Mechanistic insights into Shengxian Sanren granules' effects on chronic heart failure: A synergistic study of UPLC-Q-TOF-MS/MS and network pharmacology.

chronic heart failure (CHF) is a complex and prevalent disease affecting 2% of adults in developed countries. This number increases to 6–10% in adults over the age of 65 ([3][1], [8][2]), and on diagnosis, half of all CHF patients die within 4 years ([11][3]). In addition to the significant

To explore the potential molecular mechanism of Mongolian medicine Bawei Sanxiang San in the treatment of chronic heart failure(CHF) through network pharmacology and molecular docking technology. The active ingredients and potential targets of Bawei Sanxiang San were collected by applying TCMSP, BATMAN databases and literature mining. CHF-related genes were collected through TTD, GeneCards and CTD databases. After the potential common targets between Bawei Sanxiang San and CHF were disco-vered, the interaction network diagram of "compound-target-pathway" was constructed using Cytoscape. The intersecting targets were imported into the DAVID database for GO function and KEGG pathway enrichment analysis. Finally, the Autodock_vina software was used to molecularly dock the selected proteins with the active ingredients of Bawei Sanxiang San. The results showed that there were 60 active ingredients in Bawei Sanxiang San that might be used to treat CHF, involving 311 target genes and 7 signaling pathways that directly related to CHF, such as HIF-1 signaling pathway, TNF signaling pathway, adrenergic signaling in cardiomyocytes, aldosterone-regulated sodium reabsorption, calcium signaling pathway, cGMP-PKG signaling pathway, renin secretion. Additionally, molecular docking showed that the bioactive compounds had good binding activity with the protein receptors of key target genes. Bawei Sanxiang San might exert therapeutic effects on CHF by regulating cardiomyocytes, angiogenic and inflammation related targets and pathways in a multi-component, multi-target and multi-pathway manner.

Objective Tinglizi 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. Methods The 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. Results A 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. Conclusion Through 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.

Chronic heart failure is a complex clinical syndrome. The Chinese herbal compound preparation Jianpi Huatan Quyu recipe has been used to treat chronic heart failure; however, the underlying molecular mechanism is still not clear. To identify the effective active ingredients of Jianpi Huatan Quyu recipe and explore its molecular mechanism in the treatment of chronic heart failure. The effective active ingredients of eight herbs composing Jianpi Huatan Quyu recipe were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target genes of chronic heart failure were searched in the Genecards database. The target proteins of active ingredients were mapped to chronic heart failure target genes to obtain the common drug-disease targets, which were then used to construct a key chemical component-target network using Cytoscape 3.7.2 software. The protein-protein interaction network was constructed using the String database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed through the Metascape database. Finally, our previously published relevant articles were searched to verify the results obtained via network pharmacology. A total of 227 effective active ingredients for Jianpi Huatan Quyu recipe were identified, of which quercetin, kaempferol, 7-methoxy-2-methyl isoflavone, formononetin, and isorhamnetin may be key active ingredients and involved in the therapeutic effects of TCM by acting on STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, p65, MAPK8, MAPK14, IL6, EGFR, EDN1, FOS, and other proteins. The pathways identified by KEGG enrichment analysis include pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, AMPK signaling pathway, etc. Previous studies on Jianpi Huatan Quyu recipe suggested that this Chinese compound preparation can regulate the TNF-α, IL-6, MAPK, cAMP, and AMPK pathways to affect the mitochondrial structure of myocardial cells, oxidative stress, and energy metabolism, thus achieving the therapeutic effects on chronic heart failure. The Chinese medicine compound preparation Jianpi Huatan Quyu recipe exerts therapeutic effects on chronic heart failure possibly by influencing the mitochondrial structure of cardiomyocytes, oxidative stress, energy metabolism, and other processes. Future studies are warranted to investigate the role of the IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, and other pathways in mediating the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure.

