Research Progress on the Role and Mechanism of GDF15 in Body Weight Regulation.

BACKGROUND: Growth differentiation factor-15 (GDF15) is a member of the growth differentiation factor subfamily in the transforming growth factor beta superfamily. GDF15 has multiple functions and can regulate biological processes. High levels of GDF15 in the circulation can affect metabolic processes. Studies have shown that GDF15 is associated with changes in body weight. SUMMARY: This review reviews the current knowledge on the relationship between GDF15 and body weight change, focusing on the role and mechanism of GDF15 in body weight regulation. GDF15 plays an important role in reducing food intake, improving insulin resistance, and breaking down fat, suggesting that GDF15 has an important regulatory effect on body weight. The mechanism by which GDF15 causes reduced food intake may be related to changes in food preference, delayed gastric emptying, and conditioned taste aversion. GDF15 can combat insulin resistance induced by inflammation or protect ß cell from apoptosis. GDF15 probably promotes lipolysis through a brain-somatic tissue circuit. Several factors and related signaling pathways are also mentioned that can contribute to the effects of GDF15 on reducing weight. KEY MESSAGE: GDF15 plays an important role in weight regulation and provides a new direction for the treatment of obesity. Its effects on resisting obesity are of great significance to inhibiting the progression of metabolic diseases. It is expected to become a new target for regulating body weight, improving obesity, and treating metabolic diseases such as diabetes.

Deficiency of Tregs in hypertension-associated left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) is the most common target organ damage in hypertension. Abnormal numbers or functions of CD4+ CD25+ Foxp3+ regulatory T lymphocytes (Tregs) can cause immune disorders, which participates in LVH. This study aimed to explore the role of Tregs in LVH by investigating circulating Tregs and associated cytokine levels in hypertensive patients with or without LVH. Blood samples were collected from 83 hypertensive patients without LVH (essential hypertension group, EH), 91 hypertensive patients with LVH (left ventricular hypertrophy group, LVH), and 69 normotensive controls without LVH (control group, CG). Tregs and cytokines were measured by flow cytometry and enzyme-linked immunosorbent assays. We found that circulating Tregs were significantly lower in hypertensive patients than in CG subjects. It was lower in LVH than in EH patients. No correlation between blood pressure regulation and Tregs was found in EH or LVH patients. Furthermore, Tregs in older females were lower than those in older males among LVH patients. Additionally, serum interleukin-10 (IL-10) and transforming growth factor beta 1 (TGFß1) decreased in hypertensive patients, and interleukin-6 (IL-6) increased in LVH patients. Tregs were negatively correlated with creatine kinase, low-density lipoprotein cholesterol, apoprotein B, high-sensitivity C-reactive protein, and left ventricular mass index (LVMI) values. In general, our study demonstrates significantly decreased circulating Tregs in hypertensive LVH patients. Decreased circulating Tregs in LVH is independent of blood pressure regulation. IL-6, IL-10, and TGF-ß1 are related with LVH in hypertension.

Arterial remodeling: the role of mitochondrial metabolism in vascular smooth muscle cells.

Arterial remodeling is a common pathological basis of cardiovascular diseases such as atherosclerosis, vascular restenosis, hypertension, pulmonary hypertension, aortic dissection, and aneurysm. Vascular smooth muscle cells (VSMCs) are not only the main cellular components in the middle layer of the arterial wall but also the main cells involved in arterial remodeling. Dedifferentiated VSMCs lose their contractile properties and are converted to a synthetic, secretory, proliferative, and migratory phenotype, playing key roles in the pathogenesis of arterial remodeling. As mitochondria are the main site of biological oxidation and energy transformation in eukaryotic cells, mitochondrial numbers and function are very important in maintaining the metabolic processes in VSMCs. Mitochondrial dysfunction and oxidative stress are novel triggers of the phenotypic transformation of VSMCs, leading to the onset and development of arterial remodeling. Therefore, pharmacological measures that alleviate mitochondrial dysfunction reverse arterial remodeling by ameliorating VSMCs metabolic dysfunction and phenotypic transformation, providing new options for the treatment of cardiovascular diseases related to arterial remodeling. This review summarizes the relationship between mitochondrial dysfunction and cardiovascular diseases associated with arterial remodeling and then discusses the potential mechanism by which mitochondrial dysfunction participates in pathological arterial remodeling. Furthermore, maintaining or improving mitochondrial function may be a new intervention strategy to prevent the progression of arterial remodeling.

