Role Of Hypoxia-inducible Factor Research Articles

Recent Insights into Roles of Hypoxia-Inducible Factors in Retinal Diseases.

Hypoxia-inducible factors (HIFs) are transcriptional factors that function as strong regulators of oxygen homeostasis and cellular metabolisms. The maintenance of cellular oxygen levels is critical as either insufficient or excessive oxygen affects development and physiologic and pathologic conditions. In the eye, retinas have a high metabolic demand for oxygen. Retinal ischemia can cause visual impairment in various sight-threating disorders including age-related macular degeneration, diabetic retinopathy, and some types of glaucoma. Therefore, understanding the potential roles of HIFs in the retina is highly important for managing disease development and progression. This review focuses on the physiologic and pathologic roles of HIFs as regulators of oxygen homeostasis and cellular metabolism in the retina, drawing on recent evidence. Our summary will promote comprehensive approaches to targeting HIFs for therapeutic purposes in retinal diseases.

The Role of Hypoxia-inducible Factor-1 in Bladder Cancer.

Bladder cancer (BC) is one of the most common malignant tumors worldwide and poses a significant hazard to human health. During the development of BC, hypoxia plays a crucial role. Hypoxia-inducible factor (HIF) is a key transcription factor for hypoxic adaptation, which regulates the transcription of various genes, including inflammation, angiogenesis, and glycolytic metabolism. Recent studies have shown the precise role of HIF in various biological behaviors of BC. More importantly, a new antitumor medication targeting HIF-2 has been used to treat renal cancer. However, therapies targeting HIF-1 in BC have not yet been developed. In this review, we discussed how HIF-1 is expressed and affects the growth, metastasis, and angiogenesis of BC. At the same time, we investigated several HIF-1 inhibitors that provide new perspectives for targeting HIF-1.

The Roles of Hypoxia-inducible Factors: Potential Clinical Target in Cardiovascular Diseases

The Roles of Hypoxia-inducible Factors: Potential Clinical Target in Cardiovascular Diseases

Exploration of the association between HIF3α mRNA and lncRNA MALAT1 in laryngeal squamous cell carcinoma by correlation analysis.

Laryngeal squamous cell carcinoma (LSCC) is a significant global health burden, for which there has been limited evidence of improved survival rates. Although the roles of hypoxia-inducible factor (HIF)1α and HIF2α have been well documented in hypoxia, the involvement of HIF3α, particularly in LSCC, has been inadequately explored. The present study aimed to investigate the correlation between HIFα subunits and the hypoxia-related long noncoding RNAs (lncRNAs) MALAT1 and HOTAIR in 63 patients diagnosed with LSCC. Total RNA was extracted from fresh-frozen laryngeal tumor and adjacent normal tissues, and was subjected to reverse transcription-quantitative PCR for target detection. Statistical analyses were conducted using SPSS software, with significance set at P<0.05. The present study is the first, to the best of our knowledge, to report a positive moderate monotonic correlation (rs=0.347) and moderately strong positive linear correlation (r=0.630) between HIF3α mRNA and lncRNA MALAT1 in LSCC. Regression analysis revealed a direct association between 39.6% of both variables. Additionally, a positive correlation was observed between lncRNAs MALAT1 and HOTAIR (rs=0.353); HIF2α mRNA and lncRNA MALAT1 (rs=0.431); HIF3α mRNA and lncRNA HOTAIR (rs=0.279); and HIF3α mRNA and HIF2α mRNA (rs=0.285). Notably, a significant negative correlation (rs=-0.341) was detected between HIF3α mRNA and HIF1α mRNA, potentially indicative of the HIF switch or negative regulation. In addition, the present study investigated the association between HIFα subunits and the clinicopathological characteristics of patients. The results revealed a notable association between HIF1α transcript levels and the location of LSCC; specifically, subglottic tumors exhibited elevated HIF1α levels compared with glottic and supraglottic LSCC. Furthermore, a significant association was identified between HIF3α transcript levels and patient age (P=0.032) and positive family history (P=0.047). In conclusion, the present findings suggested a pivotal role for HIF3α in LSCC development, potentially involving direct regulation of lncRNA MALAT1. However, further research is warranted to elucidate its precise mechanisms.

Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia.

