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Role of Ascorbate and Dehydroascorbic Acid in Metabolic Integration of the Cell
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Gábor Bánhegyi, András Szarka, József Mandl
Other prolyl hydroxylases: hypoxia-inducible factor (HIF) prolyl hydroxylases (three isoforms) are localized in the cytosol. They hydroxylate HIF1α, a key transcriptional factor in the regulation of hypoxic response together with FIH (factor inhibiting HIF1), an aspartate hydroxylase. The outcome of the hydroxylation is the proteasomal degradation of HIF1α and thus the cutoff of the transcription of HIF1α-regulated genes [39].
Endothelium
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
What regulates VEGF secretion in such a way as to produce a capillary within 20-50 pm of most cells, and the highest capillary density in the most active tissues? The answer is that a shortage of O2 stimulates cells to produce hypoxia-inducible factor (HIF1), a gene-regulating protein (transcription factor). During normoxia, the a subunit of HIF1 is hydroxylated by HIF prolyl-hydroxylases and targeted for degradation by von Hippel-Lindau tumor suppressor (pVHL) protein. During hypoxia, the HIF1a and β subunits are stabilized. HIF binds to HIF responsive elements (HREs) in a gene promoter to stimulate the transcription of the VEGFA. gene, which in turn leads to angiogenesis. When sufficient new vessels have formed, the O2 supply becomes adequate, so HIF levels fall and VEGF production is switched off. If VEGF production fails to switch off, the result is a haemangioblastoma, a tumour composed largely of a dense mass of blood vessels.
Vitamin C and Somatic Cell Reprogramming
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Hypoxia-inducible factors (HIFs) are oxygen-sensing transcription factors whose stability can be regulated by prolyl hydroxylases, a subfamily of α-KGDDs [56]. HIFs are made up of α and β subunits that dimerize and translocate to the nucleus in response to hypoxia to regulate the expression of genes involved in oxygen homeostasis, glucose metabolism, angiogenesis, erythropoiesis, and iron metabolism [57,58]. Hypoxia is a key feature of the stem cell niche, known to increase the self-renewal capacity of ESCs, adult stem cells, and enhance the generation of iPSCs [57,59]. During reprogramming, the inhibition of glycolysis reduces reprogramming efficiency, whereas stimulation of glycolytic activity enhances iPSC generation [60,61], and the HIF proteins are required to initiate the metabolic switch from oxidative to glycolytic metabolism [62,63]. In conditions of hypoxia, the HIFα subunits (HIF1α and HIF2α) are stabilized and help drive the metabolic switch to glycolysis, an essential step for the initial stages of somatic cell reprogramming; however, prolonged stabilization of HIF-2α in the final stages of reprogramming will cause a significant block in the acquisition of a fully pluripotent ESC-like state [63]. Vitamin C treatment mimics conditions of normoxia, enhancing the activity of HIF prolyl hydroxylases, which hydroxylate the HIF proteins [56] and lead to the binding of an E3 ubiquitin ligase, polyubiquitination, and proteasomal degradation [56]. Vitamin C also enhances the activity of the asparaginyl hydroxylase factor inhibiting HIF-1 (FIH-1), an important suppressor of the transcriptional activity of HIF [64] that correlates with reports of vitamin C reducing the mRNA expression levels of HIF genes in leukemia cell lines [65]. Vitamin C may also have stage-specific roles in fine-tuning the process of reprogramming. When pre-iPSCs, which are trapped at an intermediate state of reprogramming, are treated with vitamin C, conversion to fully reprogrammed iPSCs is induced [6]. Given that HIF-2α suppresses reprogramming during the latter stages of iPSC generation, prolyl hydroxylase-mediated degradation of HIF-2α may be the mechanism by which vitamin C increases the efficiency of reprogramming at this crucial final step.
