bims-hypoxi Biomed News
on Hypoxia and HIF1-alpha
Issue of 2021‒05‒30
fifteen papers selected by
Ashish Kaul
University of Tsukuba
  1. MicroRNA-449a delays lung cancer development through inhibiting KDM3A/HIF-1α axis.
  2. Hypoxia inducible factor signaling in macrophages promotes lymphangiogenesis in Leishmania major infection.
  3. Long non‑coding RNA PCED1B‑AS1 promotes pancreatic ductal adenocarcinoma progression by regulating the miR‑411‑3p/HIF‑1α axis.
  4. Hypoxia-Inducible Factor 1 Alpha Is Dispensable for Host Defense of Group B Streptococcus Colonization and Infection.
  5. HIF-1 α may play a role in late pregnancy hypoxia-induced autism-like behaviors in offspring rats.
  6. Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome.
  7. Hypoxia Promotes Adipose-Derived Stem Cells to Protect Human Dermal Microvascular Endothelial Cells Against Hypoxia/Reoxygenation Injury.
  8. Identification of a Hypoxia-Related Signature for Predicting Prognosis and the Immune Microenvironment in Bladder Cancer.
  9. Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers.
  10. Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells.
  11. Procatechualdehyde improves mitochondrial energy metabolism through the HIF1α/PDK1 signaling pathway to mitigate ischemic stroke-elicited internal capsule injury.
  12. C5a complement receptor modulates odontogenic dental pulp stem cell differentiation under hypoxia.
  13. Hypoxia signaling in renal pericytes-is it safe to activate?
  14. Neuropeptides in the developing human hippocampus under hypoxic-ischemic conditions.
  15. Effect of differential hypoxia-related gene expression on glioblastoma.
  1. J Transl Med. 2021 May 27. 19(1): 224
    MicroRNA-449a delays lung cancer development through inhibiting KDM3A/HIF-1α axis.
    Shan Hu, Peng Cao, Kangle Kong, Peng Han, Yu Deng, Fan Li, Bo Zhao.
      BACKGROUND: It has been established that microRNA (miR)-449a is anti-tumorigenic in cancers, including lung cancer. Therefore, this study further explored miR-449a-mediated mechanism in lung cancer, mainly focusing on lysine demethylase 3A/hypoxia-induced factor-1α (KDM3A/HIF-1α) axis.METHODS: miR-449a, KDM3A and HIF-1α levels in lung cancer tissues and cell lines (A549, H1299 and H460) were measured. Loss- and gain-of-function assays were performed and then cell proliferation, cell cycle, apoptosis, invasion and migration were traced. The relationship between KDM3A, miR-449a and HIF-1α was verified. Tumor growth in vivo was also monitored.
    RESULTS: Both lung cancer tissues and cells exhibited reduced miR-449a and raised KDM3A and HIF-1α levels. miR-449a interacted with KDM3A; HIF-1α could bind with KDM3A. Up-regulating miR-449a hindered while suppressing miR-449a induced lung cancer development via mediating HIF-1α. Elevating KDM3A promoted cellular aggression while down-regulating KDM3A had the opposite effects. Up-regulating KDM3A or HIF-1α negated up-regulated miR-449a-induced effects on cellular growth in lung cancer. Restoring miR-449a impaired tumorigenesis in vivo in lung cancer.
    CONCLUSION: It is eventually concluded that miR-449a delays lung cancer development through suppressing KDM3A/HIF-1α axis.
    Keywords:  Hypoxia-induced factor-1α; Lung cancer; Lysine demethylase 3A; MicroRNA-449a
    DOI:  https://doi.org/10.1186/s12967-021-02881-8
  2. Infect Immun. 2021 May 24. pii: IAI.00124-21. [Epub ahead of print]
    Hypoxia inducible factor signaling in macrophages promotes lymphangiogenesis in Leishmania major infection.
    Anne Bowlin, Hayden Roys, Humphrey Wanjala, Manjunath Bettadapura, Gopinath Venugopal, Jessica Surma, M Celeste Simon, Tiffany Weinkopff.