Improvement of hemodynamic parameters in aortic stenosis patients with transcatheter valve replacement by using impedance cardiography.

Background: The hemodynamic changes of patients with aortic stenosis (AS) who underwent transcatheter valve replacement (TAVR) have not been completely investigated. Methods and results: We enrolled 74 patients with AS who underwent TAVR and assessed cardiac function changes at 1 week post-operation by impedance cardiography (ICG) in a supine position at rest for more than 15 min. Of the 74 patients, 47 had preserved left ventricular ejection fraction (LVEF ≥ 50%; preserved-LVEF group) and 27 had reduced LVEF (LVEF <50%; reduced-LVEF group). TAVR improved the cardiac structure and function, as evidenced by the decrease in the left ventricular end-diastolic (LVED), left atrial diameter (LAD), and an increase in the LVEF. We observed a decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP) level compared to that before treatment. Moreover, patients with reduced LVEF had a more significant reduction of NT-proBNP than those with preserved LVEF. Meanwhile, the blood pressure of patients had no significant differences pre- and post-operation. Based on ICG, there were no changes in the parameter of cardiac preload [thoracic fluid content (TFC)]. We observed an improvement in parameters of diastolic cardiac function [left ventricular ejection time (LVET) and pre-ejection period (PEP)]. And we detected converse results in parameters of heart systolic function [systolic time ratio (STR), cardiac output (CO), cardiac index (CI), stroke index (SI), and stroke volume (SV)] and cardiac afterload [stroke systemic vascular resistance (SSVR) and SSVR-index (SSVRI)]. In addition, TFC level was decreased in patients with thoracic volume overload after valve replacement. Subgroup analysis showed that the changes in those parameters were more noticeable in patients with reduced LVEF than that with preserved LVEF. Moreover, we observed no effects on parameters of heart systolic function and heart afterload in the LVEF ≥ 50% group before and after TAVR. Conclusion: Our data revealed a beneficial effect of TAVR in diastolic function and preload as detected by the ICG. But the LV systolic function and cardiac afterload were not improved in patients with LVEF <50%. The result indicated that ICG could be used as an important technique to monitor the cardiac condition of patients after aortic valve replacement.

Methotrexate can prevent cardiovascular events in patients with rheumatoid arthritis: An updated meta-analysis.

AIMS: The incidence of cardiovascular events (CVEs) in patients with rheumatoid arthritis (RA) is higher than that in people without RA. This may be because inflammation promotes the progression of atherosclerosis. Anti-inflammatory drugs might reduce the occurrence of CVEs in patients with RA. Methotrexate (MTX) is a conventional synthetic anti-rheumatic drug that is widely used in the treatment of RA. We performed a meta-analysis to determine whether MTX can prevent CVEs in RA patients. Then, we discussed the possibility of using MTX to prevent recurred CVEs in patients with coronary heart disease (CHD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library using the key words "methotrexate," "cardiovascular," "acute coronary syndrome," "coronary heart disease," "myocardial infarction," "angina pectoris," and "rheumatoid arthritis." The efficacy outcome was defined as a composite of CVEs, including stable angina, acute coronary syndrome, stroke, heart failure, and cardiac death. RESULTS: A total of 10 studies and 195,416 RA patients were included in our meta-analysis, and the effect size of relative risk (RR) was pooled using a fixed effect model. The results showed that MTX prevented CVEs in RA patients (RR: 0.798, 95% CI 0.726-0.876, P = .001, I2 = 27. 9%). CONCLUSION: MTX can prevent CVEs in RA patients, but there is not sufficient evidence for using MTX to treat patients with CHD.

Circular RNA in cardiovascular disease: Expression, mechanisms and clinical prospects.

