Akebia Therapeutics, a biopharmaceutical company focused on developing therapeutics based on hypoxia-inducible factor biology, strengthens its leaders
Definition of hypoxia-inducible factor 1, alpha subunit in the Definitions.net dictionary. Meaning of hypoxia-inducible factor 1, alpha subunit. What does hypoxia-inducible factor 1, alpha subunit mean? Information and translations of hypoxia-inducible factor 1, alpha subunit in the most comprehensive dictionary definitions resource on the web.
Background: During myocardial ischemia, hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury. Recent studies show that myocyte-specific hypoxia-inducible factor 2A promotes myocardial ischemia tolerance through induction of epidermal growth factor, amphiregulin. Here, the authors hypothesized that hypoxia-inducible factor 2A may enhance epidermal growth factor receptor 1 (ERBB1) expression in the myocardium that could interface between growth factors and its effect on providing tolerance to ischemia and reperfusion injury. Methods: Human myocardial tissues were obtained from ischemic heart disease patients and normal control patients to compare ERBB1 expression. Myocyte-specific Hif2a or ErbB1 knockout mice were generated to observe the effect of Hif2a knockdown in regulating ERBB1 expression and to examine the role of ERBB1 during myocardial ischemia and reperfusion injury. Results: Initial studies of myocardial tissues from patients with ischemic ...
Mitochondria have various essential functions in metabolism and in determining cell fate during apoptosis. In addition, mitochondria are also important nodes in a number of signaling pathways. For example, mitochondria can modulate signals transmitted by second messengers such as calcium. Because mitochondria are also major sources of reactive oxygen species (ROS), they can contribute to redox signaling-for example, by the production of ROS such as hydrogen peroxide that can reversibly modify cysteine residues and thus the activity of target proteins. Mitochondrial ROS production is thought to play a role in hypoxia signaling by stabilizing the oxygen-sensitive transcription factor hypoxia-inducible factor-1α. New evidence has extended the mechanism of mitochondrial redox signaling in cellular responses to hypoxia in interesting and unexpected ways. Hypoxia altered the microtubule-dependent transport of mitochondria so that the organelles accumulated in the perinuclear region, where they ...
The transcription factor hypoxia-inducible factor 1 (HIF1), which regulates oxygen homeostasis, is activated by stabilisation of the HIF1α subunit under low-oxygen conditions. Several studies have hinted that HIF1 might also have a role in cell adhesion and motility; now, Roser Buscà and colleagues (p. 2992) establish that HIF1 is important in keratinocyte migration during wound healing. The authors previously used an in vitro scratch-wound assay to show that several targets of HIF1 were upregulated in keratinocyte sheets in response to wounding, and they now show that HIF1α protein levels increase under the same conditions. Moreover, they demonstrate that HIF1α stabilisation is regulated by the PI3K-Akt pathway and, unusually, occurs under normoxic conditions. When HIF1α is depleted by siRNA, keratinocyte migration is impaired; additionally, HIF1α depletion abolishes the scratch-wound-dependent upregulation of the ECM protein laminin-332 (which is important in wound healing). The authors ...
When oxygen is limiting, cells adjust their metabolism through the transcription factors hypoxia-inducible factors (HIFs). Loss of function of VHL, a protein necessary to maintain the low abundance of HIFs under normoxic conditions, results in constitutively active HIFs and contributes to some forms of cancer, in particular clear cell renal carcinoma (ccRCC). Li et al. found through metabolomic analysis that primary human ccRCCs had higher glucose metabolism but lower gluconeogenesis than matched normal kidney tissue. The tumors universally had reduced or undetectable amounts of the enzyme fructose-1,6-bisphosphatase 1 (FBP1). Knockdown of endogenous FBP1 enhanced the proliferation of HK-2 cells, a proximal tubule cell line. Ectopic expression of FBP1 (to amounts similar to those in HK-2 cells) in a ccRCC line inhibited tumor growth when xenografted in mice and inhibited anchorage-dependent and anchorage-independent growth in culture. Ectopic expression of FBP1 in ccRCC cells reduced glycolysis ...