      Vascular remodeling is a phenomenon seen in the cutaneous lesions formed during infection with Leishmania parasites. Within the lesion, Leishmania major infection leads to the infiltration of inflammatory cells, including macrophages, and is associated with hypoxic conditions and lymphangiogenesis in the local site. This low-oxygen environment is concomitant with the expression of hypoxic inducible factors (HIFs), which initiate the expression of vascular endothelial growth factor-A (VEGF-A) in macrophages during the infection. Here, we found that macrophage hypoxia is elevated in the skin, and the HIF target Vegfa is preferentially expressed at the site of infection. Furthermore, transcripts indicative of both HIF-1α and HIF-2α activation were increased at the site of infection. Given that HIF mediates VEGF-A and that VEGF-A/VEGFR-2 signaling induces lymphangiogenesis, we wanted to investigate the link between myeloid HIF activation and lymphangiogenesis during L. major infection. We show that myeloid aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF/VEGF-A signaling promotes lymphangiogenesis (the generation of newly formed vessels within the local lymphatic network), which helps resolve the lesion by draining away inflammatory cells and fluid. Concomitant with impaired lymphangiogenesis, we find the deletion of myeloid ARNT/HIF signaling leads to an exacerbated inflammatory response associated with a heightened CD4 + Th1 immune response following L. major infection. Altogether, our data suggest that VEGF-A-mediated lymphangiogenesis occurs through myeloid ARNT/HIF activation following Leishmania major infection and this process is critical in limiting immunopathology.
    DOI:  https://doi.org/10.1128/IAI.00124-21
  3. Oncol Rep. 2021 Jul;pii: 134. [Epub ahead of print]46(1):
    Long non‑coding RNA PCED1B‑AS1 promotes pancreatic ductal adenocarcinoma progression by regulating the miR‑411‑3p/HIF‑1α axis.
    Yi Zhang, Huan Ma, Chang Chen.
      An increasing number of studies have shown that long non‑coding RNAs (lncRNAs) are crucially involved in tumorigenesis. However, the biological functions, underlying mechanisms and clinical value of lncRNA PC‑esterase domain containing 1B‑antisense RNA 1 (PCED1B‑AS1) in pancreatic ductal adenocarcinoma (PDAC) have not been determined, to the best of our knowledge. In the present study, the expression of PCED1B‑AS1, microRNA (miR)‑411‑3p and hypoxia inducible factor (HIF)‑1α mRNA in 47 cases of PDAC tissues were detected using reverse transcription‑quantitative (RT‑q)PCR. Moreover, the effects of PCED1B‑AS1 on the biological behaviors of PDAC cells were assessed using Cell Counting Kit‑8, EdU staining and Transwell assays. Bioinformatics analysis, RT‑qPCR, western blotting, dual luciferase reporter gene and RNA immunoprecipitation assays were performed to determine the regulatory relationships between PCED1B‑AS1, miR‑411‑3p and HIF‑1α. We demonstrated that PCED1B‑AS1 was significantly upregulated in PDAC tumor tissues, and its expression was associated with advanced Tumor‑Node‑Metastasis stage and lymph node metastasis. PCED1B‑AS1 knockdown inhibited PDAC cell proliferation, invasion as well as epithelial‑mesenchymal transition (EMT) in vitro. Mechanistically, PCED1B‑AS1 was shown to target miR‑411‑3p, resulting in the upregulation of HIF‑1α. In conclusion, PCED1B‑AS1 expression was upregulated in PDAC tissues and cells, and it participated in promoting the proliferation, invasion and EMT of cancer cells by modulating the miR‑411‑3p/HIF‑1α axis.
    Keywords:  PC‑esterase domain containing 1B‑antisense RNA 1; hypoxia inducible factor‑1α; microRNA‑411‑3p; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3892/or.2021.8085
  4. J Innate Immun. 2021 May 21. 1-13
    Hypoxia-Inducible Factor 1 Alpha Is Dispensable for Host Defense of Group B Streptococcus Colonization and Infection.
