Exploring the therapeutic potential of interleukin-6 receptor blockade in cardiovascular disease treatment through Mendelian randomization.

Interleukin-6 (IL-6) plays a crucial role in the pathogenesis of cardiovascular disease (CVD), and IL-6 receptor (IL-6R) blockade has emerged as a promising therapeutic option. However, their specific therapeutic effects in different types of CVDs remain unclear. This study aimed to assess the efficacy of IL-6R blockade in the management of various CVDs, including hypertension (HTN), coronary heart disease (CHD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF). The Mendelian randomization (MR) approach was utilized to investigate the therapeutic impact of IL-6R blockade on HTN, CHD, MI, AF, and HF based on the genome-wide association study (GWAS) summary statistics. MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis were used for sensitivity analysis to verify the reliability of the MR results. The Bonferroni method was used to correct for bias caused by multiple comparisons. Inverse variance weighted (IVW) results demonstrated that IL-6R blockade significantly influenced CHD (odds ratio (OR) = 0.757, 95% confidence interval (CI): 0.690 - 0.832, P = 5.804 × 10-9) and MI (OR = 0.840, 95% CI: 0.744 - 0.949, P = 0.005). However, IL-6R blockade had no significant effect on HTN (OR = 1.015, 95% CI: 0.950 - 1.084, P = 0.663), AF (OR = 0.905, 95% CI: 0.800 - 1.025, P = 0.116) and HF (OR = 1.012, 95% CI: 0.921 - 1.113, P = 0.805). Genetically predicted IL-6R blockade was associated with a protective effect on CHD and MI, but not HTN, AF and HF. This study's findings offer valuable insights for tailoring IL-6R blockade treatment for different types of CVD, and serve as a reference for future research.

Ginsenoside Rg1 treats chronic heart failure by downregulating ERK1/2 protein phosphorylation.

In this study, we investigated the potential therapeutic mechanism of ginsenoside Rg1 (GRg1) in chronic heart failure (CHF), focusing on its regulation of ERK1/2 protein phosphorylation. H9c2 cardiomyocytes and SD rats were divided into the control group, CHF (ADR) group, and CHF+ginsenoside Rg1 group using an isolated cardiomyocyte model and an in vivo CHF rat model induced by adriamycin (ADR). Cell viability, proliferation, apoptosis, and the expression of relevant proteins were measured to assess the effects of GRg1. The results showed that treatment with GRg1 increased cell activity and proliferation, while significantly reducing levels of inflammatory and apoptotic factors compared to the CHF (ADR) group. Moreover, the CHF+ginsenoside Rg1 group exhibited higher levels of Bcl-2 mRNA and protein expression, as well as lower levels of Caspase3 and Bax mRNA and protein expression, compared to the CHF (ADR) group. Notably, the CHF+ginsenoside Rg1 group displayed decreased serum NT-proBNP levels and heart weight/body weight (HW/BW) index. Furthermore, the electrocardiogram of rats in the CHF+ginsenoside Rg1 group resembled that of rats in the control group. Overall, our findings suggested that GRg1 alleviated CHF by inhibiting ERK1/2 protein phosphorylation, thereby inhibiting apoptosis, enhancing cell activity and proliferation, and reducing cardiac inflammatory responses.

Causal associations between chronic heart failure and the cerebral cortex: results from Mendelian randomization study and integrated bioinformatics analysis.

