scholarly journals Sequence Analysis and Phylogenetic Studies of Hypoxia-Inducible Factor-1α

2017 ◽  
Vol 16 ◽  
pp. 117693511771224
Author(s):  
Jagadeesha Poyya ◽  
Chandrashekhar G Joshi ◽  
D Jagadeesha Kumar ◽  
HG Nagendra
Keyword(s):  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1Α ◽  
Helix Loop Helix ◽  
Phylogenetic Studies ◽  
Sequence Variations ◽  
Potential Risk Factors ◽  
Inhibitory Domain

Hypoxia-inducible factors (HIF) belong to the basic helix loop helix–PER ARNT SIM (bHLH-PAS) family of transcription factors that induce metabolic reprogramming under hypoxic condition. The phylogenetic studies of hypoxia-inducible factor-1α (HIF-1α) sequences across different organisms/species may leave a clue on the evolutionary relationships and its probable correlation to tumorigenesis and adaptation to low oxygen environments. In this study, we have aimed at the evolutionary investigation of the protein HIF-1α across different species to decipher their sequence variations/mutations and look into the probable causes and abnormal behaviour of this molecule under exotic conditions. In total, 16 homologous sequences for HIF-1α were retrieved from the National Center for Biotechnology Information. Sequence identity was performed using the Needle program. Multiple aligned sequences were used to construct the phylogeny using the neighbour-joining method. Most of the changes were observed in oxygen-dependent degradation domain and inhibitory domain. Sixteen sequences were clustered into 5 groups. The phylogenetic analysis clearly highlighted the variations that were observed at the sequence level. Comparisons of the HIF-1α sequence among cancer-prone and cancer-resistant animals enable us to find out the probable clues towards potential risk factors in the development of cancer.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

Acellular haemoglobin attenuates hypoxia-inducible factor-1α (HIF-1α) and its target genes in haemodiluted rats

2008 ◽  
Vol 414 (3) ◽  
pp. 461-469 ◽  
Author(s):  
Dominador J. Manalo ◽  
Paul W. Buehler ◽  
Jin Hyen Baek ◽  
Omer Butt ◽  
Felice D'agnillo ◽  
...  
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Oxygen Affinity ◽  
Blood Substitutes ◽  
Oxygen Deficit ◽  
Adaptation To Hypoxia ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1Α ◽  
Haem Oxygenase ◽  
Oxide Synthase

Hb (haemoglobin)-based blood substitutes represent a class of therapeutics designed to correct oxygen deficit under conditions of anaemia and traumatic blood loss. The influences of these agents on HIF-1α (hypoxia-inducible factor-1α) target genes involved in adaptation to hypoxia have so far not been studied. In the study presented here, rats underwent 80% ET (exchange transfusion) with either HS (hetastarch) or a polymerized Hb OG (Oxyglobin®). HS induced dramatic EPO (erythropoietin) gene transcription, reaching a maximum at 4 h post-ET. In contrast, OG suppressed EPO transcription until approx. 24 h post-ET. Large plasma EPO levels that were observed post-ET with HS were significantly blunted in animals transfused with OG. OG, unlike HS, induced a sharp increase in HO-1 (haem oxygenase-1) transcription at 4 h, which declined rapidly within 24 h, whereas modest increases in iNOS [inducible (nitric oxide synthase)] and constitutive NOS [eNOS (endothelial NOS)] were detected over the control. Our results demonstrate for the first time that severe haemodilution-induced erythropoietic responses in kidneys were attenuated by a low-oxygen-affinity cell-free Hb and suggest that tissue-specific oxygen-sensing pathways can be influenced by allosterically modified Hbs.

scholarly journals Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

2021 ◽  
Vol 22 (11) ◽  
pp. 5703
Author(s):  
Vittoria Infantino ◽  
Anna Santarsiero ◽  
Paolo Convertini ◽  
Simona Todisco ◽  
Vito Iacobazzi
Keyword(s):  
Cancer Cells ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Cancer Therapeutics ◽  
High Energy ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Functional Changes

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

scholarly journals Metabolic reprogramming by HIF-1 promotes the survival of bone marrow–derived angiogenic cells in ischemic tissue

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4988-4998 ◽  
Author(s):  
Sergio Rey ◽  
Weibo Luo ◽  
Larissa A. Shimoda ◽  
Gregg L. Semenza
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Limb Ischemia ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Ischemic Tissue

Abstract A major obstacle to using bone marrow cell-based therapies for ischemic cardiovascular disease is that transplanted cells must survive in an ischemic microenvironment characterized by low oxygen, glucose, and pH. We demonstrate that treatment of bone marrow-derived angiogenic cells (BMDACs) with dimethyloxalylglycine, an α-ketoglutarate antagonist that induces hypoxia-inducible factor 1 (HIF-1) activity, results in metabolic reprogramming of these cells, with increased glucose uptake, decreased O2 consumption, increased lactate production, decreased reactive oxygen species, and increased intracellular pH. These effects are dependent on HIF-1, which transactivates target genes encoding metabolic enzymes and membrane transporters. Dimethyloxalylglycine-treated BMDACs have a significant survival advantage under conditions of low O2 and low pH ex vivo and in ischemic tissue. Combined HIF-1α-based gene and cell therapy reduced tissue necrosis even when BMDAC donors and ischemic recipient mice were 17 months old, suggesting that this approach may have therapeutic utility in elderly patients with critical limb ischemia.

