Acellular haemoglobin attenuates hypoxia-inducible factor-1α (HIF-1α) and its target genes in haemodiluted rats

2008 ◽  
Vol 414 (3) ◽  
pp. 461-469 ◽  
Author(s):  
Dominador J. Manalo ◽  
Paul W. Buehler ◽  
Jin Hyen Baek ◽  
Omer Butt ◽  
Felice D'agnillo ◽  
...  
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Oxygen Affinity ◽  
Blood Substitutes ◽  
Oxygen Deficit ◽  
Adaptation To Hypoxia ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1Α ◽  
Haem Oxygenase ◽  
Oxide Synthase

Hb (haemoglobin)-based blood substitutes represent a class of therapeutics designed to correct oxygen deficit under conditions of anaemia and traumatic blood loss. The influences of these agents on HIF-1α (hypoxia-inducible factor-1α) target genes involved in adaptation to hypoxia have so far not been studied. In the study presented here, rats underwent 80% ET (exchange transfusion) with either HS (hetastarch) or a polymerized Hb OG (Oxyglobin®). HS induced dramatic EPO (erythropoietin) gene transcription, reaching a maximum at 4 h post-ET. In contrast, OG suppressed EPO transcription until approx. 24 h post-ET. Large plasma EPO levels that were observed post-ET with HS were significantly blunted in animals transfused with OG. OG, unlike HS, induced a sharp increase in HO-1 (haem oxygenase-1) transcription at 4 h, which declined rapidly within 24 h, whereas modest increases in iNOS [inducible (nitric oxide synthase)] and constitutive NOS [eNOS (endothelial NOS)] were detected over the control. Our results demonstrate for the first time that severe haemodilution-induced erythropoietic responses in kidneys were attenuated by a low-oxygen-affinity cell-free Hb and suggest that tissue-specific oxygen-sensing pathways can be influenced by allosterically modified Hbs.

scholarly journals Hypoxia-inducible factor 1α induces osteo/odontoblast differentiation of human dental pulp stem cells via Wnt/β-catenin transcriptional cofactor BCL9

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Shion Orikasa ◽  
Nobuyuki Kawashima ◽  
Kento Tazawa ◽  
Kentaro Hashimoto ◽  
Keisuke Sunada-Nara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dental Pulp ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Dental Pulp Stem Cells ◽  
Pulp Tissue ◽  
Odontoblast Differentiation ◽  
Hypoxia Inducible Factor 1Α ◽  
Hypoxic Conditions

AbstractAccelerated dental pulp mineralization is a common complication in avulsed/luxated teeth, although the mechanisms underlying this remain unclear. We hypothesized that hypoxia due to vascular severance may induce osteo/odontoblast differentiation of dental pulp stem cells (DPSCs). This study examined the role of B-cell CLL/lymphoma 9 (BCL9), which is downstream of hypoxia-inducible factor 1α (HIF1α) and a Wnt/β-catenin transcriptional cofactor, in the osteo/odontoblastic differentiation of human DPSCs (hDPSCs) under hypoxic conditions. hDPSCs were isolated from extracted healthy wisdom teeth. Hypoxic conditions and HIF1α overexpression induced significant upregulation of mRNAs for osteo/odontoblast markers (RUNX2, ALP, OC), BCL9, and Wnt/β-catenin signaling target genes (AXIN2, TCF1) in hDPSCs. Overexpression and suppression of BCL9 in hDPSCs up- and downregulated, respectively, the mRNAs for AXIN2, TCF1, and the osteo/odontoblast markers. Hypoxic-cultured mouse pulp tissue explants showed the promotion of HIF1α, BCL9, and β-catenin expression and BCL9-β-catenin co-localization. In addition, BCL9 formed a complex with β-catenin in hDPSCs in vitro. This study demonstrated that hypoxia/HIF1α-induced osteo/odontoblast differentiation of hDPSCs was partially dependent on Wnt/β-catenin signaling, where BCL9 acted as a key mediator between HIF1α and Wnt/β-catenin signaling. These findings may reveal part of the mechanisms of dental pulp mineralization after traumatic dental injury.

scholarly journals Therapeutic effects of Hypoxia-Inducible Factor-1α (HIF-1α) on bone formation around implants in diabetic mice

2018 ◽  
Author(s):  
Sang-Min Oh ◽  
Jin-Su Shin ◽  
Il-Koo Kim ◽  
Jae-Seung Moon ◽  
Jung-Ho Kim ◽  
...  
Keyword(s):  
Bone Formation ◽  
Rna Sequencing ◽  
Normal Mouse ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mouse ◽  
Differentially Expressed ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Hypoxia Inducible Factor 1Α

AbstractPatients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1α gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1α gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1α target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1α were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1α via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

scholarly journals In Vivo Topoisomerase I Inhibition Attenuates the Expression of Hypoxia-Inducible Factor 1α Target Genes and Decreases Tumor Angiogenesis

