International Journal of Molecular Sciences

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11 pages, 3219 KiB

Open AccessArticle

Impacts of Hypoxia on Osteoclast Formation and Activity: Systematic Review

by Jen Kit Tan, Nur Shukriyah Mohamad Hazir and Ekram Alias

Int. J. Mol. Sci. 2021, 22(18), 10146; https://doi.org/10.3390/ijms221810146 - 20 Sep 2021

Cited by 11 | Viewed by 2834

Abstract

Hypoxia is evident in several bone diseases which are characterized by excessive bone resorption by osteoclasts, the bone-resorbing cells. The effects of hypoxia on osteoclast formation and activities are widely studied but remain inconclusive. This systematic review discusses the studies reporting the effect [...] Read more.

Hypoxia is evident in several bone diseases which are characterized by excessive bone resorption by osteoclasts, the bone-resorbing cells. The effects of hypoxia on osteoclast formation and activities are widely studied but remain inconclusive. This systematic review discusses the studies reporting the effect of hypoxia on osteoclast differentiation and activity. A literature search for relevant studies was conducted through SCOPUS and PUBMED MEDLINE search engines. The inclusion criteria were original research articles presenting data demonstrating the effect of hypoxia or low oxygen on osteoclast formation and activity. A total of 286 studies were identified from the search, whereby 20 studies were included in this review, consisting of four in vivo studies and 16 in vitro studies. In total, 12 out of 14 studies reporting the effect of hypoxia on osteoclast activity indicated higher bone resorption under hypoxic conditions, 14 studies reported that hypoxia resulted in more osteoclasts, one study found that the number remained unchanged, and five studies indicated that the number decreased. In summary, examination of the relevant literature suggests differences in findings between studies, hence the impact of hypoxia on osteoclasts remains debatable, even though there is more evidence to suggest it promotes osteoclast differentiation and activity. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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12 pages, 2268 KiB

Open AccessArticle

Hypoxia as a Stimulus for the Maturation of Meniscal Cells: Highway to Novel Tissue Engineering Strategies?

by Valentina Rafaela Herrera Millar, Laura Mangiavini, Umberto Polito, Barbara Canciani, Van Thi Nguyen, Federica Cirillo, Luigi Anastasia, Giuseppe Maria Peretti, Silvia Clotilde Modina and Alessia Di Giancamillo

Int. J. Mol. Sci. 2021, 22(13), 6905; https://doi.org/10.3390/ijms22136905 - 27 Jun 2021

Cited by 12 | Viewed by 2333

Abstract

The meniscus possesses low self-healing properties. A perfect regenerative technique for this tissue has not yet been developed. This work aims to evaluate the role of hypoxia in meniscal development in vitro. Menisci from neonatal pigs (day 0) were harvested and cultured under [...] Read more.

The meniscus possesses low self-healing properties. A perfect regenerative technique for this tissue has not yet been developed. This work aims to evaluate the role of hypoxia in meniscal development in vitro. Menisci from neonatal pigs (day 0) were harvested and cultured under two different atmospheric conditions: hypoxia (1% O₂) and normoxia (21% O₂) for up to 14 days. Samples were analysed at 0, 7 and 14 days by histochemical (Safranin-O staining), immunofluorescence and RT-PCR (in both methods for SOX-9, HIF-1α, collagen I and II), and biochemical (DNA, GAGs, DNA/GAGs ratio) techniques to record any possible differences in the maturation of meniscal cells. Safranin-O staining showed increments in matrix deposition and round-shape “fibro-chondrocytic” cells in hypoxia-cultured menisci compared with controls under normal atmospheric conditions. The same maturation shifting was observed by immunofluorescence and RT-PCR analysis: SOX-9 and collagen II increased from day zero up to 14 days under a hypoxic environment. An increment of DNA/GAGs ratio typical of mature meniscal tissue (characterized by fewer cells and more GAGs) was observed by biochemical analysis. This study shows that hypoxia can be considered as a booster to achieve meniscal cell maturation, and opens new opportunities in the field of meniscus tissue engineering. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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19 pages, 3679 KiB

Open AccessArticle

Different Expressions of HIF-1α and Metabolism in Brain and Major Visceral Organs of Acute Hypoxic Mice

by Lu Xu, Hua Song, Qi Qiu, Ting Jiang, Pingyun Ge, Zaiji Su, Wenhui Ma, Ran Zhang, Caihua Huang, Shanhua Li, Donghai Lin and Jiaxing Zhang

Int. J. Mol. Sci. 2021, 22(13), 6705; https://doi.org/10.3390/ijms22136705 - 23 Jun 2021

Cited by 9 | Viewed by 3517

Abstract

Hypoxia is associated with clinical diseases. Extreme hypoxia leads to multiple organs failure. However, the different effects of hypoxia on brain and visceral organs still need to be clarified, and moreover, characteristics in vulnerable organs suffering from hypoxia remain elusive. In the present [...] Read more.

