LIFE SCIENCES
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2024
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IF 5.2
Sijia Liu,Fang Guo,Tianli Zhang,Ying Zhu,Meng Lu,Xiayu Wu,Fuqin He,Ruiying Yu,Dan Yan,Zhangyin Ming,Dan Shu
Aims This research aimed to study the changes in platelet function and their underlying mechanisms in iron deficiency anemia. Main methods Initially, we evaluated platelet function in an IDA mice model. Due to the inability to accurately reduce intracellular Fe 2+ concentrations, we investigated the impact of Fe 2+ on platelet function by introducing varying concentrations of Fe 2+ . To probe the underlying mechanism, we simultaneously examined the dynamics of calcium in the cytosol, and integrin αIIbβ3 activation in Fe 2+ -treated platelets. Ferroptosis inhibitors Lip-1 and Fer-1 were applied to determine whether ferroptosis was involved in this process. Key findings Our study revealed that platelet function was suppressed in IDA mice. Fe 2+ concentration-dependently facilitated platelet activation and function in vitro. Mechanistically, Fe 2+ promoted calcium mobilization, integrin αIIbβ3 activation, and its downstream outside-in signaling. Additionally, we also demonstrated that ferroptosis might play a role in this process. Significance Our data suggest an association between iron and platelet activation, with iron deficiency resulting in impaired platelet function, while high concentrations of Fe 2+ contribute to platelet activation and function by promoting calcium mobilization, αIIbβ3 activation, and ferroptosis.
研究领域:
血液学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2021
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IF 7.658
Shuai Chen,Keyu Lv,Anish Sharda,Jun Deng,Wanjiang Zeng,Chao Zhang,Qinghua Hu,Pengfei Jin,Guangmin Yao,Xulin Xu,Zhangyin Ming,Chao Fang
Classical antithrombotics and antiplatelets are associated with high frequencies of bleeding complications or treatment failure when used as single agents. The platelet-independent fibrin generation by activated endothelium highlights the importance of vascular protection in addition to platelet inhibition in thrombosis prevention. Dihydromyricetin (DHM), the most abundant flavonoid in Ampelopsis grossedentata, has unique vasoprotective effects. This study aims to characterize the antithrombotic potential of DHM. The effects of DHM on the activation of platelets and endothelial cells were evaluated in vitro . Calcium mobilization and activation of mitogen-activated protein kinases (MAPKs) were examined as the potential targets of DHM based on molecular docking analysis. The in vivo effects of DHM were determined in FeCl 3 -injured carotid arteries and laser-injured cremasteric arterioles. The results showed that DHM suppressed a range of platelet responses including aggregation, secretion, adhesion, spreading and integrin activation, and inhibited exocytosis, phosphatidylserine exposure and tissue factor expression in activated endothelial cells. Mechanistically, DHM attenuated thrombin-induced calcium mobilization and phosphorylation of ERK1/2 and p38 both in platelets and endothelial cells. Intravenous treatment with DHM delayed FeCl 3 -induced carotid arterial thrombosis . Furthermore, DHM treatment inhibited both platelet accumulation and fibrin generation in the presence or absence of eptifibatide in the laser injury-induced thrombosis model, without prolonging ex vivo plasma coagulation or tail bleeding time. DHM represents a novel antithrombotic agent whose effects involve both inhibition of platelet activation and reduction of fibrin generation as a result of endothelial protection.
研究领域:
药理学
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心血管研究
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分子生物学
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血栓
✓ 已验证
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Ting-Ting He,Xin Li,Jie-Zhi Ma,Yuan Yang,Shiye Zhu,Jianhua Zeng,Lin Luo,Yu-Long Yin,Lin-Ying Cao
Triclocarban (TCC) and triclosan (TCS) have been detected ubiquitously in human body and evoked increasing concerns. This study aimed to reveal the induction risks of TCC and TCS on triple negative breast cancer through non-genomic GPER-mediated signaling pathways. Molecular simulation indicated that TCC exhibited higher GPER binding affinity than TCS theoretically. Calcium mobilization assay displayed that TCC/TCS activated GPER signaling pathway with the lowest observed effective concentrations (LOEC) of 10 nM/100 nM. TCC and TCS also upregulated MMP-2/9, EGFR, MAPK3 but downregulated MAPK8 via GPER-mediated signaling pathway. Proliferation assay showed that TCC/TCS induced 4 T1 breast cancer cells proliferation with the LOEC of 100 nM/1000 nM. Wound-healing and transwell assays showed that TCC/TCS promoted 4 T1 cells migration in a concentration-dependent manner with the LOEC of 10 nM. The effects of TCC on breast cancer cells proliferation and migration were stronger than TCS and both were regulated by GPER. TCC/TCS induced migratory effects were more significantly than proliferative effect. Mechanism study showed that TCC/TCS downregulated the expression of epithelial marker (E-cadherin) but upregulated mesenchymal markers (snail and N-cadherin), which was reversed by GPER inhibitor G15. These biomarkers results indicated that TCC/TCS-induced 4 T1 cells migration was a classic epithelial to mesenchymal transition mechanism regulated by GPER signaling pathway. Orthotopic tumor model verified that TCC promoted breast cancer in-situ tumor growth and distal tissue metastasis via GPER-mediated signaling pathway at human-exposure level of 10 mg/kg/d. TCC-induced tissue metastasis of breast cancer was more significantly than in-situ tumor growth. Overall, we demonstrated for the first time that TCC/TCS could activate the GPER signaling pathways to induce breast cancer progression.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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