bims-hypoxi Biomed News
on Hypoxia and HIF1-alpha
Issue of 2021–06–13
seventeen papers selected by
Ashish Kaul, University of Tsukuba
  1. Asparagus Polysaccharide inhibits the Hypoxia-induced migration, invasion and angiogenesis of Hepatocellular Carcinoma Cells partly through regulating HIF1α/VEGF expression via MAPK and PI3K signaling pathway.
  2. FLI1 mediates the selective expression of hypoxia-inducible factor-1 target genes in endothelial cells under hypoxic conditions.
  3. HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes.
  4. Prognostic significance of hypoxia-inducible factor-1α expression in advanced pharyngeal cancer without human papillomavirus infection.
  5. β-Elemene Attenuates Fibrosis after Esophageal Endoscopic Submucosal Dissection via Modulating the HIF-1α/HK2/p38-MAPK Signaling Axis.
  6. Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming.
  7. Aggregative Perivascular Tumor Cell Growth Pattern of Primary Central Nervous System Lymphomas Is Associated with Hypoxia-Related Endoplasmic Reticulum Stress.
  8. Circulating lncRNAs HIF1A-AS2 and LINLK-A: Role and Relation to Hypoxia-Inducible Factor-1α in Cerebral Stroke Patients.
  9. Involvement of the VEGF signaling pathway in immunosuppression and hypoxia stress: analysis of mRNA expression in lymphocytes mediating panting in Jersey cattle under heat stress.
  10. Effects of miR‑210‑3p on the erythroid differentiation of K562 cells under hypoxia.
  11. A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.
  12. Chronic hypoxia in pregnant mice impairs the placental and fetal vascular response to acute hypercapnia in BOLD-MRI hemodynamic response imaging.
  13. Dihydroartemisinin inhibits activation of the AIM2 inflammasome pathway and NF-κB/HIF-1α/VEGF pathway by inducing autophagy in A431 human cutaneous squamous cell carcinoma cells.
  14. Phosphorylation in Novel Mitochondrial Creatine Kinase Tyrosine Residues Render Cardioprotection against Hypoxia/Reoxygenation Injury.
  15. Glycoproteomics identifies HOMER3 as a potentially targetable biomarker triggered by hypoxia and glucose deprivation in bladder cancer.
  16. An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment.
  17. Effect of trivalent chromium on erythropoietin production and the prevention of insulin resistance in HepG2 cells.
  1. J Cancer. 2021 ;12(13): 3920-3929
    Asparagus Polysaccharide inhibits the Hypoxia-induced migration, invasion and angiogenesis of Hepatocellular Carcinoma Cells partly through regulating HIF1α/VEGF expression via MAPK and PI3K signaling pathway.
    Wei Cheng, Ziwei Cheng, Lingling Weng, Dongwei Xing, Minguang Zhang.
      Aim: Although there are so many treatment strategies used for hepatocellular carcinoma (HCC), the overall survival (OS) of HCC patients still remains very low. In our previous studies, asparagus polysaccharide (ASP) has been demonstrated to suppress proliferation, migration, invasion and angiogenesis of HCC cells under normoxic conditions in vitro. However, the inhibitory effects of ASP on the hypoxia-induced migration, invasion and angiogenesis of HCC cells still remain largely unexplored. Materials and methods: Cell Counting Kit-8 (CCK-8) assay, transwell assay, and tube formation assay were used to determine the effects of ASP on hypoxia-induced proliferation, migration, invasion and angiogenesis of HCC cells. ELISA, Western blotting analysis and immunofluorescence assay were used to confirm the effects of ASP on the expressions of HIF-1α and VEGF at the protein level. Moreover, effects of ASP on signaling pathway-related proteins were investigated by Western blotting analysis. Immunohistochemistry (IHC) assay was applied to test the effects of ASP on angiogenesis-associated proteins of tumor cells. Results: We showed that ASP effectively suppressed hypoxia-induced proliferation, migration, invasion and angiogenesis of SK-Hep1 and Hep-3B cells in a dose-dependent manner. In addition, the inhibitory effect of ASP might be partly attributed to down-regulation of HIF1α and VEGF proteins in SK-Hep1 and Hep-3B cells under hypoxic conditions. Moreover, signaling pathway study indicated that ASP significantly down-regulated the hypoxia-induced expressions of p-AKT, p-mTOR and p-ERK, while it had little effects on AKT, mTOR and ERK. Besides, SK-Hep1 xenograft tumor models in nude mice further confirmed that the inhibitory effect of ASP on xenograft tumors might be exerted partly via down-regulation of HIF1α and VEGF through blocking MAPK and PI3K signaling pathways. Conclusions: Our findings suggested that ASP suppressed the hypoxia-induced migration, invasion and angiogenesis of HCC cells partly through regulating HIF-1α/VEGF expression via MAPK and PI3K signaling pathways.
