Hypoxia-inducible Factor-1 Alpha Signaling Research Articles

Inorganic Biomaterials Shape the Transcriptome Profile to Induce Endochondral Differentiation.

Minerals play a vital role, working synergistically with enzymes and other cofactors to regulate physiological functions including tissue healing and regeneration. The bioactive characteristics of mineral-based nanomaterials can be harnessed to facilitate in situ tissue regeneration by attracting endogenous progenitor and stem cells and subsequently directing tissue-specific differentiation. Here, cellular responses of human mesenchymal stem/stromal cells to traditional bioactive mineral-based nanomaterials, such as hydroxyapatite, whitlockite, silicon-dioxide, and the emerging synthetic 2D nanosilicates are investigated. Transcriptome sequencing is utilized to probe the cellular response and determine the significantly affected signaling pathways due to exposure to these inorganic nanomaterials. Transcriptome profiles of stem cells treated with nanosilicates reveals a stabilized skeletal progenitor state suggestive of endochondral differentiation. This observation is bolstered by enhanced deposition of matrix mineralization in nanosilicate treated stem cells compared to control or other treatments. Specifically, use of 2D nanosilicates directs osteogenic differentiation of stem cells via activation of bone morphogenetic proteins and hypoxia-inducible factor 1-alpha signaling pathway. This study provides insight into impact of nanomaterials on cellular gene expression profileand predicts downstream effects of nanomaterial induction of endochondral differentiation.

Perfluorodecalin-based oxygenated emulsion as a topical treatment for chemical burn to the eye

Chemical injuries to the eye are emergencies with limited acute treatment options other than prompt irrigation and can cause permanent vision loss. We developed a perfluorodecalin-based supersaturated oxygen emulsion (SSOE) to topically deliver high concentration of oxygen to the eye. SSOE is manufactured in hyperbaric conditions and stored in a ready-to-use canister. Upon dispensation, SSOE rapidly raises partial oxygen pressure 3 times over atmospheric level. SSOE is biocompatible with human corneal cells and safe on mouse eyes in vivo. A single topical application of SSOE to the eye after alkali injury significantly promotes corneal epithelial wound healing, decreases anterior chamber exudation, and reduces optical opacity and cataract formation in mice. SSOE treatment reduces intraocular hypoxia, cell death, leukocyte infiltration, production of inflammatory mediators, and hypoxia-inducible factor 1-alpha signaling, thus hastening recovery of normal tissue integrity during the wound healing process. Here, we show that SSOE is an effective topical therapeutic in the acute treatment of ocular chemical injuries.

POU6F1 cooperates with RORA to suppress the proliferation of lung adenocarcinoma by downregulating HIF1A signaling pathway

Lung adenocarcinoma (LUAD) represents the most frequently diagnosed histological subtype of non-small cell lung cancer with the highest mortality worldwide. Transcriptional dysregulation is a hallmark of nearly all kinds of cancers. In the study, we identified that the POU domain, class 6, transcription factor 1 (POU6F1), a member of the POU family of transcription factors, was closely associated with tumor stage and death in LUAD. We revealed that POU6F1 was downregulated in LUAD tissues and downregulated POU6F1 was predictive of an unfavorable prognosis in LUAD patients. In vitro assays, including CCK8, soft agar, transwell, clone formation, wound-healing assay, and nude mouse xenograft model all revealed that POU6F1 inhibited the growth and invasion of LUAD cells. Mechanistically, POU6F1 bound and stabilized retinoid-related orphan receptor alpha (RORA) to exert the transcriptional inhibition of hypoxia-inducible factor 1-alpha (HIF1A) and alter the expression of HIF1A signaling pathway-associated genes, including ENO1, PDK1, and PRKCB, thereby leading to the suppression of LUAD cells. Collectively, these results demonstrated the suppressive role of POU6F1/RORA in the progression of LUAD and may potentially be used as a target for the treatment of LUAD.

The cognitive impairment induced via activation of hypoxia inducible factor-1 alpha signaling pathway

The cognitive impairment induced via activation of hypoxia inducible factor-1 alpha signaling pathway

Thermal treatment decreases resistance to osimertinib in non-small cell lung cancer through the EGFR/PI3K/AKT pathway.