    Gregory R Lum, Vicki Mercado, Diede van Ens, Victor Nizet, Jacqueline M Kimmey, Kathryn A Patras.
      Group B Streptococcus (GBS) is a leading cause of neonatal morbidity and mortality, and the primary source of exposure is the maternal vagina. Intrapartum antibiotic prophylaxis for GBS-positive mothers has reduced the incidence of GBS early-onset disease, however, potential long-lasting influence of an antibiotic-altered neonatal microbiota, and the frequent clinical sequelae in survivors of invasive GBS infection, compels alternative treatment options for GBS. Here, we examined the role of transcription factor hypoxia-inducible factor 1 alpha (HIF-1α), widely recognized as a regulator of immune activation during infection, in the host response to GBS. Given the importance of endogenous HIF-1α for innate immune defense, and the potential utility of HIF-1α stabilization in promoting bacterial clearance, we hypothesized that HIF-1α could play an important role in coordinating host responses to GBS in colonization and systemic disease. Counter to our hypothesis, we found that GBS infection did not induce HIF-1α expression in vaginal epithelial cells or murine macrophages, nor did HIF-1α deficiency alter GBS colonization or pathogenesis in vivo. Furthermore, pharmacological enhancement of HIF-1α did not improve control of GBS in pathogenesis and colonization models, while displaying inhibitory effects in vaginal epithelial cytokines and immune cell killing in vitro. Taken together, we conclude that HIF-1α is not a prominent aspect of the host response to GBS colonization or invasive disease, and its pharmacological modulation is unlikely to provide significant benefit against this important neonatal pathogen.
    Keywords:  Group B streptococcus; Hypoxia-inducible factor 1 alpha; Innate immunity; Macrophage; Vaginal colonization
    DOI:  https://doi.org/10.1159/000515739
  5. Behav Brain Res. 2021 May 25. pii: S0166-4328(21)00261-8. [Epub ahead of print] 113373
    HIF-1 α may play a role in late pregnancy hypoxia-induced autism-like behaviors in offspring rats.
    Weiyu Wang, Jinghua Tang, Min Zhong, Jie Chen, Tingyu Li, Ying Dai.
      Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can be caused by various factors. The present study aimed to determine whether prenatal hypoxia can lead to ASD and the role of hypoxia-inducible factor-1α (HIF-1α) in this process. We constructed a prenatal hypoxia model of pregnant rats by piping nitrogen and oxygen mixed gas, with an oxygen concentration of 10 ± 0.5%, into the self-made hypoxia chamber. Rats were subjected to different extents of hypoxia treatments at different points during pregnancy. The results showed that hypoxia for 6 hours on the 17th gestation day is most likely to lead to autistic behavior in offspring rats, including social deficits, repetitive behaviors, and impaired learning and memory. The mRNA expression level of TNF-α also increased in hypoxia groups and valproic acid (VPA) group. Western blotting analysis showed increased levels of hypoxia inducible factor 1 alpha (HIF-1α) decreased levels of phosphatase and tensin homolog (PTEN) in the hypoxic-induced autism group. Meanwhile, N-methyl D-aspartate receptor subtype 2 (NR2A) and glutamate ionotropic receptor AMPA type subunit 2 (GluR2) were upregulated in the hypoxic-induced autism group. HIF-1α might play a role in hypoxia-caused autism-like behavior and its regulatory effect is likely to be achieved by regulating synaptic plasticity.
    Keywords:  Autism spectrum disorder; behavior; hypoxia-inducible factor-1α; prenatal hypoxia
    DOI:  https://doi.org/10.1016/j.bbr.2021.113373
  6. Angiogenesis. 2021 May 27.
    Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome.
    Chih-Chieh Tsao, Julia Baumann, Sheng-Fu Huang, Diana Kindler, Aileen Schroeter, Nicole Kachappilly, Max Gassmann, Markus Rudin, Omolara O Ogunshola.
      Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying mechanisms remain unknown. Hypoxia-inducible factor-1 (HIF-1), a master regulator of injury responses, has divergent roles in different cells especially during stress scenarios. On one hand HIF-1 is neuroprotective but on the other it induces vascular permeability. Since pericytes are critical for barrier stability, we asked if pericyte HIF-1 signaling impacts barrier integrity and injury severity in a mouse model of ischemic stroke. We show that pericyte HIF-1 loss of function (LoF) diminishes ischemic damage and barrier permeability at 3 days reperfusion. HIF-1 deficiency preserved barrier integrity by reducing pericyte death thereby maintaining vessel coverage and junctional protein organization, and suppressing vascular remodeling. Importantly, considerable improvements in sensorimotor function were observed in HIF-1 LoF mice indicating that better vascular functionality post stroke improves outcome. Thus, boosting vascular integrity by inhibiting pericytic HIF-1 activation and/or increasing pericyte survival may be a lucrative option to accelerate recovery after severe brain injury.
    Keywords:  Cerebral ischemia; Pericyte coverage; Pericyte death; Vascular permeability
    DOI:  https://doi.org/10.1007/s10456-021-09796-4
  7. J Surg Res. 2021 May 20. pii: S0022-4804(21)00244-4. [Epub ahead of print]266 230-235
    Hypoxia Promotes Adipose-Derived Stem Cells to Protect Human Dermal Microvascular Endothelial Cells Against Hypoxia/Reoxygenation Injury.
    Yinhua Zhao, Yanyu Shi, Huang Lin.
      BACKGROUND: Microcirculation is important for regulating ischemia-reperfusion (I/R) injury associated with skin flap transplantation surgery. We investigated whether co-culture with adipose-derived stem cells (ADSCs) could protect human dermal microvascular endothelial cells (HDMECs) from I/R injury by inhibiting cell apoptosis and enhancing cell proliferation. We also investigated the effects of hypoxic preconditioning on ADSCs.MATERIALS AND METHODS: HDMECs were divided into four groups, control, HDMECs in normoxic culture conditions; hypoxia/reoxygenation (H/R), HDMECs in a hypoxic incubator for 8 h then in saturated aerobic culture medium for 24 h; H/R + ADSC(N), HDMECs treated similar to the H/R group then co-cultured with normoxic ADSCs; and H/R + ADSC(H), HDMECs treated similar to the H/R group then co-cultured with hypoxia preconditioned ADSCs.
    RESULTS: The rate of HDMECs apoptosis significantly increased in the H/R group, but decreased upon co-culture with ADSCs for 24 h, especially in the H/R + ADSC(H) group. Co-culture with ADSCs, especially hypoxia preconditioned ADSCs, significantly enhanced cell proliferation ability compared with that of the H/R group after 48 h and 72 h, but not after 24 h. Vascular endothelial growth factor levels were significantly higher in the H/R + ADSC(N) and H/R + ADSC(H) groups than in the H/R group.
    CONCLUSIONS: ADSCs attenuated H/R injury in endothelial cells by promoting proliferation ability and reducing apoptosis, with an increase in Vascular endothelial growth factor level, especially in the context of hypoxic preconditioning. This approach suggests the potential for an easy and safe method to reduce I/R injury associated with skin flap transplantation surgery.
    Keywords:  Adipose-derived stem cell; Human dermal microvascular endothelial cells; Hypoxia/reoxygenation; Ischemia-reperfusion injury; Skin flap
    DOI:  https://doi.org/10.1016/j.jss.2021.04.013
  8. Front Mol Biosci. 2021 ;8 613359
    Identification of a Hypoxia-Related Signature for Predicting Prognosis and the Immune Microenvironment in Bladder Cancer.
    Minxiao Jiang, Liangliang Ren, Yuanlei Chen, Huan Wang, Haiyang Wu, Sheng Cheng, Gonghui Li, Shicheng Yu.