    Keywords:  HIF-1α; VEGF; asparagus polysaccharide; hepatocellular carcinoma
    DOI:  https://doi.org/10.7150/jca.51407
  2. FEBS Open Bio. 2021 Jun 08.
    FLI1 mediates the selective expression of hypoxia-inducible factor-1 target genes in endothelial cells under hypoxic conditions.
    Guodan Zeng, Tao Wang, Jingyao Zhang, Y James Kang, Li Feng.
      The selective expression of hypoxia-inducible factor (HIF) target genes in different physiological and pathological environments forms the basis of cellular adaptation to hypoxia in development and disease. Several E26 transformation-specific (ETS) transcription factors have been shown to specifically regulate the expression of a subset of HIF-2 target genes. However, it is unknown whether there are ETS factors that specifically regulate hypoxia-induced HIF-1 target genes. The present study was undertaken to explore whether friend leukemia integration 1 (FLI1), an ETS transcription factor, regulates the expression of HIF-1 target genes. To investigate this possibility, EA.hy926 cells were exposed to 20% O2 (normoxia) or 1% O2 (hypoxia). Western blotting, immunofluorescence staining, and RT-qPCR revealed that FLI1 mRNA and protein levels increased slightly, and that the FLI1 protein co-localized with HIF-1α in the nucleus under hypoxic conditions. Further analysis showed that, in the absence of FLI1, the hypoxia-mediated induction of HIF-1 target genes was selectively inhibited. The results from immunoprecipitation and luciferase reporter assays indicated that FLI1 cooperates with HIF-1α and is required for the transcriptional activation of a subset of HIF-1 target genes with a core promoter region containing FLI1-specific binding site (FBS) in proximity to a functional hypoxia response element (HRE). Furthermore, chromatin immunoprecipitation (ChIP) analysis further confirmed the direct interaction between FLI1 and the promoter region of FLI1-dependent HIF-1 target genes under hypoxia. Together, this study demonstrates that FLI1 is involved in the transactivation of certain HIF-1 target genes in endothelial cells under hypoxic conditions.
    Keywords:  FLI1; hypoxia; hypoxia-inducible factor; transcription target gene
    DOI:  https://doi.org/10.1002/2211-5463.13220
  3. Proc Natl Acad Sci U S A. 2021 06 29. pii: e2106017118. [Epub ahead of print]118(26):
    HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes.
    Travis Peng, Shin-Yi Du, Myoungsun Son, Betty Diamond.
      Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1β, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.
    Keywords:  COVID-19; HIF-1α; HMGB1; hypoxia; type I interferon
    DOI:  https://doi.org/10.1073/pnas.2106017118
  4. J Laryngol Otol. 2021 Jun 10. 1-9
    Prognostic significance of hypoxia-inducible factor-1α expression in advanced pharyngeal cancer without human papillomavirus infection.
    S Agena, H Hirakawa, T Ikegami, H Kinjyo, N Kise, H Maeda, J Uezato, S Kondo, A Kiyuna, Y Yamashita, N Hasegawa, M Suzuki, A Ganaha.
       OBJECTIVE: This study aimed to clarify the association between both hypoxia-inducible factor-1α and glucose transporter type-1 expression and survival outcome in advanced pharyngeal cancer without human papillomavirus infection.
    METHOD: Twenty-five oropharyngeal and 55 hypopharyngeal cancer patients without human papillomavirus infection were enrolled. All patients had stage III-IV lesions and underwent concurrent chemoradiotherapy or surgery. Hypoxia-inducible factor-1α and glucose transporter type-1 expression were investigated in primary lesions by immunohistochemistry.
