Hypoxia-inducible factor explained

hypoxia-inducible factor 1, alpha subunit
Hgncid:4910
Symbol:HIF1A
Entrezgene:3091
Omim:603348
Refseq:NM_001530
Uniprot:Q16665
Chromosome:14
Arm:q
Band:21
Locussupplementarydata:-q24
aryl hydrocarbon receptor nuclear translocator
Hgncid:700
Symbol:ARNT
Altsymbols:HIF1B, bHLHe2
Entrezgene:405
Omim:126110
Refseq:NM_001668
Uniprot:P27540
Chromosome:1
Arm:q
Band:21
endothelial PAS domain protein 1
Hgncid:3374
Symbol:EPAS1
Altsymbols:HIF2A, MOP2, PASD2, HLF
Entrezgene:2034
Omim:603349
Refseq:NM_001430
Uniprot:Q99814
Chromosome:2
Arm:p
Band:21
Locussupplementarydata:-p16
aryl-hydrocarbon receptor nuclear translocator 2
Hgncid:16876
Symbol:ARNT2
Altsymbols:HIF2B, KIAA0307, bHLHe1
Entrezgene:9915
Omim:606036
Refseq:NM_014862
Uniprot:Q9HBZ2
Chromosome:1
Arm:q
Band:24
hypoxia-inducible factor 3, alpha subunit
Hgncid:15825
Symbol:HIF3A
Entrezgene:64344
Omim:609976
Refseq:NM_152794
Uniprot:Q9Y2N7
Chromosome:19
Arm:q
Band:13

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia.[1] [2] They also respond to instances of pseudohypoxia, such as thiamine deficiency.[3] [4] Both hypoxia and pseudohypoxia leads to impairment of adenosine triphosphate (ATP) production by the mitochondria.

Discovery

The HIF transcriptional complex was discovered in 1995 by Gregg L. Semenza and postdoctoral fellow Guang Wang.[5] [6] [7] In 2016, William Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza were presented the Lasker Award for their work in elucidating the role of HIF-1 in oxygen sensing and its role in surviving low oxygen conditions.[8] In 2019, the same three individuals were jointly awarded the Nobel Prize in Physiology or Medicine for their work in elucidating how HIF senses and adapts cellular response to oxygen availability.[9]

Structure

Oxygen-breathing species express the highly conserved transcriptional complex HIF-1, which is a heterodimer composed of an alpha and a beta subunit, the latter being a constitutively-expressed aryl hydrocarbon receptor nuclear translocator (ARNT).[6] [10] HIF-1 belongs to the PER-ARNT-SIM (PAS) subfamily of the basic helix-loop-helix (bHLH) family of transcription factors. The alpha and beta subunit are similar in structure and both contain the following domains:[11] [12] [13]

Symbol:HIF-1
Hypoxia-inducible factor-1
Pfam:PF11413
Symbol:HIF-1a_CTAD
HIF-1 alpha C terminal transactivation domain
Pfam:PF08778
Interpro:IPR014887
Scop:1l3e
Pdb:,,,

Members

The following are members of the human HIF family:

MemberGeneProtein
HIF-1αhypoxia-inducible factor 1, alpha subunit
HIF-1βaryl hydrocarbon receptor nuclear translocator
HIF-2αEPAS1endothelial PAS domain protein 1
HIF-2βaryl-hydrocarbon receptor nuclear translocator 2
HIF-3αhypoxia inducible factor 3, alpha subunit
HIF-3βaryl-hydrocarbon receptor nuclear translocator 3

Function

HIF1α expression in haematopoietic stem cells explains the quiescence nature of stem cells[14] for being metabolically maintaining at a low rate so as to preserve the potency of stem cells for long periods in a life cycle of an organism.

The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos and tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium.[15] It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing.[16]

In general, HIFs are vital to development. In mammals, deletion of the HIF-1 genes results in perinatal death.[17] HIF-1 has been shown to be vital to chondrocyte survival, allowing the cells to adapt to low-oxygen conditions within the growth plates of bones. HIF plays a central role in the regulation of human metabolism.[18]

Mechanism

The alpha subunits of HIF are hydroxylated at conserved proline residues by HIF prolyl-hydroxylases, allowing their recognition and ubiquitination by the VHL E3 ubiquitin ligase, which labels them for rapid degradation by the proteasome.[19] [20] This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate.[21] [22]

Inhibition of electron transfer in the succinate dehydrogenase complex due to mutations in the SDHB or SDHD genes can cause a build-up of succinate that inhibits HIF prolyl-hydroxylase, stabilizing HIF-1α. This is termed pseudohypoxia.

HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low-oxygen conditions. These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIF-1 acts by binding to hypoxia-responsive elements (HREs) in promoters that contain the sequence 5'-RCGTG-3' (where R is a purine, either A or G). Studies demonstrate that hypoxia modulates histone methylation and reprograms chromatin.[23] This paper was published back-to-back with that of 2019 Nobel Prize in Physiology or Medicine winner for Medicine William Kaelin Jr.[24] This work was highlighted in an independent editorial.[25]

It has been shown that muscle A kinase–anchoring protein (mAKAP) organized E3 ubiquitin ligases, affecting stability and positioning of HIF-1 inside its action site in the nucleus. Depletion of mAKAP or disruption of its targeting to the perinuclear (in cardiomyocytes) region altered the stability of HIF-1 and transcriptional activation of genes associated with hypoxia. Thus, "compartmentalization" of oxygen-sensitive signaling components may influence the hypoxic response.[26]

The advanced knowledge of the molecular regulatory mechanisms of HIF1 activity under hypoxic conditions contrast sharply with the paucity of information on the mechanistic and functional aspects governing NF-κB-mediated HIF1 regulation under normoxic conditions. However, HIF-1α stabilization is also found in non-hypoxic conditions through an unknown mechanism. It was shown that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure. siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. Finally, it was shown that, when endogenous NF-κB is induced by TNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner.[27] HIF-1 and HIF-2 have different physiological roles. HIF-2 regulates erythropoietin production in adult life.[28]

Repair, regeneration and rejuvenation

In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF-1a via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of Hif-1a results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF-1a can either turn off, or turn on the key process of mammalian regeneration.[29] [30] One such regenerative process in which HIF1A is involved is skin healing.[31] Researchers at the Stanford University School of Medicine demonstrated that HIF1A activation was able to prevent and treat chronic wounds in diabetic and aged mice. Not only did the wounds in the mice heal more quickly, but the quality of the new skin was even better than the original.[32] [33] [34] Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described[35] [36] and a rejuvenating effect on aged facial skin was demonstrated in patients.[37] HIF modulation has also been linked to a beneficial effect on hair loss.[38] The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physician Dominik Duscher and pharmacologist Dominik Thor, makes use of this mechanism.[39] Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.[40] [41] [42] [43]

As a therapeutic target

Anemia

Several drugs that act as selective HIF prolyl-hydroxylase inhibitors have been developed.[44] [45] The most notable compounds are: Roxadustat (FG-4592);[46] Vadadustat (AKB-6548),[47] Daprodustat (GSK1278863),[48] Desidustat (ZYAN-1),[49] and Molidustat (Bay 85-3934),[50] all of which are intended as orally acting drugs for the treatment of anemia.[51] Other significant compounds from this family, which are used in research but have not been developed for medical use in humans, include MK-8617,[52] YC-1,[53] IOX-2,[54] 2-methoxyestradiol,[55] GN-44028,[56] AKB-4924,[57] Bay 87-2243,[58] FG-2216[59] and FG-4497.[60] By inhibiting prolyl-hydroxylase enzyme, the stability of HIF-2α in the kidney is increased, which results in an increase in endogenous production of erythropoietin.[61] Both FibroGen compounds made it through to Phase II clinical trials, but these were suspended temporarily in May 2007 following the death of a trial participant taking FG-2216 from fulminant hepatitis (liver failure), however it is unclear whether this death was actually caused by FG-2216. The hold on further testing of FG-4592 was lifted in early 2008, after the FDA reviewed and approved a thorough response from FibroGen.[62] Roxadustat, vadadustat, daprodustat and molidustat have now all progressed through to Phase III clinical trials for treatment of renal anemia.