Background: Chronic heart failure (CHF) patients exhibit alterations in cerebral cortical structure and cognitive function. However, the mechanisms by which CHF affects cortical structure and functional regions remain unknown. This study aims to investigate potential causal relationship between CHF and cerebral cortical structure through Mendelian randomization (MR). Methods: The research utilized genome-wide association studies (GWAS) to explore the causal association between CHF and cerebral cortical structure. The results were primarily analyzed using the inverse-variance weighted (IVW). The reliability of the data was verified through horizontal pleiotropy and heterogeneity analysis by MR-Egger intercept test and Cochran's Q-test, respectively. Replication analysis was conducted in the Integrative Epidemiology Unit (IEU) OpenGWAS project for further validation. In addition, we collected mediator genes that mediate causality to reveal potential mechanisms. Integrated bioinformatics analysis was conducted using the Open Target Genetics platform, the STRING database, and Cytoscape software. Results: The IVW results did not reveal any significant causal association between genetically predicted CHF and the overall structure of the cerebral cortex or the surface area (SA) of the 34 functional regions of the cerebral cortex (P > 0.05). However, the results revealed that CHF increased the thickness (TH) of pars opercularis (IVW: ß = 0.015, 95% CI: 0.005-0.025, P = 3.16E-03). Replication analysis supported the causal association between CHF and pars opercularis TH (IVW: ß = 0.02, 95% CI: 0.010-0.033, P = 1.84E-04). We examined the degree centrality values of the top 10 mediator genes, namely CDKN1A, CELSR2, NME5, SURF4, PSMA5, TSC1, RPL7A, SURF6, PRDX3, and FTO. Conclusion: Genetic evidence indicates a positive correlation between CHF and pars opercularis TH.

A novel rat model of cerebral small vessel disease based on vascular risk factors of hypertension, aging, and cerebral hypoperfusion.

Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment and functional loss in elderly patients. Progressive remodeling of cerebral microvessels due to arterial hypertension or other vascular risk factors, such as aging, can cause dementia or stroke. Typical imaging characteristics of CSVD include cerebral microbleeds (CMB), brain atrophy, small subcortical infarctions, white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS). Nevertheless, no animal models that reflect all the different aspects of CSVD have been identified. Here, we generated a new CSVD animal model using D-galactose (D-gal) combined with cerebral hypoperfusion in spontaneously hypertensive rats (SHR), which showed all the hallmark pathological features of CSVD and was based on vascular risk factors. SHR were hypodermically injected with D-gal (400 mg/kg/d) and underwent modified microcoil bilateral common carotid artery stenosis surgery. Subsequently, neurological assessments and behavioral tests were performed, followed by vascular ultrasonography, electron microscopy, flow cytometry, and histological analyses. Our rat model showed multiple cerebrovascular pathologies, such as CMB, brain atrophy, subcortical small infarction, WMH, and EPVS, as well as the underlying causes of CSVD pathology, including oxidative stress injury, decreased cerebral blood flow, structural and functional damage to endothelial cells, increased blood-brain barrier permeability, and inflammation. The use of this animal model will help identify new therapeutic targets and subsequently aid the development and testing of novel therapeutic interventions. Main process of the study: Firstly, we screened for optimal conditions for mimicking aging by injecting D-gal into rats for 4 and 8 weeks. Subsequently, we performed modified microcoil BCAS intervention for 4 and 8 weeks in rats to screen for optimal hypoperfusion conditions. Finally, based on these results, we combined D-gal for 8 weeks and modified microcoil BCAS for 4 weeks to explore the changes in SHR.

Up-regulation of miR-155 protects against chronic heart failure by inhibiting HIF-1α.

BACKGROUND: Despite a crucial role of miR-155 in human cancers, its function in heart failure (HF) is still under investigation. This study was designed to explore its association with HF. METHODS: The abdominal transverse aortic constriction (TAC) was adopted for establishment of mouse HF models. qRT-PCR and WB were adopted to detect the changes of miR-155, HIF-1α, Cle-caspase-3, BCL2 and Bax levels in myocardial cells and heart tissues. The changes of cardiac function were checked by ultrasound. Additionally, luciferase reporter gene was adopted for interaction analysis of miR-155 with HIF-1α, and in situ end labelling method was used for detecting myocardial apoptosis. RESULTS: MiR-155 in myocardial tissue of HF mice was significantly down regulated. In HF mice injected with agomiR-155, the up-regulation of miR-155 strongly improved cardiac function, and also significantly lowered the protein levels of apoptosis-associated markers, C-caspase-3 and Bax, but up regulated Bcl-2. Additionally, HIF-1α was identified as the direct target of miR-155. As expected, over-expression of HIF-1α greatly reversed the effects of agomiR-155 on cardiac function and the expression of apoptosis-associated markers in heart tissues of HF mice. CONCLUSION: MiR-155 overexpression can suppress myocardial cell apoptosis through HIF-1α, and strongly alleviate the cardiac function damage in HF mice, indicating the potential of miR-155/HIF-1α axis to be a target for the diagnosis and therapy of HF.