    RESULTS: There were 41 and 39 cases with low and high hypoxia-inducible factor-1α expression, and 28 and 52 cases with low and high glucose transporter type-1 expression, respectively. There was no significant correlation between hypoxia-inducible factor-1α and glucose transporter type-1 expression. In univariate analysis, nodal metastasis, clinical stage and high hypoxia-inducible factor-1α expression, but not glucose transporter type-1 expression, predicted significantly worse prognosis. In multivariate analysis, hypoxia-inducible factor-1α overexpression was significantly correlated with poor overall survival, disease-specific survival and recurrence-free survival.
    CONCLUSION: High hypoxia-inducible factor-1α expression was an independent risk factor for poor prognosis for advanced human papillomavirus-unrelated pharyngeal cancer.
    Keywords:  Glucose Transporter Type 1; Hypoxia-Inducible Factor 1; Papillomavirus Infections; Pharyngeal Neoplasms; Prognosis
    DOI:  https://doi.org/10.1017/S0022215121001468
  5. ACS Biomater Sci Eng. 2021 Jun 10.
    β-Elemene Attenuates Fibrosis after Esophageal Endoscopic Submucosal Dissection via Modulating the HIF-1α/HK2/p38-MAPK Signaling Axis.
    Caifa Hong, Huie Zhuang, Baorang Cai, Jiangmu Chen, Sifu Huang, Taiyong Fang.
      Esophageal fibrosis and stricture after endoscopic submucosal dissection (ESD) are serious postoperative complications. Previous evidence has highlighted an anticancer role of β-elemene in esophageal squamous cell carcinoma. This study put forward a hypothesis on the inhibitory effect of β-elemene on esophageal fibrosis after ESD and aimed to elaborate the underlying mechanisms. Our initial network pharmacology analyses determined hypoxia-inducible factor-1alpha (HIF-1α), hexokinase 2 (HK2), and p38MAPK in association with the effect of β-elemene. We validated that the levels of HIF-1α, HK2, and p-p38MAPK were elevated in esophageal granulation tissue after ESD and corresponding fibroblasts. Esophageal fibroblasts were treated with β-elemene of gradient concentrations. The results indicated that β-elemene repressed the proliferation of esophageal fibroblasts and the levels of fibrosis-related factors. Further, β-elemene inhibited HIF-1α expression leading to restricted proliferation and augmented apoptosis of fibroblasts. HIF-1α induced p38MAPK phosphorylation by activating the HK2 transcription and consequently accelerated fibroblast proliferation. Together, β-elemene diminished HIF-1α expression and impaired the HK2-mediated p38MAPK phosphorylation, thereby repressing the esophageal fibrosis.
    Keywords:  endoscopic submucosal dissection; esophageal stricture; fibrosis; hexokinase 2; hypoxia-inducible factor; p38MAPK; β-elemene
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c00047
  6. Cell Death Discov. 2021 Jun 11. 7(1): 140
    Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming.
    Yi Dai, Fan Li, Yuwen Jiao, Guoguang Wang, Tian Zhan, Yunwei Xia, Hanyang Liu, Haojun Yang, Jianping Zhang, Liming Tang.
      Platinum drug treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). However, the therapeutic effect is less than satisfactory, largely due to the acquired resistance to platinum drugs. Therefore, a better understanding of the underlying mechanisms can greatly improve the therapeutic efficacy of GC. In this study, we aimed to investigate the chemo-resistance related functions/mechanisms and clinical significance of glucose-regulated protein 75 (GRP75) in GC. Here, our data showed that compared with SGC7901 cells, the expression of GRP75 was markedly higher in cisplatin-resistance cells (SGC7901CR). Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1α (HIF-1α), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CR cells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. Collectively, our study indicated that GRP75 was involved in the cisplatin-resistance of GC and that GRP75 could be a potential therapeutic target for restoring the drug response in platinum-resistance cells and a useful additive prognostic tool in guiding clinical management of GC patients.
    DOI:  https://doi.org/10.1038/s41420-021-00517-w
  7. J Cancer. 2021 ;12(13): 3841-3852
    Aggregative Perivascular Tumor Cell Growth Pattern of Primary Central Nervous System Lymphomas Is Associated with Hypoxia-Related Endoplasmic Reticulum Stress.