Inflammation and cancer

In other scenarios and in contrast to the therapy outlined above, research suggests that HIF induction in normoxia is likely to have serious consequences in disease settings with a chronic inflammatory component.[63] [64] [65] It has also been shown that chronic inflammation is self-perpetuating and that it distorts the microenvironment as a result of aberrantly active transcription factors. As a consequence, alterations in growth factor, chemokine, cytokine, and ROS balance occur within the cellular milieu that in turn provide the axis of growth and survival needed for de novo development of cancer and metastasis. These results have numerous implications for a number of pathologies where NF-κB and HIF-1 are deregulated, including rheumatoid arthritis and cancer.[66] [67] [68] [69] [70] [71] Therefore, it is thought that understanding the cross-talk between these two key transcription factors, NF-κB and HIF, will greatly enhance the process of drug development.[72]

HIF activity is involved in angiogenesis required for cancer tumor growth, so HIF inhibitors such as phenethyl isothiocyanate and Acriflavine[73] are (since 2006) under investigation for anti-cancer effects.[74] [75] [76]

Neurology

Research conducted on mice suggests that stabilizing HIF using an HIF prolyl-hydroxylase inhibitor enhances hippocampal memory, likely by increasing erythropoietin expression.[77] HIF pathway activators such as ML-228 may have neuroprotective effects and are of interest as potential treatments for stroke and spinal cord injury.[78] [79]

von Hippel–Lindau disease-associated renal cell carcinoma

Belzutifan is an hypoxia-inducible factor-2α inhibitor[80] under investigation for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma.[81] [82] [83] [84]

