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  1. Hypoxia and Proton microbeam: Role of Gap Junction Intercellular Communication in Inducing Bystander Responses on Human Lung Cancer Cells and Normal Cells
    Autsavapromporn N, Kobayashi A, Liu C, Jaikang C, Tengku Ahmad TA, Oikawa M, et al.
    Radiat Res, 2022 Feb 01;197(2):122-130.
    PMID: 34634126 DOI: 10.1667/RADE-21-00112.1
    Radiation-induced bystander effect (RIBE) has been identified as an important contributing factor to tumor resistance and normal tissue damage. However, the RIBE in cancer and normal cells under hypoxia remain unclear. In this study, confluent A549 cancer and WI-38 normal cells were subjected to condition of hypoxia or normoxia, before exposure to high-LET protons microbeam. After 6 h incubation, cells were harvested and assayed for colony formation, micronucleus formation, chromosome aberration and western blotting. Our results show that there were differences of RIBE in bystander A549 and WI-38 cells under hypoxia and normoxia. The differences were also observed in the roles of HIF-1α expression in bystander A549 and WI-38 cells under both conditions. Furthermore, inhibition of gap junction intercellular communication (GJIC) showed a decrease in toxicity of hypoxia-treated bystander A549 cells, but increased in bystander WI-38 cells. These findings clearly support that GJIC protection of bystander normal cells from toxicity while enhancing in bystander cancer cells. Together, the data show a promising strategy for high-LET radiation in designing an entire new line of drugs, either increase or restore GJIC in bystander cancer cells which in turn leads to enhancement of radiation accuracy for treatment of hypoxic tumors.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  2. Fulltext [Zinc induces normoxic accumulation of transcriptionally active hypoxia-inducible factor 1-alpha in mammary epithelial cells]
    Lee SY, Mustafa S, Ching YW, Shafee N
    Mol Biol (Mosk), 2017 3 3;51(1):104-110.
    PMID: 28251972 DOI: 10.7868/S0026898417010116
    Both zinc and the α-subunit of hypoxia-inducible factor (HIF-1α) play important roles in the remodelling of mammary gland tissues. In the present study, we examined the level and the transcriptional activity of HIF-1α in mammary cells upon zinc treatment. In MCF-7 mammary adenocarcinoma and MCF-10A mammary epithelial cell lines, the toxicity levels of zinc differ. Interestingly, both cell lines overexpress HIF-1α following zinc treatment. As it was evident from an up-regulation of its specific target gene CA9 that encodes carbonic anhydrase IX, the stabilized HIF-1α translocated to the nucleus and was transcriptionally active. Hence, we conclude that zinc causes normoxic accumulation of transcriptionally active HIF-1α by interfering with its post-translational regulation.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  3. Associations between hypoxia-inducible factor-1alpha (HIF-1alpha) gene polymorphisms and risk of developing breast cancer
    Naidu R, Har YC, Taib NA
    Neoplasma, 2009;56(5):441-7.
    PMID: 19580347
    The C1772T, G1790A and C111A polymorphisms of Hypoxia-inducible factor-1alpha (HIF-1alpha) gene were analyzed in a hospital-based Malaysian population using PCR-RFLP method. Genomic DNA was extracted from the blood samples collected from 410 breast cancer patients and 275 normal and healthy women. We investigated the association between HIF-1alpha polymorphisms and breast cancer risk, and clinico-pathological parameters in the population. The genotype and allele frequencies of C1772T (P=0.0093 vs P=0.0024) polymorphism were significantly different between the breast cancer cases and normal subjects but similar association was not observed for G1790A (P>0.05) and C111A (P>0.05) polymorphisms, respectively. Women who were CT heterozygotes (OR=1.51; 95% CI, 1.01-2.25), TT homozygotes (OR=4.03; 95% CI, 1.09-17.60) and carriers of T allele genotype (OR=1.65; 95% CI, 1.13-2.43) were significantly associated with increased risk of breast cancer. Significant relationship was observed also between T allele and breast cancer risk (OR=1.69; 95% CI, 1.20-2.40). Clinico-pathological analysis showed that 1772T allele genotype was significantly associated with nodal metastases (P=0.0478) but independent of ER status, tumor grade and patients' age (P>0.05). Our observations suggest that the polymorphic allele of C1772T may be associated with increased risk of developing breast cancer, and presence of 1772T allele may be a useful genetic marker for tumor prognosis.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics*
  4. Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells
    Choi JR, Pingguan-Murphy B, Wan Abas WA, Noor Azmi MA, Omar SZ, Chua KH, et al.