Osimertinib (OSI) resistance commonly occurs during the treatment of non-small-cell lung cancer (NSCLC). This study aims to investigate whether the thermal effects of radiofrequency ablation (RFA) can increase the sensitivity of OSI-resistant NSCLC to OSI treatment and whether OSI effectively inhibits the recurrence of OSI-resistant NSCLC following RFA treatment and improve survival of NSCLC patients. In vitro, OSI-resistant NCI-H1975 (NCI-H1975/OSIR) cells and thermotolerant NCI-H1975/OSIR (NCI-H1975/OSIR-a-h) cells were established using human NSCLC cell line NCI-H1975. Cell viability, apoptosis, sensitivity to OSI, threonine-methionine amino acid substitution at position 790 (T790M) mutation levels, and protein expression of epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), hypoxia-inducible factor-1 alpha (HIF-1a) were detected using different methods. In vivo, a nude mouse model of metastatic human lung cancer was developed and subjected to RFA treatment. The tumor growth, apoptosis, sensitivity to OSI, expression of EGFR/PI3K/AKT/HIF-1a, and CD34 levels were detected in the micrometastases of the transition zone (TZ) around the central ablation zone, and the reference zone (RZ) far from central ablation zone. NCI-H1975/OSIR and thermotolerant NCI-H1975/OSIR cell models were successfully established. Thermotolerant NCI-H1975/OSIR cells show higher sensitivity to OSI than NCI-H1975/OSIR cells and NCI-H1975 cells. OSI treatment can inhibit the EGFR/PI3K/AKT pathway and induce apoptosis in both NCI-H1975 cells and thermotolerant NCI-H1975/OSIR cells, but not in NCI-H1975/OSIR cells. In vivo, RFA treatment increases sensitivity to OSI in NCI-H1975/OSIR cell micrometastases in the TZ but not in the RZ. OSI intervention effectively inhibits the over-proliferation of micrometastases and activation of the EGFR/PI3K/AKT pathway, and induces apoptosis of micrometastases in the TZ, but shows little effects on the micrometastases in the RZ. The thermal effects can increase the sensitivity of OSI-resistant NSCLC cells to OSI through the EGFR/PI3K/AKT/HIF-1a signaling pathway, indicating that RFA combined with OSI might be a clinically effective and comprehensive therapy for the treatment of OSI-resistant NSCLC.

A Role for Hypoxia‐inducible Factor 1‐alpha (HIF1a) Signaling in Suppressing Synaptic Plasticity and Spatial Memory During Intermittent Hypoxia

Although HIF1a signaling is commonly identified as a mediator of positive homeostatic responses to hypoxia, during intermittent hypoxia (IH), a primary effect of sleep apnea, HIF1a signaling can cause oxidative stress in the body. IH‐dependent oxidative stress can lead to pathophysiological changes throughout the nervous system associated with sleep apnea. The objective of this study is to determine whether HIF1a signaling during IH opposes or facilitates IH‐dependent suppression in synaptic plasticity and spatial memory. Both adult wildtype mice (WT) and mice heterozygous for HIF1a (HIF1a+/−) were either unexposed (control) or exposed to chronic intermittent hypoxia (CIH) for 10 days. Hippocampal brain slices (350 microns thick) were prepared from mice of each group. Extracellular recordings of the field excitatory postsynaptic potential (fEPSP) were made before and after the induction of long‐term potentiation (LTP) in area CA1. While LTP occurred in brain slices of WT from both groups, the magnitude of LTP was larger in the control group (164±6% of baseline, n=5) as compared to the CIH group (115±10% of baseline, n=5). LTP in the brain slices from the HIF1a+/− exposed to CIH was 152±10% of baseline (n=5), which was greater in magnitude compared to WT LTP in the CIH group. Ongoing experiments suggest spatial memory in the Barnes Maze is unaffected by CIH in HIF1a+/−. These findings show that IH‐dependent HIF1a signaling disrupts hippocampal synaptic plasticity and spatial memory, which may contribute to cognitive impairment associated with sleep apnea.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mechanism of herbal pairs with the properties of Qi-tonifying, blood activation, blood-stasis breaking in treating coronary heart disease

ObjectiveTo investigating the molecular mechanism of herbal pairs in three types of Chinese medicinals: Qi-tonifying, blood activation, blood-stasis breaking in treatment of coronary heart disease (CHD). MethodsThe components of six herbs were searched in Chinese medicine dictionary and their target proteins were found in PubChem. CHD genes were obtained from PubMed gene database. Ingenuity Pathways Analysis was used to build the pharmacological network of three herbal pairs and CHD molecular network. The canonical pathways between each herbal pair network and CHD network was compared to decipher the molecular mechanism on three herbal pairs in treating CHD. ResultsThe network analysis showed that there were the common signal pathways of three herbal pairs in treating CHD including hypoxia signaling in the cardiovascular system, Hypoxia-inducible factor 1-alpha signaling, glucocorticoid receptor signaling, G-Protein coupled receptor signaling and pregnane X receptor/retinoid X receptor (PXR/RXR) activation. Further to analyze cardiovascular signaling, cytokine signaling and cytokine signaling, the effective molecules for three herbal pairs in treating CHD included HIF1α and estrogen receptor 1, Qi-tonifying herbal pair included albumin and matrix metallopeptidase 2, and blood-activation herbal pair included estrogen receptor 2 and peroxisome proliferator-activated receptor-γ. ConclusionEach herbal pair can affect some respective CHD-related functions and pathways, meanwhile three herbal pairs exert some mutual effects on CHD-related functions and pathways. Mutual effects of three herbal pairs may be the key components of their total molecular mechanisms and respective effects of each herbal pair may be the characteristic components of their respective molecular mechanism.

