Dataset Information

The Pharmacological Mechanisms Underlying the Protective Effect of Ginsenoside Rg3 against Heart Failure.

ABSTRACT:

Background

Heart failure represents the terminal stage of various cardiovascular diseases. This study aims to explore the pharmacological mechanisms underlying the protective effect of Ginsenoside Rg3 against heart failure.

Methods

Potential targets of Ginsenoside Rg3 were identified using SwissTargetPrediction and the Comparative Toxicogenomics Database, while heart failure-related genes were retrieved from the Comparative Toxicogenomics Database, Therapeutic Target Database, DisGeNET, and PharmGKB. Overlapping of Ginsenoside Rg3 targets with heart failure-related genes identified drug-disease interaction genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the drug-disease interaction genes to elucidate their biological functions. A protein-protein interaction network was constructed using the drug-disease interaction genes, and the hub genes were identified by topological analysis. Additionally, we validate the expression of IL-6 and TNF by real-time PCR.

Results

The intersection of Ginsenoside Rg3 targets and heart failure-related genes yielded 15 drug-disease interaction genes. Enrichment analysis highlighted the involvement of inflammation-related GO terms and KEGG pathways, such as positive regulation of interleukin-8 and -6 production, regulation of immune effector process, cytokine receptor binding, cytokine activity, adipocytokine signaling pathway, and IL-17 signaling pathway, which are implicated in the cardioprotective effect. Topological analysis revealed four hub genes: STAT3, CASP3, TNF, and IL-6. The application of Ginsenoside Rg3 significantly reversed the elevated levels of IL-6 and TNF in the isoproterenol-treated H9c2 cell line.

Conclusions

Our findings suggest that the cardioprotective effect of Ginsenoside Rg3 may be mediated through its anti-inflammation properties. Further research is required to elucidate and validate the detailed cardioprotective mechanisms of Ginsenoside Rg3.

SUBMITTER: Jia Y

PROVIDER: S-EPMC11303059 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

The Pharmacological Mechanisms Underlying the Protective Effect of Ginsenoside Rg3 against Heart Failure.

Jia Yanan Y Gong Miao M Ke Zunping Z

Cardiology research and practice 20240730

<h4>Background</h4>Heart failure represents the terminal stage of various cardiovascular diseases. This study aims to explore the pharmacological mechanisms underlying the protective effect of Ginsenoside Rg3 against heart failure.<h4>Methods</h4>Potential targets of Ginsenoside Rg3 were identified using SwissTargetPrediction and the Comparative Toxicogenomics Database, while heart failure-related genes were retrieved from the Comparative Toxicogenomics Database, Therapeutic Target Database, Dis ...[more]

PMID: 39108942

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Project description:ObjectiveTinglizi has been extensively used to treat chronic heart failure (CHF) in modern times, but the material basis and pharmacological mechanisms are still unclear. To explore the material basis and corresponding potential targets and to elucidate the mechanism of Tinglizi, network pharmacology and molecular docking methods were utilized.MethodsThe main chemical compounds and potential targets of Tinglizi were collected from the pharmacological database analysis platform (TCMSP). The corresponding genes of related action targets were queried through gene cards and UniProt database. The corresponding genes of CHF-related targets were searched through Disgenet database, and the intersection targets were obtained by drawing Venn map with the target genes related to pharmacodynamic components. Then, drug targets and disease targets were intersected and put into STRING database to establish a protein interaction network. The "active ingredient-CHF target" network was constructed with Cytoscape 3.8.2. Finally, Gene Ontology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of intersection targets were analyzed using metascape. With the aid of SYBYL software, the key active ingredients and core targets were docked at molecular level, and the results were visualized by PyMOL software. Molecular docking was carried out to investigate interactions between active compounds and potential targets.ResultsA total of 12 active components in Tinglizi were chosen from the TCMSP database, and 193 corresponding targets were predicted. Twenty-nine potential targets of Tinglizi on CHF were obtained, of which nine were the core targets of this study. Twenty GO items were obtained by GO function enrichment analysis (P < 0.05), and 10 signal pathways were screened by KEGG pathway enrichment analysis (P < 0.05), which is closely related to the treatment of CHF by Tinglizi. The constructed drug compound composition action target disease network shows that quercetin, kaempferol, and other active compounds play a key role in the whole network. The results of molecular docking showed that all the key active ingredients, such as quercetin and isorhamnetin, were able to successfully dock with ADRB2 and HMOX1 with a total score above 5.0, suggesting that these key components have a strong binding force with the targets.ConclusionThrough network pharmacology and molecular docking technology, we found that the main components of Tinglizi in the treatment of CHF are quercetin, kaempferol, β-sitosterol, isorhamnetin, and so on. The action targets are beta 2-adrenergic receptor (ADRB2), heme oxygenase 1 (HMOX1), and so on. The main pathways are advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor (HIF-1) signaling pathway, estrogen signaling pathway, and so on. They play an integrated role in the treatment of CHF.