    Biochem Biophys Res Commun, 2014 May 30;448(2):218-24.
    PMID: 24785372 DOI: 10.1016/j.bbrc.2014.04.096
    Adipose-derived stem cells (ASCs) have been found adapted to a specific niche with low oxygen tension (hypoxia) in the body. As an important component of this niche, oxygen tension has been known to play a critical role in the maintenance of stem cell characteristics. However, the effect of O2 tension on their functional properties has not been well determined. In this study, we investigated the effects of O2 tension on ASCs stemness, differentiation and proliferation ability. Human ASCs were cultured under normoxia (21% O2) and hypoxia (2% O2). We found that hypoxia increased ASC stemness marker expression and proliferation rate without altering their morphology and surface markers. Low oxygen tension further enhances the chondrogenic differentiation ability, but reduces both adipogenic and osteogenic differentiation potential. These results might be correlated with the increased expression of HIF-1α under hypoxia. Taken together, we suggest that growing ASCs under 2% O2 tension may be important in expanding ASCs effectively while maintaining their functional properties for clinical therapy, particularly for the treatment of cartilage defects.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  5. Fulltext Quantitative MS-Based Proteomics: Comparing the MCF-7 Cellular Response to Hypoxia and a 2-Oxoglutarate Analogue
    Bush JT, Chan MC, Mohammed S, Schofield CJ
    Chembiochem, 2020 06 02;21(11):1647-1655.
    PMID: 31919953 DOI: 10.1002/cbic.201900719
    The hypoxia-inducible factors (HIFs) are key transcription factors in determining cellular responses involving alterations in protein levels in response to limited oxygen availability in animal cells. 2-Oxoglutarate-dependent oxygenases play key roles in regulating levels of HIF and its transcriptional activity. We describe MS-based proteomics studies in which we compared the results of subjecting human breast cancer MCF-7 cells to hypoxia or treating them with a cell-penetrating derivative (dimethyl N-oxalylglycine; DMOG) of the stable 2OG analogue N-oxalylglycine. The proteomic results are consistent with reported transcriptomic analyses and support the proposed key roles of 2OG-dependent HIF prolyl- and asparaginyl-hydroxylases in the hypoxic response. Differences between the data sets for hypoxia and DMOG might reflect context-dependent effects or HIF-independent effects of DMOG.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics*; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  6. Hypoxia-inducible factor-1α as a predictive marker in pre-eclampsia
    Akhilesh M, Mahalingam V, Nalliah S, Ali RM, Ganesalingam M, Haleagrahara N
    Biomed Rep, 2013 Mar;1(2):257-258.
    PMID: 24648931
    The aim of this study was to determine whether or not the increased levels of hypoxia-inducible factor-1α (HIF-1α) could be used to demonstrate failed placentation in pre-eclamptic mothers. Twenty pregnant females with (pre-eclampsia group) or without pre-eclampsia (control group) were included in the present study. Antenatal and post-delivery HIF-1α transcription factor levels were measured. A significant increase was observed in the HIF-1α levels in the pre- and post-natal pre-eclampsia mothers. The findings suggest that the levels of HIF-1α in the blood of mothers with pre-eclampsia decrease after delivery of the placenta. The results confirm that there is increased HIF-1α in pre-eclampsia and a steady increase in the levels of HIF-1α could be commensurate with the possibility of a patient developing pre-eclampsia at a later trimester.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit
  7. The role of mTOR signalling pathway in hypoxia-induced cognitive impairment
    Abdo Qaid EY, Zulkipli NN, Zakaria R, Ahmad AH, Othman Z, Muthuraju S, et al.
