Network pharmacology and molecular docking analysis on Shenfu Qiangxin indicate mTOR is a potential target to treat heart failure.

BACKGROUND: Heart failure (HF) is one of the major causes of mortality worldwide with high recurrence rate and poor prognosis. Our study aimed to investigate potential mechanisms and drug targets of Shenfu Qiangxin (SFQX), a cardiotonic-diuretic traditional Chinese medicine, in treating HF. METHODS: An HF-related and SFQX-targeted gene set was established using disease-gene databases and the Traditional Chinese Medicine Systems Pharmacology database. We performed gene function and pathway enrichment analysis and constructed protein-protein interaction (PPI) network to investigate the potential mechanisms. We also performed molecular docking to analyze the interaction patterns between the active compounds and targeted protein. RESULTS: A gene set with 217 genes was identified. The gene function enrichment indicated that SFQX can regulate apoptotic process, inflammatory response, response to oxidative stress and cellular response to hypoxia. The pathway enrichment indicated that most genes were involved in PI3K-Akt pathway. Eighteen hub target genes were identified in PPI network and subnetworks. mTOR was the key gene among hub genes, which are involved in PI3K-Akt pathway. The molecular docking analysis indicated that 6 active compounds of SFQX can bind to the kinase domain of mTOR, which exerted potential therapeutic mechanisms of SFQX in treating HF. CONCLUSIONS: The results of network pharmacology analysis highlight the intervention on PI3K-Akt pathway of SFQX in the treatment of HF. mTOR is a key drug target to help protect myocardium.

Metabolic clues to aging: exploring the role of circulating metabolites in frailty, sarcopenia and vascular aging related traits and diseases.

Background: Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal the causal effect of circulating metabolites on frailty, sarcopenia and vascular aging related traits and diseases through a two-sample Mendelian Randomization (MR) analysis. Methods: Exposures were 486 metabolites analyzed in a genome-wide association study (GWAS), while outcomes included frailty, sarcopenia, arterial stiffness, atherosclerosis, peripheral vascular disease (PAD) and aortic aneurysm. Primary causal estimates were calculated using the inverse-variance weighted (IVW) method. Methods including MR Egger, weighted median, Q-test, and leave-one-out analysis were used for the sensitive analysis. Results: A total of 125 suggestive causative associations between metabolites and outcomes were identified. Seven strong causal links were ultimately identified between six metabolites (kynurenine, pentadecanoate (15:0), 1-arachidonoylglycerophosphocholine, androsterone sulfate, glycine and mannose) and three diseases (sarcopenia, PAD and atherosclerosis). Besides, metabolic pathway analysis identified 13 significant metabolic pathways in 6 age-related diseases. Furthermore, the metabolite-gene interaction networks were constructed. Conclusion: Our research suggested new evidence of the relationship between identified metabolites and 6 age-related diseases, which may hold promise as valuable biomarkers.

FGF21 at physiological concentrations regulates vascular endothelial cell function through multiple pathways.

Cardiovascular diseases are closely associated with dysfunction of vascular endothelial cells (VECs), which can be influenced by various intrinsic and extrinsic factors, including fibroblast growth factor 21 (FGF21), but the effects of serum FGF21 on VECs remain unclear. We performed a cross-sectional study nested within a prospective cohort to assess the range of physiological concentrations of fasting serum FGF21 in 212 healthy individuals. We also treated human umbilical VECs (HUVECs) with recombinant FGF21 at different concentrations. The effects of FGF21 treatment on glycolysis, nitric oxide release and reduction of intracellular reactive oxygen species were assessed. The cells were also collected for RNA transcriptomic sequencing to investigate the potential mechanisms induced by FGF21 treatment. In addition, the roles of SIRT1 in the regulation of FGF21 were evaluated by SIRT1 knockdown. The results showed that the serum FGF21 concentration in healthy individuals ranged from 15.70 to 499.96 pg/mL and was positively correlated with age and pulse wave velocity. FGF21 at 400 pg/mL was sufficient to enhance glycolysis, increase nitric oxide release and protect cells from H2O2-induced oxidative damage. The upregulated genes after FGF21 treatment were mostly enriched in metabolic pathways, whereas the downregulated genes were mostly enriched in inflammation and apoptosis signaling pathways. Moreover, SIRT1 may be involved in the regulation of some genes by FGF21. In conclusion, our data indicate that FGF21 at a level within the physiological concentration range has a beneficial effect on HUVECs and that this effect may partly depend on the regulation of SIRT1.