Circular RNAs (circRNAs) are a group of covalently closed, endogenous, non-coding RNAs, which exist widely in human tissues including the heart. Increasing evidence has shown that cardiac circRNAs play crucial regulatory roles in cardiovascular diseases (CVDs). In this review, we aimed to provide a systemic understanding of circRNAs with a special emphasis on the cardiovascular system. We have summarized the current research on the classification, biogenesis and properties of circRNAs as well as their participation in the pathogenesis of CVDs. CircRNAs are conserved, stable and have specific spatiotemporal expression; thus, they have been accepted as a potential diagnostic marker or an incremental prognostic biomarker for CVDs.

[Acupuncture at Sifeng (EX-UE 10) as adjuvant treatment for pneumonia of phlegm-heat blocking lung type in children: a randomized controlled trial].

OBJECTIVE: To observe the clinical therapeutic effect of acupuncture at Sifeng (EX-UE 10) as adjuvant treatment for pneumonia of phlegm-heat blocking lung type in children. METHODS: A total of 80 children with pneumonia of phlegm-heat blocking lung type were randomized into an observation group (40 cases, 1 case dropped off) and a control group (40 cases). In the control group, routine anti-infection and symptomatic and supportive treatment were given. On the basis of the treatment in the control group, acupuncture was applied at Sifeng (EX-UE 10) in the observation group, once every 2 days, 4 times were required. Before and after treatment, the score of clinical symptoms and signs and level of serum hypersensitive C-reactive protein (hs-CRP) were observed in the two groups. The antifebrile time, lung moist rale disappearance time, duration of antibacterial drugs and hospital stays were recorded, and the clinical therapeutic effect was evaluated in the two groups. RESULTS: After treatment, the scores of clinical symptoms and signs and levels of serum hs-CRP were reduced in the two groups (P<0.01), and the changes of scores of fever, cough and lung moist rale, secondary symptom score, total score of clinical symptoms and signs and level of serum hs-CRP in the observation group were larger than those in the control group (P<0.05, P<0.01). The antifebrile time, lung moist rale disappearance time, duration of antibacterial drugs and hospital stays in the observation group were shorter than those in the control group (P<0.05). The total effective rate was 87.2% (34/39) in the observation group, which was superior to 65.0% (26/40) in the control group (P<0.05). CONCLUSION: Acupuncture at Sifeng (EX-UE 10) as adjuvant treatment can relieve clinical symptoms, shorten duration of antibacterial drugs and hospital stays for children with pneumonia of phlegm-heat blocking lung type.

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating low-density lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.

Natural selection and genetic diversity of domain I of Plasmodium falciparum apical membrane antigen-1 on Bioko Island.

BACKGROUND: Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is a promising candidate antigen for a blood-stage malaria vaccine. However, antigenic variation and diversity of PfAMA-1 are still major problems to design a universal malaria vaccine based on this antigen, especially against domain I (DI). Detail understanding of the PfAMA-1 gene polymorphism can provide useful information on this potential vaccine component. Here, general characteristics of genetic structure and the effect of natural selection of DIs among Bioko P. falciparum isolates were analysed. METHODS: 214 blood samples were collected from Bioko Island patients with P. falciparum malaria between 2011 and 2017. A fragment spanning DI of PfAMA-1 was amplified by nested polymerase chain reaction and sequenced. Polymorphic characteristics and the effect of natural selection were analysed using MEGA 5.0, DnaSP 6.0 and Popart programs. Genetic diversity in 576 global PfAMA-1 DIs were also analysed. Protein function prediction of new amino acid mutation sites was performed using PolyPhen-2 program. RESULTS: 131 different haplotypes of PfAMA-1 were identified in 214 Bioko Island P. falciparum isolates. Most amino acid changes identified on Bioko Island were found in C1L. 32 amino acid changes identified in PfAMA-1 sequences from Bioko Island were found in predicted RBC-binding sites, B cell epitopes or IUR regions. Overall patterns of amino acid changes of Bioko PfAMA-1 DIs were similar to those in global PfAMA-1 isolates. Differential amino acid substitution frequencies were observed for samples from different geographical regions. Eight new amino acid changes of Bioko island isolates were also identified and their three-dimensional protein structural consequences were predicted. Evidence for natural selection and recombination event were observed in global isolates. CONCLUSIONS: Patterns of nucleotide diversity and amino acid polymorphisms of Bioko Island isolates were similar to those of global PfAMA-1 DIs. Balancing natural selection across DIs might play a major role in generating genetic diversity in global isolates. Most amino acid changes in DIs occurred in predicted B-cell epitopes. Novel sites mapped on a three dimensional structure of PfAMA-1 showed that these regions were located at the corner. These results may provide significant value in the design of a malaria vaccine based on this antigen.