Poria sini decoction (PSD), a significant traditional Chinese herbal formula, is effective in liver cancer (LC) and chronic heart failure (CHF); however, little is known about its concurrent targeting mechanism. Methods. This study analyzed the potential molecular mechanism of PSD against the two distinct diseases using network pharmacology approaches, including multidatabase search, pharmacokinetic screening, network construction analysis, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and molecular docking to elaborate the active components, signaling pathways, and potential mechanisms of PSD in the treatment of both LC and CHF. Results. A total of 155 active components and 193 potential targets in PSD were identified. Bioinformatics analysis revealed that quercetin, isorhamnetin, and naringenin, etc. may be potential candidate agents. TNF, AKT1, and IL6, etc. could become potential therapeutic targets. TNF-α, NF-κB, PI3K-AKT, and TRP signaling pathways might play an important role in PSD against LC and CHF. Molecular docking results showed that most screened active compounds could embed itself into target proteins with a high binding affinity, and the hydrogen bonds number ≥3 indicated a more stable conformation of the compounds and target proteins. Overall, quercetin and isorhamnetin were the main active components, and TNF and AKT1 were the primary targets for PSD treatment of LC and CHF. Conclusions. This study illustrated that quercetin contained in PSD played an important role in the treatment of LC and CHF by acting on the key gene of TP53 and downregulating the PI3K-AKT signaling pathway.

Growing a healthier heart.

The aim of this study is to elucidate the pharmacological mechanism underlying the effects of Ginseng Radix et Rhizoma (ginseng) in heart failure (HF), providing a theoretical foundation for its clinical application. The potential mechanism of ginseng in the context of HF was investigated using systems pharmacology that combined network pharmacology, Gene Expression Omnibus (GEO) analysis, molecular docking, and experimental verification. Network pharmacology was employed to identify drug-disease targets. Core gene targets were subsequently subjected to enrichment analysis by integrating network pharmacology with GEO. Molecular docking was utilized to predict the binding affinities between identified targets and ginseng compounds. Furthermore, the therapeutic efficacy of ginseng was validated in an isoproterenol (ISO)-induced rat model of HF. The modulation of key signaling pathways by ginseng was confirmed through Western blot analysis. A total of 154 potential targets of ginseng in the treatment of HF were identified through network pharmacology analysis. The analysis of GSE71613 revealed that the PI3K-Akt pathway, reactive oxygen species, oxidative phosphorylation, MAPK signaling, and Ras signaling pathways are predominantly associated with patients with HF. By integrating the findings from network pharmacology and GEO analysis, ginsenoside Rg1 and ginsenoside Rb3 were identified as the potential components in ginseng, while FN1 and PRKAA2 were recognized as key targets involved in the PI3K-AKT and AMPK pathways, respectively. Molecular docking analysis revealed a strong affinity between the potential components and the identified core targets. In vivo experiments indicated that the extract of ginseng (EPG) significantly ameliorated ISO-induced cardiac dysfunction by improving cardiac parameters such as cardiac left ventricular internal systolic diameter, left ventricular end-diastolic volume, left ventricular end systolic volume, and left ventricular ejection fraction, while also reducing malondialdehyde production. In addition, EPG was found to enhance superoxide dismutase activity and ATP levels, while concurrently reducing the levels of interleukin (IL)-1β, IL-6, and TNF-α. The extract also reduced myocardial oxygen consumption, inflammatory cell infiltration, and the number of damaged myocardial fibers. Moreover, EPG was observed to upregulate the expression of p-PI3K, p-AKT, p-AMPK, and Bcl-2, while downregulating the expression of p-NFκB, TGF-β, and Bax. The therapeutic effects of ginseng on HF are primarily mediated through the PI3K-Akt and AMPK pathways. Ginsenoside Rg1 and ginsenoside Rb3 have been identified as potential therapeutic agents for HF.

Metabolic assessment of exercise in chronic heart failure patients treated with short-term vasodilators.

