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[en] This study aimed to investigate whether autophagy mediated cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia and to validate the underlying mechanism.
[en] As part of our project to develop small size, neutral, mixed ligand oxotechnetium and oxorhenium complexes of the general formula MOL1L2, we have synthesized and characterized four novel complexes of general formula MO[EtN(CH2CH2S)2][p-O2N-C6H4S] and MO [(Et2NCH2CH2NCH2CH2S)(p-O2N-C6H4S)] where M=Re (complex 1 and complex 2) or M=Tc (complex 3 and complex 4) as a new approach for hypoxia or ischemic tissue organ imaging. Complex 1 and 2 have been synthesized by exchange reaction in equimolar quantities of the tridentate and the monodentate ligand on ReOC13(PPh3). Only the syn isomer have been isolated and characterized by elemental analysis, IR, UV-vis, and 1H NMR. Crystal datas reveal a trigonal bipyramidal geometry around the metal for complex 1 and square pyramidal geometry around the metal for complex 2. Complex 3 is prepared by exchange reaction using Tc-99m-glucoheptonate as precursor and equimolar quantities of two ligands; EtN(CH2CH2SH)2 and p-O2N-C6H4SH while complex 4 is prepared by simultaneously reacting the Et2NCH2CH2NHCH2CH2SH and p-O2N-C6H4SH ligands with the 99Tc gluconate precursor in equimolar amount in MeOH. It may be concluded that the result of SNS/S and SNN/S mixed ligand of oxotechnetium is comfirmed by comparative HPLC studies with complex 1 and complex 2, since rhenium is a surrogate of technetium
[en] Background and purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful method for assessing the extent of hypoxia in tumors. In this study, we investigated whether differences in hypoxic fraction between tumors caused by the site of growth can be detected by DCE-MRI. Materials and methods: Intradermal and intramuscular A-07 tumors were subjected to DCE-MRI, histological analysis of microvascular characteristics, and measurement of hypoxic cell fractions using a radiobiological assay and a pimonidazole-based immunohistochemical assay. Parametric images of E.F (blood perfusion) and ve (extracellular volume fraction) were produced by pharmacokinetic analysis of the DCE-MRI series. Results: The intramuscular tumors had 3-4-fold higher hypoxic fractions than the intradermal tumors, owing to a lower microvascular density. This difference in extent of hypoxia was not detectable in the parametric MR images. Most likely, larger vessel diameters compensated for the lower vessel density in the intramuscular tumors, resulting in E.F images that were similar to those of the intradermal tumors. Conclusion: Quantitative assessment of hypoxic fractions from parametric MR images may require tumor site-specific translational criteria.
[en] Hypoxia inducible factor-1 (HIF-1) monitors the cellular response to the oxygen levels in solid tumors. Under hypoxia conditions, HIF-1α protein is stabilized and forms a heterodimer with the HIF-1β subunit. The HIF-1 complex activates the transcription of numerous target genes in order to adapt the hypoxic environment in human cancer cells. In gastric cancer patients, HIF-1α activation following extended hypoxia strongly correlates with an aggressive tumor phenotype and a poor prognosis. HIF-1α activation has been also reported to occur via hypoxia-independent mechanisms such as PI3K/AKT/mTOR signaling and ROS production. This article argues for the critical roles of HIF-1α in glucose metabolism, carcinogenesis, angiogenesis, invasion, metastasis, cell survival and chemoresistance, focusing on gastric cancer
[en] Highlights: • Hypoxia-induced miR-301a promotes gemcitabine resistance under hypoxic conditions in pancreatic cancer. • TAp63, is downregulated under hypoxic conditions, and re-sensitized hypoxic pancreatic cancer cells to gemcitabine. • TAp63 promotes degradation of HIF-1α under hypoxia in pancreatic cancer. • TAp63 is a functional downstream target of miR-301a and mediates the biological property of miR-301a in pancreatic cancer. Hypoxia is a hallmark of pancreatic cancer (PC) and is associated with gemcitabine resistance. However, the mechanisms underlying hypoxia-induced gemcitabine resistance in PC remain greatly unknown. Our previous work showed that miR-301a, a hypoxia-sensitive miRNA, is involved in PC metastasis under hypoxia via regulation of its target gene P63. Here, we showed that miR-301a was upregulated in a NF-κB independent manner and promoted gemcitabine resistance under hypoxic conditions in vitro. In addition, TAp63, a member of the P63 family, reversed hypoxia-induced gemcitabine resistance by promoting degradation of HIF-1α. Furthermore, we proved that TAp63 was a functional downstream target of miR-301a and mediated the biological properties of miR-301a in PC. Taken together, these findings indicate that miR-301a exerts as a critical regulator involved in hypoxia-induced gemcitabine resistance in PC and may have potentials to be a therapeutic target for PC patients.