Molecular characteristics and induction profiles of hypoxia-inducible factor-1αand other basic helix–loop–helix and Per–Arnt–Sim domain-containing proteins identified in a carcinogenic liver flukeClonorchis sinensis

Parasitology ◽  
2018 ◽  
Vol 146 (2) ◽  
pp. 176-186
Author(s):  
Seon-Hee Kim ◽  
Gyu-Seok Oh ◽  
Woon-Mok Sohn ◽  
Kihyun Lee ◽  
Hyun-Jong Yang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Clonorchis Sinensis ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Molecular Structures ◽  
Molecular Characteristics ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Aryl Hydrocarbon ◽  
Oxygen Condition

AbstractClonorchis sinensis(C. sinensis), a trematode parasite that invades the hypoxic hepatobiliary tract of vertebrate hosts requires a considerable amount of oxygen for its sexual reproduction and energy metabolism. However, little is known regarding the molecular mechanism ofC. sinensisinvolved in the adaptation to the hypoxic environments. In this study, we investigated the molecular structures and induction patterns of hypoxia-inducible factor-1α(HIF-1α) and other basic helix–loop–helix and Per–Arnt–Sim (bHLH–PAS) domain-containing proteins such as HIF-1β, single-minded protein and aryl hydrocarbon receptor, which might prompt adaptive response to hypoxia, inC. sinensis. These proteins possessed various bHLH–PAS family-specific domains. Expression ofC. sinensis HIF-1α(CsHIF-1α) was highly induced in worms which were either exposed to a hypoxic condition or co-incubated with human cholangiocytes. In addition to oxygen, nitric oxide and nitrite affected theCsHIF-1αexpression depending on the surrounding oxygen concentration. Treatment using a prolyl hydroxylase-domain protein inhibitor under 20%-oxygen condition resulted in an increase in the CsHIF-1αlevel. Conversely, the otherbHLH–PASgenes were less responsive to these exogenous stimuli. We suggest that nitrite and nitric oxide, as well as oxygen, coordinately involve in the regulation of HIF-1αexpression to adapt to the hypoxic host environments inC. sinensis.

Role of Hypoxia Inducible Factor-1α in Alzheimer’s Disease

2021 ◽  
Vol 80 (3) ◽  
pp. 949-961
Author(s):  
Yang-Yang Wang ◽  
Zhen-Ting Huang ◽  
Ming-Hao Yuan ◽  
Feng Jing ◽  
Ruo-Lan Cai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Hypoxia Inducible Factor ◽  
Amyloid Β ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1Α ◽  
Hyperphosphorylated Tau Protein ◽  
The One ◽  
Aβ Generation

Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

scholarly journals Molecular Characterization and Response of Prolyl Hydroxylase Domain (PHD) Genes to Hypoxia Stress in Hypophthalmichthys molitrix

Animals ◽  
2022 ◽  
Vol 12 (2) ◽  
pp. 131
Author(s):  
Xiaohui Li ◽  
Meidong Zhang ◽  
Chen Ling ◽  
Hang Sha ◽  
Guiwei Zou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Silver Carp ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Early Response ◽  
Prolyl Hydroxylase ◽  
Alpha Subunit ◽  
Hypophthalmichthys Molitrix ◽  
Low Oxygen ◽  
Prolyl Hydroxylase Domain

As an economically and ecologically important freshwater fish, silver carp (Hypophthalmichthys molitrix) is sensitive to low oxygen tension. Prolyl hydroxylase domain (PHD) proteins are critical regulators of adaptive responses to hypoxia for their function of regulating the hypoxia inducible factor-1 alpha subunit (HIF-1α) stability via hydroxylation reaction. In the present study, three PHD genes were cloned from H. molitrix by rapid amplification of cDNA ends (RACE). The total length of HmPHD1, HmPHD2, and HmPHD3 were 2981, 1954, and 1847 base pair (bp), and contained 1449, 1080, and 738 bp open reading frames (ORFs) that encoded 482, 359, and 245 amino acids (aa), respectively. Amino acid sequence analysis showed that HmPHD1, HmPHD2, and HmPHD3 had the conserved prolyl 4-hydroxylase alpha subunit homolog domains at their C-termini. Meanwhile, the evaluation of phylogeny revealed PHD2 and PHD3 of H. molitrix were more closely related as they belonged to sister clades, whereas the clade of PHD1 was relatively distant from these two. The transcripts of PHD genes are ubiquitously distributed in H. molitrix tissues, with the highest expressional level of HmPHD1 and HmPHD3 in liver, and HmPHD2 in muscle. After acute hypoxic treatment for 0.5 h, PHD genes of H. molitrix were induced mainly in liver and brain, and different from HmPHD1 and HmPHD2, the expression of HmPHD3 showed no overt tissue specificity. Furthermore, under continued hypoxic condition, PHD genes exhibited an obviously rapid but gradually attenuated response from 3 h to 24 h, and upon reoxygenation, the transcriptional expression of PHD genes showed a decreasing trend in most of the tissues. These results indicate that the PHD genes of H. molitrix are involved in the early response to hypoxic stress, and they show tissue-specific transcript expression when performing physiological regulation functions. This study is of great relevance for advancing our understanding of how PHD genes are regulated when addressing the hypoxic challenge and provides a reference for the subsequent research of the molecular mechanisms underlying hypoxia adaptation in silver carp.

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