Soluble epoxide hydrolase inhibitors, t-AUCB, regulated microRNA-1 and its target genes in myocardial infarction mice.

PURPOSE: Soluble epoxide hydrolase inhibitors (sEHIs) had been demonstrated to produce cardioprotective effects against ischemia-induced lethal arrhythmias, but the exact mechanisms remain unknown. The present study was designed to investigate whether the beneficial effects of sEHIs are related to regulation of microRNA-1, which was a proarrhythmic factor in the ischemic heart. METHODS: A mousemyocardial infarction (MI) model was established by ligating the coronary artery. sEHI t-AUCB (0.2, 1, 5 mg/L in drinking-water) was administered daily seven days before MI. The incidence of arrhythmias was assessed by in vivo electrophysiologic studies. miR-1, KCNJ2 (encoding the K+ channel subunit Kir2.1), and GJA1 (encoding connexin 43 [Cx43]) mRNA were measured by real-time PCR; Kir2.1 and Cx43 protein were assessed by western blotting and immunohistochemistry. RESULTS: We demonstrated that sEHIs reduced the myocardium infarct size and incidence of inducible arrhythmias in MI mice. Up-regulation of miR-1 and down-regulation of KCNJ2/Kir2.1 and GJA1/Cx43 mRNA/protein were observed in ischemic myocaridum, whereas administration of sEHIs produced an opposite effect. In addition, miR-1 overexpression inhibited expression of the target mRNA and their corresponding proteins, whereas t-AUCB reversed the effects. Our results further revealed that PI3K/Akt signaling pathway might participate in the negatively regulation of miR-1 by sEHi. CONCLUSIONS: We conclude that sEHIs can repress miR-1, thus stimulate expression of KCNJ2/Kir2.1 and GJA1/Cx43 mRNA/protein in MI mice, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmias.

Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis.

Background Statin treatment in association with physical exercise can substantially reduce mortality in dyslipidaemic individuals. However, the available data to compare the efficacy and safety of statins and exercise combination therapy with statin monotherapy are limited. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, Embase and the Cochrane Library from database inception until December 2016. We included randomised and non-randomised studies that compared the efficacy and safety of statins and exercise combination therapy with statin monotherapy in patients with dyslipidaemia. Standardised mean differences were calculated and pooled by means of fixed effects models. The risk of bias and heterogeneity among trials was also assessed. Seven articles were assessed in terms of the efficacy of therapy and 13 from the viewpoint of therapeutic safety. Results In terms of efficacy, statins and exercise combination decreased the incidence of diabetes mellitus, improved insulin sensitivity and inflammation, but caused no change in lipid profile compared to statins alone. In terms of safety, statins and exercise combination increased peak oxygen uptake (standardised mean difference 1.01, 95% confidence interval 0.46 to 1.57) compared to statins alone. In contrast to statin-induced myopathy, chronic exercise training prior to statin treatment could counteract statin-induced adverse effects in skeletal muscle. Conclusion Statins and exercise combination therapy is more effective than statin monotherapy in terms of insulin sensitivity, inflammation and exercise capacity. The small number of studies warrants the need for more randomised controlled trials evaluating the efficacy and safety of combination therapy.

Soluble epoxide hydrolase inhibitors might prevent ischemic arrhythmias via microRNA-1 repression in primary neonatal mouse ventricular myocytes.