    Miaoxia He, Weiwei Zhang, Jianjun Wang, Lei Gao, Lijuan Jiao, Laixing Wang, Jianmin Zheng, Zailong Cai, Jianmin Yang.
      Primary central nervous system lymphomas (PCNSLs) often present a unique histopathological feature of aggregative perivascular tumor cells (APVT). Our previous studies showed that patients of PCNSL with APVTs exhibited poor long-term outcomes and increased expression of the endoplasmic reticulum stress (ERS) factor X-box-binding protein (XBP1). However, very little is known about molecular mechanism of the APVT formation in PCNSLs. The aim of this study is to determine if hypoxia-induced ERS is related to the APVT formation in PCNSLs. In this study, cell culture was used to observe the interplay between diffuse large B cell lymphoma (DLBCL) tumor cells and human brain microvascular endothelial cells (HBMECs) in different oxygen conditions. The expression of XBP1, CXCR and CD44 was manipulated by molecular cloning and siRNA technology. Mouse in vivo experiments and clinical studies were conducted to confirm our hypothesis. Our results showed that activated B-cell type-DLBCL cells easily migrated and invaded, and expressed high levels of XBP1 and stromal molecules CXCR4 and CD44 during hypoxia-induced ERS and dithiothreitol unfolded protein response (UPR). The gene upregulation (using overexpression vector) and downregulation (siRNA gene knock-out) in cultured cells and in mouse models further confirmed a close relation of the expression of XBP1, CXCR4, and CD44 with APVT formation, which is coincided with our clinical observation that increased expression of XBP1, CXCR4, and CD44 in the APVT cells in PCNSLs were associated with poor clinical outcomes. The results suggest that hypoxia-induced ERS and UPR might be associated with APVTs formation in PCNSL and its poor clinical outcomes. The results will help us better understand the progression of PCNSL with APVTs feature in daily pathological work and could be valuable for future target treatment of PCNSLs.
    Keywords:  APVT formation; Primary central nervous system lymphomas; clinical outcome; endoplasmic reticulum stress and signal transduction.; hypoxia
    DOI:  https://doi.org/10.7150/jca.54952
  8. Mol Neurobiol. 2021 Jun 05.
    Circulating lncRNAs HIF1A-AS2 and LINLK-A: Role and Relation to Hypoxia-Inducible Factor-1α in Cerebral Stroke Patients.
    Heba A Ewida, Rana K Zayed, Hebatallah A Darwish, Amira A Shaheen.
      Long noncoding RNAs (lncRNAs) have been recently recognized as key players of gene expression in cerebral pathogenesis. Thus, their potential use in stroke diagnosis, prognosis, and therapy is actively pursued. Due to the complexity of the disease, identifying stroke-specific lncRNAs remains a challenge. This study investigated the expression of lncRNAs HIF1A-AS2 and LINK-A, and their target gene hypoxia-inducible factor-1 (HIF-1) in Egyptian stroke patients. It also aimed to determine the molecular mechanism implicated in the disease. A total of 75 stroke patients were divided into three clinical subgroups, besides 25 healthy controls of age-matched and sex-matched. Remarkable upregulation of lncRNA HIF1A-AS2 and HIF1-α along with a downregulation of lncRNA LINK-A was noticed in all stroke groups relative to controls. Serum levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt (p-Akt), vascular endothelial growth factor (VEGF), and angiopoietin-1 (ANG1) as well as their receptors, malondialdehyde (MDA), and total antioxidant capacity (TAC) were significantly increased, whereas brain-derived neurotrophic factor (BDNF) levels were significantly decreased particularly in hemorrhagic stroke versus ischemic groups. Eventually, these findings support the role of lncRNAs HIF1A-AS2 and LINK-A as well as HIF1-α in activation of angiogenesis, neovascularization, and better prognosis of stroke, especially the hemorrhagic type.
    Keywords:  Cerebral stroke; HIF1-α; Non-invasive stroke biomarkers; lncRNA HIF1A-AS2; lncRNA LINK-A
    DOI:  https://doi.org/10.1007/s12035-021-02440-8
  9. BMC Vet Res. 2021 Jun 07. 17(1): 209
    Involvement of the VEGF signaling pathway in immunosuppression and hypoxia stress: analysis of mRNA expression in lymphocytes mediating panting in Jersey cattle under heat stress.
