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Low dissolved oxygen (hypoxia) poses significant challenges to aquatic ecosystems, affecting the behavior, reproduction, and survival of aquatic organisms. Some fishes respond to hypoxia by changes in gene expression, which may be regulated by the hypoxia inducible factor (HIF) family of transcription factors. HIF abundance and activity depends upon the post-translational modification of the alpha protein subunit, although several studies indicate that HIFA mRNA abundance increases in tissues of fishes exposed to hypoxia. This study reviewed reports of laboratory exposures of adult ray-finned fishes to hypoxia and used generalized linear mixed effects models to examine the influence of HIFA gene, tissue sampled, and exposure conditions in explaining the diversity of responses seen in HIFA mRNA abundance. The frequency of hypoxia-induced increases in HIFA mRNA was poorly explained by gene, tissue, or the severity of the hypoxic exposure. Rather, the frequency of reported increases was strongly related to the extent to which studies adhered to guidelines for documenting quantitative real-time PCR methods: the frequency of hypoxia-induced increases in HIFA mRNA decreased sharply in studies with more thorough description of experimental design. Future research should (a) adhere to stringent reporting of experimental design, (b) address the relative paucity of data on HIF2A and HIF3A , and (c) determine levels of HIF alpha protein subunits. By following these recommendations, it is hoped that a more complete understanding will be gained of the role of the HIF family of transcription factors in the response of fish to hypoxia. [ABSTRACT FROM AUTHOR]

Hypoxia inducible transcription factors (HIFs) mediate the hypoxic response in metazoans. When sufficient O2 is present, Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases (human PHD1-3) promote HIFα degradation via prolyl-hydroxylation. We report crystallographic, spectroscopic, and biochemical characterization of stable and inactive PHD2.Fe(III).2OG complexes. Aerobic incubation of PHD2 with Fe(II) and 2OG enables formation of PHD2.Fe(III).2OG complexes which bind HIF1-2α to give inactive PHD2.Fe(III).2OG.HIF1-2α complexes. The Fe(III) oxidation state in the inactive complexes was shown by EPR spectroscopy. L-Ascorbate hinders formation of the PHD2.Fe(III).2OG.(+/-HIFα) complexes and slowly regenerates them to give the catalytically active PHD2.Fe(II).2OG complex. Crystallographic comparison of the PHD2.Fe(III).2OG.HIF2α complex with the analogous anaerobic Fe(II) complex reveals near identical structures. Exposure of the anaerobic PHD2.Fe(II).2OG.HIF2α crystals to O2 enables in crystallo hydroxylation. The resulting PHD2.product structure, manifests conformational changes compared to the substrate structures. The results have implications for the role of the PHDs in hypoxia sensing and open new opportunities for inhibition of the PHDs and other 2OG dependent oxygenases by promoting formation of stable Fe(III) complexes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heterotopic ossification is a dynamic growth process. Diverse heterotopic ossification subtypes have diverse etiologies or induction factors, but they exhibit a similar clinical process in the intermediate and later phases of the disease. Acquired heterotopic ossification produced by trauma and other circumstances has a high incidence. OBJECTIVE: To summarize the molecular biological mechanisms linked to the occurrence and progression of acquired heterotopic ossification in recent years. METHODS: The keywords “molecular biology, heterotopic ossification, mechanisms” were searched in CNKI, Wanfang, PubMed, Embase, Web of Science, and Google Scholar databases for articles published from January 2016 to August 2022. Supplementary searches were conducted based on the obtained articles. After the collected literature was screened, 131 articles were finally included and summarized. RESULTS AND CONCLUSION: (1) The occurrence and development of acquired heterotopic ossification is a dynamic process with certain concealment, making diagnosis and treatment of the disease difficult. (2) By reviewing relevant literature, it was found that acquired heterotopic ossification involves signaling pathways such as bone morphogenetic protein, transforming growth factor-β, Hedgehog, Wnt, and mTOR, as well as core factors such as Runx-2, vascular endothelial growth factor, hypoxia-inducing factor, fibroblast growth factor, and Sox9. The core mechanism may be the interaction between different signaling pathways, affecting the body’s osteoblast precursor cells, osteoblast microenvironment, and related cytokines, thereby affecting the body’s bone metabolism and leading to the occurrence of acquired heterotopic ossification. (3) In the future, it is possible to take the heterotopic ossification-related single-cell osteogenic homeostasis as the research direction, take the osteoblast precursor cells-osteogenic microenvironment-signaling pathways and cytokines as the research elements, explore the characteristics of each element under different temporal and spatial conditions, compare the similarities and differences of the osteogenic homeostasis of different types and individuals, observe the regulatory mechanism of the molecular signaling network of heterotopic ossification from a holistic perspective. It is beneficial to the exploration of new methods for the future clinical prevention and treatment of heterotopic ossification. (4) Meanwhile, the treatment methods represented by traditional Chinese medicine and targeted therapy have become research hotspots in recent years. How to link traditional Chinese medicine with the osteogenic homeostasis in the body and combine it with targeted therapy is also one of the future research directions. (5) At present, the research on acquired heterotopic ossification is still limited to basic experimental research and the clinical prevention and treatment methods still have defects such as uncertain efficacy and obvious side effects. The safety and effectiveness of relevant targeted prevention and treatment drugs in clinical application still need to be verified. Future research should focus on clinical prevention and treatment based on basic experimental research combined with the mechanism of occurrence and development. [ABSTRACT FROM AUTHOR]

Post-pump chorea (PPC) is characterized by the development of choreiform movements following cardiopulmonary bypass (CPB) surgery. PPC occurs almost exclusively in children, and its pathophysiology remains unclear. Here we present an adult case of PPC after bovine aortic valve replacement (AVR) which exhibited dramatic and reproducible response to steroid, suggesting the presence of occult neuroinflammation. This observation suggests a novel underlying mechanism in certain subgroups of PPC, which is likely a heterogeneous condition to start with. Further research into the pathomechanisms of PPC could offer insights into managing this otherwise symptomatic control-only condition. [ABSTRACT FROM AUTHOR]

Abstract Hypoxia inducible transcription factors (HIFs) mediate the hypoxic response in metazoans. When sufficient O2 is present, Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases (human PHD1-3) promote HIFα degradation via prolyl-hydroxylation. We report crystallographic, spectroscopic, and biochemical characterization of stable and inactive PHD2.Fe(III).2OG complexes. Aerobic incubation of PHD2 with Fe(II) and 2OG enables formation of PHD2.Fe(III).2OG complexes which bind HIF1-2α to give inactive PHD2.Fe(III).2OG.HIF1-2α complexes. The Fe(III) oxidation state in the inactive complexes was shown by EPR spectroscopy. L-Ascorbate hinders formation of the PHD2.Fe(III).2OG.(+/-HIFα) complexes and slowly regenerates them to give the catalytically active PHD2.Fe(II).2OG complex. Crystallographic comparison of the PHD2.Fe(III).2OG.HIF2α complex with the analogous anaerobic Fe(II) complex reveals near identical structures. Exposure of the anaerobic PHD2.Fe(II).2OG.HIF2α crystals to O2 enables in crystallo hydroxylation. The resulting PHD2.product structure, manifests conformational changes compared to the substrate structures. The results have implications for the role of the PHDs in hypoxia sensing and open new opportunities for inhibition of the PHDs and other 2OG dependent oxygenases by promoting formation of stable Fe(III) complexes.

