The roles of reactive oxygen species (ROS), extracellular signal-regulated kinase 1/2 (ERK 1/2) and mitochondrial permeability transition pore (mPTP) in sevoflurane postconditioning induced cardioprotection against ischemia-reperfusion injury in Langendorff rat hearts were investigated. When compared with the unprotected hearts subjected to 30 min of ischemia followed by 1 h of reperfusion, exposure of 3% sevoflurane during the first 15 min of reperfusion significantly improved functional recovery, decreased infarct size, reduced lactate dehydrogenase and creatine kinase-MB release, and reduced myocardial malondialdehyde production. However, these protective effects were abolished in the presence of either ROS scavenger N-acetylcysteine or ERK 1/2 inhibitor PD98059, and accompanied by prevention of ERK 1/2 phosphorylation and elimination of inhibitory effect on mPTP opening. These findings suggested that sevoflurane postconditioning protected isolated rat hearts against ischemia-reperfusion injury via the recruitment of the ROS-ERK 1/2-mPTP signaling cascade.
Src kinase is known to regulate fibroblast migration. However, the contribution of integrin and Src kinase interaction to lung fibrosis has not been mechanistically investigated. Our data demonstrate that integrin alpha v (αV) recruited Src kinase and that leads to subsequent Src activation in fibroblasts plated on fibrotic matrix, osteopontin. Src interaction with integrin αV is required for integrin αV-mediated Src activation, and the subsequent fibroblast migration. The study identified that β5 and β3 are the major integrins for this effect on osteopontin. In contrast, integrins β1, β6, and β8 did not have a critical role in this phenomenon. Importantly, Src inhibitor significantly reduces fibroblast migration stimulated by PDGF-BB and reduced in vivo lung fibrosis in mice. Src inhibitor reduced Src activation and blocked the signaling transduction by integrin αV, inhibited migration signaling pathways and reduced extracellular matrix protein production, and blocked myofibroblast differentiation in vivo in mouse lung tissues. The present study supports that the interaction of Src Kinase and integrins plays a critical role in the development of lung fibrosis and the signaling involved may present a novel opportunity to target deadly fibrotic diseases.
a b s t r a c tAs a cleavage enzyme of precursor TNF-a, the high expression level of ADAM17 in endothelial cells is an important factor in atherosclerosis. In this study, we demonstrate that ADAM17 is the target of miR-152. We found that miR-152 could reduce TNF precursor cleavage and inhibit cell proliferation and migration by targeting ADAM17 in human umbilical vein endothelial cells (HUVECs). Furthermore, the expression pattern of miR-152 and corresponding target ADAM17 was opposite in HUVECs under hypoxic conditions. The levels of circulating miR-152 in AS patient sera were lower than those detected in the sera of normal individuals. Our results indicate that miR-152 may be involved in the development of human atherosclerosis and could be used as diagnostic biomarker or therapeutic target in atherosclerosis.
Dihydrotanshinone, a functional food in China, is an effective anti-cardiovascular disease substance isolated from Salvia miltiorrhiza (S. miltiorrhiza). Glioma is considered to be fatal due to its poor prognosis and few effective therapeutic options. In this study, we investigated the anticancer effects of S. miltiorrhiza extract dihydrotanshinone on human glioma SHG-44 cells, by using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide assay, Hoechst 33258 nuclear staining, Annexin V/propidium iodide double staining, as well as western blot analysis. The results showed that dihydrotanshinone effectively suppressed SHG-44 cells proliferation and induced apoptosis in both dose- and time-dependent manner. Moreover, we demonstrated that dihydrotanshinone increased the activation of caspases (caspase-3 and caspase-9) and the release of cytochrome c in SHG-44 cells. Overall, dihydrotanshinone could induce apoptosis and inhibit proliferation of glioma cells by regulating caspases and cytochrome c. This study suggests that dihydrotanshinone may serve as a potential treatment option for patients with glioma.
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