      Accumulating evidence indicates that hypoxia is highly associated with bladder cancer genesis, progression, and immune microenvironment. Nevertheless, few studies have identified the role of hypoxia-related genes as a prognostic signature in bladder cancer. This study aimed to establish a hypoxia-related signature with high accuracy for prognosis and immune microenvironment prediction in bladder cancer. We obtained expression profiles and clinical information from Gene Expression Omnibus and The Cancer Genome Atlas. Then the univariate Cox regression, random survival forest algorithm, and multivariate Cox regression analysis were conducted to identify the core genes and four hypoxia-related genes (ANXA2, GALK1, COL5A1, and HS3ST1) were selected to construct the signature. Kaplan-Meier survival analysis demonstrated that patients with a low-risk score had a higher disease-specific survival rate (p < 0.0001). The areas under the curve of the signature were 0.829 at 1 year, 0.869 at 3 years, and 0.848 at 5 years, respectively. Additionally, we found this hypoxia-related signature was highly correlated with tumor immune microenvironment and had the potential to predict the efficacy of immunotherapy. In summary, our study developed a hypoxia-related signature, which had high accuracy for prognosis prediction and the potential to guide the immunotherapy for bladder cancer patients.
    Keywords:  bladder cancer; disease-specific survival; hypoxia; immune microenvironment; signature
    DOI:  https://doi.org/10.3389/fmolb.2021.613359
  9. World J Gastrointest Oncol. 2021 May 15. 13(5): 312-331
    Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers.
    Ross King, Conall Hayes, Claire L Donohoe, Margaret R Dunne, Maria Davern, Noel E Donlon.
      The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases. This review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of GOCs. We focus on its bidirectional influence on inflammation and how it drives angiogenesis, innate and adaptive immune evasion, metastasis, and the reprogramming of cellular bioenergetics. The contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxia-targeted therapeutics is given. The principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.
    Keywords:  Esophageal cancer; Gastric cancer; Gastroesophageal cancer; Tumor hypoxia; Tumour microenvironment
    DOI:  https://doi.org/10.4251/wjgo.v13.i5.312
  10. Front Immunol. 2021 ;12 660944
    Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells.
    Nadia Bannoud, Tomás Dalotto-Moreno, Lucía Kindgard, Pablo A García, Ada G Blidner, Karina V Mariño, Gabriel A Rabinovich, Diego O Croci.
      Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.
    Keywords:  CD8 T cell exhaustion; Hypoxia; VEGF-A; anti cancer agents; immunosuppression
    DOI:  https://doi.org/10.3389/fimmu.2021.660944
  11. J Ethnopharmacol. 2021 May 24. pii: S0378-8741(21)00459-1. [Epub ahead of print] 114232
    Procatechualdehyde improves mitochondrial energy metabolism through the HIF1α/PDK1 signaling pathway to mitigate ischemic stroke-elicited internal capsule injury.
    Miaolin Zeng, Chongyu Shao, Huifen Zhou, Yu He, Wentao Li, Jieqiong Zeng, Xixi Zhao, Jiehong Yang, Haitong Wan.
      ETHNOPHARMACOLOGICAL RELEVANCE: The internal capsule is vulnerable to ischemia, and mild ischemic stroke often results in lesion of the internal capsule, manifested as contralateral hemiplegia. Protocatechudehyde (PCA), a potential neuroprotective agent, has shown therapeutic effects in the study of a variety of nervous system diseases, including ischemic stroke.AIM OF THE STUDY: The aim of this study was to evaluate the effects of PCA on cerebral ischemia reperfusion (CI/R)-elicited internal capsule injury and to elucidate the role of mitochondrial energy metabolism in the underlying mechanism of neuroprotective effects on ischemic stroke.
    MATERIALS AND METHODS: A rat tMCAO model was established to investigate the therapeutic effects of intravenous PCA (20, 40, and 80 mg/kg, once per day, continued for 7 days) on CI/R-induced internal capsule injury and the regulation of PCA on molecules related to mitochondrial energy metabolism. In vitro, an OGD/R model of PC12 cells was established to further verify the therapeutic mechanism of PCA.