Yopi Simargi,1– 3 Yuda Turana,4 Aziza Ghanie Icksan,5 Alida Roswita Harahap,1 Kristiana Siste,6,7 Muchtaruddin Mansyur,8 Triya Damayanti,9,10 Maryastuti Maryastuti,11 Vininta Fazharyasti,12 Indah Puspita Dewi,13,14 Yetty Ramli,15,16 Marcel Prasetyo,17,18 Cleopas Martin Rumende19,20 1Doctoral Program in Medical Science, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 2Department of Radiology, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia; 3Department of Radiology, Atma Jaya Hospital, Jakarta, Indonesia; 4Department of Neurology, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia; 5Department of Radiology, Prima Indonesia University, Medan, Indonesia; 6Department of Psychiatry, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 7Department of Psychiatry, Cipto Mangunkusumo National Central General Hospital, Jakarta, Indonesia; 8Department of Community, Occupational and Family Medicine, Faculty of Medicine, University of Indonesia, Depok, Indonesia; 9Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 10Department of Pulmonology and Respiratory Medicine, National Respiratory Center Persahabatan Hospital, Jakarta, Indonesia; 11Department of Radiology, National Respiratory Center Persahabatan Hospital, Jakarta, Indonesia; 12Department of Radiology, Gatot Soebroto Army Hospital, Jakarta, Indonesia; 13Department of Radiology, Faculty of Medicine and Health, University of Muhammadiyah Jakarta, Jakarta, Indonesia; 14Department of Radiology, Jakarta Islamic Hospital Cempaka Putih, Jakarta, Indonesia; 15Department of Neurology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 16Department Neurology, Cipto Mangunkusumo National Central General Hospital, Jakarta, Indonesia; 17Department of Radiology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 18Department of Radiology, Cipto Mangunkusumo National Central General Hospital, Jakarta, Indonesia; 19Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 20Department of Internal Medicine, Cipto Mangunkusumo National Central General Hospital, Jakarta, IndonesiaCorrespondence: Yopi Simargi, Department of Radiology, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jl. Pluit Raya No. 2, RT.21/RW.8, Penjaringan, Kec. Penjaringan, Jkt Utara, Daerah Khusus Ibukota, Jakarta, 14440, Email yopi.simargi@atmajaya.ac.idPurpose: The exact link between cognitive impairment (CI) and chronic obstructive pulmonary disease (COPD) is still limited. Thus, we aim to find the relationship and interaction of quantitative CT (QCT), lung function, HIF-1α, and clinical factors with the development of CI among COPD patients.Patients and Methods: A cross-sectional multicentre study was conducted from January 2022 to December 2023. We collected clinical data, spirometry, CT images, and venous blood samples from 114 COPD participants. Cognitive impairment assessment using the Montreal Cognitive Assessment Indonesian version (MoCA-Ina) with a cutoff value 26. The QCT analysis consists of lung density, airway wall thickness, pulmonary artery-to-aorta ratio (PA:A), and pectoralis muscles using 3D Slicer software. Serum HIF-1α analysis was performed using ELISA.Results: We found significant differences between %LAA− 950, age, COPD duration, BMI, FEV1 pp, and FEV1/FVC among GOLD grades I–IV. Only education duration was found to correlate with CI (r = 0.40; p < 0.001). We found no significant difference in HIF-1α among GOLD grades (p = 0.149) and no correlation between HIF-1α and CI (p = 0.105). From multiple linear regression, we observed that the MoCA-Ina score was influenced mainly by %LAA− 950 (p = 0.02) and education duration (p = 0.01). The path analysis model showed both %LAA and education duration directly and indirectly through FEV1 pp contributing to CI.Conclusion: We conclude that the utilization of QCT parameters is beneficial as it can identify abnormalities and contribute to the development of CI, indicating its potential utility in clinical decision-making. The MoCA-Ina score in COPD is mainly affected by %LAA− 950 and education duration. Contrary to expectations, this study concludes that HIF-1α does not affect CI among COPD patients.Keywords: chronic obstructive pulmonary disease, cognitive impairment, emphysema lung, hypoxia inducible factor

AIM: To observe the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) secretions on the relevant factors in mouse retinal astrocytes, and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A (VEGF-A) and to observe the therapeutic effect on the mouse model of retinopathy of prematurity (ROP). METHODS: Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group. MTT assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect related indicators. Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored. At last, the efficacy of exosomes of UCMSCs in a mouse ROP model was explored. Graphpad6 was used to comprehensively process data information. RESULTS: The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation. Reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased, and the ROP cell model was established after 6h of hypoxia. The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α, the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent. Compared with the ROP cell model group, the expression of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signal pathway related factors in the hUCMSCs exocrine group is significantly decreased. The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1α in ROP model tissues. HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion. CONCLUSION: In a hypoxia induced mouse retinal astrocyte model, hUCMSCs exosomes are found to effectively reduce the expression of HIF-1α and VEGF-A, which are positively correlated with the concentration of hUCMSCs exosomes. HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1α and VEGF-A proteins in ROP mice, and are positively correlated with drug dosage. Besides, they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.

Background: This study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS). Methods and results: An in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective which highlights the importance of HIF isoform-specific targeting as a novel salutary strategy for PAH treatment.

Low dissolved oxygen (hypoxia) poses significant challenges to aquatic ecosystems, affecting the behavior, reproduction, and survival of aquatic organisms. Some fishes respond to hypoxia by changes in gene expression, which may be regulated by the hypoxia inducible factor (HIF) family of transcription factors. HIF abundance and activity depends upon the post-translational modification of the alpha protein subunit, although several studies indicate that HIFA mRNA abundance increases in tissues of fishes exposed to hypoxia. This study reviewed reports of laboratory exposures of adult ray-finned fishes to hypoxia and used generalized linear mixed effects models to examine the influence of HIFA gene, tissue sampled, and exposure conditions in explaining the diversity of responses seen in HIFA mRNA abundance. The frequency of hypoxia-induced increases in HIFA mRNA was poorly explained by gene, tissue, or the severity of the hypoxic exposure. Rather, the frequency of reported increases was strongly related to the extent to which studies adhered to guidelines for documenting quantitative real-time PCR methods: the frequency of hypoxia-induced increases in HIFA mRNA decreased sharply in studies with more thorough description of experimental design. Future research should (a) adhere to stringent reporting of experimental design, (b) address the relative paucity of data on HIF2A and HIF3A, and (c) determine levels of HIF alpha protein subunits. By following these recommendations, it is hoped that a more complete understanding will be gained of the role of the HIF family of transcription factors in the response of fish to hypoxia.