External links

Notes and References

  1. Smith TG, Robbins PA, Ratcliffe PJ . The human side of hypoxia-inducible factor . British Journal of Haematology . 141 . 3 . 325–34 . May 2008 . 18410568 . 2408651 . 10.1111/j.1365-2141.2008.07029.x .
  2. Wilkins SE, Abboud MI, Hancock RL, Schofield CJ . Targeting Protein-Protein Interactions in the HIF System . ChemMedChem . 11 . 8 . 773–86 . April 2016 . 26997519 . 4848768 . 10.1002/cmdc.201600012 .
  3. Rl . Sweet . Ja . Zastre . 2013 . HIF1-α-mediated gene expression induced by vitamin B1 deficiency . International Journal for Vitamin and Nutrition Research . en . 83 . 3 . 188–197 . 10.1024/0300-9831/a000159 . 0300-9831 . 24846908.
  4. C . Marrs . D . Lonsdale . 2021-09-29 . Hiding in Plain Sight: Modern Thiamine Deficiency . Cells . en . 10 . 10 . 2595 . 10.3390/cells10102595 . free . 2073-4409 . 34685573. 8533683 .
  5. Wang GL, Semenza GL . Purification and characterization of hypoxia-inducible factor 1 . The Journal of Biological Chemistry . 270 . 3 . 1230–7 . January 1995 . 7836384 . 10.1074/jbc.270.3.1230 . 41659164 . free . doi .
  6. Wang GL, Jiang BH, Rue EA, Semenza GL . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension . Proceedings of the National Academy of Sciences of the United States of America . 92 . 12 . 5510–4 . June 1995 . 7539918 . 41725 . 10.1073/pnas.92.12.5510 . 1995PNAS...92.5510W . free . doi .
  7. Book: Acker T, Plate KH . Hypoxia and Hypoxia Inducible Factors (HIF) as Important Regulators of Tumor Physiology . Cancer Treatment and Research . Angiogenesis in Brain Tumors . 117 . 219–48 . 2004 . 15015563 . 10.1007/978-1-4419-8871-3_14 . 978-1-4613-4699-9 .
  8. Web site: Oxygen sensing – an essential process for survival . Albert Lasker Basic Medical Research Award . Albert And Mary Lasker Foundation . 2016 .
  9. Web site: How cells sense and adapt to oxygen availability . The Nobel Prize in Physiology or Medicine 2019. NobelPrize.org. Nobel Media AB . 7 October 2019 .
  10. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL . Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1 . The Journal of Biological Chemistry . 271 . 30 . 17771–8 . July 1996 . 8663540 . 10.1074/jbc.271.30.17771 . 33729273 . free . doi .
  11. Zhulin IB, Taylor BL, Dixon R . PAS domain S-boxes in Archaea, Bacteria and sensors for oxygen and redox . Trends in Biochemical Sciences . 22 . 9 . 331–3 . September 1997 . 9301332 . 10.1016/S0968-0004(97)01110-9 .
  12. Ponting CP, Aravind L . PAS: a multifunctional domain family comes to light . Current Biology . 7 . 11 . R674-7 . November 1997 . 9382818 . 10.1016/S0960-9822(06)00352-6 . 14105830 . free . doi . 1997CBio....7R.674P .
  13. Yang J, Zhang L, Erbel PJ, Gardner KH, Ding K, Garcia JA, Bruick RK . Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor . The Journal of Biological Chemistry . 280 . 43 . 36047–54 . October 2005 . 16129688 . 10.1074/jbc.M501755200 . free . 46626545 . doi .
  14. Srikanth L, Sunitha MM, Venkatesh K, Kumar PS, Chandrasekhar C, Vengamma B, Sarma PV . Anaerobic Glycolysis and HIF1α Expression in Haematopoietic Stem Cells Explains Its Quiescence Nature . Journal of Stem Cells . 10 . 2 . 97–106 . 2015 . 27125138 .
  15. Benizri E, Ginouvès A, Berra E . The magic of the hypoxia-signaling cascade . Cellular and Molecular Life Sciences . 65 . 7–8 . 1133–49 . April 2008 . 18202826 . 10.1007/s00018-008-7472-0 . 44049779 . 11131810 .
  16. Duscher D, Januszyk M, Maan ZN, Whittam AJ, Hu MS, Walmsley GG, Dong Y, Khong SM, Longaker MT, Gurtner GC . Comparison of the Hydroxylase Inhibitor Dimethyloxalylglycine and the Iron Chelator Deferoxamine in Diabetic and Aged Wound Healing . Plastic and Reconstructive Surgery . 139 . 3 . 695e–706e . March 2017 . 28234841 . 5327844 . 10.1097/PRS.0000000000003072 .
  17. Duscher D, Maan ZN, Whittam AJ, Sorkin M, Hu MS, Walmsley GG, Baker H, Fischer LH, Januszyk M, Wong VW, Gurtner GC . Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing . Plastic and Reconstructive Surgery . 136 . 5 . 1004–13 . November 2015 . 26505703 . 5951620 . 10.1097/PRS.0000000000001699 .