[en] Hypoxia inducible factor 1α (HIF-1α) plays an essential role in the adaptive response of cells to hypoxia and is associated with aggressive tumour behaviour. We have shown p27kip1, which is generally reduced in endometrial cancer, to be re-expressed in hypoxic regions. This possibly contributes to survival of cancer cells. The aim of this study was to evaluate the prognostic value of HIF-1α and p27kip expression in patients with endometrioid endometrial cancer. Expression levels of HIF-1α, CAIX, Glut-1, and p27kip1 were analyzed by immunohistochemistry. Percentage of positive cells, staining pattern (perinecrotic, diffuse, or mixed) and presence of necrosis were noted. Necrosis was correlated with shortened disease free survival (DFS) (p = 0.008) and overall survival (OS) (p = 0.045). For DFS, perinecrotic HIF-1α expression was also prognostic (p = 0.044). Moreover, high p27kip1 expression was an additional prognostic factor for these patients with perinecrotic HIF-1α expression. In multivariate Cox regression, perinecrotic HIF-expression emerged as an independent prognostic factor. Perinecrotic HIF-1α expression was significantly associated with CAIX and Glut-1 expression, pointing towards functional HIF-1. In patients with endometrioid endometrial cancer, necrosis and necrosis-related expression of HIF-1α are important prognostic factors. More aggressive adjuvant treatment might be necessary to improve the outcome of patients with these characteristics
[en] Endothelial dysfunction is a main feature of retinal neovascular diseases which are the leading cause of blindness in developed countries. Yes-associated protein (YAP) and signal transducer and activator of transcription factor 3 (STAT3) participate in angiogenesis via vascular endothelial growth factor (VEGF) signaling. Additionally, YAP can bind STAT3 in endothelial cells. In the study, dimethyloxalylglycine (DMOG) stimulated human retinal microvascular endothelial cells (HRMECs) was used as retinal endothelial hypoxia model. The proliferation of HRMECs, as well as t-YAP, p-STAT3 (Tyr705) increased, while p-YAP (Ser127), p-YAP (Ser397) decreased following hypoxia. Meanwhile, YAP and STAT3 translocated to the nucleus. YAP knockdown inhibited the proliferation, migration and tube formation of HRMECs. YAP overexpression up-regulated phosphorylation of STAT3. The YAP overexpression-induced HRMECs proliferation, migration and tube formation were reversed by S3I-201, a selective STAT3 inhibitor. YAP interacted with STAT3 to promote STAT3 nuclear translocation. Additionally, YAP and STAT3 promoted the transcription of VEGF synergistically. Finally, inhibition of YAP alleviated retinal pathological neovascularization in mouse oxygen-induced retinopathy (OIR) model. In summary, activated YAP interacted with STAT3 to promote the activation and nuclear translocation of STAT3, hence boosted the proliferation, migration and tube formation of HRMECs via VEGF signaling following hypoxia. The data will further elucidate the mechanisms of retinal neovascular diseases.
[en] Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion. In order to perform the studies, we employed optimal cell culture methods and hypoxic conditions, lentivirus-mediated knockdown of protein expression, Western Blot analysis, migration assays and immunoprecipitation. We determined statistical significance by unpaired t-test. In this report, we show that U87MG, LN229 and LN308 glioma cells express CXCR7 and that exposure to hypoxia upregulates CXCR7 protein expression in these cell lines. CXCR7-expressing U87MG, LN229 and LN308 glioma cells migrated towards stromal-derived factor (SDF)-1α/CXCL12 in hypoxic conditions in the Boyden chamber assays. While shRNA-mediated knockdown of CXCR7 expression did not affect the migration of any of the three cell lines in normoxic conditions, we observed a reduction in the migration of LN229 and LN308, but not U87MG, glioma cells towards SDF-1α in hypoxic conditions. In addition, knockdown of CXCR7 expression in LN229 and LN308 glioma cells decreased levels of SDF-1α-induced phosphorylation of ERK1/2 and Akt. Inhibiting CXCR4 in LN229 and LN308 glioma cells that were knocked down for CXCR7 did not further reduce migration towards SDF-1α in hypoxic conditions and did not affect the levels of phosphorylated ERK1/2 and Akt. Analysis of immunoprecipitated CXCR4 from LN229 and LN308 glioma cells revealed co-precipitated CXCR7. Taken together, our findings indicate that both CXCR4 and CXCR7 mediate glioma cell migration towards SDF-1α in hypoxic conditions and support the development of therapeutic agents targeting these receptors
[en] Highlights: • p75NTR levels are increased in hypoxic glioma cells in vivo and in vitro. • p75NTR contributes to HIF-1 and HIF-2 stability at hypoxia. • Hypoxia-induced glioma stemness and migration depends in part on p75NTR. Tumor hypoxia is associated with several features of aggressive glioma growth, including migration, invasion, and stemness. Most of the cellular adaptation to hypoxia is mediated by the hypoxia-inducible factors HIF-1α and HIF-2α, but regulation of these factors by both oxygen-dependent and –independent mechanisms in brain tumors is only partially understood. Here, we show that the p75 neurotrophin receptor (p75NTR) is stabilized at hypoxia in murine glioma in vivo, as well as in primary human glioma cultures in vitro. Expression of p75NTR resulted in increased stabilization of HIF-1α and HIF-2α, and RNAi or pharmacologic targeting of p75NTR diminished HIF stabilization and HIF-dependent signaling at hypoxia. Consequentially, p75NTR inhibition resulted in decreased migration, invasion, and stemness in response to hypoxia, suggesting that p75NTR is a central regulator of hypoxia-induced glioma aggressiveness. Together, our findings support the literature that identifies p75NTR as a potential therapeutic target in brain tumors.