Ischemic arrhythmias are the main causes of sudden cardiac death. It has been reported that soluble epoxide hydrolase inhibitors (sEHis) could prevent arrhythmias; however, the underlying molecular mechanisms remain unclear. In recent years, the proarrhythmic role of microRNA-1 (miR-1) has been investigated. This study aimed to elucidate whether sEHis prevented ischemic arrhythmias by suppressing miR-1. The primary neonatal mouse ventricular myocyte model of miR-1 overexpression was established by incubating with agonist microONTM mmu-miR-1a-3p agomir (DAEDstainTM Dye) (agomiR-1). The sEHi, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), was administered following miR-1 overexpression. Quantitative real-time PCR (qPCR) and western blotting were used to test alterations in the expression of miR-1 and its target mRNAs GJA1 and KCNJ2 and their respective encoded proteins connexin 43 (Cx43) and the K+ channel subunit (Kir2.1). The whole-cell patch-clamp technique was used to record the alterations of the inward rectifying K+ current (IK1). Compared with the control group, miR-1 levels were significantly increased in the agomiR-1 group (p < 0.05), which suggested the successful construction of the miR-1 overexpression model. Compared with the control group, the levels of GJA1 and KCNJ2 mRNAs and Cx43 and Kir2.1 proteins in the agomiR-1 group were significantly decreased, and IK1 was significantly impaired (all p < 0.05). The miR-1 levels were dose-dependently decreased by t-AUCB, whereas t-AUCB dose-dependently increased the levels of GJA1 and KCNJ2 mRNAs and Cx43 and Kir2.1 proteins. Furthermore, t-AUCB restored the impaired IK1 (all p < 0.05). In conclusion, the sEHi t-AUCB has the ability to down-regulate proarrhythmic miR-1 and up-regulate its target genes and proteins, eventually restoring IK1.

Proprotein convertase subtilisin/kexin type 9 potentially influences cholesterol uptake in macrophages and reverse cholesterol transport.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptor (LDLRs) molecules expressed on the cell surface. Gene inactivation of PCSK9 reduces the areas of atherosclerotic lesions in mice, and the effect is mainly dependent on LDLRs. Furthermore, a positive relationship between PCSK9 and cholesterol accumulation in the wall of the aorta has been established. However, the mechanism remains unknown. As PCSK9 is mainly expressed in atherosclerotic plaque and in the liver, we hypothesize that PCSK9 might increase oxidized LDL uptake and impair macrophage-mediated reverse cholesterol transport, contributing to the development of atherosclerosis.

Effects of soluble epoxide hydrolase inhibitor on the expression of fatty acid synthase in peripheral blood mononuclear cell in patients with acute coronary syndrome.

BACKGROUND: Researches have shown that soluble epoxide hydrolase inhibitors (sEHi) can protect against the development of atherosclerosis. Simultaneously, emerging evidences have implicated the association between fatty acid synthase (FAS) and acute coronary syndrome (ACS). We tested the hypothesis that sEHi could reduce the occurrence of ACS by regulating FAS. METHODS: Hospitalized ACS patients were selected as the ACS group (n = 65) while healthy normal subjects as the control group (n = 65). The blood levels of lipoproteins, fasting glucose, myocardial enzyme and high-sensitivity C-reactive protein (hs-CRP) were measured within 24 hours after admission. The peripheral blood mononuclear cells (PBMCs) were isolated and cultured. Trans-4-[4-(3-Adamantan-1-ylureido)cyclohexyloxy] benzoic acid (t-AUCB), a kind of sEHi, was then added to cells in various concentrations (0, 10, 50, 100 µmol/L). The expression of FAS, interleukin-6 (IL-6) mRNA and protein was detected by real-time PCR or Western blot, respectively. RESULTS: (1) Compared with the control group, the serum concentration of hs-CRP in the ACS group was increased (P<0.05). The expression of FAS, IL-6 mRNA and protein were significantly increased in PBMCs from the ACS group (all P<0.05). Moreover, the levels of FAS and IL-6 mRNA were positively correlated with the serum concentration of hs-CRP (r = 0.685, P<0.01; r = 0.715, P<0.01) respectively. (2) The expression of FAS, IL-6 mRNA and protein in PBMCs from the ACS group were dose-dependently inhibited by sEHi (all P<0.05). CONCLUSIONS: sEH inhibition regulated FAS and inhibited inflammation in cultured PBMCs from ACS patients, a mechanism that might prevent rupture of atherosclerotic lesions and protect against development of ACS.