Luteolin Ameliorates Experimental Pulmonary Arterial Hypertension via Suppressing Hippo-YAP/PI3K/AKT Signaling Pathway

Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.

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Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00245.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. L349-L359 ◽

Cited By ~ 11

Author(s):

Hsin-Hsien Li ◽

Hsao-Hsun Hsu ◽

Gwo-Jyh Chang ◽

I-Chen Chen ◽

Wan-Jing Ho ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Arterial Remodeling ◽

Peroxisome Proliferator Activated Receptor ◽

Pulmonary Arterial ◽

And Migration ◽

Pparγ Expression

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (Gs), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARγ but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPARγ in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARγ in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPARγ. This study identified a novel EP4-PKA-PPARγ pathway, and we propose EP4 as a potential therapeutic target for PAH.

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Effects of Rhizopus Nigricans Exopolysaccharide on Proliferation, Apoptosis, and Migration of Breast Cancer MCF-7 Cells and Akt Signaling Pathway

International Journal of Polymer Science ◽

10.1155/2021/5621984 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Aizhai Xiang ◽

Chen Ling ◽

Wei Zhang ◽

Honggang Chen

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Akt Signaling ◽

Migration And Invasion ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Rhizopus Nigricans ◽

And Migration ◽

The Impact ◽

Mcf 7

Objective. To study the effect of Rhizopus nigricans exopolysaccharide EPS1-1 on the proliferation, apoptosis, and migration of breast cancer MCF-7 cells. Methods. Human breast cancer MCF-7 cells were cultured in vitro and treated with different concentrations of EPS1-1. The effect of EPS1-1 on cell proliferation was tested by the CCK-8 experiment, and the effect of EPS1-1 on cell apoptosis was determined by flow cytometry. And the scratch test was used to detect the impact of EPS1-1 on cell migration. Western blot then was used to measure the expression changes of related proteins in the Akt signaling pathway. Results. Compared with the control group, treatment with EPS1-1 significantly reduced the proliferation, migration, and invasion ability of MCF-7 cells and promoted the apoptosis of MCF-7 cells in a dose-dependent manner. In terms of the underlying mechanism, EPS1-1 can significantly inhibit the phosphorylation of Akt at threonine 308 and serine 473 and cause the expression changes of downstream proliferation-related genes CCND1 and p21, apoptosis-related genes Bcl-2 and Bax, and migration-related genes Vimentin and E-cadherin in terms of their protein levels. Conclusion. EPS1-1 can inhibit the proliferation, migration, and invasion of breast cancer MCF-7 cells and promote the apoptosis of MCF-7 cells by inhibiting the activation of the Akt signaling pathway. Therefore, EPS1-1 can be used as a potential new drug or adjuvant drug for the treatment of breast cancer.

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Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model

Zeitschrift für Naturforschung C ◽

10.1515/znc-2020-0004 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Aifeng Chen ◽

Shibiao Ding ◽

Liangliang Kong ◽

Jianpu Xu ◽

Fei He ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Cardiac Muscle ◽

Rat Model ◽

Dependent Manner ◽

Arterial Remodeling ◽

Pulmonary Arterial ◽

Dose Dependent

AbstractPulmonary arterial hypertension (PAH) is a group of diseases with an increase of pulmonary artery pressure (PAP) and pulmonary vascular resistance. Here, the effects of safflower injection, a preparation of Chinese herbs, was investigated in a monocrotaline (MCT)-induced PAH rat model. PAP, carotid artery pressure (CAP), and the right ventricular hypertrophy index (RVHI) increased in the PAH group, while safflower injection was able to inhibit this increase to similar levels as observed in the normal group. The arteriole wall of the lungs and cardiac muscle were thickened and edema was observed in the PAH group, while these pathologies were improved in the herb-treated group in a dose-dependent manner. MCT treatment induced proliferation of pulmonary artery smooth muscle cells (PASMCs), which was inhibited by safflower injection in a dose-dependent manner. Our experimental results demonstrated that safflower injection can regulate pulmonary arterial remodeling through affecting the expression of connective tissue growth factor, transforming growth factor-β, integrin, collagen or fibronectin, which subsequently affected the thicknesses of the arteriole walls of the lungs and cardiac muscle, and thereby benefits the control of PAH. This means safflower injection improved the abnormalities in PAP, CAP and RVHI, and pulmonary arterial remodeling through regulation of remodeling factors.

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miR-340 Inhibits the Development of Hepatocellular Carcinoma by Down-Regulating Akt Signaling Pathway

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2590 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1785-1791

Author(s):

Tangpeng Xu ◽

Changli Ruan ◽

Xu Bin ◽

Mengxue Hu

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Signaling Pathway ◽

Akt Signaling ◽

Pathological Grade ◽

Akt Signaling Pathway ◽

Invasion And Migration ◽

Proliferation Ability ◽

And Migration ◽

Cancer Tissues

Hepatocellular carcinoma (HCC) is a serious threat to human health. miR-340 participates in HCC pathogenesis, but its specific mechanism is not completely clear. Therefore, our study assessed the mechanism by how miR-340 involves in HCC. The cancer tissues and paracancerous tissues of HCC patients were collected. miR-340 mimics/NC and Akt siRNA were transfected into HepG2 cells followed by analysis of miR-304 and EMT-related molecules expression by Real-time PCR, cell invasion and migration by Transwell assay, cell proliferation ability by CCK8 assay as well as p-Akt and p-mTOR level by Western blot. miR-340 in HCC tissues was significantly downregulated compared to adjacent tissues (P <0.001). With increased pathological grade, miR-340 expression was decreased gradually. p-Akt and p-mTOR in HCC tissues was significantly upregulated and elevated gradually with increased pathological grade. p-Akt and p-mTOR was negatively associated with miR-340 (P <0.001). After overexpression of miR-340, HepG2 cell proliferation, invasion, migration and epithelialization were significantly inhibited, and p-Akt and p-mTOR was reduced. When Akt expression was interfered with siRNA, cell proliferation and epithelialization was further inhibited. miR-340 inhibits the development of hepatocellular carcinoma through Akt signaling pathway.

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