    Jian Wang, Yang Xiang, Shisong Jiang, Hongchang Li, Flurin Caviezel, Suporn Katawatin, Monchai Duangjinda.
       BACKGROUND: Extreme panting under heat stress threatens dairy cattle milk production. Previous research has revealed that the gas exchange-mediated respiratory drive in critically ill dairy cattle with low O2 saturation induces panting. Vascular endothelial growth factor (VEGF) signaling may play important roles in immunosuppression and oxidative stress during severe respiratory stress responses in heat-stressed cattle. The objectives of this study were to transcriptomically analyze mRNA expression mediating heat-induced respiratory stress-associated panting, evaluate gas exchange, screen hub genes, and verify the expression of proteins encoded by differentially expressed genes in lymphocyte pathways.
    RESULTS: Jersey cattle were naturally heat-exposed. Physiological data were collected for response evaluation, and blood was collected for gas exchange and gene expression assays at 06:00, 10:00 and 14:00 continuously for 1 week. Lymphocytes were isolated from whole-blood samples for mRNA-seq and expression analysis of key pathway genes/proteins. The cattle respiration rates differed with time, averaging 51 bpm at 06:00, 76 bpm at 10:00, and 121 bpm at 14:00 (p < 0.05). Gas exchange analysis showed that both pH and pCO2 differed with time: they were 7.41 and 41 mmHg at 06:00, 7.45 and 37.5 mmHg at 10:00, and 7.49 and 33 mmHg at 14:00, respectively (p < 0.01). Sixteen heat-related differentially expressed genes (DEGs; 13 upregulated and 3 downregulated) were screened between 212 DEGs and 1370 heat stress-affected genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) hub gene functional analysis annotated eleven genes to signal transduction, six genes to the immune response, and five genes to the endocrine response, including both prostaglandin-endoperoxide synthase 2 (PTGS2) and VEGF. Gene Ontology (GO) functional enrichment analysis revealed that oxygen regulation was associated with the phosphorus metabolic process, response to oxygen levels, response to decreased oxygen levels, response to hypoxia and cytokine activity terms. The main signaling pathways were the VEGF, hypoxia inducible factor-1(HIF-1), cytokine-cytokine receptor interaction and TNF pathways. Four genes involved Integrin beta 3 (ITBG3), PTGS2, VEGF, and myosin light chain 9 (MYL9) among the 16 genes related to immunosuppression, oxidative stress, and endocrine dysfunction were identified as participants in the VEGF signaling pathway and oxygenation.
    CONCLUSION: These findings help elucidate the underlying immune and oxygen regulation mechanisms associated with the VEGF signaling pathway in heat-stressed dairy cattle.
    Keywords:  Dairy cattle; Heat stress; Immune; Lymphocytes; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1186/s12917-021-02912-y
  10. Mol Med Rep. 2021 Aug;pii: 563. [Epub ahead of print]24(2):
    Effects of miR‑210‑3p on the erythroid differentiation of K562 cells under hypoxia.
    Caiyan Hu, Yupeng Yan, Chengbing Fu, Jin Ding, Tiantian Li, Shuqiong Wang, Liu Fang.
      GATA binding protein 1 (GATA‑1) is one of the most important hematopoietic transcription factors in the production of blood cells, such as platelets, eosinophils, mast cells and erythrocytes. GATA‑1 regulates the participation of microRNA (miRNAs/miRs) in erythroid differentiation under normoxia. However, GATA‑1 expression and the regulation of miR‑210‑3p in the context of erythroid differentiation under hypoxia remain unknown. The present study examined the expression levels of GATA‑1 and miR‑210‑3p in the model of erythroid differentiation in K562 cells under hypoxia, and determined the effects of GATA‑1, miR‑210‑3p and SMAD2 on erythroid differentiation through lentivirus transfection experiments. The present study detected increased GATA‑1 expression under hypoxia. Moreover, miR‑210‑3p was identified as a positive regulator of erythroid differentiation, which was upregulated both during erythroid differentiation and in GATA‑1 overexpression experiments under hypoxia. Importantly, in the K562 cell model of erythroid differentiation under hypoxia, miR‑210‑3p was upregulated in a GATA‑1‑dependent manner. Using a double luciferase reporter assay, miR‑210‑3p was identified as a downstream target of GATA‑1‑mediated regulation of erythropoiesis. Gain‑ or loss‑of‑function analysis of miR‑210‑3p identified its importance in erythroid differentiation. Furthermore, it was found that SMAD2 may be a downstream target gene for miR‑210‑3p. Bioinformatics predictions suggested that SMAD2 mediated miR‑210‑3p‑induced regulation of erythroid differentiation. Collectively, the present study provides novel insights into the miRNA regulation of erythroid differentiation.