The HIF signaling pathway is a crucial way in which tumors can circumvent the constraints of regions of low oxygen (hypoxia) to induce angiogenesis and maintain proliferation. The oxygen regulated subunit of the transcription factor hypoxia-inducible factor 1 (HIF1), HIF1αlpha, is a positive factor in tumor growth and its expression has been correlated with poor patient prognosis in a number of settings.. We here present in vitro and in vivo data for a novel series of orally available small-molecule HIF signaling modulators that show nanomolar inhibition of the HIF signaling pathway in addition to potent anti-proliferative activity against a large number of cell lines derived from solid and blood tumors (EC50 in the range 1-100nM). Phenotypically, the compounds elicit an initial G2/M arrest, followed by the induction of caspase-3/7 and the onset of apoptosis.. The in vitro results also translate into in vivo animal models. The lead compounds from the series show efficacy in tumor xenograft ...
The vascular endothelial growth factors (VEGF) plays major roles during tumor development. VEGF expression is regulated by the transcription factor HIF (hypoxia inducible factor) which is very sensitive to oxygene variations. We will show here that HIF1alpha is today a good prognostic and diagnostic marker for an increasing number of cancers from various origins. Furthermore, the reduction of the expression or the activity of HIF1alpha impairs tumour angiogenesis and subsequently growth. Altogether, these results suggest that HIF1alpha could be an interesting target in cancer therapy.
TY - JOUR. T1 - Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. AU - Bosch-Marce, Marta. AU - Okuyama, Hiroaki. AU - Wesley, Jacob B.. AU - Sarkar, Kakali. AU - Kimura, Hideo. AU - Liu, Ye V.. AU - Zhang, Huafeng. AU - Strazza, Marianne. AU - Rey, Sergio. AU - Savino, Lindsey. AU - Zhou, Yi Fu. AU - McDonald, Karin R.. AU - Na, Youn. AU - Vandiver, Scott. AU - Rabi, Alireza. AU - Shaked, Yuval. AU - Kerbel, Robert. AU - LaVallee, Theresa. AU - Semenza, Gregg L.. PY - 2007/12/1. Y1 - 2007/12/1. N2 - Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function ...
Synthesis and biological evaluation of meta-carborane-containing phenoxyacetanilides as inhibitors of hypoxia-inducible factor (HIF)-1 transcriptional activitySynthesis and biological evaluation of meta-carborane-containing phenoxyacetanilides as inhibitors of hypoxia-inducible factor (HIF)-1 transcriptional activity ...
BACKGROUND Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an essential role in oxygen homeostasis. The expression of HIF-1alpha-inducible genes is associated with tumor progression. p21 mediates cell cycle arrest and is one of the downstream genes targeted by HIF-1. PATIENTS AND METHODS We examined the relationship between HIF-1alpha and p21 expression, apoptosis and tumor progression using tissue specimens obtained surgically from 126 patients with gastric cancer. RESULTS Immunohistochemical analysis indicated that loss of p21 expression correlated positively with patient age and tumor size. Lymph node metastasis was significantly more frequent in tumors with loss of p21 expression (P = 0.022). HIF-1alpha-positive/p21-negative tumors had a lower apoptotic index than any other tumor samples, and patients with HIF-1alpha-positive/p21-negative tumors also had a significantly poorer prognosis than the other patient populations. CONCLUSION These results suggest that loss of HIF-1alpha-dependent
Tumour progression is characterized by massive cellular proliferation associated with alterations of the tumour microenvironment. Hence, the tumour microenvironment is considered to be of great...
Hypoxia-inducible factor-1alpha is a critical mediator of hypoxia induced apoptosis in cardiac H9c2 and kidney epithelial HK-2 cells. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
In the present era of ever-increasing antibiotic resistance and increasingly complex and immunosuppressed patient populations, physicians and
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Insight into Hypoxia Tolerance in Cowpea Bruchid: Metabolic Repression and Heat Shock Protein Regulation via Hypoxia-Inducible Factor 1. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Scientists revealed that CD55 is a novel target of hypoxia-inducible factor HIF-2α in neuroblastoma (NB) cells. They showed that HIF-2α expression is sufficient to sustain stem-like features of NB cells, whereas CD55 protein upon HIF-2α expression contributes to growth of colonies and to invasion of cells, but not to stemness features. [Oncogenesis ...
Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.
