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Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
Most solid cancerous tumors outrun their blood supply with the result that the center of the lesion is hypoxic and drives cancer progression (Schito and Semenza 2016). It is therefore not surprising that HIF-1α is upregulated in these tumors. In addition, there may be loss of function of the von Hippel-Lindau (VHL) protein, which results in increased expression of both HIF-1α and HIF-2α. There is consequently considerable interest in the use of chemotherapeutic agents against cancer that function as HIF-1 inhibitors, which is a very active area of research.
Juvenile Polyposis Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Rafael Parra-Medina, Elizabeth E. Montgomery, Paula Quintero-Ronderos, Edgar Garavito
The fact that some tumor samples do not show expression of certain proteins, even though there is evidence of gene structural alteration, suggests epigenetic factors acting as a second hit. They may contribute to the inactivation of genes controlling cell cycle or promoting the activity of tumor progression genes [16]. The relationship of hypoxia with modification of cell behavior is also well described. When a tumor cell divides, the oxygen supply diminishes, thus activating the cell response to hypoxia which depends on the stability of hypoxia-inducible factor 1-alpha (HIF1a). HIF1a is a transcription factor that trans-activates the genes related to erythrocyte production, angiogenesis, and reprogramming of cell metabolism by the increase in aerobic glycolysis [19]. HIF1a also induces expression of genes associated with EMT such as Twist, Snail, Slug, and ZEB1/2, which act during tumor progression, invasion, and metastasis. Therefore, hypoxia modulates the cell behavior, increasing the survival and tumor progression [19]. Finally, the EMT is also related to epigenetic factors that alter the cadherin E expression due to its promoter methylation and the expression of Snail and Slug due to the DNA methylation in their first intronic region. Moreover, miRNAs such as miRNA-200, which is associated with epithelial differentiation, are inhibited by ZEB1 (an EMT activator). Contrarily, p53 increases the expression of miRNA-200. Therefore, a loss of function of this gene is associated with a greater EMT [22]. Any of these factors could be at play in the progression of juvenile polyps to carcinoma.
Ascorbate and the Hypoxic Response in Cancer
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Christina Wohlrab, Caroline Kuiper, Gabi U. Dachs
HIF-1 has been implicated in the progression from benign to preneoplastic to malignant lesions. For example, HIF-1α and specific target genes were increasingly expressed in human endometrial tissue, from normal to premalignant to adenocarcinoma [36] and were also increasingly expressed with each clinical stage of endometrial adenocarcinoma [37]. Similarly, HIF-1α protein was increasingly expressed in human gastric tissue, from gastritis to metaplasia to dysplasia to adenocarcinoma [38].
Network pharmacology and in vitro experimental verification to explore the mechanism of Sanhua decoction in the treatment of ischaemic stroke
Published in Pharmaceutical Biology, 2022
Wei Zhang, Li Zhang, Wen jun Wang, Shanbo Ma, Mingming Wang, Minna Yao, Ruili Li, Wei wei Li, Xian Zhao, Dongmei Hu, Yi Ding, Jingwen Wang
In this study, our experiments verified that SHD increased the phosphorylation of PI3K, Akt and CREB1. Network pharmacological analysis indicated that the TNF signalling pathway is likely the second most important pathway for SHD protection against ischaemic brain injury. The study by Boehme et al. (2016) demonstrated that proinflammatory cytokines (such as IL-6 and TNF-α) were biomarkers of the recurrence of vascular events. The release of IL-6 after ischaemic stroke induces brain injury and hippocampal neuron necrosis by activating the NMDA receptor and upregulating JNK (Armstead et al. 2019). Moreover, the results showed that treatment with SHD extract reduced the expression level of TNF-α and IL-6, indicating that SHD attenuated ischaemic brain injury by inhibiting the expression of TNF-α and IL-6. The HIF-1 pathway is another crucial pathway for SHD in ischaemic stroke. HIF-1 is a transcription factor that plays a key role in the transcriptional adaptation of cells to hypoxia (Davis et al. 2018). Numerous studies have shown that activation of HIF-1 may be a potential therapeutic strategy for achieving significant neuroprotection after ischaemic stroke (Karuppagounder and Ratan 2012). Protection against ischaemic brain injury via SHD-mediated regulation of the HIF-1 signalling pathway should be confirmed in further studies.