Ginsenoside Rb3 reduces ox-LDL-induced injury in human aortic endothelial cells by regulating the miR-513a-5p/ZBTB20 axis.

BACKGROUND: Atherosclerosis (AS) is a common vascular disease, and its main influencing factor is endothelial damage caused by oxidized low-density lipoprotein (ox-LDL). As one of the main active ingredients of ginseng, ginsenoside Rb3 has anti-inflammatory and anti-oxidative effects. However, the role of ginsenoside Rb3 in endothelial injury induced by ox-LDL is not clear. OBJECTIVES: This study aimed to evaluate the effect and potential mechanism of ginsenoside Rb3 action on ox-LDL-treated human aortic endothelial cells (HAECs). MATERIAL AND METHODS: The HAECs treated with ox-LDL were used to establish an in vitro AS model. The viability of the HAECs was analyzed with Cell Counting Kit-8 (CCK-8). Flow cytometry was performed to assess the apoptosis. Oxidative stress, inflammation and endothelial dysfunction were evaluated using enzyme-linked immunosorbent assay (ELISA) and western blotting. The levels of miR-513a-5p were assessed using quantitative real-time polymerase chain reaction (qPCR). A dual-luciferase assay was performed to analyze the relationship between miR-513a-5p and a zinc finger and BTB domain-containing protein (ZBTB20). RESULTS: Exposure of HAECs to ox-LDL (50 µg/mL) reduced cell viability, superoxide dismutase (SOD) activity and endothelial nitric oxide synthase (eNOS) expression, while increasing the levels of malondialdehyde (MDA), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and soluble intercellular adhesion molecule-1 (sICAM-1). The pretreatment with Rb3 markedly enhanced cell viability and decreased ox-LDL-induced oxidative stress, inflammation and endothelial dysfunction in HAECs. The ox-LDL decreased the level of miR-513a-5p, which was reversed by Rb3 pretreatment. The ZBTB20 was a target of miR-513a-5p in HAECs, and ox-LDL upregulated ZBTB20 expression, which was reversed by Rb3 pretreatment. The protective effect of Rb3 on ox-LDL-induced HAECs was diminished by miR-513a-5p inhibition, which was reversed by ZBTB20 knockdown. CONCLUSIONS: Ginsenoside Rb3 reduces the effects of ox-LDL on HAECs by regulating the miR-513a-5p/ZBTB20 axis, which provides a theoretical basis for the treatment of AS.

Electroacupuncture Improves Intestinal Motility through Exosomal miR-34c-5p Targeting SCF/c-Kit Signaling Pathway in Slow Transit Constipation Model Rats.

Background: The pathogenesis of slow transit constipation (STC) is associated with exosomal miR-34c-5p. Electroacupuncture (EA) improves gastrointestinal motility in gastrointestinal disorders, especially STC. Our study aimed to explore the mechanism by which EA improves intestinal motility by modulating the release of exosomes and the transmission of exosomal miR-34c-5p. Methods: Fifty rats were randomly divided into five groups. STC model rats were induced, and GW4869, the exosome release inhibitor, was used to inhibit the release of exosome. The serum exosomes were authenticated under a transmission electron microscope and nanoparticle tracking analysis. RT-qPCR detected the expression of miR-34c-5p in serum exosomes and colonic tissues. The fecal number in 24 hours, Bristol scores, and intestinal transit rates were used to assess intestinal motility. Subsequently, hematoxylin and eosin (H&E) staining was used to examine the colonic mucosal histology. Finally, the expression of stem cell factor (SCF) and receptor tyrosine kinase (c-Kit) protein was measured using immunohistochemistry staining. Results: We found that EA upregulated exosomal miR-34c-5p in serum and downregulated miR-34c-5p in colonic tissues (P < 0.01). EA improved fecal numbers in 24 hours, Bristol scores, and intestinal transit rates in STC rats (P < 0.01). EA recovered the colonic histological structure and enhanced the expression of SCF and c-Kit protein (P < 0.01). The therapeutic effect of EA was attenuated after inhibiting the release of the exosome. Conclusion: Our results indicated that EA improves intestinal motility in STC rats by transporting of exosomal miR-34c-5p targeting the SCF/c-Kit signaling pathway.