    Int J Neurosci, 2021 May;131(5):482-488.
    PMID: 32202188 DOI: 10.1080/00207454.2020.1746308
    Hypoxia has been associated with cognitive impairment. Many studies have investigated the role of mTOR signalling pathway in cognitive functions but its role in hypoxia-induced cognitive impairment remains controversial. This review aimed to elucidate the role of mTOR in the mechanisms of cognitive impairment that may pave the way towards the mechanistic understanding and therapeutic intervention of hypoxia-induced cognitive impairment. mTORC1 is normally regulated during mild or acute hypoxic exposure giving rise to neuroprotection, whereas it is overactivated during severe or chronic hypoxia giving rise to neuronal cells death. Thus, it is worth exploring the possibility of maintaining normal mTORC1 activity and thereby preventing cognitive impairment during severe or chronic hypoxia.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  8. Fulltext Inhibition of Raf-MEK-ERK and hypoxia pathways by Phyllanthus prevents metastasis in human lung (A549) cancer cell line
    Lee SH, Jaganath IB, Manikam R, Sekaran SD
    BMC Complement Altern Med, 2013 Oct 20;13:271.
    PMID: 24138815 DOI: 10.1186/1472-6882-13-271
    BACKGROUND: Lung cancer constitutes one of the malignancies with the greatest incidence and mortality rates with 1.6 million new cases and 1.4 million deaths each year. Prognosis remains poor due to deleterious development of multidrug resistance resulting in less than 15% lung cancer patients reaching five years survival. We have previously shown that Phyllanthus induced apoptosis in conjunction with its antimetastastic action. In the current study, we aimed to determine the signaling pathways utilized by Phyllanthus to exert its antimetastatic activities.

    METHODS: Cancer 10-pathway reporter array was performed to screen the pathways affected by Phyllanthus in lung carcinoma cell line (A549) to exert its antimetastatic effects. Results from this array were then confirmed with western blotting, cell cycle analysis, zymography technique, and cell based ELISA assay for human total iNOS. Two-dimensional gel electrophoresis was subsequently carried out to study the differential protein expressions in A549 after treatment with Phyllanthus.

    RESULTS: Phyllanthus was observed to cause antimetastatic activities by inhibiting ERK1/2 pathway via suppression of Raf protein. Inhibition of this pathway resulted in the suppression of MMP2, MMP7, and MMP9 expression to stop A549 metastasis. Phyllanthus also inhibits hypoxia pathway via inhibition of HIF-1α that led to reduced VEGF and iNOS expressions. Proteomic analysis revealed a number of proteins downregulated by Phyllanthus that were involved in metastatic processes, including invasion and mobility proteins (cytoskeletal proteins), transcriptional proteins (proliferating cell nuclear antigen; zinc finger protein), antiapoptotic protein (Bcl2) and various glycolytic enzymes. Among the four Phyllanthus species tested, P. urinaria showed the greatest antimetastatic activity.

    CONCLUSIONS: Phyllanthus inhibits A549 metastasis by suppressing ERK1/2 and hypoxia pathways that led to suppression of various critical proteins for A549 invasion and migration.

    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  9. Fulltext Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53
    Abd-Aziz N, Stanbridge EJ, Shafee N
    J Gen Virol, 2016 Dec;97(12):3174-3182.