Post-pump chorea (PPC) is characterized by the development of choreiform movements following cardiopulmonary bypass (CPB) surgery. PPC occurs almost exclusively in children, and its pathophysiology remains unclear. Here we present an adult case of PPC after bovine aortic valve replacement (AVR) which exhibited dramatic and reproducible response to steroid, suggesting the presence of occult neuroinflammation. This observation suggests a novel underlying mechanism in certain subgroups of PPC, which is likely a heterogeneous condition to start with. Further research into the pathomechanisms of PPC could offer insights into managing this otherwise symptomatic control-only condition.

Abstract Purpose Liver function of intensive care patients is routinely monitored by static blood pathology. For specific indications, liver specific cytochrome activity may be measured by the commercially available maximum liver function capacity (LiMAx) test via quantification of the cytochrome P450 1A2 (CYP1A2) dependent C-methacetin metabolism. Sedation with the volatile anesthetic isoflurane was suspected to abrogate the correlation of LiMAx test with global liver function. We hypothesized that isoflurane has a CYP1A2-activity and LiMAx test result decreasing effect. Methods In this monocentric, observational clinical study previously liver healthy intensive care patients, scheduled to be changed from propofol to isoflurane sedation, were enrolled. LiMAx testing was done before, during and after termination of isoflurane sedation. Results The mean LiMAx value decreased during isoflurane sedation. Septic patients (n = 11) exhibited lower LiMAx values compared to non-septic patients (n = 11) at all time points. LiMAx values decreased with isoflurane from 140 ± 82 to 30 ± 34 µg kg−1 h−1 in the septic group and from 253 ± 92 to 147 ± 131 µg kg−1 h−1 in the non-septic group while laboratory markers did not imply significant hepatic impairment. Lactate increased during isoflurane inhalation without clinical consequence. Conclusion Sepsis and isoflurane have independently demonstrated an effect on reducing the hepatic CYP1A2-activity. A network model was constructed that could explain the mechanism through the influence of isoflurane on hypoxia inducible factor (HIF-1α) by upregulation of the hypoxia-inducible pathway and the downregulation of CYP1A2-activity via the ligand-inducible pathway. Thus, the increased anaerobic metabolism may result in lactate accumulation. The influence of isoflurane sedation on the validated correlation of global liver function with CYP1A2-activity measured by LiMAx testing needs to be investigated in more detail.

Abstract Background More than 800 000 people die by suicide annually. The heritability of suicide is 30%–50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia‐inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single‐nucleotide polymorphism (SNP), in suicide completers and controls. Methods The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). Results No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (

Aims In hypoxia, endothelial cells (ECs) proliferate, migrate, and form new vasculature in a process called angiogenesis. Recent studies have suggested that ECs rely on glycolysis to meet metabolic needs for angiogenesis in ischaemic tissues, and several studies have investigated the molecular mechanisms integrating angiogenesis and endothelial metabolism. Here, we investigated the role of stem cell factor (SCF) and its receptor, cKIT, in regulating endothelial glycolysis during hypoxia-driven angiogenesis. Methods and results SCF and cKIT signalling increased the glucose uptake, lactate production, and glycolysis in human ECs under hypoxia. Mechanistically, SCF and cKIT signalling enhanced the expression of genes encoding glucose transporter 1 (GLUT1) and glycolytic enzymes via Akt- and ERK1/2-dependent increased translation of hypoxia inducible factor 1A (HIF1A). In hypoxic conditions, reduction of glycolysis and HIF-1α expression using chemical inhibitors significantly reduced the SCF-induced in vitro angiogenesis in human ECs. Compared with normal mice, mice with oxygen-induced retinopathy (OIR), characterized by ischaemia-driven pathological retinal neovascularization, displayed increased levels of SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzymes in the retina. Moreover, cKIT-positive neovessels in the retina of mice with OIR showed elevated expression of GLUT1 and glycolytic enzymes. Further, blocking SCF and cKIT signalling using anti-SCF neutralizing IgG and cKIT mutant mice significantly reduced the expression of HIF-1α, GLUT1, and glycolytic enzymes and decreased the pathological neovascularization in the retina of mice with OIR. Conclusion We demonstrated that SCF and cKIT signalling regulate angiogenesis by controlling endothelial glycolysis in hypoxia and elucidated the SCF/cKIT/HIF-1α axis as a novel metabolic regulation pathway during hypoxia-driven pathological angiogenesis. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are still one of the diseases that lead to high mortality. Currently, drugs for preventing and treating cardiovascular diseases can significantly improve symptoms, but there are still shortcomings in reducing mortality rates. Therefore, new drugs that can improve symptoms and reduce mortality are needed. As a kind of hydroxylase inhibitor, roxadustat can effectively improve the symptoms of hypoxia by regulating the expression of hypoxia inducible factor (HIF). HIF is involved in almost all developmental, pathological or physiological processes in the body, including erythropoietin production, iron uptake, and metablism, cellular differentiation, energy metablism, inflammation and immune regulation. At present, the drug has a good prospect in the treatment of renal anemia, but it is rarely used in cardiovascular diseases. In this paper, the effects of roxadustat on cardiovascular diseases were systematically and comprehensively discussed, and some help was provided for the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Purpose: Liver function of intensive care patients is routinely monitored by static blood pathology. For specific indications, liver specific cytochrome activity may be measured by the commercially available maximum liver function capacity (LiMAx) test via quantification of the cytochrome P450 1A2 (CYP1A2) dependent C-methacetin metabolism. Sedation with the volatile anesthetic isoflurane was suspected to abrogate the correlation of LiMAx test with global liver function. We hypothesized that isoflurane has a CYP1A2-activity and LiMAx test result decreasing effect. Methods: In this monocentric, observational clinical study previously liver healthy intensive care patients, scheduled to be changed from propofol to isoflurane sedation, were enrolled. LiMAx testing was done before, during and after termination of isoflurane sedation. Results: The mean LiMAx value decreased during isoflurane sedation. Septic patients (n = 11) exhibited lower LiMAx values compared to non-septic patients (n = 11) at all time points. LiMAx values decreased with isoflurane from 140 ± 82 to 30 ± 34 µg kg−1 h−1 in the septic group and from 253 ± 92 to 147 ± 131 µg kg−1 h−1 in the non-septic group while laboratory markers did not imply significant hepatic impairment. Lactate increased during isoflurane inhalation without clinical consequence. Conclusion: Sepsis and isoflurane have independently demonstrated an effect on reducing the hepatic CYP1A2-activity. A network model was constructed that could explain the mechanism through the influence of isoflurane on hypoxia inducible factor (HIF-1α) by upregulation of the hypoxia-inducible pathway and the downregulation of CYP1A2-activity via the ligand-inducible pathway. Thus, the increased anaerobic metabolism may result in lactate accumulation. The influence of isoflurane sedation on the validated correlation of global liver function with CYP1A2-activity measured by LiMAx testing needs to be investigated in more detail. [ABSTRACT FROM AUTHOR]