Potential molecular mechanism of the Xiexin capsule in the intervention of dyslipidemia based on bioinformatics and molecular docking.

Introduction: Objective: bioinformatic methods and molecular docking technology were used to predict the active components, targets, and related biological pathways of the Xiexin capsule in the intervention for dyslipidemia, exploring its mechanism. Methods: the active components and targets of the Xiexin capsule were screened by the TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform )database. Genecards (The Human Gene Database), OMIM (Online Mendelian Inheritance in Man), PharmGkb (Pharmacogenomics Knowledge Base database), TTD (Therapeutic Target Database), and Drugbank platforms were used to search the disease targets of dyslipidemia. The Cytoscape 3.8.0 software was used to construct the 'component-target' network diagram, and the STRING (functional protein association networks) platform was used to analyze protein-protein interaction (PPI). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) enrichment analyses were performed by R language data packets to predict the mechanism of action. The AutoDockVina and PyMol software were used to dock the key active components in the Xiexin capsule and the core proteins in PPI. Results: a total of 66 effective components were screened, involving 114 targets; 87 key active compounds were screened from the 'drug-component-target' diagram. The PPI network mainly involved core proteins such as PTGS2 (prostaglandin-endoperoxide synthase 2), PTGS1 (prostaglandin-endoperoxide synthase 1), and HSP90AA1 (heat shock protein 90 alpha family class A member 1). GO and KEGG enrichment analysis results of common targets mainly involved hormone-mediated signaling pathway, steroid hormone response, lipid transport and metabolism, regulation of cholesterol storage, cyclooxygenase pathway, and other biological pathways, as well asMM PPAR (peroxisome proliferators-activated receptor) signaling pathway, IL-17 (interleukin 17) signaling pathway, PI3K-Akt (protein kinase b) signaling pathway, FcεRI signaling pathway, and other related pathways. Molecular docking verification showed that quercetin had the best binding with the core target protein HSP90AA1, and HSP90AA1 was the target protein with the best binding activity for the key chemical components in Xiexin capsules. Conclusion: the main chemical components in the Xiexin capsules may participate in the regulation of PPAR and other signaling pathways by regulating key genes such as ESR1 (estrogen receptor 1), MAPK14 (mitogen-activated protein kinase 14), and HSP90AA1, to exert the pharmacological effect of the intervention on dyslipidemia.