Close association between lifestyle and circulating FGF21 levels: A systematic review and meta-analysis.

Background: The impact of lifestyle factors on circulating fibroblast growth factor 21 (cFGF21) remains unclear. We conducted this systematic review and meta-analysis to evaluate the association between lifestyle factors and cFGF21 levels. Methods: We included studies that evaluated the effects of different lifestyles on cFGF21 concentration in adults, which included smoking, exercise, diets, alcohol consumption and weight loss. Random effects models or fixed effects models were used for meta-analysis to calculate the standardized mean difference (SMD) and 95% confidence interval according to the heterogeneity among studies. Study quality was assessed using the Newcastle-Ottawa Scale for cohort studies, the Joanna Briggs Institution Checklist for cross-sectional studies, and the PEDro scale for experimental studies. Results: A total of 50 studies with 1438 individuals were included. Overall, smoking, a hypercaloric carbohydrate-rich diet, a hypercaloric fat-rich diet, amino acid or protein restriction, excessive fructose intake and alcohol consumption significantly upregulated cFGF21 levels (p<0.05), whereas fish oil intake and calorie restriction with sufficient protein intake significantly decreased cFGF21 (p<0.05). Compared to the preexercise cFGF21 level, the cFGF21 level significantly increased within 3 hours postexercise (p<0.0001), while it significantly decreased in the blood sampled >6 h postexercise (p=0.01). Moreover, higher exercise intensity resulted in higher upregulation of cFGF21 at 1-hour post exercise (p=0.0006). Conclusion: FGF21 could serve as a potential biomarker for the assessment of different lifestyle interventions. When it is used for this purpose, a standard study protocol needs to be established, especially taking into consideration the intervention types and the sampling time post-intervention. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021254758, identifier CRD42021254758.

High-Level Serum Fibroblast Growth Factor 21 Concentration Is Closely Associated With an Increased Risk of Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

Background: The association between fibroblast growth factor 21 (FGF21) and cardiovascular disease (CVD) risk remains unclear. We conducted this systematic review and meta-analysis to evaluate the association between FGF21 and CVDs, and relevant vascular parameters. Methods: PubMed and Web of Science databases were systematically searched to identify relevant studies published before March 2021. The FGF21 concentration was compared between individuals with and without CVDs. The effect of FGF21 on CVD risk was assessed by using hazard ratio (HR) and odds ratio (OR). The association between FGF21 and vascular parameters was assessed by Pearson's r. Study quality was assessed using Newcastle-Ottawa Scale and Joanna Briggs Institution Checklist. Results: A total of 29,156 individuals from 30 studies were included. Overall, the serum FGF21 concentration was significantly higher in CVD patients (p < 0.001), especially for coronary artery disease (CAD) (p < 0.001) and hypertension (p < 0.001). The pooled OR (p = 0.009) and HR (p < 0.001) showed that the risk of CVDs increased with FGF21. The linear association between FGF21 and vascular parameters, including pulse wave velocity (r = 0.32), carotid intima-media thickness (r = 0.21), ankle-brachial index (r = 0.33), systolic blood pressure (r = 0.13), and diastolic blood pressure (r = 0.05), was insignificant. The incidence of overall CVDs (p = 0.03) was significantly higher in individuals with higher FGF21 levels. Conclusion: High-level serum FGF21 concentration is closely associated with an increased risk of CVDs, which may be independent of vascular parameters. A standard FGF21 classification threshold needs to be established before clinical use for CVD risk assessment. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=241968, identifier: CRD42021241968.