Hypoxia-inducible factor 1A (HIF1A) regulates expression of genes implicated in various aspects of oncogenesis, including angiogenesis, cell survival, metastasis, and glucose metabolism. Overexpression or hypoxia-induced stabilization of HIF1A has been associated with poor prognosis in cancer patients, making HIF1A and its associated pathway a high-profile target for anticancer therapies. We sought to develop a live-cell assay to monitor abundance of endogenous HIF1A and HIF1A-inducible proteins that could be used to identify potent and specific inhibitors of the hypoxia signaling pathway. To accomplish this goal, mammalian cell lines were edited by CRISPR using a Cas9:crRNA ribonucleoprotein complex with a single-stranded oligonucleotide donor DNA to introduce the HiBiT tag at the C-terminus of HIF1A and a number of known hypoxia-inducible proteins, including BNIP3, ANKRD37, HILDPA and KLF10. The 11 amino acid HiBiT peptide and its complementing 18 kDa polypeptide, known as LgBiT, spontaneously ...
In embryonic stem (ES) cell tumors, the hypoxia-inducible transcription factor, HIF- 1[alpha], has been shown to be a tumor suppressor, and HIF-1[alpha]-expressing cells have been shown to localize preferentially in vivo ...
Sigma-Aldrich offers abstracts and full-text articles by [Christian Hanna, Susan C Hubchak, Xiaoyan Liang, Benaya Rozen-Zvi, Paul T Schumacker, Tomoko Hayashida, H William Schnaper].
만성 부비동염(축농증)에 동반되는 코폴립(콧속 물혹)은 수술적 치료 후에도 재발이 잦은 편이고, 스테로이드 외에는 뚜렷한 약물치료법이 없는 실정이다. 스테로이드 치료 역시 국소 요법을 제외하고는 장기간 처방이 어렵고, 스테로이드에 내성을 보이는 코폴립 환자도 상당수 있어서 코폴립은 새로운 치료법이 꼭 필요한 이비인후과 질환이다. 본 연구진은 새로운 코폴립 치료 타겟을 발굴하기 위해 코폴립 조직에서 빈번하게 관찰되는 비점막 재형성(remodeling)에 주목했다. 그 결과로 HIF-1 (hypoxia-inducible factor-1)라는 저산소유도인자가 상피-간엽 전환(EMT, epithelial-to-mesenchymal remodeling)이라는 현상을 통해 코폴립의 형성에 기여할 수 있다는 연구결과를 2012년에 발표한 바 있다 (Shin et al, AJRCCM 2012). HIF-1은 암의 저산소 적응과 전이와 관련하여 많이 연구되어온 ...
HIF1A (hypoxia-inducible aspect 1) may be the professional regulator from the cellular response to hypoxia and it is implicated in cancers development. 1; HRE, hypoxia-response component; LC, liquid chromatography; LDHA, lactate dehydrogenase A; miRNA, microRNA; MS/MS, tandem MS; NEDD8, neural-precursor-cell-expressed down-regulated 8 developmentally; NP-40, P40 Nonidet; NT, Non-Targeting; PABPC1, poly(A)-binding proteins C1; Skillet2, poly(A) nuclease … Continue reading HIF1A (hypoxia-inducible aspect 1) may be the professional regulator from the. ...
One of the most important factors in the cellular response to hypoxia is hypoxia-inducible factor (HIF), which transcriptionally activates genes…
HIF阻害剤(経路に合図することの標的を妨げる)がいろいろな分析のために使われて、いくつかは臨床試験に入りました。そして、それは新しいガン療法です。
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The hypoxic response in humans is mediated by the hypoxia-inducible transcription factor (HIF), for which prolyl hydroxylases (PHDs) act as oxygen-sensing components. The evolutionary origins of the HIF system have been previously unclear. We demonstrate a functional HIF system in the simplest animal, Trichoplax adhaerens: HIF targets in T. adhaerens include glycolytic and metabolic enzymes, suggesting a role for HIF in the adaptation of basal multicellular animals to fluctuating oxygen levels. Characterization of the T. adhaerens PHDs and cross-species complementation assays reveal a conserved oxygen-sensing mechanism. Cross-genomic analyses rationalize the relative importance of HIF system components, and imply that the HIF system is likely to be present in all animals, but is unique to this kingdom.