ANGI-08RADIOGENOMIC rCBV-IMAGING VISUALIZES THE DISTINCT ANGIOGENESIS TRANSCRIPTOME SIGNATURES OF IDH MUTANT AND WILD-TYPE GLIOMAS

BACKGROUND: The recent identification of isocitrate dehydrogenase (IDH) mutations in gliomas and several other cancers suggests that this pathway is involved in oncogenesis; however effector functions are complex and yet incompletely understood. To study the regulatory effects of IDH on hypoxia-inducible-factor 1-alpha (HIF1A), a driving force in hypoxia-initiated angiogenesis, we performed mRNA-expression and functional, as well as genotype/imaging phenotype correlation analysis. METHODS: We studied differential mRNA-expression profiles from 288 samples with low-grade and anaplastic gliomas from The Cancer Genome Atlas (TCGA) of HIF1A and related downstream signaling on a single-gene and pathway level, as well as upstream biological causes and probable downstream effects between mutant and wild-type IDH tumors. Genotype/imaging phenotype correlation analysis was performed in a separate (local) dataset with relative cerebral blood volume (rCBV) MRI - an estimate of tumor angiogenesis - in 73 treatment-naive patients with low-grade and anaplastic gliomas. RESULTS: We show decreased expression of HIF1A-target genes on a single-gene and pathway level, strong inhibition of upstream regulators such as HIF1A and downstream biological functions such as angio- and vasculogenesis in IDH-mutant tumors. Our radiogenomic imaging approach revealed increased levels of rCBV in IDH wild-type tumors, where a one-unit increase in rCBV corresponded to a two-third decrease in the odds for an IDH-mutation and correctly predicted IDH mutation status in 88% of patients. CONCLUSION: Together, these findings show that IDH-mutation status is associated with a distinct angiogenesis transcriptome signature which is non-invasively predictable with rCBV-imaging.

Hypoxia-inducible factor-1 alpha signaling: Regulation of vascular endothelial growth factor-dependent angiogenesis during ovarian corpus luteum development in mammals

The corpus luteum (CL) is a temporary endocrine structure in mammals, which is the site of intense capillary network (angiogenesis). The angiogenesis is a process of vascular growth that is mainly limited to the reproductive system in healthy adult animals, which enables the hormone-producing cells to obtain the oxygen, nutrients and also precursors necessary to synthesize and release different hormones essential for the maintenance of ovarian functions. Vascular endothelial growth factor (VEGF) is thought to play a paramount role in the regulation of normal and abnormal angiogenesis in the ovary, especially in the newly formed CL. Recent studies have also indicated that hypoxia is important for establishing the vascular system during the CL development, which induces hypoxia-inducible factor (HIF)-1a expression in luteal cells (LCs). Therefore, the molecular regulation of luteal VEGF expression during CL development becomes more important to be explored. Based on our recent research findings, the present review will clarify the role of HIF-1a signaling in VEGF-dependent angiogenesis during CL development. Investigations of the angiogenic mechanisms may lead to new strategies in treatment for fertility control and for some types of ovarian dysfunction, such as polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS) and ovarian neoplasia. Key words: Phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR), hypoxia-inducible factor (HIF)-1a, vascular endothelial growth factor (VEGF), prolyl-hydroxylase (PHD), corpus luteum.

Hypoxia regulates choline kinase expression through hypoxia-inducible factor-1 alpha signaling in a human prostate cancer model.

The intensity of the total choline (tCho) signal in spectroscopic images of tumors is spatially heterogeneous. The likewise heterogeneous physiologic tumor microenvironment may contribute to this heterogeneity. We therefore investigated the relationship between hypoxia, choline metabolites, and choline kinase (Chk) in a human prostate cancer model. Human PC-3 prostate cancer cells were engineered to express enhanced green fluorescent protein (EGFP) under hypoxic conditions. These PC-3-5HRE-EGFP cells were characterized in culture and as tumors transplanted in mice using (1)H magnetic resonance spectroscopy (MRS) and MRS imaging (MRSI) combined with EGFP fluorescence microscopy and imaging. Hypoxic EGFP-fluorescing tumor regions colocalized with regions of high tCho in combined MRSI and optical imaging studies. Cellular phosphocholine (PC) and tCho concentrations as well as Chk expression levels significantly increased following exposure of PC-3 cells to hypoxia. A putative promoter region located 5' of the translation start site of the human chk-alpha gene was cloned and luciferase (Luc)-based reporter vector constructs were generated. Luc reporter assays provided evidence that some of the putative hypoxia response elements (HRE) within this putative chk-alpha promoter region functioned in vitro. Chromatin immunoprecipitation assays using an antibody against hypoxia-inducible factor (HIF)-1 alpha showed that HIF-1 can directly bind this region of the endogenous chk-alpha promoter in hypoxic PC-3-5HRE-EGFP cells. These data suggest that HIF-1 activation of HREs within the putative chk-alpha promoter region can increase Chk-alpha expression within hypoxic environments, consequently increasing cellular PC and tCho levels within these environments.