    Keywords:  GATA‑1; SMAD2; erythroid differentiation; hypoxia; miR‑210‑3p
    DOI:  https://doi.org/10.3892/mmr.2021.12202
  11. FASEB J. 2021 Jul;35(7): e21645
    A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.
    Huong Nguyen, Jia Yi Koh, Hainan Li, Argel Islas-Robles, Sai Pranathi Meda Venkata, Jie-Mei Wang, Terrence J Monks.
      Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin-methylglyoxal scavenging reaction, (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl) guanidine (IMZ), was recently characterized and identified in the urine of type-2 diabetic patients. Here, we report the pro-angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro-angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia-inducible factor-1 alpha (HIF-1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post-ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro-angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro-angiogenic agents for the treatment of PAD.
    Keywords:  angiogenesis; endothelial nitric oxide synthase; hypoxia-inducible factor-1 alpha; metformin; methylglyoxal
    DOI:  https://doi.org/10.1096/fj.202002674RR
  12. Placenta. 2021 Jun 03. pii: S0143-4004(21)00159-4. [Epub ahead of print]110 29-38
    Chronic hypoxia in pregnant mice impairs the placental and fetal vascular response to acute hypercapnia in BOLD-MRI hemodynamic response imaging.
    Yehuda Ginosar, Zohar Bromberg, Nathalie Nachmanson, Ilana Ariel, Galina Skarzinski, Lital Hagai, Uriel Elchalal, Joel Shapiro, Rinat Abramovitch.
       INTRODUCTION: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model).
    METHODS: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O2;E13.5-17.5) and early-onset hypoxia (12%O2;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO2). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained.
    RESULTS: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only.
    CONCLUSIONS: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury.
    Keywords:  Animals; Fetal asphyxia; Fetal growth restriction; Hypercapnia; Hypoxia; MESH terms): mice; Magnetic resonance imaging; Placenta; Pregnancy
    DOI:  https://doi.org/10.1016/j.placenta.2021.05.006
  13. Int J Med Sci. 2021 ;18(12): 2705-2715
    Dihydroartemisinin inhibits activation of the AIM2 inflammasome pathway and NF-κB/HIF-1α/VEGF pathway by inducing autophagy in A431 human cutaneous squamous cell carcinoma cells.
    Yajie Wang, Zhijia Li, Muzhou Teng, Junlin Liu.
      The therapeutic effect of dihydroartemisinin (DHA) against cutaneous squamous cell carcinoma (cSCC) has been previously demonstrated; however, the underlying mechanism remains unclear. This study sought to verify the therapeutic effect of DHA against cSCC and explore its underlying mechanism in A431 cSCC cells. This study reported that DHA inhibited A431 cells proliferation in a time- and concentration-dependent manner and promoted A431 cells apoptosis. Moreover, DHA inhibited the invasion and migration of A431 cells. Mechanistically, DHA promoted autophagy and inhibited activation of the absent in melanoma 2 (AIM2) inflammasome pathway and NF-κB/HIF-1α/VEGF pathway. Treatment of A431 cells with the mTOR inhibitor, and autophagy promoter, rapamycin also inhibited these two pathways. In conclusion, DHA inhibited activation of the AIM2 inflammasome pathway and NF-κB/HIF-1α/VEGF pathway by promoting autophagy in A431 cells, thus accounting for its therapeutic effect. Induction of autophagy by DHA may be mediated by inhibiting the mTOR pathway and promoting reactive oxygen species production.