  18. Formenti F, Constantin-Teodosiu D, Emmanuel Y, Cheeseman J, Dorrington KL, Edwards LM, Humphreys SM, Lappin TR, McMullin MF, McNamara CJ, Mills W, Murphy JA, O'Connor DF, Percy MJ, Ratcliffe PJ, Smith TG, Treacy M, Frayn KN, Greenhaff PL, Karpe F, Clarke K, Robbins PA . Regulation of human metabolism by hypoxia-inducible factor . Proceedings of the National Academy of Sciences of the United States of America . 107 . 28 . 12722–7 . July 2010 . 20616028 . 2906567 . 10.1073/pnas.1002339107 . 2010PNAS..10712722F . free . doi .
  19. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ . The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis . Nature . 399 . 6733 . 271–5 . May 1999 . 10353251 . 10.1038/20459 . 4427694 . 1999Natur.399..271M .
  20. News: Perkel J . Seeking a Cellular Oxygen Sensor . 7 October 2019 . The Scientist . May 2001.
  21. Semenza GL . Hydroxylation of HIF-1: oxygen sensing at the molecular level . Physiology . 19 . 4 . 176–82 . August 2004 . 15304631 . 10.1152/physiol.00001.2004 . 2434206 .
  22. News: Russo E . Discovering HIF Regulation . 7 October 2019 . The Scientist . April 2003.
  23. Batie M, Frost J, Frost M, Wilson JW, Schofield P, Rocha S . Hypoxia induces rapid changes to histone methylation and reprograms chromatin . Science . 363 . 6432 . 1222–1226 . March 2019 . 30872526 . 10.1126/science.aau5870 . 78093369 . 2019Sci...363.1222B . free .
  24. Chakraborty AA, Laukka T, Myllykoski M, Ringel AE, Booker MA, Tolstorukov MY, Meng YJ, Meier SR, Jennings RB, Creech AL, Herbert ZT, McBrayer SK, Olenchock BA, Jaffe JD, Haigis MC, Beroukhim R, Signoretti S, Koivunen P, Kaelin WG . Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate . Science . 363 . 6432 . 1217–1222 . March 2019 . 30872525 . 7336390 . 10.1126/science.aaw1026 . 2019Sci...363.1217C .
  25. Gallipoli P, Huntly BJ . Histone modifiers are oxygen sensors . Science . 363 . 6432 . 1148–1149 . March 2019 . 30872506 . 10.1126/science.aaw8373 . 78091150 . 2019Sci...363.1148G .
  26. Wong W, Goehring AS, Kapiloff MS, Langeberg LK, Scott JD . mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha . Science Signaling . 1 . 51 . ra18 . December 2008 . 19109240 . 2828263 . 10.1126/scisignal.2000026 .
  27. van Uden P, Kenneth NS, Rocha S . Regulation of hypoxia-inducible factor-1alpha by NF-kappaB . The Biochemical Journal . 412 . 3 . 477–84 . June 2008 . 18393939 . 2474706 . 10.1042/BJ20080476 .
  28. Haase VH . Hypoxic regulation of erythropoiesis and iron metabolism . American Journal of Physiology. Renal Physiology . 299 . 1 . F1-13 . July 2010 . 20444740 . 2904169 . 10.1152/ajprenal.00174.2010 .
  29. Web site: eurekalert.org staff . Scientist at LIMR leads study demonstrating drug-induced tissue regeneration . eurekalert.org . Lankenau Institute for Medical Research (LIMR) . 3 June 2015 . 3 July 2015 .
  30. Zhang Y, Strehin I, Bedelbaeva K, Gourevitch D, Clark L, Leferovich J, Messersmith PB, Heber-Katz E . Drug-induced regeneration in adult mice . Science Translational Medicine . 7 . 290 . 290ra92 . June 2015 . 26041709 . 4687906 . 10.1126/scitranslmed.3010228 .
  31. Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, Paik KJ, Duscher D, Gurtner GC, Lorenz HP, Longaker MT . The Role of Hypoxia-Inducible Factor in Wound Healing . Advances in Wound Care . 3 . 5 . 390–399 . May 2014 . 24804159 . 4005494 . 10.1089/wound.2013.0520 .
  32. Duscher D, Neofytou E, Wong VW, Maan ZN, Rennert RC, Inayathullah M, Januszyk M, Rodrigues M, Malkovskiy AV, Whitmore AJ, Walmsley GG, Galvez MG, Whittam AJ, Brownlee M, Rajadas J, Gurtner GC . Transdermal deferoxamine prevents pressure-induced diabetic ulcers . Proceedings of the National Academy of Sciences of the United States of America . 112 . 1 . 94–9 . January 2015 . 25535360 . 4291638 . 10.1073/pnas.1413445112 . 2015PNAS..112...94D . free . doi .
