• HIF
• NSC
• embryonic neurogenesis
• hypoxia
• neocortex
• neural progenitor cells
• vascularization

• Humans
• Animals
• Pregnancy
• Female
• Neural Stem Cells/metabolism
• Neurons/metabolism
• Neurogenesis/genetics
• Hypoxia/metabolism
• Oxygen/metabolism
• Mammals

• Apoptosis
• Differentiation
• Exosome
• Hypoxia
• Neural stem cell
• Proliferation

• Humans
• Phosphatidylinositol 3-Kinases/metabolism
• Cell Proliferation
• Neural Stem Cells/metabolism
• Cell Differentiation/physiology
• Hypoxia/metabolism
• Cell Hypoxia/physiology
• Oxygen/pharmacology
• Oxygen/metabolism
• Cells, Cultured

• 81971152 National Natural Science Foundation of China
• 2019-ZD-0742 Natural Science Foundation of Liaoning Province

• HIF-1
• autophagy
• hypoxia
• mTORC1
• neural stem cells
• proliferation

• molecular neuroscience
• psychiatric disorders

• Animals
• Dopamine/metabolism
• Dopaminergic Neurons/metabolism
• Female
• Humans
• Hypoxia/metabolism
• Mesencephalon/metabolism
• Mice
• Pregnancy
• Tyrosine 3-Monooxygenase/metabolism

• Department of Health | National Health and Medical Research Council (NHMRC)

Children operated on for a simple congenital heart defect (CHD) are at risk of neurodevelopmental abnormalities. Abnormal cortical development and folding have been observed in fetuses with CHD. We examined whether sulcal folding patterns in adults operated on for simple CHD in childhood differ from those of healthy controls, and whether such differences are associated with neuropsychological outcomes.

Patients (mean age, 24.5 years) who underwent childhood surgery for isolated atrial septal defect (ASD; n=33) or ventricular septal defect (VSD; n=30) and healthy controls (n=37) were enrolled. Sulcal pattern similarity to healthy controls was determined using magnetic resonance imaging and looking at features of sulcal folds, their intersulcal relationships, and sulcal graph topology. The sulcal pattern similarity values were tested for associations with comprehensive neuropsychological scores. Patients with both ASD and VSD had decreased sulcal pattern similarity in the left hemisphere compared with controls. The differences were found in the left temporal lobe in the ASD group and in the whole left hemisphere in the VSD group (P=0.033 and P=0.039, respectively). The extent of abnormal left hemispheric sulcal pattern similarity was associated with worse neuropsychological scores (intelligence, executive function, and visuospatial abilities) in the VSD group, and special educational support in the ASD group.

Adults who underwent surgery for simple CHD in childhood display altered left hemisphere sulcal folding patterns, commensurate with neuropsychological scores for patients with VSD and special educational support for ASD. This may indicate that simple CHD affects early brain development.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

• adult
• brain
• congenital heart defect
• magnetic resonance imaging
• sulcal pattern

White matter hyperintensities of presumed vascular origin are frequently observed on magnetic resonance imaging in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply–demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion- and diffusion-weighted magnetic resonance imaging in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity—the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared with normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply–demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

• MRI
• capillary dysfunction
• cerebral blood flow
• fibertracking
• white matter hyperintensities

Hypoxia is the most critical factor for maintaining stemness. During embryonic development, neural stem cells (NSCs) reside in hypoxic niches, and different levels of oxygen pressure and time of hypoxia exposure play important roles in the development of NSCs. Such hypoxic niches exist in adult brain tissue, where the neural precursors originate. Hypoxia-inducible factors (HIFs) are key transcription heterodimers consisting of regulatory α-subunits (HIF-1α, HIF-2α, HIF-3α) and a constitutive β-subunit (HIF-β). Regulation of downstream targets determines the fate of NSCs. In turn, the stability of HIFs-α is regulated by prolyl hydroxylases (PHDs), whose activity is principally modulated by PHD substrates like oxygen (O₂), α-ketoglutarate (α-KG), and the co-factors ascorbate (ASC) and ferrous iron (Fe²⁺). It follows that the transcriptional activity of HIFs is actually determined by the contents of O₂, α-KG, ASC, and Fe²⁺. In normoxia, HIFs-α are rapidly degraded via the ubiquitin-proteasome pathway, in which PHDs, activated by O₂, lead to hydroxylation of HIFs-α at residues 402 and 564, followed by recognition by the tumor suppressor protein von Hippel–Lindau (pVHL) as an E3 ligase and ubiquitin labeling. Conversely, in hypoxia, the activity of PHDs is inhibited by low O₂ levels and HIFs-α can thus be stabilized. Hence, suppression of PHD activity in normoxic conditions, mimicking the effect of hypoxia, might be beneficial for preserving the stemness of NSCs, and it is clinically relevant as a therapeutic approach for enhancing the number of NSCs in vitro and for cerebral ischemia injury in vivo. This study will review the putative role of PHD inhibitors on the self-renewal of NSCs.