2011 ◽  
Vol 18 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Eric Guérin ◽  
Wolfgang Raffelsberger ◽  
Erwan Pencreach ◽  
Armin Maier ◽  
Agnès Neuville ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Topoisomerase I ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α

scholarly journals Sequence Analysis and Phylogenetic Studies of Hypoxia-Inducible Factor-1α

2017 ◽  
Vol 16 ◽  
pp. 117693511771224
Author(s):  
Jagadeesha Poyya ◽  
Chandrashekhar G Joshi ◽  
D Jagadeesha Kumar ◽  
HG Nagendra
Keyword(s):  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1Α ◽  
Helix Loop Helix ◽  
Phylogenetic Studies ◽  
Sequence Variations ◽  
Potential Risk Factors ◽  
Inhibitory Domain

Hypoxia-inducible factors (HIF) belong to the basic helix loop helix–PER ARNT SIM (bHLH-PAS) family of transcription factors that induce metabolic reprogramming under hypoxic condition. The phylogenetic studies of hypoxia-inducible factor-1α (HIF-1α) sequences across different organisms/species may leave a clue on the evolutionary relationships and its probable correlation to tumorigenesis and adaptation to low oxygen environments. In this study, we have aimed at the evolutionary investigation of the protein HIF-1α across different species to decipher their sequence variations/mutations and look into the probable causes and abnormal behaviour of this molecule under exotic conditions. In total, 16 homologous sequences for HIF-1α were retrieved from the National Center for Biotechnology Information. Sequence identity was performed using the Needle program. Multiple aligned sequences were used to construct the phylogeny using the neighbour-joining method. Most of the changes were observed in oxygen-dependent degradation domain and inhibitory domain. Sixteen sequences were clustered into 5 groups. The phylogenetic analysis clearly highlighted the variations that were observed at the sequence level. Comparisons of the HIF-1α sequence among cancer-prone and cancer-resistant animals enable us to find out the probable clues towards potential risk factors in the development of cancer.

scholarly journals HIF-stabilization prevents delayed fracture healing

2020 ◽  
Author(s):  
Annemarie Lang ◽  
Sarah Helfmeier ◽  
Jonathan Stefanowski ◽  
Aditi Kuppe ◽  
Vikram Sunkara ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Hypoxia Inducible Factor ◽  
Cost Effective ◽  
Supporting Cell ◽  
Adaptation To Hypoxia ◽  
Preventive Strategy ◽  
Low Oxygen ◽  
Cellular Adaptation

AbstractThe initial phase of fracture healing decides on success of bone regeneration and is characterized by an inflammatory milieu and low oxygen tension (hypoxia). Negative interference with or prolongation of this fine-tuned initiation phase will ultimately lead to a delayed or incomplete healing such as non-unions which then requires an effective and gentle therapeutic intervention. Common reasons include a dysregulated immune response, immunosuppression or a failure in cellular adaptation to the inflammatory hypoxic milieu of the fracture gap and a reduction in vascularizing capacity by environmental noxious agents (e.g. rheumatoid arthritis, smoking). The hypoxia-inducible factor (HIF)-1α is responsible for the cellular adaptation to hypoxia, activating angiogenesis and supporting cell attraction and migration to the fracture gap. Here, we hypothesized that stabilizing HIF-1α could be a cost-effective and low-risk prevention strategy of fracture healing disorders. Therefore, we combined a well-known HIF-stabilizer – deferoxamine (DFO) – and a less known HIF-enhancer – macrophage migration inhibitory factor (MIF) – to synergistically induce improved fracture healing. Stabilization of HIF-1α enhanced calcification and osteogenic differentiation of MSCs in vitro. In vivo, the application of DFO with or without MIF during the initial healing phase accelerated callus mineralization and vessel formation in a clinically relevant mouse-osteotomy-model in a compromised healing setting. Our findings provide support for a promising preventive strategy towards bone healing disorders in patients with a higher risk due to e.g. delayed neovascularization by accelerating fracture healing using DFO and MIF to stabilize HIF-1α.

scholarly journals Sclareol Inhibits Hypoxia-Inducible Factor-1α Accumulation and Induces Apoptosis in Hypoxic Cancer Cells

2021 ◽  
Author(s):  
Somayeh Vandghanooni ◽  
Zahra Farajzadeh Vahid ◽  
Ailar Nakhlband ◽  
Mir Babak Bahadori ◽  
Morteza Eskandani
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
A549 Cells ◽  
Annexin V ◽  
Hypoxic Condition ◽  
Protein Quantification ◽  
Adaptation To Hypoxia ◽  
Protein Accumulation ◽  
Dna Ladder ◽  
Dapi Staining