  33. Duscher D, Trotsyuk AA, Maan ZN, Kwon SH, Rodrigues M, Engel K, Stern-Buchbinder ZA, Bonham CA, Barrera J, Whittam AJ, Hu MS, Inayathullah M, Rajadas J, Gurtner GC . Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds . Journal of Controlled Release . 308 . 232–239 . August 2019 . 31299261 . 10.1016/j.jconrel.2019.07.009 . 196350143 .
  34. Bonham CA, Rodrigues M, Galvez M, Trotsyuk A, Stern-Buchbinder Z, Inayathullah M, Rajadas J, Gurtner GC . Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice . Wound Repair and Regeneration . 26 . 3 . 300–305 . May 2018 . 30152571 . 6238634 . 10.1111/wrr.12667 .
  35. Web site: duscher hif - Search Results - PubMed. 2020-12-04. PubMed. en.
  36. Pagani A, Kirsch BM, Hopfner U, Aitzetmueller MM, Brett EA, Thor D, Mela P, Machens HG, Duscher D . Deferiprone Stimulates Aged Dermal Fibroblasts Via HIF-1α Modulation . Aesthetic Surgery Journal . June 2020 . 41 . 4 . 514–524 . 32479616 . 10.1093/asj/sjaa142 .
  37. Duscher D, Maan ZN, Hu MS, Thor D . A single-center blinded randomized clinical trial to evaluate the anti-aging effects of a novel HSF-based skin care formulation . Journal of Cosmetic Dermatology . 19 . 11 . 2936–2945 . November 2020 . 32306525 . 10.1111/jocd.13356 . 216031505 . free . doi .
  38. Houschyar KS, Borrelli MR, Tapking C, Popp D, Puladi B, Ooms M, Chelliah MP, Rein S, Pförringer D, Thor D, Reumuth G, Wallner C, Branski LK, Siemers F, Grieb G, Lehnhardt M, Yazdi AS, Maan ZN, Duscher D . Molecular Mechanisms of Hair Growth and Regeneration: Current Understanding and Novel Paradigms . Dermatology . 236 . 4 . 271–280 . 2020 . 32163945 . 10.1159/000506155 . 212693280 . free . doi .
  39. Web site: Tomorrowlabs. Tomorrowlabs. 2020-12-04. Tomorrowlabs. en.
  40. Web site: Kosmetikbranche: Wie das Beauty-Start-up Tomorrowlabs den Markt erobert. 2020-12-04. www.handelsblatt.com. de.
  41. Web site: Das neue Beauty-Investment von Michael Pieper - HZ. 2020-12-04. Handelszeitung. de.
  42. Web site: andrea.hodoschek. 2020-08-03. Milliardenmarkt Anti-Aging: Start-up aus Österreich mischt mit. 2020-12-04. kurier.at. de.
  43. Web site: Ein Protein gegen das Altern und für das Geldverdienen. 2020-12-04. nachrichten.at. de.
  44. Bruegge K, Jelkmann W, Metzen E . Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-alpha hydroxylases . Current Medicinal Chemistry . 14 . 17 . 1853–62 . 2007 . 17627521 . 10.2174/092986707781058850 .
  45. Maxwell PH, Eckardt KU . HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond . Nature Reviews. Nephrology . 12 . 3 . 157–68 . March 2016 . 26656456 . 10.1038/nrneph.2015.193 . 179020 .
  46. Becker K, Saad M . A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat . Advances in Therapy . 34 . 4 . 848–853 . April 2017 . 28290095 . 10.1007/s12325-017-0508-9 . 9818825 . free . doi .
  47. Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH . Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease . Kidney International . 90 . 5 . 1115–1122 . November 2016 . 27650732 . 10.1016/j.kint.2016.07.019 . free . doi .
  48. Ariazi JL, Duffy KJ, Adams DF, Fitch DM, Luo L, Pappalardi M, Biju M, DiFilippo EH, Shaw T, Wiggall K, Erickson-Miller C . Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia . The Journal of Pharmacology and Experimental Therapeutics . 363 . 3 . 336–347 . December 2017 . 28928122 . 10.1124/jpet.117.242503 . 25100284 . free . doi .
  49. Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, Parikh DP, Heading H, Patel HB, Gupta RJ, Shah CY, Patel MR, Dholakia VN, Sukhadiya R, Jain MR, Parmar KV, Barot K . Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers . Clinical Pharmacokinetics . 57 . 1 . 87–102 . January 2018 . 28508936 . 5766731 . 10.1007/s40262-017-0551-3 .
  50. Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U . Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects . PLOS ONE . 9 . 11 . e111838 . 2014 . 25392999 . 4230943 . 10.1371/journal.pone.0111838 . 2014PLoSO...9k1838F . free . doi .