Background: More than 800 000 people die by suicide annually. The heritability of suicide is 30%–50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia‐inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single‐nucleotide polymorphism (SNP), in suicide completers and controls. Methods: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). Results: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. Conclusion: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF‐related genetic studies, including those of rs17004038, are necessary with larger sample sizes. [ABSTRACT FROM AUTHOR]

Introduction The aim of our study was to evaluate the efficacy of novel drugs from the group of hypoxia-inducible factor prolyl hydroxylase inhibitors, using roxadustat as an example, in the treatment of anemia occurring in kidney recipients. In the study, we included data from recent original papers that examined the efficacy of these drugs in the treatment of post-transplant anemia. We assumed an absolute increase in hemoglobin concentration as a factor expressing the effectiveness of the therapy. Aim of the study The aim of our study was to evaluate the efficacy of novel drugs from the group of hypoxia-inducible factor prolyl hydroxylase inhibitors, using roxadustat as an example, in the treatment of anemia occurring in kidney recipients. In the study, we included data from recent original papers that examined the efficacy of these drugs in the treatment of post-transplant anemia. We assumed an absolute increase in hemoglobin concentration as a factor expressing the effectiveness of the therapy. Materials and Methods This review was conducted using publications available in databases such as PubMed, Google Scholar, Scopus and ScienceDirect. These databases were searched using keywords such as hypoxia-inducible factor prolyl hydroxylase inhibitor, roxadustat, anemia, kidney transplant, posttransplant anemia, chronic kidney disease. The time range of published articles was set to 2017-2024, and some older publications were included if they were considered to bring valuable background information necessary for understanding the issue. Articles written in English and Polish were sought; however, all publications used in this review were in English. The main reason of bias of this study may be the limited group of participants that may not be sufficiently representative, the lack of randomization in some studies, and the limited number of publications in the problem area.

Objective(s): The primary gene mutations associated with nasopharyngeal carcinoma (NPC) are located within the phosphoinositide 3-kinase-mammalian target of rapamycin signaling pathways, which have inhibitory effects on autophagy. Compounds that target autophagy could potentially be used to treat NPC. However, autophagy-related molecular targets in NPC remain to be elucidated. We aimed to examine levels of autophagy-related genes, including autophagy-related 4B cysteine peptidase (ATG4B) and gamma-aminobutyric acid (GABA) type A receptor-associated protein-like 1 (GABARAPL1), in NPC cells and explored their potential role as novel targets for the treatment of NPC.Materials and Methods: The mRNA and protein expression of autophagy-related genes were detected in several NPC cells. Levels of GABARAPL1 were modified by either overexpression or knockdown, followed by examining downstream targets using RT-qPCR and western blotting. The role of GABARAPL1 in NPC proliferation and apoptosis was examined by flow cytometry. Furthermore, the role of GABARAPL1 was assessed in vivo using a nude mouse xenograft tumor model. The underlying mechanism by which GABARAPL1 regulated nasopharyngeal tumor growth was investigated.Results: Autophagy-related 4B cysteine peptidase (ATG4B), GABARAPL1, and Unc-51-like kinase 1 (ULK1) were significantly down-regulated in multiple NPC cell lines. Overexpression of GABARAPL1 up-regulated the expression of autophagy-related proteins, decreased the level of hypoxia-inducible factor (HIF)-2α, and induced apoptosis in NPC cells. Importantly, overexpression of GABARAPL1 slowed tumor growth. Western blotting showed that autophagy was activated, and HIF-2α was down-regulated in tumor tissues.Conclusion: HIF-2α, as a substrate for autophagic degradation, may play an interesting role during NPC progression.

Hypoxia inducible factors (HIF) are hypoxia-sensitive transcription factors that are the primary regulators of the cellular response to hypoxia. Hypoxia inducible factors induce inflammation, lipid metabolism, endothelial dysfunction, proliferation of vascular smooth muscle cells (VSMC), and regulate the development of cardiovascular diseases (CVD). This paper reviews the role of hypoxia inducible factors in CVD and the progress of the mechanism of action in recent years, and discusses the role and mechanism of hypoxia inducible factors on vascular constituent cell types and its relationship with the occurrence and development of CVD. It can provide a reference for analyzing the pathogenesis of CVD and discovering new therapeutic targets. The aim is to provide a theoretical reference for further understanding the role and mechanism of hypoxia inducible factors in the pathogenesis of CVD, and to provide a basis for the design of novel effective therapeutic agents targeting hypoxia inducible factors. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is one of the important complications of the perioperative period, and associated with increased risk of chronic kidney disease, renal replacement therapy requirements, increased cost, and risk of mortality. In this overview, we summarized baseline confounders and surgical procedure related risk factors contributing to the perioperative AKI, which may serve as risk scores, improve early diagnosis, contribute to prevention, and early management of AKI. There are immediate needs for context specific clinical prediction scores and novel biomarkers to very early diagnose AKI. Preventive guidance provided by Kidney Disease: Improving Global Outcomes is a helpful practical tool for clinicians. Potential roles of novel biomarkers and their context specific contributions require further exploration and close attention. Perioperative hemodynamics and oxygenation appear to contribute to AKI. Therefore, while their optimization can be recommended, their detailed and context specific roles need further explored. Overall, decreased exposure to nephrotoxic agents is recommended to further decrease the impact of perioperative AKI.

Preeclampsia is a placental vascular pathology and hypoxia is known to influence placental angiogenesis. Hypoxia Inducible Factors (HIF1α and HIF3α) mediate the response to cellular oxygen concentration and bind to hypoxia response element of target genes. However the mechanism regulating above activity is not well-understood. We investigated if placental DNA methylation (DNAm) and expression of HIF1α and 3α genes are altered and associated with pre-eclampsia, placental weight and birth outcomes. Using a cohort comprising women with preeclampsia [N = 100, delivering at term (N = 43) and preterm (N = 57)] and normotensive controls (N = 100), we analysed DNAm in HIF1α and 3α, and their mRNA expression in placentae, employing pyrosequencing and quantitative real-time PCR, respectively. We observed significant hypermethylation at cg22891070 of HIF3α in preeclampsia placentae compared to controls (β = 1.5%, p = 0.04). CpG8 in the promoter region of HIF1α, showed marginally significant hypomethylation in preterm preeclampsia compared to controls (β = − 0.15%, p = 0.055). HIF1α expression was significantly lower in preterm preeclampsia compared to controls (mean ± SE = 10.16 ± 2.00 vs 4.25 ± 0.90, p = 0.04). Further, DNAm in HIF1α promoter region was negatively associated with its expression levels (β = − 0.165, p = 0.024). Several CpGs in HIF1α were negatively associated with placental weight and birth outcomes including birth weight (β range = − 0.224–0.300) and birth length [β range = − 0.248 to − 0.301 (p < 0.05 for all)]. Overall, we demonstrate altered DNAm in HIF1α and HIF3α in preeclampsia placentae, also associated with various birth outcomes. Correlation of DNAm in HIF1α and its expression suggests a possible role in the pathogenesis of pre-eclampsia. Further investigations on interactions between HIF1α and HIF3α in preeclampsia would be interesting. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is one of the important complications of the perioperative period, and associated with increased risk of chronic kidney disease, renal replacement therapy requirements, increased cost, and risk of mortality. In this overview, we summarized baseline confounders and surgical procedure related risk factors contributing to the perioperative AKI, which may serve as risk scores, improve early diagnosis, contribute to prevention, and early management of AKI. There are immediate needs for context specific clinical prediction scores and novel biomarkers to very early diagnose AKI. Preventive guidance provided by Kidney Disease: Improving Global Outcomes is a helpful practical tool for clinicians. Potential roles of novel biomarkers and their context specific contributions require further exploration and close attention. Perioperative hemodynamics and oxygenation appear to contribute to AKI. Therefore, while their optimization can be recommended, their detailed and context specific roles need further explored. Overall, decreased exposure to nephrotoxic agents is recommended to further decrease the impact of perioperative AKI. [ABSTRACT FROM AUTHOR]

