[367] MEMORY READ OUT OF HYPOXIA-INDUCIBLE FACTOR (HIF) 1 ALPHA AS NOVEL TOOL TO DETERMINE TISSUE OXYGEN: EVIDENCE FOR HYPOXIC HEPATOCELLULAR OXYGEN LEVELS IN VIVO

Background:: It was known that the response of tumor cells to radiation is closely related to tissue oxygen level and fractionated radiotherapy allows reoxygenation of hypoxic tumor cells. Non-invasive mapping of tissue oxygen level may hold great importance in clinic. Objective: The aim of this study is to evaluate the role of oxygen-enhanced MR imaging in the detection of tissue oxygen levels between fractionated radiotherapy. Methods: A cohort of 10 patients with brain metastasis was recruited. Quantitative oxygen enhanced MR imaging was performed prior to, 30 minutes and 22 hours after first fractionated radiotherapy. Results: The ΔR1 (the difference of longitudinal relaxivity between 100% oxygen breathing and air breathing) increased in the ipsilateral tumor site and normal tissue by 242% and 152%, respectively, 30 minutes after first fractionated radiation compared to pre-radiation levels. Significant recovery of ΔR1 in the contralateral normal tissue (p < 0.05) was observed 22 hours compared to 30 minutes after radiation levels. Conclusion: R1-based oxygen-enhanced MR imaging may provide a sensitive endogenous marker for oxygen changes in the brain tissue between fractionated radiotherapy.

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Effect of acute hypoxia on microcirculatory and tissue oxygen levels in rat cremaster muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00591.2004 ◽

2005 ◽

Vol 98 (4) ◽

pp. 1177-1184 ◽

Cited By ~ 29

Author(s):

Paul C. Johnson ◽

Kim Vandegriff ◽

Amy G. Tsai ◽

Marcos Intaglietta

Keyword(s):

Acute Hypoxia ◽

Hypoxic Exposure ◽

Cremaster Muscle ◽

Tissue Oxygen ◽

Oxygen Levels ◽

Oxygen Fraction ◽

Arterial Blood ◽

S Period ◽

Inspired Oxygen

Repeated exposure to brief periods of hypoxia leads to pathophysiological changes in experimental animals similar to those seen in sleep apnea. To determine the effects of such exposure on oxygen levels in vivo, we used an optical method to measure Po2 in microcirculatory vessels and tissue of the rat cremaster muscle during a 1-min step reduction of inspired oxygen fraction from 0.21 to 0.07. Under control conditions, Po2 was 98.1 ± 1.9 Torr in arterial blood, 52.2 ± 2.8 Torr in 29.0 ± 2.7-μm arterioles, 26.8 ± 1.7 Torr in the tissue interstitium near venous capillaries, and 35.1 ± 2.6 Torr in 29.7 ± 1.9-μm venules. The initial fall in Po2 during hypoxia was significantly greater in arterial blood, being 93% complete in the first 10 s, whereas it was 68% complete in arterioles, 47% at the tissue sites, and 38% in venules. In the 10- to 30-s period, the fall in normalized tissue and venular Po2 was significantly greater than in arterial Po2. At the end of hypoxic exposure, Po2 at all measurement sites had fallen very nearly in proportion to that in the inspired gas, but tissue oxygen levels did not reach critical Po2. Significant differences in oxyhemoglobin desaturation rate were also observed between arterial and microcirculatory vessels during hypoxia. In conclusion, the fall in microcirculatory and tissue oxygen levels in resting skeletal muscle is significantly slower than in arterial blood during a step reduction to an inspired oxygen fraction of 0.07, and tissue Po2 does not reach anaerobic levels.