  51. Cases A . The latest advances in kidney diseases and related disorders . Drug News & Perspectives . 20 . 10 . 647–54 . December 2007 . 18301799 .
  52. Debenham JS, Madsen-Duggan C, Clements MJ, Walsh TF, Kuethe JT, Reibarkh M, Salowe SP, Sonatore LM, Hajdu R, Milligan JA, Visco DM, Zhou D, Lingham RB, Stickens D, DeMartino JA, Tong X, Wolff M, Pang J, Miller RR, Sherer EC, Hale JJ . Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia . Journal of Medicinal Chemistry . 59 . 24 . 11039–11049 . December 2016 . 28002958 . 10.1021/acs.jmedchem.6b01242 .
  53. Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW . YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1 . Journal of the National Cancer Institute . 95 . 7 . 516–25 . April 2003 . 12671019 . 10.1093/jnci/95.7.516 . doi .
  54. Deppe J, Popp T, Egea V, Steinritz D, Schmidt A, Thiermann H, Weber C, Ries C . Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor . Archives of Toxicology . 90 . 5 . 1141–50 . May 2016 . 26082309 . 10.1007/s00204-015-1549-y . 2016ArTox..90.1141D . 16938364 .
  55. Wang R, Zhou S, Li S . Cancer therapeutic agents targeting hypoxia-inducible factor-1 . Current Medicinal Chemistry . 18 . 21 . 3168–89 . 2011 . 21671859 . 10.2174/092986711796391606 .
  56. Minegishi H, Fukashiro S, Ban HS, Nakamura H . Discovery of Indenopyrazoles as a New Class of Hypoxia Inducible Factor (HIF)-1 Inhibitors . ACS Medicinal Chemistry Letters . 4 . 2 . 297–301 . February 2013 . 24900662 . 4027554 . 10.1021/ml3004632 .
  57. Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S, von Köckritz-Blickwede M, Thienphrapa W, Corle C, Jeung SN, Kotsakis A, Shalwitz RA, Johnson RS, Nizet V . A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection . Journal of Molecular Medicine . 90 . 9 . 1079–89 . September 2012 . 22371073 . 3606899 . 10.1007/s00109-012-0882-3 .
  58. Görtz GE, Horstmann M, Aniol B, Reyes BD, Fandrey J, Eckstein A, Berchner-Pfannschmidt U . Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Graves' Ophthalmopathy-Implications for Smoking . The Journal of Clinical Endocrinology and Metabolism . 101 . 12 . 4834–4842 . December 2016 . 27610652 . 10.1210/jc.2016-1279 . free . doi .
  59. Beuck S, Schänzer W, Thevis M . Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis . Drug Testing and Analysis . 4 . 11 . 830–45 . November 2012 . 22362605 . 10.1002/dta.390 . free .
  60. Silva PL, Rocco PR, Pelosi P . FG-4497: a new target for acute respiratory distress syndrome? . Expert Review of Respiratory Medicine . 9 . 4 . 405–9 . August 2015 . 26181437 . 10.1586/17476348.2015.1065181 . 5817105 .
  61. Hsieh MM, Linde NS, Wynter A, Metzger M, Wong C, Langsetmo I, Lin A, Smith R, Rodgers GP, Donahue RE, Klaus SJ, Tisdale JF . HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques . Blood . 110 . 6 . 2140–7 . September 2007 . 17557894 . 1976368 . 10.1182/blood-2007-02-073254 .
  62. Web site: The FDA Accepts the Complete Response for Clinical Holds of FG-2216/FG-4592 for the Treatment of Anemia . 2008-10-28 . https://web.archive.org/web/20150923175524/http://www.astellas.com/en/corporate/news/pdf/080402_eg.pdf . 2015-09-23 . dead .
  63. Eltzschig HK, Bratton DL, Colgan SP . Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases . Nature Reviews. Drug Discovery . 13 . 11 . 852–69 . November 2014 . 25359381 . 4259899 . 10.1038/nrd4422 .
  64. Salminen A, Kaarniranta K, Kauppinen A . AMPK and HIF signaling pathways regulate both longevity and cancer growth: the good news and the bad news about survival mechanisms . Biogerontology . 17 . 4 . 655–80 . August 2016 . 27259535 . 10.1007/s10522-016-9655-7 . 4386269 .
  65. Taylor CT, Doherty G, Fallon PG, Cummins EP . Hypoxia-dependent regulation of inflammatory pathways in immune cells . The Journal of Clinical Investigation . 126 . 10 . 3716–3724 . October 2016 . 27454299 . 5096820 . 10.1172/JCI84433 .
  66. Cummins EP, Keogh CE, Crean D, Taylor CT . The role of HIF in immunity and inflammation . Molecular Aspects of Medicine . 47-48 . 24–34 . 2016 . 26768963 . 10.1016/j.mam.2015.12.004 . 10197/9767 . free .