Ye et al54 found that, in endothelial cells, a gain-of-function mutation of Frizzled-4, increases the level of the transcription factor Sox 17. Through in vitro assays, these authors observed that Sox 17 is required for Norrin/Frizzled-4/Lrp-mediated angiogenesis in a 3D matrix gel. Sox17 may bind β-catenin and influence its transcriptional activity,71,72 but how and at which level these 2 transcription factors act on angiogenesis in vivo is still unknown.. TCF4/β-catenin complex increases von Hippel-Lindau tumor suppressor,73 which is required for inactivation of the transcription factor hypoxia-inducible factor (HIF)1α, which, in turn, is a potent inducer of vascular endothelial growth factor (VEGF). In addition, HIF1 α competes with TCF4 for direct binding to β-catenin.74 β-Catenin/HIF1α interaction occurs at the promoter regions of HIF1α target genes and increases their expression. Taken together, these data suggest that at low levels of oxygen, the interaction of β-catenin with ...
Ye et al54 found that, in endothelial cells, a gain-of-function mutation of Frizzled-4, increases the level of the transcription factor Sox 17. Through in vitro assays, these authors observed that Sox 17 is required for Norrin/Frizzled-4/Lrp-mediated angiogenesis in a 3D matrix gel. Sox17 may bind β-catenin and influence its transcriptional activity,71,72 but how and at which level these 2 transcription factors act on angiogenesis in vivo is still unknown.. TCF4/β-catenin complex increases von Hippel-Lindau tumor suppressor,73 which is required for inactivation of the transcription factor hypoxia-inducible factor (HIF)1α, which, in turn, is a potent inducer of vascular endothelial growth factor (VEGF). In addition, HIF1 α competes with TCF4 for direct binding to β-catenin.74 β-Catenin/HIF1α interaction occurs at the promoter regions of HIF1α target genes and increases their expression. Taken together, these data suggest that at low levels of oxygen, the interaction of β-catenin with ...
Title: Hypoxia Inducible Factor-1 as a Therapeutic Target in Cerebral Ischemia. VOLUME: 4 ISSUE: 3. Author(s):Penelope Aguilera, Edgar Vazquez-Contreras, Carlos Daniel Gomez-Martínez and Maria Elena Chanez Cardenas. Affiliation:Laboratorio de Patologia Vascular Cerebral, Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez. Av Insurgentes Sur 3877, Mexico D.F. 14269, Mexico.. Keywords:Hypoxia inducible factor, ischemic preconditioning, prolyl hydroxylase, cerebral ischemia. Abstract: Cerebral ischemia is the third leading cause of death in industrialized countries and an important health system problem with no efficient treatment to date. The reduction in oxygen and glucose supply triggers a cascade of events such as excitotoxicity, oxidative stress, inflammation, apoptosis, and an adjustment of the gene expression program. The hypoxia inducible factor-1 (HIF-1) is a transcription factor that mediates the adaptive responses to the reduction in oxygen availability. HIF-1 ...
The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant ...
The phosphatidylinositol 3-kinase (PI3K) signaling pathway has inherent oncogenic potential. It is up-regulated in diverse human cancers by either a gain of function in PI3K itself or in its downstream target Akt or by a loss of function in the negative regulator PTEN. However, the complete consequences of this up-regulation are not known. Here we show that insulin and epidermal growth factor or an inactivating mutation in the tumor suppressor PTEN specifically increase the protein levels of hypoxia-inducible factor (HIF) 1alpha but not of HIF-1beta in human cancer cell lines. This specific elevation of HIF-1alpha protein expression requires PI3K signaling. In the prostate carcinoma-derived cell lines PC-3 and DU145, insulin- and epidermal growth factor-induced expression of HIF-1alpha was inhibited by the PI3K-specific inhibitors LY294002 and wortmannin in a dose-dependent manner. HIF-1beta expression was not affected by these inhibitors. Introduction of wild-type PTEN into the PTEN-negative ...
The kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13K5) and cultured the organs under normoxic (20% 02/5% CO2) or hypoxic (5% 02/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. El3K5 cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-alpha l), increased under hypoxic conditions in E13K5. When we cultured E13Ks( with the HIF-1 alpha inhibitor digoxin or with siRNA targeting HIF-l alpha under hypoxic conditions, we did not observe increased UB branching. In ...