Hypoxia is associated with clinical diseases. Extreme hypoxia leads to multiple organs failure. However, the different effects of hypoxia on brain and visceral organs still need to be clarified, and moreover, characteristics in vulnerable organs suffering from hypoxia remain elusive. In the present study, we first aimed to figure out the hypoxic sensitivity of organs. Adult male mice were exposed to 6% O₂ or 8% O₂ for 6 h. Control mice were raised under normoxic conditions. In vivo and in vitro imaging of anti-HIF-1α-NMs-cy5.5 nanocomposites showed that the expression level of hypoxia-inducible factor (HIF-1α) was the highest in the liver, followed by kidney and brain. HIF-1α was detected in the hepatocytes of liver, distal convoluted tubules of kidney and neurons of cerebral cortex. The liver, kidney and brain showed distinct metabolic profiles but an identical change in glutamate. Compared with kidney and brain, the liver had more characteristic metabolites and more disturbed metabolic pathways related to glutaminolysis and glycolysis. The level of O-phosphocholine, GTP, NAD and aspartate were upregulated in hypoxic mice brain, which displayed significant positive correlations with the locomotor activity in control mice, but not in hypoxic mice with impaired locomotor activities. Taken together, the liver, kidney and brain are the three main organs of the body that are strongly respond to acute hypoxia, and the liver exhibited the highest hypoxic sensitivity. The metabolic disorders appear to underlie the physiological function changes. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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12 pages, 1485 KiB

Open AccessArticle

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

by Franziska Dengler, Sofia Sova, Antti M. Salo, Joni M. Mäki, Peppi Koivunen and Johanna Myllyharju

Int. J. Mol. Sci. 2021, 22(8), 4038; https://doi.org/10.3390/ijms22084038 - 14 Apr 2021

Cited by 1 | Viewed by 2662

Abstract

The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in “physiological hypoxia” and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression [...] Read more.

The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in “physiological hypoxia” and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1^−/−, Hif-p4h-2 hypomorph and Hif-p4h-3^−/− mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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19 pages, 4276 KiB

Open AccessArticle

HIF-1α and Pro-Inflammatory Signaling Improves the Immunomodulatory Activity of MSC-Derived Extracellular Vesicles

by Marta Gómez-Ferrer, Estela Villanueva-Badenas, Rafael Sánchez-Sánchez, Christian M. Sánchez-López, Maria Carmen Baquero, Pilar Sepúlveda and Akaitz Dorronsoro

Int. J. Mol. Sci. 2021, 22(7), 3416; https://doi.org/10.3390/ijms22073416 - 26 Mar 2021

Cited by 32 | Viewed by 3723

Abstract

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, [...] Read more.

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EV_MSC-T-HIF^c). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EV_MSC-T-HIF^c suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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17 pages, 6108 KiB

Open AccessArticle

Hypoxia-Induced Alpha-Globin Expression in Syncytiotrophoblasts Mimics the Pattern Observed in Preeclamptic Placentas

by Zahra Masoumi, Lena Erlandsson, Eva Hansson, Mattias Magnusson, Eva Mezey and Stefan R. Hansson

Int. J. Mol. Sci. 2021, 22(7), 3357; https://doi.org/10.3390/ijms22073357 - 25 Mar 2021

Cited by 5 | Viewed by 2428

Abstract

Preeclampsia (PE) is a pregnancy disorder associated with placental dysfunction and elevated fetal hemoglobin (HbF). Early in pregnancy the placenta harbors hematopoietic stem and progenitor cells (HSPCs) and is an extramedullary source of erythropoiesis. However, globin expression is not unique to erythroid cells [...] Read more.