  67. Hua S, Dias TH . Hypoxia-Inducible Factor (HIF) as a Target for Novel Therapies in Rheumatoid Arthritis . Frontiers in Pharmacology . 7 . 184 . 2016 . 27445820 . 4921475 . 10.3389/fphar.2016.00184 . free . doi .
  68. Ezzeddini R, Taghikhani M, Somi MH, Samadi N, Rasaee, MJ . Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma . Life Sciences . 224 . 169–176 . May 2019 . 30914315 . 10.1016/j.lfs.2019.03.056 . 85532042 .
  69. Singh D, Arora R, Kaur P, Singh B, Mannan R, Arora S . Overexpression of hypoxia-inducible factor and metabolic pathways: possible targets of cancer . Cell & Bioscience . 7 . 62 . 2017 . 29158891 . 5683220 . 10.1186/s13578-017-0190-2 . free .
  70. Huang Y, Lin D, Taniguchi CM . Hypoxia inducible factor (HIF) in the tumor microenvironment: friend or foe? . Science China Life Sciences . 60 . 10 . 1114–1124 . October 2017 . 29039125 . 6131113 . 10.1007/s11427-017-9178-y .
  71. Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ . Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance . Journal of Physiology and Biochemistry . 77 . 2 . 249–260 . May 2021 . 33730333 . 10.1007/s13105-021-00791-3 . 232300877 .
  72. D'Ignazio L, Bandarra D, Rocha S . NF-κB and HIF crosstalk in immune responses . The FEBS Journal . 283 . 3 . 413–24 . February 2016 . 26513405 . 4864946 . 10.1111/febs.13578 .
  73. Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL . Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization . Proceedings of the National Academy of Sciences of the United States of America . 106 . 42 . 17910–5 . October 2009 . 19805192 . 2764905 . 10.1073/pnas.0909353106 . 2009PNAS..10617910L . free . doi .
  74. Syed Alwi SS, Cavell BE, Telang U, Morris ME, Parry BM, Packham G . In vivo modulation of 4E binding protein 1 (4E-BP1) phosphorylation by watercress: a pilot study . The British Journal of Nutrition . 104 . 9 . 1288–96 . November 2010 . 20546646 . 3694331 . 10.1017/S0007114510002217 .
  75. Semenza GL . Evaluation of HIF-1 inhibitors as anticancer agents . Drug Discovery Today . 12 . 19–20 . 853–9 . October 2007 . 17933687 . 10.1016/j.drudis.2007.08.006 .
  76. Melillo G . Inhibiting hypoxia-inducible factor 1 for cancer therapy . Molecular Cancer Research . 4 . 9 . 601–5 . September 2006 . 16940159 . 10.1158/1541-7786.MCR-06-0235 . 21525087 . free . doi .
  77. Adamcio B, Sperling S, Hagemeyer N, Walkinshaw G, Ehrenreich H . Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice . Behavioural Brain Research . 208 . 1 . 80–4 . March 2010 . 19900484 . 10.1016/j.bbr.2009.11.010 . 20395457 .
  78. Xing J, Lu J . HIF-1α Activation Attenuates IL-6 and TNF-α Pathways in Hippocampus of Rats Following Transient Global Ischemia . Cellular Physiology and Biochemistry . 39 . 2 . 511–20 . 2016 . 27383646 . 10.1159/000445643 . 30553076 . free . doi .
  79. Chen H, Li J, Liang S, Lin B, Peng Q, Zhao P, Cui J, Rao Y . Effect of hypoxia-inducible factor-1/vascular endothelial growth factor signaling pathway on spinal cord injury in rats . Experimental and Therapeutic Medicine . 13 . 3 . 861–866 . March 2017 . 28450910 . 5403438 . 10.3892/etm.2017.4049 .
  80. Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E . Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis . Nat Med . 27. 5. 802–805. April 2021 . 33888901 . 10.1038/s41591-021-01324-7 . 9128828 . 233371559 .
  81. Web site: Belzutifan . SPS - Specialist Pharmacy Service . 18 March 2021 . 25 April 2021 . 26 April 2021 . https://web.archive.org/web/20210426052135/https://www.sps.nhs.uk/medicines/belzutifan/ . dead .
  82. MHRA awards first 'innovation passport' under new pathway . RAPS . 25 April 2021.
  83. Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482) . Merck . Business Wire . 16 March 2016 . 25 April 2021.
  84. Web site: FDA Grants Priority Review to Belzutifan for von Hippel-Lindau Disease–Associated RCC. 2021-04-26. Cancer Network. 16 March 2021 .

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