    PMID: 27902314 DOI: 10.1099/jgv.0.000623
    Newcastle disease virus (NDV) is a candidate agent for oncolytic virotherapy. Despite its potential, the exact mechanism of its oncolysis is still not known. Recently, we reported that NDV exhibited an increased oncolytic activity in hypoxic cancer cells. These types of cells negatively affect therapeutic outcome by overexpressing pro-survival genes under the control of the hypoxia-inducible factor (HIF). HIF-1 is a heterodimeric transcriptional factor consisting of a regulated α (HIF-1α) and a constitutive β subunit (HIF-1β). To investigate the effects of NDV infection on HIF-1α in cancer cells, the osteosarcoma (Saos-2), breast carcinoma (MCF-7), colon carcinoma (HCT116) and fibrosarcoma (HT1080) cell lines were used in the present study. Data obtained showed that a velogenic NDV infection diminished hypoxia-induced HIF-1α accumulation, leading to a decreased activation of its downstream target gene, carbonic anhydrase 9. This NDV-induced downregulation of HIF-1α occurred post-translationally and was partially abrogated by proteasomal inhibition. The process appeared to be independent of the tumour suppressor protein p53. These data revealed a correlation between NDV infection and HIF-1α downregulation, which highlights NDV as a promising agent to eliminate hypoxic cancer cells.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  10. Fulltext High throughput silencing identifies novel genes in endometrioid endometrial cancer
    Md Fuzi AA, Omar SZ, Mohamed Z, Mat Adenan NA, Mokhtar NM
    Taiwan J Obstet Gynecol, 2018 Apr;57(2):217-226.
    PMID: 29673664 DOI: 10.1016/j.tjog.2018.02.009
    OBJECTIVE: To validate the gene expression profile obtained from the previous microarray analysis and to further study the biological functions of these genes in endometrial cancer. From our previous study, we identified 621 differentially expressed genes in laser-captured microdissected endometrioid endometrial cancer as compared to normal endometrial cells. Among these genes, 146 were significantly up-regulated in endometrial cancer.

    MATERIALS AND METHODS: A total of 20 genes were selected from the list of up-regulated genes for the validation assay. The qPCR confirmed that 19 out of the 20 genes were up-regulated in endometrial cancer compared with normal endometrium. RNA interference (RNAi) was used to knockdown the expression of the upregulated genes in ECC-1 and HEC-1A endometrial cancer cell lines and its effect on proliferation, migration and invasion were examined.

    RESULTS: Knockdown of MIF, SOD2, HIF1A and SLC7A5 by RNAi significantly decreased the proliferation of ECC-1 cells (p < 0.05). Our results also showed that the knockdown of MIF, SOD2 and SLC7A5 by RNAi significantly decreased the proliferation and migration abilities of HEC-1A cells (p < 0.05). Moreover, the knockdown of SLC38A1 and HIF1A by RNAi resulted in a significant decrease in the proliferation of HEC1A cells (p < 0.05).

    CONCLUSION: We have identified the biological roles of SLC38A1, MIF, SOD2, HIF1A and SLC7A5 in endometrial cancer, which opens up the possibility of using the RNAi silencing approach to design therapeutic strategies for treatment of endometrial cancer.

    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/physiology
  11. Mesua ferrea stem bark extract induces apoptosis and inhibits metastasis in human colorectal carcinoma HCT 116 cells, through modulation of multiple cell signalling pathways
    Asif M, Shafaei A, Abdul Majid AS, Ezzat MO, Dahham SS, Ahamed MBK, et al.
    Chin J Nat Med, 2017 Jul;15(7):505-514.