• HIFs
• NSCs
• PHDs
• hypoxia
• inhibitors

Stroke-induced endothelial cell injury leads to destruction of cerebral microvasculature and significant damage to the brain tissue. A subacute phase of cerebral ischemia is associated with regeneration involving the activation of vascular remodeling, neuroplasticity, neurogenesis, and neuroinflammation processes. Effective restoration and improvement of blood supply to the damaged brain tissue offers a potential therapy for stroke. microRNAs (miRNAs) are recently identified small RNA molecules that regulate gene expression and significantly influence the essential cellular processes associated with brain repair following stroke. A number of specific miRNAs are implicated in regulating the development and propagation of the ischemic tissue damage as well as in mediating post-stroke regeneration. In this review, I discuss the functions of the miRNA miR-155 and the effect of its in vivo inhibition on brain recovery following experimental cerebral ischemia. The article introduces new and unexplored approach to cerebral regeneration: regulation of brain tissue repair through a direct modulation of specific miRNA activity.

• cerebral blood flow
• dMCAO
• functional recovery
• miR-155
• microRNA
• post-stroke inflammation

• Cancer metabolism
• Cancer stem cells
• Glioblastoma
• Glioma stem cells
• Microenvironment

• Animals
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Glioma/metabolism
• Glioma/pathology
• Glycolysis
• Humans
• Neoplastic Stem Cells/metabolism
• Signal Transduction
• Tumor Microenvironment

• R01 NS048959 NINDS NIH HHS
• R56 NS048959 NINDS NIH HHS

MicroRNA (miR)-210 is the most consistently and predominantly up-regulated miR in response to hypoxia in multiple cancer cells. The roles of miR-210 in rat adrenal gland pheochromocytoma (PC-12) cells remain unknown. We aimed to explore the possible effect of miR-210 in neonatal brain injury. We explored the potential molecular mechanism by using PC-12 cells under hypoxia. Scramble miRs, miR-210 mimic, miR-210 inhibitor or its negative control were respectively transfected into PC-12 cells. Cell viability, migration, invasion and apoptosis were also assessed to evaluate hypoxia-induced cell injury. The expression level of miR-210 was identified by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Apoptosis-related protein expression as well as key kinases in the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signal pathway was studied by Western blot analysis. Hypoxia suppressed cell viability, migration and invasion, but promoted apoptosis through activation of mitochondrial- and caspase-dependent pathways. Hypoxia markedly induced up-regulation of miR-210 in PC-12 cells. Overexpression of miR-210 protected PC-12 cells against hypoxia-induced injury. Bcl-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) was proven to be a target gene of miR-210 in PC-12 cells. miR-210 overexpression ameliorated the hypoxia-induced injury in PC-12 cells by down-regulating BNIP3. Hypoxia-induced alterations of key kinases in the PI3K/AKT/mTOR signal pathway were affected by aberrant expression of BNIP3. These findings suggested that miR-210 protected PC-12 cells against hypoxia-induced injury by targeting BNIP3, involving the PI3K/AKT/mTOR signal pathway.

• BNIP3
• PI3K/AKT/mTOR signal pathway
• hypoxic injury
• microRNA-210
• neonatal brain injury

