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1.
Cell Calcium ; 95: 102367, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33610907

RESUMO

Accumulating evidence has revealed the mechanosensitive ion channel protein Piezo1 is contributing to tumorigenesis. However, its role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we demonstrated that Piezo1 was expressed in the HepG2 cell line and depletion of Piezo1 impaired proliferation and migration, as well as increased apoptosis in these cells. Using a Piezo1-specific activator, Yoda1, we identified that calcium entry induced by Yoda1 resulted in phosphorylation of JNK, p38, and ERK, thereby activating the mitogen-activated protein kinase (MAPK) pathway, in a dose- and time-dependent manner. More strikingly, Piezo1 activation integrated with YAP signaling to control the nuclear translocation of YAP and regulation of its target genes. JNK, p38, and ERK (MAPK signaling) regulated Yoda1-induced YAP activation. Consistent with the association of calpain with Piezo1, we also found that calpain activity was decreased by siRNA-mediated knockdown of Piezo1. In addition, the growth of HCC tumors was inhibited in Piezo1 haploinsufficient mice. Together, our findings establish that the Piezo1/MAPK/YAP signaling cascade is essential for HepG2 cell function. These results highlight the importance of Piezo1 in HCC and the potential utility of Piezo1 as a biomarker and therapeutic target.

2.
J Int Med Res ; 48(8): 300060520939742, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32762413

RESUMO

OBJECTIVES: Heart failure (HF) is a common and potentially fatal condition. In 2015, HF affected approximately 40 million people globally. Evidence showing that the use of nitrates can improve clinical outcomes in patients with HF is limited. This study aimed to assess the effect of nitrates on functional capacity and exercise time in patients with HF. METHODS: PubMed, Cochrane Library, and Embase databases were reviewed for articles on the use of nitrates and other treatments for patients with HF. The primary endpoints were the 6-minute walk test distance, exercise time, and quality of life. Secondary endpoints were all-cause mortality, arrhythmia, hospitalization, and worsening HF. The weighted mean difference, risk ratio, and 95% confidence interval were calculated. RESULTS: A total of 14 related studies that comprised 26,321 patients were included. No significant differences were found in the 6-minute walk test distance, exercise time, and quality of life between the nitrate and control treatment groups. There were also no differences in all-cause mortality, the incidence of arrhythmia, hospitalization, and worsening HF between these two groups. CONCLUSION: Patients with HF who receive nitrate treatment do not have better quality of life or exercise capacity compared with controls.

3.
Front Pharmacol ; 11: 768, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32523536

RESUMO

Piezo1, a mechanosensitive Ca2+-permeable non-selective cationic ion channel protein, is involved in a wide range of biological processes and plays crucial roles in vascular development. However, the pharmacology of this protein is in its infancy. Yoda1, the first specific chemical activator of Piezo1 channels, can activate Piezo1 in absence of mechanical stimulation. Hence, we sought to identify inhibitors of Yoda1 from Traditional Chinese Medicine (TCM). Intracellular Ca2+ measurements were conducted in human umbilical vein endothelial cells (HUVECs), HEK 293T cells overexpressing TRPC5 and TRPM2 channels, as well as in CHO K1 cells overexpressing TRPV4 channels. We identified tubeimoside I (TBMS1) as a strong inhibitor of the Yoda1 response and demonstrated its selectivity for the Piezo1 channels. Similarly, Yoda1-induced inhibitory results were obtained in Piezo1 wild-type overexpressed cells, murine liver endothelial cells (MLECs), and macrophages. The physiological responses of TBMS1 were identified by isometric tension, which can inhibit Yoda1 relaxation of aortic rings. Our results demonstrated that TBMS1 can effectively antagonize Yoda1 induced Piezo1 channel activation. This study sheds light on the existence of Yoda1 inhibitors and improves the understanding of vascular pharmacology through Piezo1 channels.

4.
Iran J Basic Med Sci ; 23(2): 251-256, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32405369

RESUMO

Objectives: To observe and determine the effect and mechanism of psoralen on tumor necrosis factor-α (TNF-α)-induced muscle atrophy. Materials and Methods: Three sets of C2C12 cells, including blank control, TNF-α (10 or 20 ng/ml) treatment and a TNF-α (10 or 20 ng/ml) plus psoralen (80 µM) administration were investigated. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) assay. Western blot analysis was used to detect protein expression of atrophic markers. Flowcytometry was used to observe the effect of psoralen on apoptosis. A quantitative real-time PCR (qRT-PCR) assay was performed to detect the mRNA level of miR-675-5P. Results: TNF-α (1, 10, 20 and 100 ng/ml) treatment inhibited C2C12 myoblast viability (P<0.001), while 24 hr of psoralen administration increased the viability, and lowered TNF-α cytotoxicity (P<0.001). MURF1, MAFbx, TRIM62 and GDF15 expressions were significantly increased in TNF-α (10 ng/ml or 20 ng/ml)-treated group (P<0.001), and psoralen could significantly decrease the expression of these proteins (P<0.001). Apoptotic rate of C2C12 myoblasts was increased after TNF-α (10 ng/ml and 20 ng/ml) treatment, and was significantly decreased after psoralen treatment (P<0.001). miR-675-5P was increased in TNF-α-treated C2C12 myoblasts compared to control group, and it was significantly decreased after psoralen treatment. Conclusion: Psoralen could reduce TNF-α-induced cytotoxicity, atrophy and apoptosis in C2C12 myoblasts. The therapeutic effect of psoralen may be achieved by down-regulating miR-675-5P.

5.
Med Sci Monit ; 26: e919665, 2020 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-32008037

RESUMO

BACKGROUND Sepsis-induced myopathy (SIM) is a complication of sepsis that results in prolonged mechanical ventilation, long-term functional disability, and increased patient mortality. This study aimed to use bioinformatics analysis to identify hub genes and molecular pathways involved in SIM, to identify potential diagnostic or therapeutic biomarkers. MATERIAL AND METHODS The Gene Expression Omnibus (GEO) database was used to acquire the GSE13205 expression profile. The differentially expressed genes (DEGs) in cases of SIM and healthy controls, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the limma R/Bioconductor software package and clusterProfiler package in R, respectively. The protein-protein interaction (PPI) network data of DEGs was retrieved using the STRING database and analyzed using the Molecular Complex Detection (MCODE) Cytoscape software plugin. RESULTS A total of 196 DEGs were obtained in SIM samples compared with healthy samples, including 93 upregulated genes. The DEGs were significantly upregulated in mineral absorption, and the interleukin-17 (IL-17) signaling pathway and 103 down-regulated genes were associated with control of the bile secretion signaling pathway. A protein-protein interaction (PPI) network was constructed with 106 nodes and 192 edges. The top two important clusters were selected from the PPI by MCODE analysis. There were 16 hub genes with a high degree of connectivity in the PPI network that were selected, including heme oxygenase 1 (HMOX1), nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1), and metallothionein (MT)-1E. CONCLUSIONS Bioinformatics network analysis identified key hub genes and molecular mechanisms in SIM.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Doenças Musculares/etiologia , Doenças Musculares/genética , Sepse/complicações , Transdução de Sinais , Análise por Conglomerados , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Mapas de Interação de Proteínas/genética , Regulação para Cima/genética
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