    Keywords:  AIM2 inflammasome pathway; NF-κB/HIF-1α/VEGF pathway; autophagy; cutaneous squamous cell carcinoma; dihydroartemisinin
    DOI:  https://doi.org/10.7150/ijms.57167
  14. J Lipid Atheroscler. 2021 May;10(2): 223-239
    Phosphorylation in Novel Mitochondrial Creatine Kinase Tyrosine Residues Render Cardioprotection against Hypoxia/Reoxygenation Injury.
    Nammi Park, Jubert Marquez, Maria Victoria Faith Garcia, Ippei Shimizu, Sung Ryul Lee, Hyoung Kyu Kim, Jin Han.
       Objective: Ischemic cardiomyopathy (ICM) is the leading cause of heart failure. Proteomic and genomic studies have demonstrated ischemic preconditioning (IPC) can assert cardioprotection against ICM through mitochondrial function regulation. Considering IPC is conducted in a relatively brief period, regulation of protein expression also occurs very rapidly, highlighting the importance of protein function modulation by post-translational modifications. This study aimed to identify and analyze novel phosphorylated mitochondrial proteins that can be harnessed for therapeutic strategies for preventing ischemia/reperfusion (I/R) injury.
    Methods: Sprague-Dawley rat hearts were used in an ex vivo Langendorff system to simulate normal perfusion, I/R, and IPC condition, after which the samples were prepared for phosphoproteomic analysis. Employing human cardiomyocyte AC16 cells, we investigated the cardioprotective role of CKMT2 through overexpression and how site-directed mutagenesis of putative CKMT2 phosphorylation sites (Y159A, Y255A, and Y368A) can affect cardioprotection by measuring CKMT2 protein activity, mitochondrial function and protein expression changes.
    Results: The phosphoproteomic analysis revealed dephosphorylation of mitochondrial creatine kinase (CKMT2) during ischemia and I/R, while preserving its phosphorylated state during IPC. CKMT2 overexpression conferred cardioprotection against hypoxia/reoxygenation (H/R) by increasing cell viability and mitochondrial adenosine triphosphate level, preserving mitochondrial membrane potential, and reduced reactive oxygen species (ROS) generation, while phosphomutations, especially in Y368, nullified cardioprotection by significantly reducing cell viability and increasing ROS production during H/R. CKMT2 overexpression increased mitochondrial function by mediating the proliferator-activated receptor γ coactivator-1α/estrogen-related receptor-α pathway, and these effects were mostly inhibited by Y368A mutation.
    Conclusion: These results suggest that regulation of quantitative expression and phosphorylation site Y368 of CKMT2 offers a unique mechanism in future ICM therapeutics.
    Keywords:  Creatine kinase, mitochondrial form; Hypoxia; Mitochondria; Phosphorylation; Reoxygenation
    DOI:  https://doi.org/10.12997/jla.2021.10.2.223
  15. J Exp Clin Cancer Res. 2021 Jun 09. 40(1): 191
    Glycoproteomics identifies HOMER3 as a potentially targetable biomarker triggered by hypoxia and glucose deprivation in bladder cancer.
    Andreia Peixoto, Dylan Ferreira, Rita Azevedo, Rui Freitas, Elisabete Fernandes, Marta Relvas-Santos, Cristiana Gaiteiro, Janine Soares, Sofia Cotton, Beatriz Teixeira, Paula Paulo, Luís Lima, Carlos Palmeira, Gabriela Martins, Maria José Oliveira, André M N Silva, Lúcio Lara Santos, José Alexandre Ferreira.
       BACKGROUND: Muscle invasive bladder cancer (MIBC) remains amongst the deadliest genitourinary malignancies due to treatment failure and extensive molecular heterogeneity, delaying effective targeted therapeutics. Hypoxia and nutrient deprivation, oversialylation and O-glycans shortening are salient features of aggressive tumours, creating cell surface glycoproteome fingerprints with theranostics potential.