Introducción: Objetivo: se utilizaron métodos bioinformáticos y técnicas de acoplamiento molecular para predecir componentes efectivos, objetivos y vías biológicas relacionadas de la cápsula Xiexin en la intervención de dislipidemia y explorar su mecanismo. Métodos: los componentes activos y los objetivos de la cápsula Xiexin fueron seleccionados por la base de datos TCMSP. Se utilizaron plataformas Genecards, OMIM, PharmGkb, Therapeutic Target Database y Drugbank para buscar dianas de la enfermedad en la dislipidemia. El diagrama reticular "componente-diana" fue construido por el software Cytoscape 3.7.0, y la interacción proteína-proteína (PPI) fue analizada por la plataforma STRING. Los análisis de enriquecimiento de Gene Ontology (GO) y Kyoto Encyclopedia of Genes and Genomics se realizaron mediante paquetes de datos en lenguaje R para predecir mecanismo de acción. El software AutoDockVina y PyMol se utilizó para unir componentes activos clave de la cápsula Xiexin y las proteínas clave de la PPI. Resultados: se seleccionaron 65 componentes activos y 114 dianas. Veintitrés compuestos activos clave fueron seleccionados a partir de la tabla "componentes farmacéuticos-dianas". Las redes PPI incluyen principalmente proteínas básicas como PTGS2, PTGS1 y HSP90AA1. Los resultados del análisis de enriquecimiento de GO y KEGG en los objetivos comunes se refieren principalmente a la vía de señalización mediada por esteroides, la respuesta hormonal esteroidea, el transporte y metabolismo lipídicos, la regulación del almacenamiento de colesterol, la vía de la ciclooxigenasa y otras vías biológicas, así como la vía de señalización de PPAR, IL-17, PI3K-Akt, FcεRI y otras vías relacionadas. La prueba de acoplamiento molecular mostró que la quercetina se une mejor a la proteína diana central HSP90AA1, que es la proteína diana con la mejor actividad de unión de los componentes químicos clave de la cápsula Xiexin. Conclusión: los principales componentes químicos de la cápsula Xiexin pueden participar en la regulación de la PPAR y otras vías de señalización mediante la regulación de genes clave como ESR1, MAPK14 (mitogen-activated protein kinase 14), HSP90AA1, por lo que pueden desempeñar un papel farmacológico en la intervención de dislipidemia.

Polygonatum sibiricum polysaccharides (PSP) improve the palmitic acid (PA)-induced inhibition of survival, inflammation, and glucose uptake in skeletal muscle cells.

Polygonatum sibiricum polysaccharides (PSP) can decrease the levels of fasting blood glucose, total cholesterol, and triglyceride (TG) in hyperlipidemic and diabetic animals. It can also reduce inflammatory cytokines and promote glucose uptake in adipocytes. However, the underlying molecular mechanisms of PSP in improving insulin resistance (IR) in skeletal muscle remain unclear. In this study, palmitic acid (PA) induced an IR model in L6 myotubes. After treatment, cell proliferation was measured using the CCK8. miR-340-3p, glucose transporter 4 (GLUT-4), and interleukin-1 receptor-associated kinase 3 (IRAK3) expression was measured by qRT-PCR. IRAK3 protein levels were measured by Western blotting. Glucose in the cell supernatant, TG concentration in L6 myotubes, and the levels of IL-1ß, IL-6, and TNF-α were measured by an ELISA. We found that cell survival, glucose uptake, and GLUT-4 expression in L6 myotubes were significantly suppressed, while lipid accumulation and inflammatory factor levels were enhanced by PA stimulation. Furthermore, PSP treatment markedly alleviated these effects. Interestingly, PSP also significantly reduced the upregulated expression of miR-340-3p in the L6 myotube model of IR. Furthermore, overexpression of miR-340-3p reversed the beneficial effects of PSP in the same IR model. miR-340-3p can bind to the 3'-untranslated regions of IRAK3. Additionally, PA treatment inhibited IRAK3 expression, whereas PSP treatment enhanced IRAK3 expression in L6 myotubes. Additionally, miR-340-3p also inhibited IRAK3 expression in L6 myotubes. Taken together, PSP improved inflammation and glucose uptake in PA-treated L6 myotubes by regulating miR-340-3p/IRAK3, suggesting that PSP may be suitable as a novel therapeutic agent for IR.

Effects of Enalapril on TLR2/NF-κB Signaling Pathway and Inflammatory Factors in Rabbits with Chronic Heart Failure.

Chronic heart failure (CHF) refers to the state of persistent heart failure, which is a complex clinical syndrome of various advanced heart diseases. The toll-like receptor 2 (TLR2)/nuclear transcription factor-κB (NF-κB) signal transduction pathway is one of the pathological mechanisms of CHF. Adriamycin can significantly induce the upregulation of TLR2 expression. Angiotensin-converting enzyme inhibitors (ACEI) are commonly used drugs for the treatment of CHF. In our study, the CHF model was established by injection of doxorubicin into the rabbit ear vein. The effect of enalapril on the TLR2/NF-κB signaling pathway in CHF rabbits has been analyzed and determined. Our research results showed that enalapril reduced the inflammatory response by inhibiting the activation of the TLR2/NF-κB signaling pathway, thereby improving cardiac structure, myocardial remodeling, and cardiac function.