Hypoxia-inducible factor stabilisation-related lncRNAs in retinopathy of prematurity
Published in Journal of Obstetrics and Gynaecology, 2023
Mengkai Du, Zhenghui Cui, Deqin Chen, Yanmin Chen, Zhu Cao, Danqing Chen
In summary, our data matched the mRNA analysis results from Hoppe et al. (2016), which showed that DMOG stabilisation action involved pathways for retinovascular protection against OIR, while RXD played a crucial role both in the retina and the liver. This result demonstrated that the use of low-dose, intermittent HIF prolyl-hydroxylase inhibitor can be used to treat oxygen toxicity. Through co-expression analysis, we found that some DElncRNAs regulated key genes in the HIF-1 pathway, including Vegfa, Pgk1, Eno1 and Vhl, are involved in retinal activity and retinal diseases. In conclusion, DElncRNAs are regulatory factors involved in the related pathways in the process of reducing oxygen toxicity. For instance, Gm12758 and Gm15283 regulate the HIF-pathway in the retina and the liver, regulating the expression of Vegfa, Pgk1, Pfkl, Eno1, Eno1b and Aldoa, and these two DElncRNAs are crucial for the complete mechanism of combating oxygen toxicity in RXD treatment.
Influence of acute and chronic kidney failure in rats on the disposition and pharmacokinetics of ZYAN1, a novel prolyl hydroxylase inhibitor, for the treatment of chronic kidney disease-induced anemia
Published in Xenobiotica, 2018
Harilal Patel, Amit Arvind Joharapurkar, Vrajesh Bhaskarbhai Pandya, Vishal Jagjivanbhai Patel, Samadhan Govind Kshirsagar, Prakash Patel, Bhavesh Gevriya, Mukul R. Jain, Nuggehally R. Srinivas, Pankaj Ramanbhai Patel, Ranjit C. Desai
While recombinant human EPO (rhEPO) are employed for treating anemia observed with renal failure (Cody & Hodson, 2016), the treatment with rhEPO poses a risk of cardiovascular morbidities (Koulouridis et al., 2013). Therefore, it is highly desirable to develop alternative therapies to rhEPO that manifest equivalent efficacy in the treatment of anemia while avoiding excessive plasma EPO levels and associated cardiovascular risks. With this background, HIF-prolyl hydroxylase (HIF-PH) inhibitors provide a novel therapeutic approach to the treatment of anemia that is based on mimicking the hypoxia-driven expression of endogenous EPO in the kidney. HIF-PH inhibitors are currently being evaluated in clinical studies for the treatment of anemia (Buch et al., 2015). We have discovered a novel HIF-PH inhibitor, ZYAN1, which is under clinical development. ZYAN1 consistently induced EPO and erythropoiesis after oral administration in rodent and non-rodent species, and it was effective in rat models of renal and inflammatory anemia (Jain et al., 2016).
Expression and role of HIF-1α and HIF-2α in tissue regeneration: a study of hypoxia in house gecko tail regeneration
Published in Organogenesis, 2019
Titta Novianti, Vetnizah Juniantito, Ahmad Aulia Jusuf, Evy Ayu Arida, Sri Widia A. Jusman, Mohamad Sadikin
HIF-1 and HIF-2is a heterodimer molecule that consists of α and β subunits. The β subunit is an aryl hydrocarbon nuclear translocator and is found in the cell nucleus. HIF-1β activity is not affected by hypoxic conditions, while the α subunits (HIF-1α and HIF-2α) induces adaptation to hypoxic conditions. HIF-1α also plays a role in oxygen homeostasis. In normoxic conditions, HIF-1α undergoes hydroxylation at proline residues was produced by HIF-prolyl hydroxylase. Degradation is induced by ubiquitination, and the α subunit is degraded by proteasomes. However, in hypoxic conditions, the hydroxylation process does not occur; instead, HIF-1α and HIF-2α migrate into the nucleus and bind to HIF-β to form HIF-1 or HIF-2, which in turn bind to the promoters of target genes.16–18