Hepatoma upregulated protein (HURP) is a multifunctional protein with clinical promise. This protein has been demonstrated to be a predictive marker for the outcome in high-risk prostate cancer (PCa) patients, besides being a resistance factor in PCa. Although changes in oxygen tension (pO₂) are associated with PCa aggressiveness, the role of hypoxia in the regulation of tumor progression genes such as HURP has not yet been described. We hypothesized that pO₂ alteration is involved in the regulation of HURP expression in PCa cells. In the present study, PCa cells were incubated at 2% O₂ (hypoxia) and 20% O₂ (normoxia) conditions. Hypoxia reduced cell growth rate of PCa cells, when compared to the growth rate of cells cultured under normoxia (p < 0.05). The decrease in cell viability was accompanied by fivefold (p < 0.05) elevated rate of vascular endothelial growth factor (VEGF) release. The expression of VEGF and the hypoxia-inducible metabolic enzyme carbonic anhydrase 9 were elevated maximally nearly 61-fold and 200-fold, respectively (p < 0.05). Noted in two cell lines (LNCaP and C4-2B) and independent of the oxygen levels, HURP expression assessed at both mRNA and protein levels was reduced. However, the decrease was more pronounced in cells cultured under hypoxia (p < 0.05). Interestingly, the analysis of patients’ specimens by Western blot revealed a marked increase of HURP protein (fivefold), when compared to control (cystoprostatectomy) tissue (p < 0.05). Immunohistochemistry analysis showed an increase in the immunostaining intensity of HURP and the hypoxia-sensitive molecules, hypoxia-inducible factor 1-alpha (HIF-1α), VEGF, and heat-shock protein 60 (HSP60) in association with tumor grade. The data also suggested a redistribution of subcellular localization for HURP and HIF-1α from the nucleus to the cytoplasmic compartment in relation to increasing tumor grade. Analysis of HURP Promoter for HIF-1-binding sites revealed presence of four putative HIF binding sites on the promoter of DLGAP5/HURP gene in the non-translated region upstream from the start codon, suggesting association between HIF-1α and the regulation of HURP protein. Taken together, our findings suggest a modulatory role of hypoxia on the expression of HURP. Additionally our results provide basis for utilization of tumor-associated molecules as predictors of aggressive PCa.

• C4-2B
• HURP
• LNCaP
• hypoxia
• prostate cancer
• tumor

Hypoxia is associated with the increased malignancy of a broad range of solid tumours. While very severe hypoxia has been widely shown to induce cell cycle arrest, the impact of pathophysiological hypoxia on tumour cell proliferation is poorly understood. The aim of this study was to investigate the effect of different oxygen levels on glioblastoma (GBM) cell proliferation and survival. GBM is an extremely aggressive brain tumour with a heterogeneous oxygenation pattern. The effects of a range of oxygen tensions on GBM cell lines and primary cells were assessed using flow cytometry. Results indicate that cell cycle distribution and viability are unaffected by long term exposure (24–96 h) to pathophysiological levels of oxygen (1–8% O₂). Both transient cell cycle arrest and small amounts of cell death could only be detected when cells were exposed to severe hypoxia (0.1% O₂). No significant changes in p21 protein expression levels were detected. These findings reinforce the importance of using physiologically relevant oxygen tensions when investigating tumour hypoxia, and help to explain how solid tumours can be both hypoxic and highly proliferative, as is the case with GBM.

• Brain tumours
• Cell cycle
• Cell death
• Glioblastoma
• HIF
• Hypoxia
• Tumour microenvironment

• cell viability
• in vitro culture
• medium replacement
• oxygen concentration
• reactive oxygen species

• HIF
• Hypoxia sensing
• Prolyl hydroxylase
• Stroke

Use of allogeneic cancer cells-based immunotherapy for treatment of established prostate cancer (PCa) has only been marginally effective. One reason for failure could stem from the mismatch of antigenic signatures of vaccine cells and cancer in situ. Hence, it is possible that vaccine cells expressed antigens differently than tumor cells in situ. We hypothesized that cells grown in vitro at low oxygen tension (pO₂) provide a better antigen match to tumors in situ and could reveal a more relevant antigenic landscape than cells grown in atmospheric pO₂.

We tested this hypothesis by comparing PCa cells propagated at pO₂ = 2 kPa and 20 kPa. To identify potential tumor-associated antigens (TAAs), we prepared PCa cell lysates, resolved them by two-dimensional electrophoresis and immunoblotting using spontaneous antibodies from plasma derived from PCa patients and control subjects. Antibody-labeled spots were analyzed by MALDI-TOF mass spectrometry and validated by ELISA. We selected hypoxia-regulated HSP70 and hnRNP L and hypoxia-independent HSP60 and determined the frequency of plasma samples reacting with these molecules.

Frequency of HSP60-reactive plasma was low in healthy controls [1.3 % (1/76)], while it was elevated in PCa patients [13.0 % (7/54); p < 0.05]. These data suggest a humoral immune response to HSP60 in PCa. Levels of autoantibodies to HSP70 did not differ from healthy controls [3.7 % (2/54)] in PCa patients [5.3 % (2/38)]. Similarly, hnRNP L autoantibodies did no differ between healthy controls [6.1 % (3/49)] and PCa patients [5.3 % (2/38)].