Project description:Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.

Project description:We previously found that the levels of metabolite N-acetylglutamine were significantly increased in urine samples of patients with heart failure (HF) and in coronary artery ligation (CAL)-induced HF mice, whereas the expression of its specific metabolic-degrading enzyme aminoacylase-1 (ACY1) was markedly decreased. In the current study, we investigated the role of ACY1 in the pathogenesis of HF and the therapeutic effects of 20(S)-ginsenoside Rg3 in HF experimental models in vivo and in vitro. HF was induced in mice by CAL. The mice were administered Rg3 (7.5, 15, 30 mg · kg-1· d-1, i.g.), or positive drug metoprolol (Met, 5.14 mg · kg-1· d-1, i.g.), or ACY1 inhibitor mono-tert-butyl malonate (MTBM, 5 mg · kg-1 · d-1, i.p.) for 14 days. We showed that administration of MTBM significantly exacerbated CAL-induced myocardial injury, aggravated cardiac dysfunction, and pathological damages, and promoted myocardial fibrosis in CAL mice. In Ang II-induced mouse cardiac fibroblasts (MCFs) model, overexpression of ACY1 suppressed the expression of COL3A1 and COL1A via inhibiting TGF-β1/Smad3 pathway, whereas ACY1-siRNA promoted the cardiac fibrosis responses. We showed that a high dose of Rg3 (30 mg · kg-1· d-1) significantly decreased the content of N-acetylglutamine, increased the expression of ACY1, and inhibited TGF-β1/Smad3 pathway in CAL mice; Rg3 (25 μM) exerted similar effects in Ang II-treated MCFs. Meanwhile, Rg3 treatment ameliorated cardiac function and pathological features, and it also attenuated myocardial fibrosis in vivo and in vitro. In Ang II-treated MCFs, the effects of Rg3 on collagen deposition and TGF-β1/Smad3 pathway were slightly enhanced by overexpression of ACY1, whereas ACY1 siRNA partially weakened the beneficial effects of Rg3, suggesting that Rg3 might suppress myocardial fibrosis through ACY1. Our study demonstrates that N-acetylglutamine may be a potential biomarker of HF and its specific metabolic-degrading enzyme ACY1 could be a potential therapeutic target for the prevention and treatment of myocardial fibrosis during the development of HF. Rg3 attenuates myocardial fibrosis to ameliorate HF through increasing ACY1 expression and inhibiting TGF-β1/Smad3 pathway, which provides some references for further development of anti-fibrotic drugs for HF.

Project description:ObjectivesThe purposes of this study were to determine why chronic obstructive pulmonary disease (COPD) is associated with heart failure (HF). Specific objectives included whether COPD is associated with myocardial fibrosis, whether myocardial fibrosis is associated with hospitalization for HF and death in COPD, and whether COPD and smoking are associated with myocardial inflammation.BackgroundCOPD is associated with HF independent of shared risk factors. The underlying pathophysiological mechanism is unknown.MethodsA prospective, multicenter, longitudinal cohort study of 572 patients undergoing cardiac magnetic resonance (CMR), including 450 patients with COPD and 122 age- and sex-matched patients with a median: 726 days (interquartile range: 492 to 1,160 days) follow-up. Multivariate analysis was used to examine the relationship between COPD and myocardial fibrosis, measured using cardiac magnetic resonance (CMR). Cox regression analysis was used to examine the relationship between myocardial fibrosis and outcomes; the primary endpoint was composite of hospitalizations for HF or all-cause mortality; secondary endpoints included hospitalizations for HF and all-cause mortality. Fifteen patients with COPD, 15 current smokers, and 15 healthy volunteers underwent evaluation for myocardial inflammation, including ultrasmall superparamagnetic particles of iron oxide CMR.ResultsCOPD was independently associated with myocardial fibrosis (p < 0.001). Myocardial fibrosis was independently associated with the primary outcome (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.08 to 1.20; p < 0.001), hospitalization for HF (HR: 1.25 [95% CI: 1.14 to 1.36]); p < 0.001), and all-cause mortality. Myocardial fibrosis was associated with outcome measurements more strongly than any other variable. Acute and stable COPD were associated with myocardial inflammation.ConclusionsThe associations between COPD, myocardial inflammation and myocardial fibrosis, and the independent prognostic value of myocardial fibrosis elucidate a potential pathophysiological link between COPD and HF.

Dataset Information

The Pharmacological Mechanisms Underlying the Protective Effect of Ginsenoside Rg3 against Heart Failure.

Background

Methods

Results

Conclusions

Publications

The Pharmacological Mechanisms Underlying the Protective Effect of Ginsenoside Rg3 against Heart Failure.

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