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Signal Transduct Target Ther ; 6(1): 329, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087


It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. ( identifier: NCT01681316).

Biotechnol Lett ; 37(2): 475-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25312921


Embryoid bodies (EBs) with large starting numbers of embryonic stem cells (ESCs) have a greater degree of cardiac differentiation than from low numbers of EBs. However, the biological roles of signaling molecules in these effects are not well understood. Here, we show that groups of EBs with different starting numbers of ESCs had differential gene expression patterns for Wnt5a and Wnt11. Wnt11 significantly increased the percentage of beating EBs by up-regulating the expression of the cardiac-specific genes. Wnt5a did not show these effects. Moreover, Wnt11 significantly increased the level of phosphorylated Jun N-terminal kinase. The inhibition of the JNK pathway by SP600125 blocked the effects of Wnt11. Thus, enrichment of cardiac differentiation in groups of EBs with a larger starting number of ESCs is mediated by the Wnt11-JNK pathway.

Diferenciação Celular/fisiologia , Corpos Embrioides/fisiologia , Células-Tronco Embrionárias/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Miócitos Cardíacos/metabolismo , Proteínas Wnt/metabolismo , Animais , Linhagem Celular , Camundongos , Miócitos Cardíacos/citologia , Proteínas Wnt/genética
Mol Cell Biochem ; 380(1-2): 67-72, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23606057


Neuregulin-1ß (NRG-1ß)/ErbB signaling plays crucial roles in the cardiac differentiation of mouse embryonic stem cells (ESCs), but its roles and the underlying mechanisms in cardiac differentiation are incompletely understood. This study showed that NRG-1ß significantly increased the percentage of beating embryoid bodies (EBs) and up-regulated the gene expressions of Nkx2.5, GATA4, α-actin, MLC-2v, and ANF in a time-dependent manner, with no effect on the gene expressions of HCN4 and Tbx3. Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and α-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time-dependent manner. Moreover, the up-regulation of transcripts for Nkx2.5 and GATA4 by NRG-1ß was blocked by the extracellular signal-related kinases (ERK) 1/2 inhibitor, U0126. However, U0126 could not inhibit the transcript up-regulations of MLC-2v and ANF by NRG-1ß. The protein quantitation results were consistent with those of gene quantitation. Our results suggest that NRG-1ß/ErbB signaling plays critical roles in the cardiac differentiation of mouse ESCs and in the subtype specification of cardiomyocytes in a time-dependent manner. The ERK1/2 pathway may be involved in the early cardiogenesis, but not in the subtype specification of cardiomyocytes.

Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neuregulina-1/farmacologia , Transdução de Sinais/efeitos dos fármacos , Actinas/genética , Animais , Fator Natriurético Atrial/genética , Butadienos/farmacologia , Diferenciação Celular/genética , Linhagem Celular , Corpos Embrioides/citologia , Corpos Embrioides/efeitos dos fármacos , Corpos Embrioides/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Receptores ErbB/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Fator de Transcrição GATA4/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Cadeias Leves de Miosina/genética , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Quinazolinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas com Domínio T/genética , Fatores de Tempo , Fatores de Transcrição/genética , Tirfostinas/farmacologia