The issues of epidemiology, pathophysiology and basic principles of treatment of chronic heart failure in patients with type 2 diabetes mellitus are considered. Attention is paid to both means of glycemic correction and treatment of chronic heart failure directly, taking into account the effectiveness, cardiovascular safety of drugs, as well as their impact on the course and prognosis of chronic heart failure. The results of randomized clinical trials to study the effectiveness of various groups of drugs for the treatment of chronic heart failure in patients with type 2 diabetes mellitus are presented. It is indicated that the overall goal of the treatment of type 2 diabetes mellitus is to achieve and maintain glycemic control, as well as to reduce the risk of long-term complications, in particular chronic heart failure. The goal of chronic heart failure treatment is to improve the clinical condition and quality of life of patients, to reduce the frequency of hospitalizations and mortality. The appointment of some groups of hypoglycemic drugs has a neutral or negative effect on the course and prognosis of chronic heart failure, so their use is limited or not recommended in the treatment of patients with type 2 diabetes mellitus and chronic heart failure. The emphasis is on those classes of drugs that have demonstrated significant advantages in influencing the morbidity and mortality associated with chronic heart failure and type 2 diabetes mellitus in comparison with other drugs, namely, inhibitors of the sodium-dependent glucose cotransporter type 2 and angiotensin receptor inhibitors II and neprilisin (sacubitril / valsartan). Experts call such classes of drugs as sodium-dependent glucose cotransporter type 2, angiotensin receptor inhibitors II and neprilisin, mineralocorticoid receptor antagonists and beta-blockers as the "Fantastic Four", given the significant positive effect of their combined use on the course and prognosis of chronic heart failure. Modern approaches to the treatment of chronic heart failure in patients with type 2 diabetes mellitus are based on the updated guidelines of the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure, as well as on the recommendations of the American Diabetes Association for the classification, prevention and treatment of heart failure in patients with diabetes. Conclusion. The most important achievements in recent years, which have significantly improved the treatment outcomes of patients with chronic heart failure and type 2 diabetes mellitus, include: the development of new classes of drugs; conducting large-scale randomized clinical trials that demonstrated the benefits of certain groups of drugs in terms of their impact on the development, course and prognosis of chronic heart failure in type 2 diabetes mellitus, and updated comprehensive and balanced therapy for these patients

This study aims to explore the material basis and mechanism of Baoyuan decoction in the treatment of chronic heart failure by network pharmacology and molecular docking technology. There are 144 effective active ingredients and 253 targets in Baoyuan decoction. The key ingredients mainly include flavonoids such as quercetin, naringenin and glazin. There are 240 intersecting targets between Baoyuantang and chronic heart failure, and its core targets include jun proto-oncogene, signal transducer and activator of transcription 3, tumor protein 53, transcription factor p65, mitogen-activated protein kinase 14, estrogen receptor 1, etc. The gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis results show that it mainly involves 2475 biological processes, 104 cell components, 253 molecular functions and 174 related signals pathway. It mainly regulates the evolutionary processes including nutritional response, inflammatory response, oxidative stress response, apoptosis signal pathway etc., through the cell components such as cytoplasm, cell membrane and synapse, and exerts the molecular functions of DNA binding transcription factor, RNA polymerase II specific DNA binding transcription factor, serine/ threonine kinase activity, ubiquitin-like protein ligase binding, through phosphatidylinositol 3 kinaseprotein kinase B, Mitogen-activated protein kinase 14, Advanced glycation end products-receptor for AGE, Interleukin-17, apoptosis, cancer and other signaling pathways to play a role in the treatment of chronic heart failure effect.

ABSTRACTThe long non-coding RNA, maternally expressed gene 3 (MEG3), are involved in myocardial fibrosis and compensatory hypertrophy, but its role on cardiomyocyte apoptosis and autophagy in heart failure (HF) remains unclear. The aim of this study was to investigate the effect of MEG3 on cardiomyocyte apoptosis and autophagy and the underlying mechanism. A mouse model of HF was established by subcutaneous injection of isoproterenol (ISO) for 14 days, and an in vitro oxidative stress injury model was replicated with H2O2 for 6 h. SiRNA-MEG3 was administered in mice and in vitro cardiomyocytes to knock down MEG3 expression. Our results showed that cardiac silencing of MEG3 can significantly ameliorate ISO-induced cardiac dysfunction, hypertrophy, oxidative stress, apoptosis, excessive autophagy and fibrosis induced by ISO. In addition, inhibition of MEG3 attenuated H2O2-induced cardiomyocyte oxidative stress, apoptosis and autophagy in vitro. Downregulation of MEG3 significantly inhibited excessive cardiomyocyte apoptosis and autophagy induced by ISO and H2O2 through miRNA-129-5p/ATG14/Akt signaling pathways, and reduced H2O2-induced cardiomyocyte apoptosis by inhibiting autophagy. In conclusion, inhibition of MEG3 ameliorates the maladaptive cardiac remodeling induced by ISO, probably by targeting the miRNA-129-5p/ATG14/Akt signaling pathway and may provide a tool for pharmaceutical intervention.

Exploring the effective components and mechanism of Shengmaiyin (Dangshen Prescription) on the treatment of chronic heart failure based on chinmedomics strategy.