    RESULTS: Results showed that PCA dose-dependently attenuated neurological deficit, reduced cerebral infarction, alleviated histopathological damage, and improved mitochondrial ultrastructure of the internal capsule after CI/R. Moreover, PCA reversed the upregulation of HIF1α, PDK1 and pPDHA1 expression induced by CI/R and significantly increased the content of acetyl-CoA, ATP, and the activity of ATP synthase. In vitro, PCA treatment promoted cell survival, inhibited apoptosis, attenuated the dissipation of mitochondrial membrane potential in OGD/R-treated PC12 cells, and these therapeutic effects were reversed by the combination of cobalt chloride (CoCl2), a specific pharmacological inducer of HIF1a expression.
    CONCLUSIONS: These results indicate that PCA exerts a protective effect against CI/R-induced internal capsule injury and improves mitochondrial energy metabolism in the internal capsule, and the mechanism is associated with the inhibition of HIF1α/PDK1 signaling pathway.
    Keywords:  Energy metabolism; HIF1α; Internal capsule; Ischemic stroke; Mitochondria; Protocatechudehyde
    DOI:  https://doi.org/10.1016/j.jep.2021.114232
  12. Connect Tissue Res. 2021 May 24. 1-10
    C5a complement receptor modulates odontogenic dental pulp stem cell differentiation under hypoxia.
    Ryan Pasiewicz, Yessenia Valverde, Raghuvaran Narayanan, Ji-Hyun Kim, Muhammad Irfan, Nam-Seob Lee, Anne George, Lyndon F Cooper, Satish B Alapati, Seung Chung.
      Aim: Alterations in the microenvironment change the phenotypes of dental pulp stem cells (DPSCs). The role of complement component C5a in the differentiation of DPSCs is unknown, especially under oxygen-deprived conditions. The aim of this study was to determine the effect of C5a on the odontogenic differentiation of DPSCs under normoxia and hypoxia.Material and Methods: Human DPSCs were subjected to odontogenic differentiation in osteogenic media and treated with the C5a receptor antagonist-W54011 under normal and hypoxic conditions (2% oxygen). Immunochemistry, western blot, and PCR analysis for the various odontogenic differentiation genes/proteins were performed.Results: Our results demonstrated that C5a plays a positive role in the odontogenic differentiation of DPSCs. C5a receptor inhibition resulted in a significant decrease in odontogenic differentiation genes, such as DMP1, ON, RUNX2, DSPP compared with the control. This observation was further supported by the Western blot data for DSPP and DMP1 and immunohistochemical analysis. The hypoxic condition reversed this effect.Conclusions: Our results demonstrate that C5a regulates the odontogenic DPSC differentiation under normoxia. Under hypoxia, C5a exerts a reversed function for DPSC differentiation. Taken together, we identified that C5a and oxygen levels are key initial signals during pulp inflammation to control the odontogenic differentiation of DPSCs, thereby, providing a mechanism for potential therapeutic interventions for dentin repair and vital tooth preservation.
    Keywords:  C5a; C5a receptor; DPSC; differentiation; hypoxia; odontoblast
    DOI:  https://doi.org/10.1080/03008207.2021.1924696
  13. Kidney Int. 2021 Jun;pii: S0085-2538(21)00209-X. [Epub ahead of print]99(6): 1267-1269
    Hypoxia signaling in renal pericytes-is it safe to activate?
    Savannah Herbek, Daniel L Edmonston, Tomokazu Souma.
      While excitement has grown for the use of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors for treating renal anemia, multiple preclinical studies have shown the complex and cell-type-dependent roles of HIFs in kidney disease pathogenesis, including renal fibrosis. Pan et al. now clearly show that activating the HIF signaling in the Gli1-lineage myofibroblasts restores erythropoietin production while not adversely affecting matrix production, mitigating the concerns of exacerbated fibrosis by HIF prolyl hydroxylase inhibitors.