Effects of the Wenyang Zhenshuai Granule on the Expression of LncRNA-MiR143HG/miR-143 Regulating ERK5 in H9C2 Cardiomyocytes.

Chronic heart failure (CHF) is a complex clinical syndrome caused by a variety of heart problems, with a high incidence. The 5-year survival rate of patients with clinical symptoms is similar to that of malignant tumors. Wenyang Zhenshuai granules are a safe and effective granule of traditional Chinese medicine components, including aconite, dried ginger, licorice, and red ginseng. In contemporary clinical applications, it is widely used in acute and chronic heart insufficiency, coronary heart disease, and arrhythmia. This research cultured H9C2 cardiomyocytes and divided them into the normal control group, LncRNA-MiR143HG overexpression group, LncRNA-MiR143HG silence group, Adriamycin (ADR) group, ADR + medicated serum group, ADR + LncRNA-MiR143HG overexpression + medicated serogroup, and ADR + LncRNA-MiR143HG silence + medicated serogroup. The cells of each group were treated differently, and the survival rate of each group of cells and the expression levels of LncRNA-MiR143HG/miR-143 and ERK5 were detected at the end of the experiment, and the expression of LncRNA-MiR143HG/miR-143 in H9C2 cardiomyocytes was regulated by Wenyang Zhenshuai granules' impact. The results of this study showed that, in the doxorubicin-induced H9C2 cardiomyocyte injury model, the expression of miR-143 was upregulated, and the expression of LncRNA-MiR143HG and ERK5 was significantly downregulated. Wenyang Zhenshuai granules can downregulate the expression of miR-143 to promote ERK5 protein expression and phosphorylation. The process is regulated by LncRNA-MiR143HG/miR-143, which may be one of its important mechanisms for the treatment of chronic heart failure.

Effects of Wenyangzhenshuai Granule on ERK1/2 and ERK5 activity in the myocardial tissue in a rabbit model of adriamycin-induced chronic heart failure.

OBJECTIVE: To elucidate the effects of Wenyangzhenshuai granule on expression of extracellular signal-regulated kinase 1/2 (ERK1/2) and 5 (ERK5) in the myocardial tissue using a rabbit model of adriamycin-induced chronic heart failure. MATERIALS AND METHODS: Rabbits were divided into heart failure positive control, adriamycin injection, and adriamycin injection with Wenyangzhenshuai treatment (low, medium and high dose) groups. Cardiac function and cardiac hypotrophy were measured in all groups. Besides, myocardial expression of ERK1/2 and ERK5 phosphorylation were evaluated by Western blotting and ERK1/2 and ERK5 mRNA levels by RT-PCR. The cardiac structure and cardiac function were also compared using histology staining and electron microscope. RESULTS: Adriamycin injection led to cardiac failure reflected by decreased left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), E/A ratio, and increased cardiac hypertrophy, both of which have been improved by Wenyangzhenshuai granule treatment (all P<0.05). Mechanistically, increased P-ERK1/2 and decreased P-ERK5 levels were observed in myocardial tissues of mice treated with Adriamycin for 8 weeks. However, such signaling change could be partially corrected by Wenyangzhenshuai treatment. In addition, no significant difference was detected in the expression of ERK1/2 and ERK5 mRNA levels between adriamycin injection groups and Wenyangzhenshuai treatment groups (P>0.05), indicating an alteration in the activity/phosphorylation levels of these proteins instead of the transcription levels. CONCLUSION: we found a beneficial effect of Wenyangzhenshuai treatment in partially decelerating the progression of CHF. Such effect was probably through the role of Wenyangzhenchuan in diminishing p-ERK1/2 and raising p-ERK5 level in myocardial tissue.