Purpose: To investigate potential beneficial effects of tocotrienols which have been suggested to inhibit hypoxia-inducible factor (HIF) pathway, on partial bladder outlet obstruction (PBOO)-induced bladder pathology. Materials and Methods: PBOO was surgically created in juvenile male mice. Sham-operated mice were used as controls. Animals received daily oral administration of either tocotrienols (T3) or soybean oil (SBO, vehicle) from day 0 to 13 post-surgery. Bladder function was examined in vivo by void spot assay. At 2 weeks post-surgery, the bladders were subjected to physiological evaluation of detrusor contractility in vitro using bladder strips, histology by H&E staining and collagen imaging, and gene expression analyses by quantitative PCR. Results: A significant increase in the number of small voids was observed after 1 week of PBOO compared to the control groups. At 2 weeks post-surgery, PBOO+SBO mice showed a further increase in the number of small voids, which was not observed in PBOO+T3 group. PBOO-induced decrease in detrusor contractility was similar between two treatments. PBOO induced bladder hypertrophy to the same degree in both SBO and T3 treatment groups, however, fibrosis in the bladder was significantly less prominent in the T3 group than the SBO group following PBOO (1.8- vs. 3.0-fold increase in collagen content compared to the control). Enhanced levels of HIF target genes in the bladders were observed in PBOO+SBO group, but not in PBOO+T3 group compared to the control. Conclusions: Oral tocotrienol treatment reduced the progression of urinary frequency and bladder fibrosis by suppressing HIF pathways triggered by PBOO.

The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor α (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. A previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα-Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα-Sox9 pathway in regulating OPC differentiation.SIGNIFICANCE STATEMENT Promoting disturbed developmental myelination is a promising option in treating diffuse white matter injury, previously called periventricular leukomalacia, a major form of brain injury affecting premature infants. In the developing CNS, hypoxia-inducible factor α (HIFα) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is severely disturbed in preterm infants affected with diffuse white matter injury, is incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFα-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury.

The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

Background: The study is aimed to investigate the metabolic alterations and changes in biochemical parameters associated with extended mask. Methods: It was a prospective comparative study conducted on 129 participants comprised of 37 healthy controls and 92 health care workers using different kind of masks like, cloth mask, surgical masks and N95-FFR/PPE. Two samples on day-1 and day-10 were collected for analysis of blood gas parameters, serum hypoxia-inducible factor-α (HIF-α), and erythropoietin (EPO). Results: Oxygen saturation percentage (sO2) of 72.68 (P = 0.033) was significantly low, whereas, Na+ (P = 0.05) and Ca2+ (P < 0.001) were raised in exposed individuals than the healthy controls. The serum HIF-α level of 3.26 ng/mL, was considerable higher in the exposed individuals than controls (P = 0.001). pO2 and sO2 were the lowest and HIF-α and EPO were raised in N95-FFR/PPE of all mask users (P < 0.01). A significant difference was evidenced for pCO2, pH, Na+, Ca2+, and EPO in the exposed group. A positive correlation between the duration of mask use (in hours) with HIF-α (r = 0.247, P = 0.005) and Ca2+ (r = 0.306, P < 0.001) was observed. The major complaints in N95-FFR/PPE users were headache (15.2%) and polydipsia (33.3%). Conclusion: The study findings depicted a significant metabolic alterations in PPE/N95 users which could be due to chronic hypoxic exposure of the tissues.

Objective To unravel the possible mechanism of the role of recombinant human high mobility group box 1 (rhHMGB1) protein in regulating the angiogenesis of endothelial cells. Methods Endothelial cells were divided into the control group, bone marrow mesenchymal stem cells (MSC) supernatant group and rhHMGB1 group. The proliferation and survival of endothelial cells were detected by cell counting kit(CCK)-8 assay. The relative expression levels of vascular endothelial growth factor (VEGF), Yes-associated protein (YAP), CD31 and hypoxia inducible factor (HIF)-1α proteins were determined by Western blot. The relative expression levels of VEGF, YAP, CD31 and HIF-1α messenger RNA (mRNA) were detected by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). The migration ability of endothelial cells was assessed by Transwell chamber test. The localization of YAP was detected by immunofluorescence staining. Results Compared with the control group, the migration rate of endothelial cells was increased in the rhHMGB1 group (P<0.05), and the cell migration rate was enhanced over time. Compared with the control group, the relative expression levels of VEGF and p-YAP proteins were up-regulated in the MSC supernatant group, and the differences were statistically significant (both P<0.05). Compared with the control group, the relative expression levels of VEGF and HIF-1α proteins, VEGF and CD31 mRNA and YAP and p-YAP proteins were up-regulated, and YAP/p-YAP ratio was increased in the rhHMGB1 group, and the differences were statistically significant (all P<0.05). Compared with the MSC supernatant group, the relative expression levels of CD31 mRNA and YAP protein were up-regulated, and the YAP/p-YAP ratio was increased in the rhHMGB1 group, and the differences were statistically significant (all P<0.05). Conclusions Exogenous high-concentration rhHMGB1 may promote the migration ability of endothelial cells and upregulate the expression levels of angiogenesis-related proteins by regulating the recruitment of YAP to the nucleus. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic disease that is characterized by intestinal inflammation. Epithelial damage and loss of intestinal barrier function are believed to be the hallmark pathologies of the disease. In IBD, the resident and infiltrating immune cells consume much oxygen, rendering the inflamed intestinal mucosa hypoxic. In hypoxia, the hypoxia-inducible factor (HIF) is induced to cope with the lack of oxygen and protect intestinal barrier. Protein stability of HIF is tightly controlled by prolyl hydroxylases (PHDs). Stabilization of HIF through inhibition of PHDs is appearing as a new strategy of IBD treatment. Studies have shown that PHD-targeting is beneficial to the treatment of IBD. In this Review, we summarize the current understanding of the role of HIF and PHDs in IBD and discuss the therapeutic potential of targeting PHD-HIF pathway for IBD treatment. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction and subsequent hypoxia. In patients with OSA, severity and number of these hypoxic events positively correlate with the extent of associated cardiovascular pathology. The molecular mechanisms underlying intermittent hypoxia (IH)-driven cardiovascular disease in OSA, however, remain poorly understood—partly due to the lack of adequate experimental models. Here, we present a novel experimental approach that utilizes primary human endothelial cells cultivated under shear stress. Oxygen partial pressure dynamics were adopted in our in vitro model according to the desaturation-reoxygenation patterns identified in polysomnographic data of severe OSA patients (n = 10, with 892 severe desaturations, SpO2<80%). Using western blot analysis, we detected a robust activation of the two major inflammatory pathways ERK and NF-κB in endothelial cells, whereas no HIF1α and HIF2α protein stabilization was observed. In line with these findings, mRNA and protein expression of the pro-inflammatory adhesion and signaling molecule ICAM-1 and the chemokine CCL2 were significantly increased. Hence, we established a novel in vitro model for deciphering OSA-elicited effects on the vascular endothelium. First data obtained in this model point to the endothelial activation of pro-inflammatory rather than hypoxia-associated pathways in OSA. Future studies in this model might contribute to the development of targeted strategies against OSA-induced, secondary cardiovascular disease. [ABSTRACT FROM AUTHOR]