    METHODS: A glycomics guided glycoproteomics workflow was employed to identify potentially targetable biomarkers using invasive bladder cancer cell models. The 5637 and T24 cells O-glycome was characterized by mass spectrometry (MS), and the obtained information was used to guide glycoproteomics experiments, combining sialidase, lectin affinity and bottom-up protein identification by nanoLC-ESI-MS/MS. Data was curated by a bioinformatics approach developed in-house, sorting clinically relevant molecular signatures based on Human Protein Atlas insights. Top-ranked targets and glycoforms were validated in cell models, bladder tumours and metastases by MS and immunoassays. Cells grown under hypoxia and glucose deprivation disclosed the contribution of tumour microenvironment to the expression of relevant biomarkers. Cancer-specificity was validated in healthy tissues by immunohistochemistry and MS in 20 types of tissues/cells of different individuals.
    RESULTS: Sialylated T (ST) antigens were found to be the most abundant glycans in cell lines and over 900 glycoproteins were identified potentially carrying these glycans. HOMER3, typically a cytosolic protein, emerged as a top-ranked targetable glycoprotein at the cell surface carrying short-chain O-glycans. Plasma membrane HOMER3 was observed in more aggressive primary tumours and distant metastases, being an independent predictor of worst prognosis. This phenotype was triggered by nutrient deprivation and concomitant to increased cellular invasion. T24 HOMER3 knockdown significantly decreased proliferation and, to some extent, invasion in normoxia and hypoxia; whereas HOMER3 knock-in increased its membrane expression, which was more pronounced under glucose deprivation. HOMER3 overexpression was associated with increased cell proliferation in normoxia and potentiated invasion under hypoxia. Finally, the mapping of HOMER3-glycosites by EThcD-MS/MS in bladder tumours revealed potentially targetable domains not detected in healthy tissues.
    CONCLUSION: HOMER3-glycoforms allow the identification of patients' subsets facing worst prognosis, holding potential to address more aggressive hypoxic cells with limited off-target effects. The molecular rationale for identifying novel bladder cancer molecular targets has been established.
    Keywords:  Bladder cancer; Cancer microenvironment; Glycomics; Glycoproteomics; Precision oncology; Targetable biomarkers
    DOI:  https://doi.org/10.1186/s13046-021-01988-6
  16. Front Immunol. 2021 ;12 680435
    An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment.
    Raefa Abou Khouzam, Shyama Prasad Rao, Goutham Hassan Venkatesh, Nagwa Ahmed Zeinelabdin, Stephanie Buart, Maxime Meylan, Manjunath Nimmakayalu, Stéphane Terry, Salem Chouaib.
      Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature's ability to discern an immune "cold", hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.
    Keywords:  hypoxia; immunosuppresive; immunotharapy; microenvironment; pancreatic cancer; prognostic; signature; tumor inflammation
    DOI:  https://doi.org/10.3389/fimmu.2021.680435
  17. Arch Biochem Biophys. 2021 Jun 04. pii: S0003-9861(21)00209-5. [Epub ahead of print] 108960
    Effect of trivalent chromium on erythropoietin production and the prevention of insulin resistance in HepG2 cells.
    Kazuhiko Nishimura, Suzuka Iitaka, Hiroshi Nakagawa.
      In erythropoietin (EPO)-producing HepG2 cells, we investigated the effect of trivalent chromium (Cr) on the promotion of EPO production and the induction of insulin resistance. Cr increased hypoxia-inducible factor (HIF)-1α protein, EPO mRNA expression and EPO protein levels in HepG2 cells. The effect of Cr on EPO production was inhibited by inhibition of proliferator-activated receptor γ (PPARγ). Insulin resistance was induced by culturing with insulin resistance induction medium supplemented with palmitic acid for 24 h. When Cr was added to the medium, the increase in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 mRNA expression levels and the decrease in the ratio of phosphorylated Akt to Akt protein were suppressed, and the induction of insulin resistance prevented. When a PPARγ inhibitor or siPPARγ was added together with Cr, the inhibitory effect of Cr on the induction of insulin resistance disappeared. In addition, pretreatment with siEPO suppressed the increase in EPO mRNA expression, and the inhibitory effect on the induction of insulin resistance due to the addition of Cr was significantly reduced. These results suggest that the inhibition of insulin resistance induction by Cr in HepG2 cells involves the promotion of EPO production mediated by PPARγ, in addition to other PPARγ-mediated activities.
    Keywords:  Chromium; Erythropoietin; Insulin resistance
    DOI:  https://doi.org/10.1016/j.abb.2021.108960
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