Preeclampsia (PE) is a pregnancy disorder associated with placental dysfunction and elevated fetal hemoglobin (HbF). Early in pregnancy the placenta harbors hematopoietic stem and progenitor cells (HSPCs) and is an extramedullary source of erythropoiesis. However, globin expression is not unique to erythroid cells and can be triggered by hypoxia. To investigate the role of the placenta in increasing globin levels previously reported in PE, flow cytometry, histological and immunostaining and in situ analyses were used on placenta samples and ex vivo explant cultures. Our results indicated that in PE pregnancies, placental HSPC homing and erythropoiesis were not affected. Non-erythroid alpha-globin mRNA and protein, but not gamma-globin, were detected in syncytiotrophoblasts and stroma of PE placenta samples. Similarly, alpha-globin protein and mRNA were upregulated in normal placenta explants cultured in hypoxia. The upregulation was independent of HIF1 and NRF2, the two main candidates of globin transcription in non-erythroid cells. Our study is the first to demonstrate alpha-globin mRNA expression in syncytiotrophoblasts in PE, induced by hypoxia. However, gamma-globin was only expressed in erythrocytes. We conclude that alpha-globin, but not HbF, is expressed in placental syncytiotrophoblasts in PE and may contribute to the pathology of the disease. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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22 pages, 3874 KiB

Open AccessArticle

Transcriptomic Analysis of Human Astrocytes In Vitro Reveals Hypoxia-Induced Mitochondrial Dysfunction, Modulation of Metabolism, and Dysregulation of the Immune Response

by Scott P. Allen, Rajpinder Singh Seehra, Paul R. Heath, Benjamin P. C. Hall, Jessica Bates, Claire J. Garwood, Martyna M. Matuszyk, Stephen B. Wharton and Julie E. Simpson

Int. J. Mol. Sci. 2020, 21(21), 8028; https://doi.org/10.3390/ijms21218028 - 28 Oct 2020

Cited by 19 | Viewed by 3895

Abstract

Hypoxia is a feature of neurodegenerative diseases, and can both directly and indirectly impact on neuronal function through modulation of glial function. Astrocytes play a key role in regulating homeostasis within the central nervous system, and mediate hypoxia-induced changes in response to reduced [...] Read more.

Hypoxia is a feature of neurodegenerative diseases, and can both directly and indirectly impact on neuronal function through modulation of glial function. Astrocytes play a key role in regulating homeostasis within the central nervous system, and mediate hypoxia-induced changes in response to reduced oxygen availability. The current study performed a detailed characterization of hypoxia-induced changes in the transcriptomic profile of astrocytes in vitro. Human astrocytes were cultured under normoxic (5% CO₂, 95% air) or hypoxic conditions (1% O₂, 5% CO₂, 94% N₂) for 24 h, and the gene expression profile assessed by microarray analysis. In response to hypoxia 4904 genes were significantly differentially expressed (1306 upregulated and 3598 downregulated, FC ≥ 2 and p ≤ 0.05). Analysis of the significant differentially expressed transcripts identified an increase in immune response pathways, and dysregulation of signalling pathways, including HIF-1 (p = 0.002), and metabolism, including glycolysis (p = 0.006). To assess whether the hypoxia-induced metabolic gene changes observed affected metabolism at a functional level, both the glycolytic and mitochondrial flux were measured using an XF bioanalyser. In support of the transcriptomic data, under physiological conditions hypoxia significantly reduced mitochondrial respiratory flux (p = 0.0001) but increased basal glycolytic flux (p = 0.0313). However, when metabolically stressed, hypoxia reduced mitochondrial spare respiratory capacity (p = 0.0485) and both glycolytic capacity (p = 0.0001) and glycolytic reserve (p < 0.0001). In summary, the current findings detail hypoxia-induced changes in the astrocyte transcriptome in vitro, identifying potential targets for modifying the astrocyte response to reduced oxygen availability in pathological conditions associated with ischaemia/hypoxia, including manipulation of mitochondrial function, metabolism, and the immune response. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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27 pages, 2758 KiB

Open AccessArticle

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

by Nancy Farfán, Jaime Carril, Martina Redel, Marta Zamorano, Maureen Araya, Estephania Monzón, Raúl Alvarado, Norton Contreras, Andrea Tapia-Bustos, María Elena Quintanilla, Fernando Ezquer, José Luis Valdés, Yedy Israel, Mario Herrera-Marschitz and Paola Morales

Int. J. Mol. Sci. 2020, 21(20), 7800; https://doi.org/10.3390/ijms21207800 - 21 Oct 2020

Cited by 23 | Viewed by 4502

Abstract

Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from [...] Read more.

Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-α+IFN-γ (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 °C for 21 min. Thereafter, 16 μL of MSC-S (containing 6 μg of protein derived from 2 × 10⁵ preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione); (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation; (iii) increased NQO1 antioxidant protein; (iv) reduced neuroinflammation (decreasing nuclearNF-κB/p65 levels and microglial reactivity); (v) decreased cleaved-caspase-3 cell-death; (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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20 pages, 6998 KiB

Open AccessArticle

Influence of Hypoxic and Hyperoxic Preconditioning on Endothelial Function in a Model of Myocardial Ischemia-Reperfusion Injury with Cardiopulmonary Bypass (Experimental Study)

by Irina A. Mandel, Yuri K. Podoksenov, Irina V. Suhodolo, Darya A. An, Sergey L. Mikheev, Andrey Yu. Podoksenov, Yulia S. Svirko, Anna M. Gusakova, Vladimir M. Shipulin and Andrey G. Yavorovskiy

Int. J. Mol. Sci. 2020, 21(15), 5336; https://doi.org/10.3390/ijms21155336 - 27 Jul 2020

Cited by 4 | Viewed by 2806

Abstract

The aim of the experiment was to evaluate the effect of preconditioning based on changes in inspiratory oxygen fraction on endothelial function in the model of ischemia-reperfusion injury of the myocardium in the condition of cardiopulmonary bypass. The prospective randomized study included 32 [...] Read more.

The aim of the experiment was to evaluate the effect of preconditioning based on changes in inspiratory oxygen fraction on endothelial function in the model of ischemia-reperfusion injury of the myocardium in the condition of cardiopulmonary bypass. The prospective randomized study included 32 rabbits divided into four groups: hypoxic preconditioning, hyperoxic preconditioning, hypoxic-hyperoxic preconditioning, and control group. All animals were anesthetized and mechanically ventilated. We provided preconditioning, then started cardiopulmonary bypass, followed by induced acute myocardial infarction (ischemia 45 min, reperfusion 120 min). We investigated endothelin-1, nitric oxide metabolites, asymmetric dimethylarginine during cardiopulmonary bypass: before ischemia, after ischemia, and after reperfusion. We performed light microscopy of myocardium, kidney, lungs, and gut mucosa. The endothelin-1 level was much higher in the control group than in all preconditioning groups after ischemia. The endothelin-1 even further increased after reperfusion. The total concentration of nitric oxide metabolites was significantly higher after all types of preconditioning compared with the control group. The light microscopy of the myocardium and other organs revealed a diminished damage extent in the hypoxic-hyperoxic preconditioning group as compared to the control group. Hypoxic-hyperoxic preconditioning helps to maintain the balance of nitric oxide metabolites, reduces endothelin-1 hyperproduction, and enforces organ protection. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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Review

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23 pages, 3370 KiB

Open AccessReview

AMPK–mTOR Signaling and Cellular Adaptations in Hypoxia

by Yoomi Chun and Joungmok Kim

Int. J. Mol. Sci. 2021, 22(18), 9765; https://doi.org/10.3390/ijms22189765 - 9 Sep 2021

Cited by 81 | Viewed by 10135

Abstract

Cellular energy is primarily provided by the oxidative degradation of nutrients coupled with mitochondrial respiration, in which oxygen participates in the mitochondrial electron transport chain to enable electron flow through the chain complex (I–IV), leading to ATP production. Therefore, oxygen supply is an [...] Read more.

Cellular energy is primarily provided by the oxidative degradation of nutrients coupled with mitochondrial respiration, in which oxygen participates in the mitochondrial electron transport chain to enable electron flow through the chain complex (I–IV), leading to ATP production. Therefore, oxygen supply is an indispensable chapter in intracellular bioenergetics. In mammals, oxygen is delivered by the bloodstream. Accordingly, the decrease in cellular oxygen level (hypoxia) is accompanied by nutrient starvation, thereby integrating hypoxic signaling and nutrient signaling at the cellular level. Importantly, hypoxia profoundly affects cellular metabolism and many relevant physiological reactions induce cellular adaptations of hypoxia-inducible gene expression, metabolism, reactive oxygen species, and autophagy. Here, we introduce the current knowledge of hypoxia signaling with two-well known cellular energy and nutrient sensing pathways, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1). Additionally, the molecular crosstalk between hypoxic signaling and AMPK/mTOR pathways in various hypoxic cellular adaptions is discussed. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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15 pages, 6595 KiB

Open AccessReview

Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution

by Yair Romero and Arnoldo Aquino-Gálvez

Int. J. Mol. Sci. 2021, 22(15), 8335; https://doi.org/10.3390/ijms22158335 - 3 Aug 2021

Cited by 14 | Viewed by 4321

Abstract

Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the [...] Read more.

Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the activation of the hypoxia response, promoting cell survival even during chronic conditions. The role of hypoxia-inducible factors (HIFs) as master regulators of this adaptation is crucial in both lung cancer and idiopathic pulmonary fibrosis, which have shown the active transcriptional signature of this pathway. Emerging evidence suggests that interconnected feedback loops such as metabolic changes, fibroblast differentiation or extracellular matrix remodeling contribute to HIF overactivation, making it an irreversible phenomenon. This review will focus on the role of HIF signaling and its possible overlapping in order to identify new opportunities in therapy and regeneration. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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20 pages, 9508 KiB

Open AccessReview

Hypoxia and the Receptor for Advanced Glycation End Products (RAGE) Signaling in Cancer

by Sakshi Taneja, Stefan W. Vetter and Estelle Leclerc

Int. J. Mol. Sci. 2021, 22(15), 8153; https://doi.org/10.3390/ijms22158153 - 29 Jul 2021

Cited by 12 | Viewed by 4020

Abstract

Hypoxia is characterized by an inadequate supply of oxygen to tissues, and hypoxic regions are commonly found in solid tumors. The cellular response to hypoxic conditions is mediated through the activation of hypoxia-inducible factors (HIFs) that control the expression of a large number [...] Read more.

Hypoxia is characterized by an inadequate supply of oxygen to tissues, and hypoxic regions are commonly found in solid tumors. The cellular response to hypoxic conditions is mediated through the activation of hypoxia-inducible factors (HIFs) that control the expression of a large number of target genes. Recent studies have shown that the receptor for advanced glycation end products (RAGE) participates in hypoxia-dependent cellular adaptation. We review recent evidence on the role of RAGE signaling in tumor biology under hypoxic conditions. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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24 pages, 21350 KiB

Open AccessReview

Impact of Hypoxia over Human Viral Infections and Key Cellular Processes

by Antonia Reyes, Luisa F. Duarte, Mónica A. Farías, Eduardo Tognarelli, Alexis M. Kalergis, Susan M. Bueno and Pablo A. González

Int. J. Mol. Sci. 2021, 22(15), 7954; https://doi.org/10.3390/ijms22157954 - 26 Jul 2021

Cited by 11 | Viewed by 3511

Abstract

Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, [...] Read more.

Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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31 pages, 1638 KiB

Open AccessReview

The Hypoxia–Long Noncoding RNA Interaction in Solid Cancers

by Seung Wan Son, Ba Da Yun, Mun Gyu Song, Jin Kyeong Lee, Soo Young Choi, Hyo Jeong Kuh and Jong Kook Park

Int. J. Mol. Sci. 2021, 22(14), 7261; https://doi.org/10.3390/ijms22147261 - 6 Jul 2021

Cited by 12 | Viewed by 3251

Abstract

Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as [...] Read more.

Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as stemness, angiogenesis, invasion, metastasis, and the resistance towards apoptotic cell death and therapeutic resistance; therefore, hypoxia has been considered as a potential hurdle for cancer therapy. Growing evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated in cancer and take part in gene regulatory networks owing to their various modes of action through interacting with proteins and microRNAs. In this review, we focus attention on the relationship between hypoxia/HIFs and lncRNAs, in company with the possibility of lncRNAs as candidate molecules for controlling cancer. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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33 pages, 4007 KiB

Open AccessReview

Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

by Thuy-Hang Nguyen, Stephanie Conotte, Alexandra Belayew, Anne-Emilie Declèves, Alexandre Legrand and Alexandra Tassin

Int. J. Mol. Sci. 2021, 22(13), 7220; https://doi.org/10.3390/ijms22137220 - 5 Jul 2021

Cited by 20 | Viewed by 5189

Abstract

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms [...] Read more.

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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