IntroductionValve calcification (VC) is a widespread complication in chronic kidney disease (CKD) patients. VC is an active process with the involvement of in situ osteogenic transition of valve interstitial cells (VICs). VC is accompanied by the activation of hypoxia inducible factor (HIF) pathway, but the role of HIF activation in the calcification process remains undiscovered.Methods and resultUsing in vitro and in vivo approaches we addressed the role of HIF activation in osteogenic transition of VICs and CKD-associated VC. Elevation of osteogenic (Runx2, Sox9) and HIF activation markers (HIF-1α and HIF-2α) and VC occurred in adenine-induced CKD mice. High phosphate (Pi) induced upregulation of osteogenic (Runx2, alkaline-phosphatase, Sox9, osteocalcin) and hypoxia markers (HIF-1α, HIF-2α, Glut-1), and calcification in VICs. Down-regulation of HIF-1α and HIF-2α inhibited, whereas further activation of HIF pathway by hypoxic exposure (1% O2) or hypoxia mimetics [desferrioxamine, CoCl2, Daprodustat (DPD)] promoted Pi-induced calcification of VICs. Pi augmented the formation of reactive oxygen species (ROS) and decreased viability of VICs, whose effects were further exacerbated by hypoxia. N-acetyl cysteine inhibited Pi-induced ROS production, cell death and calcification under both normoxic and hypoxic conditions. DPD treatment corrected anemia but promoted aortic VC in the CKD mice model.DiscussionHIF activation plays a fundamental role in Pi-induced osteogenic transition of VICs and CKD-induced VC. The cellular mechanism involves stabilization of HIF-1α and HIF-2α, increased ROS production and cell death. Targeting the HIF pathways may thus be investigated as a therapeutic approach to attenuate aortic VC.

Lihong Chen,1 Yunyi Gao,2 Yan Li,1 Chun Wang,1 Dawei Chen,1 Yun Gao,1 Xingwu Ran1 1Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Medical Affairs, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xingwu Ran, Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guo Xue Lane, Chengdu, 610041, People’s Republic of China, Tel +86 028-85422046, Email ranxingwu@163.comBackground: Obstructive sleep apnea is prevalent in patients with diabetic foot ulcers, while the effect of intermittent hypoxia on wound healing is unclear. The objective of this study was to investigate the effect of severe intermittent hypoxia on wound healing.Methods: C57BL/6 mice were exposed to 5 weeks of severe intermittent hypoxia or normoxia. The wound healing rate were assessed. The gene expression of CD206 and HIF-2α was tested in vivo and in vitro. Inflammatory factors in RAW264.7 macrophages were measured to investigate the effect of intermittent hypoxia on macrophage polarization. The proliferation of HUVECs and HaCaT cells was also assessed after exposure to intermittent hypoxia.Results: Severe intermittent hypoxia decreased wound healing at day 3. The expression of CD206 and HIF-2α was significantly decreased after exposure to severe intermittent hypoxia. In vitro, severe intermittent hypoxia significantly promoted M1 phenotype polarization of RAW264.7 macrophages and increased the expression of proinflammatory factors (IL-1β and TNF-α). Severe intermittent hypoxia also decreased the proliferation of HUVECs cultured in endothelial cell medium and HaCaT cells cultured in high glucose DMEM.Conclusion: Severe intermittent hypoxia could lead to M1 but not M2 macrophage polarization through downregulation of HIF-2α, and then lead to impaired wound healing.Keywords: wound and injuries, intermittent hypoxia, wound healing, inflammation, hypoxia inducible factor

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We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified. Density of corpus callosal capillaries were measured after lectin staining and hypoxia measured by Hypoxyprobe. Numbers of oligodendrocytes were quantified by immunohistochemistry. We next used hypoxiamimesis as a surrogate to hypoxia by comparing cerebral hypoxia inducible factor (HIF) stabilization to hepatic HIF stabilization. Hyperoxia induced hypomyelination and a reduction of corpus callosal capillaries. Hyperoxia decreased numbers of oligodendrocytes with an increase in corpus callosal fibrosis and apoptosis. Cerebral hypoxiamimesis induced hypomyelination whereas hepatic hypoxiamimesis alone increased myelination, oligodendrocyte numbers, and corpus callosal capillary density. Hepatic HIF-1 dependence on myelination was confirmed using the cre/lox hepatic HIF-1 knockout. These findings suggest that hyperoxia can induce hypomyelination through vasoobliteration and subsequent ischemia, adding a potential oxygen induced mechanism to the diverse causes of periventricular leukomalacia of the severely preterm infant. Targeting hepatic HIF-1 alone led to increased myelination. [ABSTRACT FROM AUTHOR]

A 24-h hypoxia exposure experiment was conducted to determine how hypoxia exposure induce liver angiogenesis in largemouth bass. Nitrogen (N 2) was pumped into water to exclude dissolved oxygen into 1.2 ± 0.2 mg/L, and liver tissues were sampled during hypoxia exposure of 0 h, 4 h, 8 h, 12 h, 24 h and re-oxygenation for 12 h. Firstly, the results showed that hypoxia exposure promoted the angiogenesis occurrence by immunohistochemical analysis of vascular endothelial growth factor receptor 2 (VEGFR2). Secondly, the concentration of vasodilation factor increased and it's activity was elevated during 8 h exposure, such as nitric oxide (NO) and nitric oxide synthase (NOS) (p < 0.05). Thirdly, hypoxia exposure promoted angiogenesis through up-regulation the expression of matrix metalloproteinase 2 (MMP-2), jagged, protein kinase B (AKT), phosphoinositide-3-kinase (PI3K), mitogen-activated protein kinase (MAPK) at 4 h; contrarily, the expression of inhibiting angiogenesis genes presented up-regulated at 8 h (p < 0.05), such as matrix metalloproteinase inhibitor-2 (TIMP-2), matrix metalloproteinase inhibitor-3 (TIMP-3). Finally, the genes and proteins that regulate angiogenesis presented obvious chronological order. Parts of them promoted the budding and extension of blood vessels were up-regulated during 4 h–8 h (p < 0.05), such as vascular endothelial growth factor a (VEGFA), VEGFR2, monocarboxylic acid transporter 1 (MCT1), CD147, prolyl hydroxylase (PHD), nuclear factor kappa-B (NF-κB); other part of them promoted blood vessel maturation were highly expressed during 12 h–24 h (p < 0.05), such as angiogenin-1 (Ang-1) and angiogenin-2 (Ang-2). In short, acute hypoxia can promote the liver angiogenesis of largemouth bass by HIF - dependent pathway. • Hypoxia promote the liver angiogenesis in largemouth bass. • Hypoxia modulate VEGF pathway and downstream genes. • MCT1 and HIF pathway are key factors regulating angiogenesis during hypoxia exposure. [ABSTRACT FROM AUTHOR]