Nickel nanoparticles induce epithelial-mesenchymal transition in human bronchial epithelial cells via the HIF-1α/HDAC3 pathway
Published in Nanotoxicology, 2022
Jiali Yuan, Yiqun Mo, Yuanbao Zhang, Yue Zhang, Qunwei Zhang
HIF-1α, a subunit of hypoxia-inducible factor 1 (HIF-1), can be rapidly degraded by proteasomes via prolyl hydroxylases (PHDs)-mediated hydroxylation and von Hippel-Lindau (VHL)-mediated ubiquitination in normoxic conditions (Gonzalez, Xie, and Jiang 2018). However, this canonical regulation of HIF-1α is impaired in hypoxic conditions, leading to its nuclear translocation and to form a functional dimer, HIF-1, with HIF-1β (Ohh et al. 2000). HIF-1 is broadly involved in multiple cellular events and diseases by binding to the hypoxia response elements (HRE) on target genes, including hypoxia adaptation of tumor cells and tissue fibrosis (Harms, Li, and Cunningham 2010; Thirlwell et al. 2011). Therapies developed against HIF-1α also displayed favorable clinical promise in restraining immune evasion and drug resistance in tumor cells, as well as radiation or bleomycin-induced pulmonary fibrosis (Chen et al. 2021; Wu et al. 2022). HIF-1α could directly or indirectly affect the EMT process by transcriptionally regulating the expression of EMT-related transcription factors or genes, crosstalk with the EMT driver TGF-β1, or epigenetically modulating histone acetylation (Erin et al. 2020). Our previous studies have shown that exposure to Nano-Ni caused HIF-1α nuclear accumulation in human monocytes (U937), epidermal keratinocytes (HaCaT), and bronchial epithelial cells (BEAS-2B) (Mo et al. 2021; Wan et al. 2011; Yuan et al. 2021). This raises the intriguing possibility that Nano-Ni may cause EMT through Nano-Ni-induced HIF-1α nuclear accumulation.
Liver transcriptome analysis reveals biological pathways and transcription factors in response to high ammonia exposure
Published in Inhalation Toxicology, 2022
Daojie Li, Shuangzhao Chen, Chun Liu, Baoxing Wei, Xiaoping Li
Tissue hypoxia induced by high environmental ammonia has been reported in fish, and high levels of ammonia increased affinity of hemoglobin to combine with ammonia molecules and induced oxygen-free condition (Kim et al. 2017). By constructing the protein–protein and TF–target interaction networks of DEGs, we identified some core genes. Among them, HIF-1α encoded by HIF1A gene is a major hypoxia-induced transcription factor that regulate tissue response to low oxygen condition (Caprara et al. 2011). UBXN7 is a cofactor protein that is involved in the regulation of the HIF-1α levels, and high level of UBXN7 leads to HIF-1α accumulation under a condition of hypoxia (Di Gregorio et al. 2021). Our results showed that the UBXN7 and HIF1A gene were significantly up-regulated after ammonia exposure, in addition, we found 9 target genes of HIF-1α significantly changed their expression, for example, PIK3CA, TLR2, PTGS2, RORA, HBEGF were up-regulated and the expression of ACE, ASS1 and MMP2 were down-regulated, suggesting that ammonia may cause a hypoxic state in the pig liver. In hypoxic conditions, energy metabolism is often disturbed (Bruder et al. 2004; Feron 2009). In our results, genes associated with linoleic acid metabolism and glycolysis showed decreased expression in the ammonia group, indicating that ammonia may induce hepatic hypoxia and disturb energy metabolism.