Hypoxia inducible factors (HIF1 and HIF2) have emerged as central regulators of the activity of myeloid cells at inflammatory sites where O|sup|2|/sup| is frequ...
Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.. ...
The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2 alpha protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n = 90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1 alpha and HIF-2 alpha expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1 alpha and HIF-2 alpha, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. ...
In this study, we presented that the hypoxic condition corresponding to the oxygen levels in the tissue microenvironment protects peripheral T cells from Ag receptor stimulation-triggered AICD, indicating a possible role of local oxygen concentrations in regulation of immune reactions.. AICD of peripheral T cells is likely to be coregulated by a variety of factors including environmental constituents. These regulatory mechanisms involve costimulatory molecules (7), humoral factors, or chemicals (5), all of which have been shown to involve the Fas/Fas-L system or Bcl-family proteins. Similarly, but mechanistically distinct from AICD, Ag receptor stimulation in naive T cells has been shown to result in apoptosis, in which NF-κB and p73 play a critical role (27). In the present study, we have demonstrated that hypoxia attenuates AICD in peripheral T cells through HIF-1α-mediated expression of AM possibly via an autocrine regulatory loop mechanism. Strikingly, among the hypoxia-inducible and cell ...
The pharmacological modulation of putative renoprotective factors hypoxia-inducible factor-1α (HIF-1α) and HIF-1α-regulated vascular endothelial growth factor-A (VEGF-A) in the kidney has therapeutic interest. In human renal proximal tubular HK2 cells, prostaglandin E2 (PGE2) up-regulates HIF-1α and VEGF-A through epidermal growth factor receptor (EGFR)-dependent up-regulation of retinoic acid receptor-β (RARβ). Here we studied the role of mitogen-activated protein kinases (MAPKs) ERK1/2 and p38 and their target kinase, mitogen- and stress activated kinase-1 (MSK1), in the signaling cascade. Treatment of HK2 cells with PGE2 resulted in increased phosphorylation of EGFR, the three studied kinases and the histone H3 (Ser10) at the RARβ gene promoter (the latter has been proposed as a molecular signature of the activated RARβ gene promoter). Prevention of the phosphorylation of EGFR, ERK1/2, p38 MAPK or MSK1 is by incubating, respectively, with AG1478, PD98059, SB203580 or H89 allowed to ...
Inhibition of the insulin-like growth factor-1 receptor (IGF-1R) signaling represents an attractive therapeutic strategy for cancer treatment. A first generation IGF-1R inhibitor BMS-536924, however, was associated with potent CYP3A4 induction mediated by pregnane X receptor (PXR, NR1I2) transactivation. Structural activity-based modification led to the synthesis of BMS-665351 with no PXR activity while maintaining its ability to inhibit IGF-1R. However, BMS-665351 significantly induces CYP3A4 expression in human primary hepatocytes (HPHs). Here, we report a novel non-classical constitutive androstane receptor (CAR, NR1I3)-related pathway of BMS-665351-mediated CYP3A4 induction. BMS-665351 treatment resulted in significant induction of CYP3A4 in HPHs and HepG2 cells, but failed to activate either PXR or CAR in cell-based reporter assays. Moreover, BMS-665351 at concentrations that induce CYP3A4 expression was unable to translocate human CAR from the cytoplasm to the nucleus of HPHs, which ...
The ToxTracker assay is a state-of-the-art stem cell-based reporter assay that provides mechanistic insight into genotoxic properties of compounds. ToxTracker ACE (Aneugen Clastogen Evaluation) is an extended version of the ToxTracker assay and includes direct discrimination between an aneugenic and a clastogenic mode-of-action of genotoxic compounds. ToxTracker ACE combines the power of 6 fluorescent reporter cell lines for detection of DNA damage, oxidative stress and protein damage with cell cycle analyses and detection of polyploidy. This unique combination gives unparalleled mechanistic insight into the hazardous properties of chemicals and pharmaceuticals in a single assay. The information generated is particularly useful in Mode-of-Action (MoA) and Adverse-Outcome Pathway (AOP) approaches.. ...