Objective To explore regulation mechanism of carboxyamidotriazole-orotate (CTO) on oncogenic phenotype of mouse glioma-associated macrophages. Methods Bone marrow-derived macrophages(BMDMs) or RAW264.7 macrophages (tumor associated macrophages,TAMs) were prepared by super-culture of mouse glioma GL261 cells. The mRNA of TAMs oncogenic mediators was detected by qPCR. The oxygen consumption rate (OCR) of TAMs was measured by Seahorse bioenergy method. The protein level of hypoxia-inducible factor-1 α(HIF-1α), hypoxia-inducible factor-2 α (HIF-2α) and peroxisome proliferator-activated receptor (PPAR) co-activator factor-1 β (PGC-1β) in TAMs was detected by Western blot. Results CTO decreased M1-related mediators such as IL-1β, IL-6 and TNF-α(P＜0.001) and M2-related mediators such as IL-10, ARG-1 and TGF-β1(P＜0.001) in TAMs. CTO significantly down-regulated OCR in TAMs (P＜0.01); The protein level of HIF-1α and of HIF-2α in TAMs was down-regulated by CTO(P＜0.01),which was contrary to the effect of carboxycyanide-4-trifluormethoxyphenylhydrazone (FCCP),which in turn promoted mitochondrial oxygen consumption. CTO significantly reduced PGC-1β protein in TAMs (P＜0.001),an effect consistent with rotenone(RTN), a mitochondrial respiratory chain inhibitor. Conclusions A decreased oxidative phosphorylation down-regulates the expression of PGC-1β and destabilizes HIF-1α and HIF-2α, thus affects the production of several M1 and M2 phenotypes of carcinogenic mediators in TAMs, which may be a potential mechanism through which CTO improves the chemotherapy efficacy of glioblastoma.

This study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS). An in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1–5 (all p<0.0001). Combined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents. [Display omitted] • Dapagliflozin modulated cell stress signalings through augmentation of anti-oxidants and hypoxia-induced factor (HIF)-1α. • Roxadustat stabilized the HIF-1α level and enhanced generation of angiogenesis factors. • Combined Dapagliflozin-Roxadustat offered a synergistic effect on cardiorenal protection against CRS-associated damages. [ABSTRACT FROM AUTHOR]

[Display omitted] Hypoxia-inducible factors (HIF) are interesting targets for multiple therapeutic indications. While HIF activation is desired for the treatment of anemia-related and ischemic diseases, HIF inhibition is of tremendous interest to anti-cancer drug development. Different signaling events within the HIF pathway are being targeted by drug discovery programs, with a special interest in HIF-selective (possibly also HIF1/2 isoform-selective) compounds. In this study, we applied recently developed cell-based split-nanoluciferase HIF heterodimerization assays to study the effects of compounds, targeting HIF activity by various mechanisms of action. This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Changes in treatment time and in the assay protocol allowed to assess direct and indirect effects on HIFα-HIFβ heterodimerization. In addition to the evaluation of applications of these new bioassays regarding pharmacological characterizations, benefits and considerations are discussed related to the use of cellular, luminescent-based bioassays. Briefly, benefits include the bidirectional nature of the biological readout, the upstream mechanism of detection, the differentiation between HIF1 and HIF2 effects and the simulation of various conditions. Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols. [ABSTRACT FROM AUTHOR]

The clear cell renal cell carcinoma (ccRCC) is the most frequent and the most aggresive subtype of renal cell carcinoma usually detected at an already advanced stage. It might even be observed as a metabolic disease since complex molecular changes and disturbed redox homeostasis are its hallmark. As certain changes are characteristic for tumorigenesis, while some other for metastatic disease, the identification of metabolic modifications could also point out the stage of tumor progression. Hypoxia inducible factor, as a factor regulating transcription of genes encoding glycolytic enzymes, as well as controlling lipid accumulation, has a particular place in ccRCC development. Additionaly, disturbed redox homeostasis induces the Keap1/Nrf2 pathway which further modulates the synthesis of phase-II detoxifying metabolism enzymes. The upregulation of glutathione transferases, Pi class especially, inhibits kinase-dependent apoptosis that is essential in tumor progression. Furthermore, hydrogen peroxide (H2O2) acts as a signaling molecule conveying redox signals, while superoxide dismutase, as well as glutathione peroxidase are enzymes involved in its production and degradation. Hence, the activity of these enzymes impacts hydrogen peroxide levels and consequentially the ability of ccRCC cells to evade negative effect of reactive oxygen species.

Oxygen‐sensing mechanisms have evolved to allow organisms to respond and adapt to oxygen availability. In metazoans, oxygen‐sensing is predominantly mediated by the hypoxia inducible factors (HIFs). These transcription factors are stabilised when oxygen is limiting, activating genes involved in angiogenesis, cell growth, pH regulation and metabolism to reset cell function and adapt to the cellular environment. However, the recognition that other cellular pathways and enzymes can also respond to changes in oxygen abundance provides further complexity. Dissecting this interplay of oxygen‐sensing mechanisms has been a key research goal. Here, we review how genetic approaches have contributed to our knowledge of oxygen‐sensing pathways which to date have been predominantly focused on the HIF pathway. We discuss how genetic studies have advanced the field and outline the implications and limitations of such approaches for the development of therapies targeting oxygen‐sensing mechanisms in human disease. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nvAMD) is the leading cause of severe vision loss in the elderly in the developed world. While the introduction of therapies targeting vascular endothelial growth factor (VEGF) has provided the first opportunity to significantly improve vision in patients with nvAMD, many patients respond inadequately to current anti-VEGF therapies. It was recently demonstrated that expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4), synergizes with VEGF to promote choroidal neovascularization (CNV) in mice and correlates with reduced response to anti-VEGF therapy in patients with nvAMD. Here, we report that expression of ANGPTL4 in patients with nvAMD increases following treatment with anti-VEGF therapy and that this increase is dependent on accumulation of hypoxia-inducible factor (HIF)-1α in response to inhibition of VEGF/KDR signaling in the retinal pigment epithelium (RPE). We therefore explored HIF-1 inhibition with 32-134D, a recently developed pharmacologic HIF-inhibitor, for the treatment of nvAMD. 32-134D prevented the expression of both VEGF and ANGPTL4 and was at least as effective as aflibercept in treating CNV in mice. Moreover, by preventing the increase in HIF-1α accumulation in the RPE in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective than either drug alone for the treatment of CNV. Collectively, these results help explain why many patients with nvAMD respond inadequately to anti-VEGF therapy and suggest that the HIF inhibitor 32-134D will be an effective drug-alone or in combination with current anti-VEGF therapies-for the treatment of patients with this blinding disease., Competing Interests: Competing interests statement:G.L.S. and A.S. are co-founders of and hold equity in HIF Therapeutics, Inc. S.S., Y.H., G.L.S., and A.S. are inventors on provisional patent application PCT/US2022/039883. This arrangement has been reviewed and approved by the Johns Hopkins University in accordancewith its conflict of interest policies.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective which highlights the importance of HIF isoform-specific targeting as a novel salutary strategy for PAH treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mitra, Yi, Dai and de Jesus Perez.)