    DOI:  https://doi.org/10.1016/j.kint.2021.02.014
  14. J Anat. 2021 May 24.
    Neuropeptides in the developing human hippocampus under hypoxic-ischemic conditions.
    Joaquín González Fuentes, Ricardo Insausti Serrano, Sandra Cebada Sánchez, Maria José Lagartos Donate, Eloy Rivas Infante, María Del Mar Arroyo Jiménez, María Del Pilar Marcos Rabal.
      The perinatal period, sensitive for newborn survival, is also one of the most critical moments in human brain development. Perinatal hypoxia due to reduced blood supply to the brain (ischemia) is one of the main causes of neonatal mortality. Brain damage caused by perinatal hypoxia-ischemia (HI) can lead to neuro- and psychological disorders. However, its impact seems to be region-dependent, with the hippocampus being one of the most affected areas. Among the neuronal populations of the hippocampus, some interneuron groups - such as somatostatin- or neuropeptide Y-expressing neurons - seem to be particularly vulnerable. The limited information available about the effects of HI in the hippocampus comes mainly from animal models and adult human studies. This article presents an immunohistochemical analysis of somatostatin (SOM) and neuropeptide Y (NPY) expression in the developing human hippocampus after perinatal HI. Two rostrocaudal sections of the body of the hippocampus were analysed, and the number of immunostained cells in the polymorphic layer of the dentate gyrus (DG) and the pyramidal cell layer and stratum oriens of the CA3, CA2 and CA1 fields of the hippocampus proper were quantified. The results showed a lower density of both neuropeptides in hypoxic compared to control cases. In the HI group, the number of SOM-immunoreactive cell bodies was statistically significantly lower in the pyramidal cell layer and stratum oriens of CA1, while the number of NPY-expressing neurons was statistically lower in the pyramidal cell layer of CA2. Besides, the number of SOM-expressing neurons was significantly higher in the stratum oriens of CA1 compared to that in CA2. In sum, we observed a different vulnerability of SOM- and NPY-containing neurons in the developing human hippocampus following perinatal HI damage. Our results could contribute to a better understanding of the behaviour of these neuronal populations under stressful conditions during the perinatal period.
    Keywords:  brain development; hippocampus; hypoxia-ischemia; neuropeptide Y; somatostatin
    DOI:  https://doi.org/10.1111/joa.13458
  15. J Int Med Res. 2021 May;49(5): 3000605211013774
    Effect of differential hypoxia-related gene expression on glioblastoma.
    Chao-Qun Lin, Lu-Kui Chen.
      OBJECTIVE: Glioblastoma (GB) is a refractory malignancy with a high rate of recurrence and treatment resistance. Hypoxia-related genes are promising prognostic indicators for GB, so we herein developed a reliable hypoxia-related gene risk scoring model to predict the prognosis of patients with GB.METHOD: Gene expression profiles and corresponding clinicopathological features of patients with GB were obtained from the Cancer Genome Atlas (TCGA; n = 160) and Gene Expression Omnibus (GEO) GSE7696 (n = 80) databases. Univariate and multivariate Cox regression analyses of differentially expressed hypoxia-related genes were performed using R 3.5.1 software.
    RESULT: Fourteen prognosis-related genes were identified and used to construct a risk signature. Patients with high-risk scores had significantly lower overall survival (OS) than those with low-risk scores. The median risk score was used as a critical value and for OS prediction in an independent external verification GSE7696 cohort. Risk score was not significantly affected by clinical-related factors. We also developed a prediction nomogram based on the TCGA training set to predict survival rates, and included six independent prognostic parameters in the TCGA prediction model.
    CONCLUSION: We determined a reliable hypoxia-related gene risk scoring model for predicting the prognosis of patients with GB.
    Keywords:  Glioblastoma; hypoxia; nomogram; prognostic; risk scoring model; the Cancer Genome Atlas
    DOI:  https://doi.org/10.1177/03000605211013774
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