Metabolic reprogramming occurs to meet cancer cells' high energy demand. Its function is essential to the survival of malignancies. Comparing cancer cells to non-malignant cells has revealed that cancer cells have altered metabolism. Several pathways, particularly mTOR, Akt, PI3K, and HIF-1 (hypoxia-inducible factor-1) modulate the metabolism of cancer. Among other aspects of cancer biology, gene expression in metabolism, survival, invasion, proliferation, and angiogenesis of cells are controlled by HIF-1, a vital controller of cellular responsiveness to hypoxia. This article examines various cancer cell metabolisms, metabolic alterations that can take place in cancer cells, metabolic pathways, and molecular aspects of metabolic alteration in cancer cells placing special attention on the consequences of hypoxia-inducible factor and summarising some of their novel targets in the treatment of cancer including leukemia. A brief description of HIF-1α's role and target in a few common types of hematological malignancies (leukemia) is also elucidated in the present article.

The Role of Hypoxia-inducible Factor in Mycobacterium tuberculosis-infected Macrophages

Tuberculosis is caused by Mycobacterium tuberculosis infection. During M. tuberculosis infection, there is a decrease in the partial pressure of oxygen in the granuloma microenvironment, which causes the hypoxia-inducible factor (HIF) to become stable. HIF functions as a transcription factor that regulates the expression of genes crucial for metabolic adaptation in hypoxic conditions. Recent research suggests that HIF plays a vital role in infectious and inflammatory conditions. Several studies have demonstrated that HIF signaling can enhance macrophages antimicrobial activity and bactericidal effect against M. tuberculosis, such as increasing macrophage autophagy, enhancing the effects of rifampicin, inhibiting p38 MAPK signaling, enhancing the regulation of effector antimicrobial pathways mediated by human β defensin 2 (hBD2) and vitamin D receptor (VDR), redirecting energy metabolism to glycolysis, and producing various cytokines. All these responses ultimately result in the inhibition of intracellular M. tuberculosis growth. HIF has therapeutic implications, potentially being a new candidate for host-directed therapy as a complement to existing antituberculosis drugs. Understanding the role of HIF in macrophages during M. tuberculosis infection and comprehending the host-pathogen relationship with M. tuberculosis is advantageous for developing future therapies.Keywords: Mycobacterium tuberculosis, macrophages, hypoxia-inducible factor

The Role of Hypoxia Inducible Factor (HIF) 1α in the Pathogenesis of Liver Cirrhosis: A Narrative Literature Review

The small changes in oxygen tension that occur during viral hepatitis, metabolic disorders, steatohepatitis, inflammation, and carcinogenesis are sufficient to increase hypoxic response, namely an increase in HIF. HIF is a protein that belongs to the PAS (period circadian protein-aryl hydrocarbon receptor nuclear translocator-single-minded protein) family. HIF regulates the adaptation of cells to oxygen. HIF is a transcription factor containing α and β subunits. The expression of the α subunit is oxygen-dependent, while the β subunit is expressed continuously and independently of oxygen. HIFs regulate various signaling events by binding to specific DNA sequences known as hypoxia response elements (HREs) in target genes, leading to an increase or decrease in their transcription. HIF-1α is a key regulator of hypoxia signaling.

The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1α) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1α in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1α expression and the intracellular pathway of HIF-1α induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1α expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1α in human liver tissue. Intrahepatic HIF-1α expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1α was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1α expression was not elevated. In human liver tissue samples, HIF-1α expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1α expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.

Impact of Hypoxia-Induced miR-210 on Pancreatic Cancer.

Pancreatic cancer (PC) poses significant clinical challenges, with late-stage diagnosis and limited therapeutic options contributing to its dismal prognosis. A hallmark feature of PC is the presence of a profoundly hypoxic tumour microenvironment, resulting from various factors such as fibrotic stroma, rapid tumour cell proliferation, and poor vascularization. Hypoxia plays a crucial role in promoting aggressive cancer behaviour, therapeutic resistance, and immunosuppression. Previous studies have explored the molecular mechanisms behind hypoxia-induced changes in PC, focusing on the role of hypoxia-inducible factors (HIFs). Among the myriad of molecules affected by hypoxia, microRNA-210 (miR-210) emerges as a central player. It is highly responsive to hypoxia and regulated by HIF-dependent and HIF-independent pathways. miR-210 influences critical cellular processes, including angiogenesis, metastasis, and apoptosis, all of which contribute to PC progression and resistance to treatment. Understanding these pathways provides insights into potential therapeutic targets. Furthermore, investigating the role of miR-210 and its regulation in hypoxia sheds light on the potential development of early diagnostic strategies, which are urgently needed to improve outcomes for PC patients. This review delves into the complexities of PC and introduces the roles of hypoxia and miR-210 in the progression of PC.