    PMID: 28807224 DOI: 10.1016/S1875-5364(17)30076-6
    Considering the great potential of natural products as anticancer agents, the present study was designed to explore the molecular mechanisms responsible for anticancer activities of Mesua ferrea stem bark extract against human colorectal carcinoma. Based on MTT assay results, bioactive sub-fraction (SF-3) was selected for further studies using HCT 116 cells. Repeated column chromatography resulted in isolation of less active α-amyrin from SF-3, which was identified and characterized by GC-MS and HPLC methods. α-amyrin and betulinic acid contents of SF-3 were measured by HPLC methods. Fluorescent assays revealed characteristic apoptotic features, including cell shrinkage, nuclear condensation, and marked decrease in mitochondrial membrane potential in SF-3 treated cells. In addition, increased levels of caspases-9 and -3/7 levels were also observed in SF-3 treated cells. SF-3 showed promising antimetastatic properties in multiple in vitro assays. Multi-pathway analysis revealed significant down-regulation of WNT, HIF-1α, and EGFR with simultaneous up-regulation of p53, Myc/Max, and TGF-β signalling pathways in SF-3 treated cells. In addition, promising growth inhibitory effects were observed in SF-3 treated HCT 116 tumour spheroids, which give a hint about in vivo antitumor efficacy of SF-3 phytoconstituents. In conclusion, these results demonstrated that anticancer effects of SF-3 towards colon cancer are through modulation of multiple molecular pathways.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  12. Effect of 17β-estradiol on mediators involved in mesenchymal stromal cell trafficking in cell therapy of diabetes
    Mirzamohammadi S, Aali E, Najafi R, Kamarul T, Mehrabani M, Aminzadeh A, et al.
    Cytotherapy, 2015 Jan;17(1):46-57.
    PMID: 25457279 DOI: 10.1016/j.jcyt.2014.06.009
    Mesenchymal stromal cells (MSCs) have shown great promise for cell therapy of a wide range of diseases such as diabetes. However, insufficient viability of transplanted cells reaching to damaged tissues has limited their potential therapeutic effects. Expression of estrogen receptors on stem cells may suggest a role for 17β-estradiol (E2) in regulating some functions in these cells. There is evidence that E2 enhances homing of stem cells. Induction of hypoxia-inducible factor-1α (HIF-1α) by E2 and the profound effect of HIF-1α on migration of cells have previously been demonstrated. We investigated the effect of E2 on major mediators involved in trafficking and subsequent homing of MSCs both in vitro and in vivo in diabetic rats.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/drug effects
  13. Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes
    Hafez P, Chowdhury SR, Jose S, Law JX, Ruszymah BHI, Mohd Ramzisham AR, et al.
    Cardiovasc Eng Technol, 2018 09;9(3):529-538.
    PMID: 29948837 DOI: 10.1007/s13239-018-0368-8
    Developing experimental models to study ischemic heart disease is necessary for understanding of biological mechanisms to improve the therapeutic approaches for restoring cardiomyocytes function following injury. The aim of this study was to develop an in vitro hypoxic/re-oxygenation model of ischemia using primary human cardiomyocytes (HCM) and define subsequent cytotoxic effects. HCM were cultured in serum and glucose free medium in hypoxic condition with 1% O2 ranging from 30 min to 12 h. The optimal hypoxic exposure time was determined using Hypoxia Inducible Factor 1α (HIF-1α) as the hypoxic marker. Subsequently, the cells were moved to normoxic condition for 3, 6 and 9 h to replicate the re-oxygenation phase. Optimal period of hypoxic/re-oxygenation was determined based on 50% mitochondrial injury via 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and cytotoxicity via lactate dehydrogenase (LDH) assay. It was found that the number of cells expressing HIF-1α increased with hypoxic time and 3 h was sufficient to stimulate the expression of this marker in all the cells. Upon re-oxygenation, mitochondrial activity reduced significantly whereas the cytotoxicity increased significantly with time. Six hours of re-oxygenation was optimal to induce reversible cell injury. The injury became irreversible after 9 h as indicated by > 60% LDH leakage compared to the control group cultured in normal condition. Under optimized hypoxic reoxygenation experimental conditions, mesenchymal stem cells formed nanotube with ischemic HCM and facilitated transfer of mitochondria suggesting the feasibility of using this as a model system to study molecular mechanisms of myocardial injury and rescue.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  14. Fulltext Electrospun deferoxamine nanofiber for diabetic wound healing
    Tracey Anastacia Jeckson, Sreenivas Patro Sisinthy, Neo Yun Ping
    Malaysian Journal of Medicine and Health Sciences, 2019;15(102):46-46.
