Objective— Hypoxic pulmonary hypertension (HPH) is characterized by proliferative vascular remodeling. Abnormal pulmonary artery smooth muscle cells proliferation and endothelial dysfunction are the primary cellular bases of vascular remodeling. AQP1 (aquaporin-1) is regulated by oxygen level and has been observed to play a role in the proliferation and migration of pulmonary artery smooth muscle cells. The role of AQP1 in HPH pathogenesis has not been directly determined to date. To determine the possible roles of AQP1 in the pathogenesis of HPH and explore its possible mechanisms. Approach and Results— Aqp1 knockout mice were used, and HPH model was established in this study. Primary pulmonary artery smooth muscle cells, primary mouse lung endothelial cells, and lung tissue sections from HPH model were used. Immunohistochemistry, immunofluorescence and Western blot, cell cycle, apoptosis, and migration analysis were performed in this study. AQP1 expression was upregulated by chronic hypoxia exposure, both in pulmonary artery endothelia and medial smooth muscle layer of mice. Aqp1 deficiency attenuated the elevation of right ventricular systolic pressures and mitigated pulmonary vascular structure remodeling. AQP1 deletion reduced abnormal cell proliferation in pulmonary artery and accompanied with accumulation of HIF (hypoxia-inducible factor). In vitro, Aqp1 deletion reduced hypoxia-induced proliferation, apoptosis resistance, and migration ability of primary cultured pulmonary artery smooth muscle cells and repressed HIF-1α protein stability. Furthermore, Aqp1 deficiency protected lung endothelial cells from apoptosis in response to hypoxic injury. Conclusions— Our data showed that Aqp1 deficiency could attenuate hypoxia-induced vascular remodeling in the development of HPH. AQP1 may be a potential target for pulmonary hypertension treatment.

BackgroundBackground: Bisphenol A (BPA) is an estrogen‐like chemical widely contained in daily supplies. There is evidence that environmental exposure to BPA could contribute to the development of hormone‐related cancers. As is reported in numerous studies, melatonin, an endogenous hormone secreted by the pineal gland, could markedly inhibit estrogen‐induced proliferation of breast cancer (BC) cells. In this study, we intended to reveal the effects of melatonin on BPA‐induced proliferation of estrogen receptor‐positive BC cells.MethodsMethods: We used methyl thiazolyl tetrazolium, luciferase reporter gene and western blotting assays to testify the effect of melatonin on BPA‐mediated proliferation of MCF‐7 and T47D cells.ResultsMethyl thiazolyl tetrazolium and colony formation assays showed that melatonin could significantly abolish BPA‐elevated cell proliferation. Meanwhile, BPA‐upregulated phosphorylation of ERK and AKT was decreased by melatonin treatment. Mechanistically, we found that BPA was capable of upregulating the protein levels of steroid receptor coactivators (SRC‐1, SRC‐3), as well as promoting the estrogen response element activity. However, the addition of melatonin could remarkably block the elevation of steroid receptor coactivators expression and estrogen response element activity triggered by BPA.ConclusionConclusions: Therefore, these results demonstrated that melatonin could abrogate BPA‐induced proliferation of BC cells. Therapeutically, melatonin could be regarded as a potential medication for BPA‐associated BC.

In this study, a synthetic high-density lipoprotein (sHDL), peptide-based nanocarrier loaded with docetaxel (DTX) was constructed, against breast cancer. The thermodynamic and molecular dynamic analyses were conducted to examine the stability of nanoparticles synthesized from mimetic peptide 5 A and various types of phospholipids. Furthermore, the cellular uptake and in vivo fluorescence imaging analysis experiments, with scavenger receptor B-I (SR-BI) were carried out to examine the tumor-targeting ability of sHDL. The nanoparticles were investigated for their pharmacodynamic and cytotoxic effects to show their effectivity as anti-tumor agents. The results showed that the synthesized sHDL nanoparticles exhibited a high payload of DTX, sustained drug release properties, and excellent biocompatibility. Moreover, DTX-sHDL nanoparticles enhanced the uptake of DTX, increased the cytotoxicity against MCF-7 cells, and reduced the off-target side-effects to normal cells. Finally, experiments in 4T1 cell line-bearing mice indicate that inhibition of tumor growth by DTX-sHDL nanoparticles was superior to that of free DTX group. Thus, the sHDL nanoparticles are a promising drug delivery vehicle for improving the efficacy of anti-cancer drugs.

Glioblastoma (GBM) recurrence is attributed to the presence of therapy‐resistant glioblastoma stem cells. Steroid receptor coactivator‐1 (SRC‐1) acts as an oncogenic regulator in many human tumors. The relationship between SRC‐1 and GBM has not yet been studied. Herein, we investigate the role of SRC‐1 in GBM. In this study, we found that SRC‐1 expression is positively correlated with grades of glioma and inversely correlated with glioma patient’s prognosis. Steroid receptor coactivator‐1 promotes the proliferation, migration, and tumor growth of GBM cells. Notably, SRC‐1 knockdown suppresses the stemness of GBM cells. Mechanistically, long noncoding RNA X‐inactive specific transcript (XIST) is regulated by SRC‐1 at the posttranscriptional level and mediates the function of SRC‐1 in promoting stemness‐like properties of GBM. Steroid receptor coactivator‐1 can promote the expression of Kruppel‐like factor 4 (KLF4) through the XIST/microRNA (miR)‐152 axis. Additionally, arenobufagin and bufalin, SRC small molecule inhibitors, can reduce the proliferation and stemness of GBM cells. This study reveals SRC‐1 promotes the stemness of GBM by activating the long noncoding RNA XIST/miR‐152/KLF4 pathway and provides novel markers for diagnosis and therapy of GBM.

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