Exploring mRNA translation strategies for hypoxia adaptation across distantly related metazoans.

Adaptation to variations in oxygen concentration is a conserved mechanism in all metazoans. Extensive studies have been focused on the roles of hypoxia-inducible factors (HIFs) in response to hypoxia. However, HIF1α is not conserved in all animals, and HIF2α and HIF3α are only observed in vertebrates. In this review, we discuss mechanisms enabling three cross-species to adapt to hypoxic conditions. Using transcriptomic data of hypoxia-induced genes from distantly related metazoans, we analyzed the enrichment and conservation of mRNA determinants such as transcript, CDS, 5'UTR and 3'UTR size. We found that long genes are enriched in hypoxia-induced transcripts and might be translated in a 3'UTR-dependent manner. We hope our work can provide a new direction on investigating alternative mechanisms for mRNA translation under hypoxia.

Role of hypoxia-inducible factor in postoperative delirium of aged patients: A review.

Postoperative delirium is common, especially in older patients. Delirium is associated with prolonged hospitalization, an increased risk of postoperative complications, and significant mortality. The mechanism of postoperative delirium is not yet clear. Cerebral desaturation occurred during the maintenance period of general anesthesia and was one of the independent risk factors for postoperative delirium, especially in the elderly. Hypoxia stimulates the expression of hypoxia-inducible factor-1 (HIF-1), which controls the hypoxic response. HIF-1 may have a protective role in regulating neuron apoptosis in neonatal hypoxia-ischemia brain damage and may promote the repair and rebuilding process in the brain that was damaged by hypoxia and ischemia. HIF-1 has a neuroprotective effect during cerebral hypoxia and controls the hypoxic response by regulating multiple pathways, such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. On the other hand, anesthetics have been reported to inhibit HIF activity in older patients. So, we speculate that HIF plays an important role in the pathophysiology of postoperative delirium in the elderly. The activity of HIF is reduced by anesthetics, leading to the inhibition of brain protection in a hypoxic state. This review summarizes the possible mechanism of HIF participating in postoperative delirium in elderly patients and provides ideas for finding targets to prevent or treat postoperative delirium in elderly patients.

Impairment of HIF-2α Expression Induced the Compensatory Overexpression of the HIF-1α/SDF-1 Axis to Promote Wound Healing.

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1α and the upregulation of HIF-2α. Notably, HIF-2α impairment resulted in the compensatory overexpression of HIF-1α and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2α kd/null mice (kd/null), the functions of HIF-2α in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2α, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1α, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2α in the inflammation phase of the wound healing process through the HIF-1α/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2α is a new concept for wound therapy.

The Brain at High Altitude: From Molecular Signaling to Cognitive Performance.

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity.

MTORC1 Deficiency Prevents the Development of MC903-Induced Atopic Dermatitis through the Downregulation of Type 2 Inflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczema and itching. Recently, mTORC, a central regulator of cellular metabolism, has been reported to play a critical role in immune responses, and manipulation of mTORC pathways has emerged as an effective immunomodulatory drug. In this study, we assessed whether mTORC signaling could contribute to the development of AD in mice. AD-like skin inflammation was induced by a 7-day treatment of MC903 (calcipotriol), and ribosomal protein S6 was highly phosphorylated in inflamed tissues. MC903-induced skin inflammation was ameliorated significantly in Raptor-deficient mice and exacerbated in Pten-deficient mice. Eosinophil recruitment and IL-4 production were also decreased in Raptor deficient mice. In contrast to the pro-inflammatory roles of mTORC1 in immune cells, we observed an anti-inflammatory effect on keratinocytes. TSLP was upregulated in Raptor deficient mice or by rapamycin treatment, which was mediated by hypoxia-inducible factor (HIF) signaling. Taken together, these results from our study indicate the dual roles of mTORC1 in the development of AD, and further studies on the role of HIF in AD are warranted.

Mechanism of HIFs in osteoarthritis.