    MyJurnal
    Introduction: Diabetic foot ulcer (DFU) is the most distressing complication of diabetes mellitus and often associated with risk of non-traumatic lower extremity amputations. Available formulations and wound dressings for DFU treatment are unfortunately less effective both on controlling and healing DFU. Issues commonly found are associated with providing an optimum environment which facilitates healing process; moist environment, effective oxygen exchange, preventing infection, controlling exudate and also patients compliance. The challenge is therefore to develop a novel drug delivery which address this unmet medical need for better wound treatment of chronic and slow healing DFU. This study aimed to develop a biomaterial based nanofibrous wound dressing formulation containing deferoxamine (DFO), which reported as a potential therapeutic approach to improve wound healing. Deferoxamine regulates the expression and increase stability of hypoxia-inducible factor-1α (HIF-1 α), growthfactor that crucial in wound repair, and thus increase neovascularization. Preparation and characterization of chosen polymers; chitosan/ alginate/polyvinyl alcohol (PVA) for nanofiber formulation will be carried out. Such biodegradable polymer nanofiber is a great benefit for drug delivery owing to its high surface area to volume ratio and high porosity which creates ideal environment to aid in wound healing. Methods: Nanofibers loaded DFO will be fabricated by electrospinning
    method that utilizes electrostatic force to produce fine fibers from the polymeric solution. Results: Various polymers concentrations and ratios are investigated to obtain the desired fibers characteristics. The selected optimized DFO nanofibers will be studied for its efficacy in wound healing through in-vivo animal studies. Conclusion: The proposed formulation would be an ideal low cost novel wound dressing with improved healing potential for efficient treatment
    of diabetic foot ulcer.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit
  15. Bortezomib attenuates HIF-1- but not HIF-2-mediated transcriptional activation
    Abd-Aziz N, Stanbridge EJ, Shafee N
    Oncol Lett, 2015 Oct;10(4):2192-2196.
    PMID: 26622817
    Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism for its action is that it prevents the proteasomal degradation of proapoptotic proteins, leading to enhanced apoptosis. Although the α subunit of hypoxia-inducible factor (HIF)-1 is not degraded with bortezomib treatment, the heterodimeric HIF-1 fails to transactivate target genes. HIF-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for the survival of hypoxic tumor cells. The majority of reports have focused on the effects of bortezomib on the transcriptional activities of HIF-1, but not HIF-2. The present study investigated the effects of bortezomib on HIF-2 activity in cancer cells with different levels of HIF-1α and HIF-2α subunits. HIF-α subunit levels were detected using specific antibodies, while HIF transcriptional activities were evaluated using immunodetection, reverse transcription-polymerase chain reaction and luciferase reporter assay. Bortezomib treatment was found to suppress the transcription and expression of CA9, a HIF-1-specific target gene; however, it had minimal effects on EPO and GLUT-1, which are target genes of both HIF-1 and HIF-2. These data suggest that bortezomib attenuates the transcriptional activity only of HIF-1, and not HIF-2. This novel finding on the lack of an inhibitory effect of bortezomib on HIF-2 transcriptional activity has implications for the improvement of design and treatment modalities of bortezomib and other PI drugs.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit
  16. Fulltext PI3K/Akt activity has variable cell-specific effects on expression of HIF target genes, CA9 and VEGF, in human cancer cell lines
    Shafee N, Kaluz S, Ru N, Stanbridge EJ
    Cancer Lett, 2009 Sep 8;282(1):109-15.
