Deciphering mechanism of the herbal formula WuShen in the treatment of postinfarction heart failure.

BACKGROUND: Numerous clinical studies reported the effectiveness of herbal formula WuShen (WS) in treating cardiovascular diseases, yet relevant basic research was rarely conducted. METHODS AND RESULTS: Twelve main bioactive compounds of WS decoction were identified using the ultra-performance liquid chromatography-LTQ-Orbitrap mass spectrometer. A total of 137 active compounds with 613 targets were predicted by network pharmacology; their bioinformatic annotation and human microarray data suggested that wounding healing, inflammatory response, and gap junction were potentially the major therapeutic modules. A rat model of post-myocardial infarction (MI) heart failure (HF) was used to study the effects of WS on cardiac function, adverse cardiac remodeling, and experimental arrhythmias. Rats treated with WS led to a significantly improved pump function and reduced susceptibility to both ventricular tachycardia and atrial fibrillation, and restricted adverse cardiac remodeling partly via inhibiting TGFß1/SMADs mediated extracellular matrix deposition and Rac1/NOX2/CTGF/Connexin43 -involved gap junction remodeling. CONCLUSIONS: The present study highlights that WS can be applied to the treatment of heart failure and the upstream therapy for atrial fibrillation and ventricular tachycardia through its preventive effect on adverse cardiac remodeling.

The pleiotropic association between IL-10 levels and CVD prognosis: Evidence from a meta-analysis.

We examined the precise association between IL-10 levels and cardiovascular disease (CVD) prognosis and explored the pleiotropic role of IL-10 in different cardiac pathologies. We performed a meta-analysis of cross-sectional and longitudinal studies investigating IL-10 levels. Meta-regression analyses were used to determine the cause of the discrepancies. To assess publication bias, funnel plots were constructed, and Egger's tests were performed. Data from the GSE58015 dataset were used to investigate the levels of IL-10 under certain conditions. Because of substantial heterogeneity in the data used to compare the IL-10 levels between patients with CVD and healthy people, we could not determine the differences between the healthy controls and patients with ischemic or nonischemic pathologies (p > 0.05). The analysis of the association between IL-10 levels and CVD prognosis indicated that higher IL-10 levels were significantly associated with a poor prognosis in patients with nonischemic pathologies (HR = 1.10, 95% CI = 1.00-1.20, p = 0.043) but differentially associated with the prognosis of patients with ischemic pathologies based on the sampling time point (before percutaneous coronary intervention (PCI): HR = 4.90, 95% CI = 1.24-19.30, p < 0.001; after PCI: HR = 0.57, 95% CI = 0.43-0.75, p = 0.023). The meta-regression analysis showed that the pooled HR of the IL-10 levels was positively correlated with the IL-10/IL-6 ratio (ß = 0.644, p = 0.024). The funnel plots and Egger's tests revealed no statistically significant bias in our meta-analysis (p > 0.1). Furthermore, our data mining analysis supported our findings. Our analysis showed that IL-10 levels may be pleiotropically associated with the CVD prognosis possibly based on the type of pathology, disease stage and levels of other proinflammatory factors, such as IL-6.

Hispaglabridin B, a constituent of liquorice identified by a bioinformatics and machine learning approach, relieves protein-energy wasting by inhibiting forkhead box O1.

BACKGROUND AND PURPOSE: Liquorice is the root of Glycyrrhiza glabra, which is a popular food in Europe and China that has previously shown benefits for skeletal fatigue and nutrient metabolism. However, the mechanism and active ingredients remain largely unclear. The aim of this study was to investigate the active ingredients of liquorice for muscle wasting and elucidate the underlying mechanisms. EXPERIMENTAL APPROACH: RNA-Seq and bioinformatics analysis were applied to predict the main target of liquorice. A machine learning model and a docking tool were used to predict active ingredients. Isotope labelling experiments, immunostaining, Western blots, qRT-PCR, ChIP-PCR and luciferase reporters were utilized to test the pharmacological effects in vitro and in vivo. The reverse effects were verified through recombination-based overexpression. KEY RESULTS: The liposoluble constituents of liquorice improved muscle wasting by inhibiting protein catabolism and fibre atrophy. We further identified FoxO1 as the target of liposoluble constituents of liquorice. In addition, hispaglabridin B (HB) was predicted as an inhibitor of FoxO1. Further studies determined that HB improved muscle wasting by inhibiting catabolism in vivo and in vitro. HB also markedly suppressed the transcriptional activity of FoxO1, with decreased expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1. CONCLUSIONS AND IMPLICATIONS: HB can serve as a novel natural food extract for preventing muscle wasting in chronic kidney disease and possibly other catabolic conditions.

FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3ß-related pathways.

Colorectal cancer stem cells (CSCs), characterized by self-renewal ability and high expression of proliferative genes, contribute to the chemoresistance of colorectal cancer (CRC). We aimed to identify the molecular mechanisms underlying CRC chemoresistance through comprehensive bioinformatics screenings and experimental confirmation of gene functions. We found that high expression of FGF1 intracellular binding protein (FIBP) was correlated with chemoresistance and poor prognosis in CRC patients. Therefore, the chemoresistant CRC cell line HCT116-CSC with high expression of the stem cell markers CD44 and CD133 was established for further phenotypic tests. FIBP knockdown inhibited proliferation, enhanced chemotherapy effects, and attenuated the stemness markers of CRC cells in vivo and in vitro. Through RNA-seq and gene set enrichment analysis, we identified cyclin D1 as a key downstream target in FIBP-regulated cell cycle progression and proliferation. Moreover, FIBP bound to GSK3ß, inhibited its phosphorylation at Tyr216, and activated ß-catenin/TCF/cyclin D1 signaling in HCT116-CSCs. Additional GSK3ß knockdown reversed the FIBP silencing-induced inhibition of proliferation and decreased stemness marker expression in HCT116-CSCs. Furthermore, DNA methylation profiling suggested that FIBP regulated the stemness of CRC cells via methylation activity that was dependent on GSK3ß but independent of ß-catenin signaling. Our data illuminate the potential of FIBP as a novel therapeutic target for treating chemoresistant CRC through inhibition of GSK3ß-related signaling.