosis, 5 studies were examined. The staged CAS and CABG procedure was associated with a lower rate of mortality (OR = 2.046, 95% CI = 1.304-3.210, P = .002) compared to Syn CEA and CABG. CONCLUSION: The Syn CAS and CABG was linked to a higher risk of peri-operative stroke compared to staged CAS and CABG. Additionally, patients undergoing staged CAS and CABG exhibited a significantly decreased risk of 30-day mortality compared to Syn CEA and CABG. Future randomized trials or prospective cohorts are essential to confirm and validate these findings.