The developmental regulation of body size is a fundamental life-history characteristic that in most animals is tied to the transition from juvenile to adult form. In holometabolous insects, this transition is ostensibly initiated at the attainment of a critical weight in the final larval instar. It has been hypothesized that the size-sensing mechanism used to determine attainment of critical weight exploits oxygen limitation as a larvae grows beyond the oxygen-delivery capacity of its fixed tracheal system; that is, developmentally induced cellular hypoxia initiates the synthesis of the molting hormone ecdysone by the prothoracic gland. We tested this hypothesis in Drosophila by assaying cellular hypoxia throughout the third larval instar at 21 and 10 kPa O2, using the activity of the HIF (hypoxia inducible factor)-signaling pathway as a measure of hypoxia. While HIF signaling was elevated at low levels of environmental O2, it did not markedly increase during development at either oxygen level, and was only suppressed by hyperoxia after feeding had ceased. Further, changes in HIF signaling in the prothoracic gland alone did not alter body size or developmental time in a way that would be expected if cellular hypoxia in the prothoracic gland was part of the critical weight mechanism. Our data do show, however, that reduced HIF signaling in the prothoracic gland decreases survival and retards development at 10 kPa O2, suggesting that prothoracic HIF signaling is a necessary part of the beneficial plasticity mechanism that controls growth and development in response to low oxygen level., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Hypoxic-ischemic encephalopathy (HIE) in newborns is associated with high morbidity and mortality, with many babies suffering long-term neurological deficits. Currently, treatment options are limited to therapeutic hypothermia, which is not appropriate for use in all babies. Previous studies have shown protective effects of increasing the transcription factor--hypoxia-inducible factor-1 (HIF-1) in animal models, by using mild hypoxia or compounds that act as prolyl hydroxylase inhibitors (PHIs). Here, we aimed to examine the neuroprotective actions of an orally active, small molecule PHI, GSK1120360A in a neonatal rat model of hypoxia-ischemia (HI) compared to another PHI, desferrioxamine (DFX). Sprague-Dawley rats underwent HI surgery on postnatal day 7 (P7), where unilateral carotid artery occlusion was performed followed by hypoxia (8% oxygen, 3 h). Initial testing showed that GSK1120360A and erythropoietin levels were detectable in plasma at 6 h following oral exposure to GSK1120360A. For the short- term neuroprotection study, pups were assigned to receive either saline (s.c), desferrioxamine (DFX-200 mg/kg, s.c), methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. Histological analysis showed that GSK1120360A in this setting reduced brain injury size 7 days after HI, compared to the methylcellulose vehicle control group. DFX had no significant effect on injury size compared to saline group at the same 7 day timepoint. In the long-term neuroprotection study, pups were randomly assigned to be administered methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. On P42, rats underwent behavioural testing using the forelimb grip strength, grid walking and novel object recognition tasks, and brains were collected for histological analysis. Long-term behavioural deficits were observed in grid walking, grip strength and novel object recognition tests after HI which were not improved in the GSK1120360A treatment group compared to the methylcellulose group. Similarly, there was no improvement in injury size on P42 in the GSK1120360A study group compared to the methylcellulose group. Here, we have shown that GSK1120360A can reduce brain injury at 7 days but that this neuroprotective benefit is not maintained when examined at 5 weeks after HI. [ABSTRACT FROM AUTHOR]

BACKGROUND: At present, exosomes have made remarkable progress as new biomarkers for disease diagnosis in hypoxia-related diseases and tumor diseases, and have become potential players in the prevention and treatment of hypoxia-related diseases. OBJECTIVE: To explore the mechanism of exosomes interference with hypoxia-related signaling pathways to change the occurrence and development of hypoxia-related diseases at the molecular level, so as to provide a basis for the research and treatment of hypoxia-related diseases. METHODS: Using the search terms of “hypoxia, exosomes, signal pathway” in Chinese and English, articles published from January 2016 to May 2021 were retrieved from PubMed, Medline, CNKI, and Wanfang databases. Finally, 56 articles were included for analysis. RESULTS AND CONCLUSION: (1) In hypoxic environment, exosomes are closely related to some hypoxia-related signaling pathways. Exosomes-mediated hypoxia signaling pathways may be involved in altering the pathogenesis of hypoxia-related diseases and tumor. (2) Through hypoxia inducible factor, phosphatidylinositol 3-kinase/serine/threonine kinase, nuclear factor κB, transforming growth factor β and other hypoxia-related signaling pathways, exosomes released by donor cells, carrying their information and accepted by recipient cells, mediate important physiological and pathological processes, such as immune response, cell proliferation, migration, angiogenesis, and tumor invasion in diseases. (3) In hypoxia-related inflammatory diseases, exosomes can induce the activation of the above-mentioned hypoxia signaling pathways to reduce inflammatory damage. (4) However, in tumor diseases, exosomes mediate the activation of above hypoxia-related signaling pathways, which accelerate the angiogenesis of tumor sites and promote the invasion and metastasis of tumor cells, resulting in the progression of tumor. This effect may be associated with the cell origin of exosomes. Further exploration is needed to understand its specific regulatory mechanism. [ABSTRACT FROM AUTHOR]

Simple Summary: Thoraco-abdominal paraganglioma and pheochromocytoma (PPGL) are pathogenically linked to mutations in SDH genes. Loss-of-function of SDH has been associated with stabilization of HIF2α, which otherwise would be degraded via oxygen-sensitive mechanisms. SDH dysfunction also predispose to the development of paragangliomas arising at the carotid body or other head and neck paraganglia (HNPGL). Although PPGL and HNPGL share similar features, they have certain clinical and genetic peculiarities. By comparison of HIF2α expression in HNPGL and PPGL, we found that functional HIF2α is overexpressed in 80% of PPGLs, including those with SDH mutations as compared with non-tumor tissue. However, HIF2α is already highly expressed in the carotid body under physiologic conditions, and it is not overexpressed in HNPGL. These data suggest that selective HIF2α inhibitors already in clinical trials may benefit a wide spectrum of PPGL. Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2α-regulated genes COX4I2 and ADORA2A. In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent. [ABSTRACT FROM AUTHOR]