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Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo

Science ◽

10.1126/science.1103786 ◽

2004 ◽

Vol 306 (5704) ◽

pp. 2087-2090 ◽

Cited By ~ 167

Author(s):

E. G. Meyron-Holtz

Keyword(s):

Regulatory Protein ◽

Iron Regulatory Protein ◽

Mammalian Tissue ◽

Tissue Oxygen ◽

Oxygen Levels

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Effects of cyclosporine pretreatment on tissue oxygen levels and cytochrome oxidase activity. A study in the skeletal muscle- model for ischemia and reperfusion impact

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0032-1332480 ◽

2013 ◽

Vol 61 (S 01) ◽

Author(s):

D Troitzsch ◽

JM Hasenkam ◽

H Nygaard ◽

RG Moosdorf ◽

S Vogt

Keyword(s):

Skeletal Muscle ◽

Cytochrome Oxidase ◽

Oxidase Activity ◽

Muscle Model ◽

Ischemia And Reperfusion ◽

Tissue Oxygen ◽

Cytochrome Oxidase Activity ◽

Oxygen Levels

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Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release

Cell Death and Disease ◽

10.1038/s41419-021-03789-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Virginia Egea ◽

Kai Kessenbrock ◽

Devon Lawson ◽

Alexander Bartelt ◽

Christian Weber ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Human Mesenchymal Stem Cells ◽

Target Cells ◽

Autophagic Flux ◽

Stromal Cell Derived Factor

AbstractBone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

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miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

Cancer Biomarkers ◽

10.3233/cbm-203112 ◽

2021 ◽

pp. 1-12

Author(s):

Pengli Wang ◽

Dan Zheng ◽

Hongyang Qi ◽

Qi Gao

Keyword(s):

Pancreatic Cancer ◽

Hypoxia Inducible Factor ◽

Immunofluorescence Assay ◽

Luciferase Assay ◽

Interacting Protein ◽

Over Expression ◽

Thioredoxin Interacting Protein ◽

Cellular Processes ◽

And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

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A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Nature Communications ◽

10.1038/s41467-021-23448-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Guodong Li ◽

Chung-Nga Ko ◽

Dan Li ◽

Chao Yang ◽

Wanhe Wang ◽

...

Keyword(s):

Wound Healing ◽

Small Molecule ◽

Hypoxia Inducible Factor ◽

Diabetic Patients ◽

Diabetic Mice ◽

Impaired Wound Healing ◽

Von Hippel Lindau ◽

Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽

10.1038/s41388-020-01590-8 ◽

2021 ◽

Author(s):

Yinyin Xu ◽

Jing Guo ◽

Jing Liu ◽

Ying Xie ◽

Xin Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Combined Treatment ◽

Hypoxia Inducible Factor ◽

Bone Destruction ◽

Bone Lesions ◽

Myeloma Cells ◽

Downstream Target ◽

Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by apatinib

Cell Death and Disease ◽

10.1038/s41419-021-03646-3 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Zheng Chen ◽

Xiangyu Wei ◽

Xueyi Wang ◽

Xuan Zheng ◽

Bowen Chang ◽

...

Keyword(s):

Tumor Cell ◽

Hypoxia Inducible Factor ◽

Mitochondrial Respiratory Chain ◽

Metabolic Reprogramming ◽

Tumor Cell Apoptosis ◽

Survival Gene ◽

A Subunit ◽

Tumor Types

AbstractNADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a subunit of Complex I of the mitochondrial respiratory chain, which is important in metabolic reprogramming and oxidative stress in multiple cancers. However, the biological role and molecular regulation of NDUFA4L2 in glioblastoma (GBM) are poorly understood. Here, we found that NDUFA4L2 was significantly upregulated in GBM; the elevated levels were correlated with reduced patient survival. Gene knockdown of NDUFA4L2 inhibited tumor cell proliferation and enhanced apoptosis, while tumor cells initiated protective mitophagy in vitro and in vivo. We used lentivirus to reduce expression levels of NDUFA4L2 protein in GBM cells exposed to mitophagy blockers, which led to a significant enhancement of tumor cell apoptosis in vitro and inhibited the development of xenografted tumors in vivo. In contrast to other tumor types, NDUFA4L2 expression in GBM may not be directly regulated by hypoxia-inducible factor (HIF)-1α, because HIF-1α inhibitors failed to inhibit NDUFA4L2 in GBM. Apatinib was able to effectively target NDUFA4L2 in GBM, presenting an alternative to the use of lentiviruses, which currently cannot be used in humans. Taken together, our data suggest the use of NDUFA4L2 as a potential therapeutic target in GBM and demonstrate a practical treatment approach.

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