Calcium antagonists have, to date, shown disappointing effect in chronic heart failure (CHF), possibly due to their cardiodepressant effects and/or reflex increases in sympathetic tone. Mibefradil is a new, selective T-channel calcium antagonist which has no relevant effects on cardiac contractility, sympathetic activity or neurohormonal levels. This study compares the effect of mibefradil with an angiotensin-converting enzyme (ACE) inhibitor on systemic and cardiac hemodynamics, cardiac structure and survival in a rat model of CHF. Rats underwent coronary artery ligation followed by 9 months treatment with mibefradil, cilazapril or no treatment. Both mibefradil and cilazapril increased survival rate to a similar extent over the study treatment period. Both periods reduced systolic blood pressure compared with untreated rats, although the reduction was slightly more marked with cilazapril than mibefradil. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures without any change in the first derivative LV pressure over time or heart rate. Mibefradil decreased LV weight without effecting right ventricular (RV) weight. Both drugs normalized LV collagen density. The data from this study show that long-term treatment with mibefradil results in a survival benefit comparable to that observed with an ACE inhibitor in a rat model of CHF. Mibefradil was also associated with improvements in cardiac hemodynamics, a reduction in LV weight and fibrosis. Mibefradil may be beneficial in the treatment of CHF.

MicroRNA-30a-5p (miR-30a-5p) has been identified as a marker of heart failure; however, its functional mechanisms in chronic heart failure (CHF) remain unknown. We aim to investigate the role of miR-30a-5p targeting sirtuin-1 (SIRT1) in myocardial remodeling in CHF via the nuclear factor-κB/NOD-like receptor 3 (NF-κB/NLRP3) signaling pathway. CHF rat models were established using aortic coarctation. The expression of miR-30a-5p, SIRT1, and the NF-κB/NLRP3 signaling pathway-related factors in CHF rats was determined. The CHF rats were then respectively treated with altered miR-30a-5p or SIRT1 to explore their roles in cardiac function, myocardial function, inflammatory response, pathological changes, and cardiomyocyte apoptosis. The binding relation between miR-30a-5p and SIRT1 was confirmed. MiR-30a-5p was upregulated whereas SIRT1 was downregulated in myocardial tissues of CHF rats. MiR-30a-5p inhibition or SIRT1 overexpression improved cardiac and myocardial function, and suppressed the inflammatory response,alleviated pathological changes and inhibitedcardiomyocyte apoptosis in CHF rats. MiR-30a-5p targeted SIRT1 to regulate the NF-κB/NLRP3 signaling pathway. In CHF rats, downregulated miR-30a-5p and silenced SIRT1 could reverse the beneficial effects of downregulated miR-30a-5p. Inhibited miR-30a-5p inhibits CHF progression via the SIRT1-mediated NF-κB/NLRP3 signaling pathway.

The study aimed to explore the mechanism and targets of Shenfu Injection in the regulation of inflammatory injury in chronic heart failure rats based on the high mobility group box-1/Toll like receptor 4/nuclear factor kappa-B(HMGB1/TLR4/NF-κB) signaling pathway. The rat model of chronic heart failure was established using isoproterenol. The modeled rats were divided into three groups by random number table: the model group, Shenfu group and glycopyrrolate group, and the normal group was also set. The rats were administrated for 15 consecutive days, and on the following day after the last administration, they were sacrificed for sample collection. The cardiac mass index and left ventricular mass index of the rats in each group were measured, and the echocardiogram was used to analyze the cardiac function indices, and ELISA to test the inflammatory indices in rat serum. The pathological morphology and fibrosis status of rat heart tissues were observed by HE staining and Masson staining, respectively. The content of HMGB1 was determined by immunofluorescence staining. The protein and mRNA expression of HMGB1/TLR4/TLR4 signaling pathway was detected by Western blot and RT-qPCR, respectively. The results showed that the chronic heart failure rat model was successfully prepared. The rats in the model group had reduced cardiac function, increased levels of HMGB1 and inflammatory factors(P&lt;0.05), and elevated protein and mRNA expression of HMGB1, TLR4, MyD88, and NF-κB P65 in myocardial tissue(P&lt;0.05), with fibrous connective tissue hyperplasia, inflammatory cell infiltration and severe fibrosis. Shenfu Injection improved cardiac function, decreased the levels of HMGB1 and inflammatory factors(P&lt;0.05) and the protein and mRNA expression of HMGB1, TLR4, MyD88, and NF-κB P65 in myocardial tissue(P&lt;0.05), ameliorated interstitial fibrous connective tissue hyperplasia and inflammatory cell infiltration, and reduced fibrosis. In conclusion, Shenfu Injection can reduce inflammatory damage and improve cardiac function in chronic heart failure rats by regulating the HMGB1/TLR4/NF-κB signaling pathway.