Purpose: The hypoxia in solid tumors is associated with the resistance to chemo/radiotherapy. Hypoxia-inducible factor-1 (HIF-1) plays a key role in cell remodeling to hypoxia. Therefore, the inhibition of HIF-1 accumulation is considered a hopeful strategy for the treatment of cancer. Here, we aimed to evaluate the geno- and cytotoxicity properties of sclareol, a natural bicyclic diterpene alcohol, on A549 cells in CoCl2-induced hypoxia. Methods: The cytotoxicity and apoptosis-inducing properties of sclareol on the A549 cell were evaluated using MTT assay and Annexin V/PI staining, respectively in hypoxia. DAPI staining, DNA ladder, and comet assay were used to evaluate the genotoxicity. Further, the qPCR technique was employed to assess the expression of HIF-1α, HIF-1β, and downstream target genes (GluT1, and Eno1). Finally, the level of HIF-1α protein was evaluated through Western blotting in sclareol-treated cells in hypoxia. Results: The inhibitory concentration (IC50) of sclareol against A549 cells was 8 μg/mL at 48 h in hypoxia. The genotoxicity of sclareol was confirmed in the cells treated with sclareol in hypoxia. Sclareol induced ~46% apoptosis and also necrosis in the hypoxic condition. The qPCR analyses showed an enhanced suppression of HIF-1α, HIF-1β, GluT1, and Eno1 due to the sclareol treatment in the hypoxia. Moreover, protein quantification analysis showed dose-dependently degradation of HIF-1α in hypoxia upon treatment with sclareol. Conclusion: The results obtained here indicate that sclareol possesses dose-dependent cytotoxicity effects against A549 cells in hypoxia through inhibition of HIF-1α protein accumulation, increasing cell sensitivity to intracellular oxygen levels, and disruption of cell adaptation to hypoxia.

scholarly journals Metabolic reprogramming by HIF-1 promotes the survival of bone marrow–derived angiogenic cells in ischemic tissue

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4988-4998 ◽  
Author(s):  
Sergio Rey ◽  
Weibo Luo ◽  
Larissa A. Shimoda ◽  
Gregg L. Semenza
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Limb Ischemia ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Ischemic Tissue

Abstract A major obstacle to using bone marrow cell-based therapies for ischemic cardiovascular disease is that transplanted cells must survive in an ischemic microenvironment characterized by low oxygen, glucose, and pH. We demonstrate that treatment of bone marrow-derived angiogenic cells (BMDACs) with dimethyloxalylglycine, an α-ketoglutarate antagonist that induces hypoxia-inducible factor 1 (HIF-1) activity, results in metabolic reprogramming of these cells, with increased glucose uptake, decreased O2 consumption, increased lactate production, decreased reactive oxygen species, and increased intracellular pH. These effects are dependent on HIF-1, which transactivates target genes encoding metabolic enzymes and membrane transporters. Dimethyloxalylglycine-treated BMDACs have a significant survival advantage under conditions of low O2 and low pH ex vivo and in ischemic tissue. Combined HIF-1α-based gene and cell therapy reduced tissue necrosis even when BMDAC donors and ischemic recipient mice were 17 months old, suggesting that this approach may have therapeutic utility in elderly patients with critical limb ischemia.

Materials Biotechnology and Blood Substitutes

MRS Bulletin ◽  
1991 ◽  
Vol 16 (9) ◽  
pp. 78-81 ◽  
Author(s):  
Nir Kossovsky ◽  
David Millett
Keyword(s):  
Synergistic Effects ◽  
Immune Surveillance ◽  
Oxygen Affinity ◽  
Blood Substitutes ◽  
Oxygen Binding ◽  
Low Oxygen ◽  
Cooperative Effects ◽  
Sigmoidal Curve ◽  
Hemoglobin Molecule ◽  
High Oxygen Affinity

Blood is a dispersion of formed elements in an aqueous colloid. The combined mass of the formed elements of blood measure on average 30 ml per kg body weight, or about the same weight as the liver. The colloidal phase of blood contains numerous organic factors that play important primary and supporting roles in homeostasis, including immune surveillance, coagulation, and nutrient transport.Erythrocytes (red blood cells) are the principle formed elements and provide the life-sustaining function, in conjunction with the heart, lungs, blood vessels and kidneys, of transporting and protecting the oxygen-carrying pigment, hemoglobin, to the tissues. The oxygen-binding properties of hemoglobin are sensitive to factors such as the cooperative effects of O2 binding, pH and CO2 levels, and the presence of other metabolic intermediates such as 2,3-diphosphoglycerate. The synergistic effects of these factors produce a well-known sigmoidal curve plot of the relationship between oxygen affinity and the partial pressure of oxygen (pO2): there is high oxygen affinity in the lung where the pO2 is high, and a low oxygen affinity in the tissues, where the pO2 is low. Uptake and delivery of oxygen by hemoglobin is associated with considerable spatial rearrangement of the hemoglobin molecule.Blood is a non-Newtonian suspension. Its viscosity is a function of both the vascular diameter and the concentration of erythrocytes. At a normal hematocrit of 40%, the viscosity of blood ranges between 2 and 4 Pa s as measured in tubes ranging 10–1,500 μm diameter. The osmolality of blood serum is 275–295 mOsm/1.

Sign in / Sign up

Export Citation Format

Share Document