Osteoarthritis (OA) is a common disabling disease which has a high incidence rate in the elderly. Studies have found that many factors are involved in the pathogenesis of OA. Hypoxia-inducible factors (HIFs) are core regulators that induce hypoxia genes, repair the cellular oxygen environment, and play an important role in the treatment of OA. For example, HIF-1α can maintain the stability of the articular cartilage matrix, HIF-2α is able to cause chondrocyte apoptosis and intensify in-flammatory response, and HIF-3α may be the target gene of HIF-1α and HIF-2α, thereby playing a negative regulatory role. This review examines the mechanism of HIFs in cartilage extracellular matrix degradation, apoptosis, inflammatory reaction, autophagy and then further expounds on the roles of HIFs in OA, consequently providing theoretical support for the pathogenesis of OA and a new target for OA treatment.

The role of hypoxia-inducible factor 1 alpha (HIF-1α) modulation in heavy metal toxicity.

Hypoxia-inducible factor 1 (HIF-1) is an oxygen-sensing transcriptional regulator orchestrating a complex of adaptive cellular responses to hypoxia. Several studies have demonstrated that toxic metal exposure may also modulate HIF-1α signal transduction pathway, although the existing data are scarce. Therefore, the present review aims to summarize the existing data on the effects of toxic metals on HIF-1 signaling and the potential underlying mechanisms with a special focus on prooxidant effect of the metals. The particular effect of metals was shown to be dependent on cell type, varying from down- to up-regulation of HIF-1 pathway. Inhibition of HIF-1 signaling may contribute to impaired hypoxic tolerance and adaptation, thus promoting hypoxic damage in the cells. In contrast, its metal-induced activation may result in increased tolerance to hypoxia through increased angiogenesis, thus promoting tumor growth and contributing to carcinogenic effect of heavy metals. Up-regulation of HIF-1 signaling is mainly observed upon Cr, As, and Ni exposure, whereas Cd and Hg may both stimulate and inhibit HIF-1 pathway. The mechanisms underlying the influence of toxic metal exposure on HIF-1 signaling involve modulation of prolyl hydroxylases (PHD2) activity, as well as interference with other tightly related pathways including Nrf2, PI3K/Akt, NF-κB, and MAPK signaling. These effects are at least partially mediated by metal-induced ROS generation. Hypothetically, maintenance of adequate HIF-1 signaling upon toxic metal exposure through direct (PHD2 modulation) or indirect (antioxidant) mechanisms may provide an additional strategy for prevention of adverse effects of metal toxicity.

Potential Effect of Nigella sativa on Osteoporosis in Ovariectomized Rats: Possible Role of Hypoxia Inducible Factor 1-α

Potential Effect of Nigella sativa on Osteoporosis in Ovariectomized Rats: Possible Role of Hypoxia Inducible Factor 1-α

Role of hypoxia inducible factor/vascular endothelial growth factor/endothelial nitric oxide synthase signaling pathway in mediating the cardioprotective effect of dapagliflozin in cyclophosphamide-induced cardiotoxicity.

Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway. Forty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS. Our data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection. DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.

The role of hypoxia-inducible factors in breast cancer stem cell specification.

Breast tumor is heterogeneous cancer with high morbidity and mortality rates, particularly in developing countries. Despite new efforts to reduce the breast cancer implications, the number of newly diagnosed cases is increasing worldwide. It is believed that cancer stem cells (CSCs) are responsible for the implication of cancers including breast cancer. Although CSCs compose a small population in tumor bulks, they play a crucial role in tumor initiation, progression, metastasis, and chemotherapeutic resistance. These events are mediated by the hypoxia-inducible factor (HIF) pathway which regulates the transcription of genes involved in CSC maintenance and tumorigenesis. In this review, we discussed the mechanisms by which hypoxia- or chemotherapy-induced HIFs promote breast CSC specification.

HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment.

A role for hypoxia-inducible factors (HIFs) in hypoxia-dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF-dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF-dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia-dependent alterations by activating HIF-dependent transcription to alter nutrient import, export, and utilization. In recent years, the concept of metabolic competition has been proposed for critical substrates, including glucose, lactate, glutamine, arginine, and tryptophan. In this review, we discuss how HIF-mediated mechanisms control nutrient sensing and availability in the TME, the competition for nutrients, and the metabolic cross-talk between tumor and stromal cells.