Overall our results suggest the value of hypoxia as a modifier of the cellular and antigenic landscape of PCa cells. By modifying the immune reactivity of PCa cells in culture, manipulation of pO₂ can be proposed as a new avenue for improving diagnosis, prognosis and immunotherapy for PCa.

• Animals
• Brain/metabolism
• Cell Proliferation
• Dentate Gyrus/metabolism
• Gene Expression
• Hypoxia/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Male
• Neural Stem Cells/metabolism
• Neurogenesis/physiology
• Oxygen Consumption
• Prosencephalon/metabolism
• Rats
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor A/metabolism

• l-type voltage-dependent ca²⁺ channels
• hypoxia
• cell proliferation
• pc12 cells

• Animals
• Apoptosis
• Calcium Channels/genetics
• Calcium Channels/metabolism
• Calcium Channels, L-Type/genetics
• Calcium Channels, L-Type/metabolism
• Calcium Signaling
• Cell Hypoxia
• Cell Proliferation
• Gene Expression
• Hypoxia-Inducible Factor 1, alpha Subunit/physiology
• PC12 Cells
• Rats
• Transcriptional Activation

Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.

• Zac1
• Cell fate decisions
• Neural stem cells
• Genomic imprinting
• Igf2-H19
• Dlk1
• p57^Kip2
• Necdin
• Differentiation
• Imprinted gene networks

• TUNEL staining
• apoptosis
• cleaved caspase 3
• hypoxia inducible transcription factors
• neuroprotection
• vascular endothelial growth factor

Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired.

• Alzheimer’s disease
• HIF-1α
• Wnt signaling pathway
• hippocampus
• hypoxia
• neurogenesis
• β-catenin

• Flk1 signaling
• HIF1α signaling
• Hypoxia
• Midbrain neurogenesis

• Animals
• Cell Survival
• Dopaminergic Neurons/cytology
• Mice
• Mice, Transgenic
• Neurogenesis
• Signal Transduction
• Substantia Nigra/embryology
• Substantia Nigra/growth & development
• Substantia Nigra/metabolism
• Vascular Endothelial Growth Factor Receptor-2/genetics
• Vascular Endothelial Growth Factor Receptor-2/metabolism

To study whether hypoxia influences the stem-like properties of ovarian cancer cells and their biological behavior under hypoxia.

Ovarian cancer cell lines ES-2 and OVCAR-3 were cultivated in different oxygen tensions for proliferation, cell cycling and invasion analyses. The clonogenic potential of cells was examined by colony formation and sphere formation assays. Stem cell surface markers, SP and CD44^bright and CD44^dim cells were analyzed by flow cytometry. Protein expression of HIF-1α, HIF-2α, Ot3/4 and Sox2 were investigated by Western blotting.

Both cell lines cultivated at hypoxic condition grew relatively slowly with extended G0/G1 phase. However, if the cells were pre-treated under 1% O₂ for 48 hrs before brought back to normoxia, the cells showed significantly higher proliferation rate with higher infiltration capability, and significant more colonies and spheres, in comparison to the cells always cultivated under normoxia. CD44^bright cells expressed significantly higher levels of Oct3/4 and Sox2 than the CD44^dim cells and formed significantly more clones and spheres examined in vitro. Hypoxic treatment of the cells resulted in stronger CD44 expression in both cell lines, and stronger CD133 expression in the OVCAR-3 cell line. In parallel with these findings, significantly increased number of side population (SP) cells and up-regulated expression of Oct3/4 and Sox2 in both ES-2 and OVCAR-3 cell lines were observed.

We conclude that ovarian cancer cells survive hypoxia by upgrading their stem-like properties through up-regulation of stemness-related factors and behave more aggressively when brought back to higher oxygen environment.

• hypoxia
• neural stem cells
• neural conversion
• neural differentiation
• embryonic stem cells

• Cell Death
• Cell Differentiation/drug effects
• Cell Differentiation/physiology
• Cell Line
• Embryonic Stem Cells/cytology
• Embryonic Stem Cells/metabolism
• Humans
• Mesencephalon/cytology
• Mesencephalon/metabolism
• Models, Biological
• Motor Neurons/cytology
• Motor Neurons/metabolism
• Neural Stem Cells/cytology
• Neural Stem Cells/metabolism
• Oxygen/metabolism
• Oxygen/pharmacology

• G0800784 Medical Research Council
• G0300300 Medical Research Council
• Wellcome Trust
• G0800487(87418) Medical Research Council
• G0800487 Medical Research Council
• G0701476 Medical Research Council