    PMID: 19342157 DOI: 10.1016/j.canlet.2009.03.004
    The phosphatidylinositol 3-kinase/Akt (PI3K) pathway regulates hypoxia-inducible factor (HIF) activity. Higher expression of HIF-1alpha and carbonic anhydrase IX (CAIX), a hypoxia-inducible gene, in HT10806TG fibrosarcoma cells (mutant N-ras allele), compared to derivative MCH603 cells (deleted mutant N-ras allele), correlated with increased PI3K activity. Constitutive activation of the PI3K pathway in MCH603/PI3K(act) cells increased HIF-1alpha but, surprisingly, decreased CAIX levels. The cell-type specific inhibitory effect on CAIX was confirmed at the transcriptional level whereas epigenetic modifications of CA9 were ruled out. In summary, our data do not substantiate the generalization that PI3K upregulation leads to increased HIF activity.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics*
  17. Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein
    Mohamed AS, Hanafi NI, Sheikh Abdul Kadir SH, Md Noor J, Abdul Hamid Hasani N, Ab Rahim S, et al.
    Cell Biochem Funct, 2017 Oct;35(7):453-463.
    PMID: 29027248 DOI: 10.1002/cbf.3303
    In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca2+ ]i ), and sphingosine-1-phosphate (S1P)-receptor via Gαi -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca2+ ]i , and S1P-Gαi -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl2 ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gαi inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl2 on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl2 -induced [Ca2+ ]i dynamic alteration. Pharmacological inhibition of the Gαi -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl2 detrimental effects, except for cell viability and [Ca2+ ]i . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl2 effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl2 -induced [Ca2+ ]i dynamic changes. We conclude that UDCA cardioprotection against CoCl2 -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gαi -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile acid and is currently used to treat liver diseases. Recently, UDCA is shown to have a cardioprotection effects; however, the mechanism of UDCA cardioprotection is still poorly understood. The current data generated were the first to show that UDCA is able to inhibit the activation of HIF-1α and p53 protein during CoCl2 -induced hypoxia in cardiomyocytes. This study provides an insight of UDCA mechanism in protecting cardiomyocytes against hypoxia.
    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  18. Fulltext Deferoxamine preconditioning to restore impaired HIF-1α-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats
    Mehrabani M, Najafi M, Kamarul T, Mansouri K, Iranpour M, Nematollahi MH, et al.
    Cell Prolif, 2015 Oct;48(5):532-49.
    PMID: 26332145 DOI: 10.1111/cpr.12209
    OBJECTIVES: Both excessive and insufficient angiogenesis are associated with progression of diabetic complications, of which poor angiogenesis is an important feature. Currently, adipose-derived stem cells (ADSCs) are considered to be a promising source to aid therapeutic neovascularization. However, functionality of these cells is impaired by diabetes which can result from a defect in hypoxia-inducible factor-1 (HIF-1), a key mediator involved in neovascularization. In the current study, we sought to explore effectiveness of pharmacological priming with deferoxamine (DFO) as a hypoxia mimetic agent, to restore the compromised angiogenic pathway, with the aid of ADSCs derived from streptozotocin (STZ)-induced type 1 diabetic rats ('diabetic ADSCs').

    MATERIALS AND METHODS: Diabetic ADSCs were treated with DFO and compared to normal and non-treated diabetic ADSCs for expression of HIF-1α, VEGF, FGF-2 and SDF-1, at mRNA and protein levels, using qRT-PCR, western blotting and ELISA assay. Activity of matrix metalloproteinases -2 and -9 were measured using a gelatin zymography assay. Angiogenic potential of conditioned media derived from normal, DFO-treated and non-treated diabetic ADSCs were determined by in vitro (in HUVECs) and in vivo experiments including scratch assay, three-dimensional tube formation testing and surgical wound healing models.

    RESULTS: DFO remarkably enhanced expression of noted genes by mRNA and protein levels and restored activity of matrix metalloproteinases -2 and -9. Compromised angiogenic potential of conditioned medium derived from diabetic ADSCs was restored by DFO both in vitro and in vivo experiments.

    CONCLUSION: DFO preconditioning restored neovascularization potential of ADSCs derived from diabetic rats by affecting the HIF-1α pathway.

    Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
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