Gentronix is pleased to announce the introduction of its new early genotoxicity screening assay BlueScreen HC. BlueScreen HC is a human cell-based reporter assay that monitors expression of the GADD45a gene, a P53 target that is up-regulated in response to all types of genotoxic stress. To coincide with the expansion of cell-based screening services, Gentronix has also announced the introduction of its in vitro Comet assay service.
Background: Hypoxia induces adaptive and pathogenic cellular responses, many of which are controlled by microRNA (miRNA). Plasma-based extracellular miRNA have been measured in ischemic and hypoxia-dependent cardiovascular diseases; yet, their regulation and in vivo biological functions remain enigmatic.. Objective: Determine the role of the hypoxia-inducible miR-210 as a circulating messenger controlling hypoxic adaptation in recipient vascular tissue.. Results: MiR-210 is released from hypoxic (4.8 fold-change+ 0.2 SEM) and re-oxygenated (7.5 fold change+0.3) vascular endothelial cells in culture. Plasma levels of miR-210 are elevated in mice chronically exposed to hypoxia (2.1 fold-change+0.4, N=6 mice/group). MiR-210 is also up-regulated in plasma from humans subjected chronically to high altitude (3.7 fold-change+0.7, N=5 Andean women/group at week 36 pregnancy residing at high and low altitudes) and from PAD patients with intermittent claudication (3.5 fold-change+0.7 vs. healthy control, ...
Homo sapiens hypoxia-inducible factor prolyl 4-hydroxylase (PH-4), transcript variant 3, mRNA. (H00054681-R02) - Products - Abnova
Homo sapiens hypoxia-inducible factor prolyl 4-hydroxylase (PH-4), transcript variant 1, mRNA. (H00054681-R03) - Products - Abnova
HIF-3 alpha (hypoxia-inducible factor 3-alpha/ HIF3A) represents an isoform of HIF-alpha subunits which heterodimerize with stable beta subunit (HIF-beta) for the regulation of HIF target genes through binding to hypoxia response elements/HRE in the promoter regions.
The signal transduction events that modulate the expression of HIF-1α, as well as the subsequent expression of VEGF and other HIF-1-regulated genes, are currently under intensive scrutiny. The results of the present study confirm and extend the earlier report that rapamycin inhibits both the stabilization of HIF-1α and the transcriptional activity of HIF-1 in hypoxic cancer cells (50). Furthermore, we provide genetic evidence to support the conclusion that the rapamycin target protein, mTOR, functions as a positive regulator of HIF-1 activation by hypoxia or the hypoxia-mimetic agent, CoCl2.. A synthesis of the available data indicates that at least two integrated signaling pathways promote the accumulation of HIF-1α in mammalian cells. The first pathway is triggered by hypoxia or CoCl2 and involves the inhibition of a family of PHDs that modify Pro-564 and Pro-402 of HIF-1α (5, 21, 22, 27, 41). The second pathway is triggered by polypeptide growth factors or oncogenic mutations (e.g., PTEN ...
Hypoxia inducible factor-1 (HIF-1) is a key regulator in hypoxia. It has been suggested to be a critical regulator of neurological outcomes following ischemic s...
As well documented,15 the overall activity of HIF-1 is determined by the level of intracellular HIF-1α. In the past decade, the mechanisms of HIF-1α regulation have become a field of intense research and much information concerning it has been gained. In this study, we show that differentiation-inducing concentrations of ATRA rapidly increase HIF-1α protein but not its mRNA during the induced differentiation of both NB4 and U937 cells. ATRA also significantly increased the accumulation of HIF-1α protein induced by tetracycline withdrawal in engineered U937 cells, in which expression of HIF-1α mRNA was not under the control of the endogenous promoter of HIF-1α gene. Of note, NB4 and U937 cells presented different dynamic courses of changes in HIF-1α protein levels: the increase of HIF-1α protein was rapid but transitory in ATRA-treated NB4 cells, while ATRA induced a lasting increase of HIF-1α protein in U937 cells. All these observations indicate that ATRA accumulates HIF-1α protein ...
1MZE: Structure of Factor-Inhibiting Hypoxia-Inducible Factor 1: An Asparaginyl Hydroxylase Involved in the Hypoxic Response Pathway