Annexin A2 (Anxa2), a multifunctional protein with RNA-binding capabilities, is frequently overexpressed in various tumors, and its expression is highly correlated with malignant progression. In this study, we demonstrate for the first time that Anxa2 was co-expressed with glycolytic genes, suggesting its potential role as a regulator of glycolysis. RNA-protein interaction assay revealed that Anxa2 interacted with 3'-UTR of H2AX mRNA and protected it from miRNA-mediated degradation. Up-regulated Histone-H2AX enhances the expression of glycolytic genes including GLUT1, HK2, PGK1, ENO1, PKM2, GAPDH and LDHA via stabilizing hypoxia-inducible factor 1-alpha (HIF1α), thereby accelerating lactic acid production and secretion. (20S) G-Rh2, a natural compound targeting Anxa2, significantly interfered the Anxa2-H2AX mRNA interaction, and inhibited subsequent glycolysis progression. We propose that Anxa2 acts as a novel regulator in glycolysis via enhancing H2AX expression, and (20S) G-Rh2 may exert its anti-cancer activity by targeting Anxa2-H2AX-HIF1α-glycolysis axis in human hepatoma HepG2 cells.

Therapeutic angiogenesis offers a promising strategy for patients with critical limb-threatening ischemia (CLTI) who are unsuitable candidates for revascularization. However, the optimal administration sites for gene therapy agents, such as pCK-HGF-X7, remains undefined. Clinical trials commonly employ multiple intramuscular injections at sites of arterial occlusion; yet the necessity and efficacy of such extensive and repetitive protocols remains unclear. Targeted injections into ischemic tissues or their margins may improve therapeutic outcomes. Moreover, the molecular mechanisms by which hepatocyte growth factor (HGF)/c-Met signaling regulates hypoxia-inducible factor-1α (HIF-1α) expression under hypoxic conditions are not fully understood. This study aims to elucidate these molecular mechanisms in endothelial cells under hypoxic conditions and to identify the most effective injection sites for therapeutic angiogenesis agents. The effects of various HGF isoforms/complexes on human aortic endothelial cells (HAECs) were evaluated under normoxic and hypoxic conditions, focusing on proliferation, migration, and tube formation. Pathway inhibitors were used to explore the underlying mechanisms in hypoxic HAECs, and the findings were validated in a rat hindlimb ischemia model. Results demonstrated that HGF723 and HGF728 activated the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, regulating HIF expression and significantly enhanced endothelial cell proliferation, migration, and tube formation, particularly under hypoxia. Despite these cellular effects, HGF treatment did not significantly improve tissue perfusion or neovascularization in normal rat hindlimbs. However, in ischemic rat hindlimbs, it markedly promoted angiogenesis and improved tissue perfusion in the gastrocnemius muscle. These findings indicate that therapeutic angiogenesis agents should primarily target hypoxic tissues, extending to the interface between normoxic and hypoxic regions, to optimize treatment efficacy.

Hypoxia is a hallmark of the tumor microenvironment (TME), and it plays a crucial role in the occurrence and progression in vascular tumors. Under hypoxic conditions, hypoxia-inducible factor 1-alpha (HIF-1α) is stabilized, inducing changes in the expression of various target genes involved in angiogenesis, metabolism, and cell survival. This includes the upregulation of pro-angiogenic factors like VEGF, which promotes the formation of dysfunctional blood vessels, contributing to the worsening of the hypoxic microenvironment. At the same time, hypoxia induces a metabolic shift toward glycolysis, even in the presence of oxygen, supporting tumor cell survival and proliferation by providing necessary energy and biosynthetic precursors. This review discusses the molecular mechanisms by which hypoxia regulates angiogenesis and metabolic reprogramming in vascular tumors, highlighting the intricate link between these processes, and explores potential therapeutic strategies to target these pathways in order to develop effective treatment strategies for patients.

A mid-IR laser absorption spectrometer configured with an interband cascade laser (ICL) was used to measure acetaldehyde concentrations in the headspace gas of cell culture media samples obtained from the culturing of breast cancer cells in a flow perfusion bioreactor. Measurements were performed by bubbling lab air through a media sample and passing the exhaust gas through a long optical path gas cell where rotational-vibrational modes of acetaldehyde were excited by the ICL. Acetaldehyde concentrations were determined from peak-to-peak voltages for the two strongest acetaldehyde absorption features within a spectral region spanning 1770.20 cm-1 to 1770.35 cm-1. Three different media samples obtained from cells cultured with the same nominal conditions had headspace acetaldehyde concentrations of 412 ppb, 513 ppb, and 390 ppb, while two media samples with imposed hypoxia or cobalt chloride stabilization of hypoxia inducible factor 1-alpha (HIF-1α) had higher acetaldehyde concentrations, 815 ppb and 536 ppb, respectively. These results establish experimental proof-of-concept for the ability of mid-IR laser absorption spectroscopy to measure acetaldehyde in cell culture media headspace, allowing observation of HIF-1α driven shifts in cancer cell metabolism.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Although advances in targeted agents have greatly improved the prognosis of patients with AML in recent years, those who fail to achieve remission or relapse after remission are still in urgent need of novel therapeutic strategies. The hypoxia signaling pathway is involved in various biological processes, and hypoxia-inducible factor alpha (HIF-α) is considered a potential therapeutic target in AML. The bone marrow microenvironment is known to be in a state of chronic hypoxia, which is important for hematopoietic stem cells to maintain quiescence, and provides leukemic stem cells with a refuge from immune defenses and chemotherapeutic agents. Therefore, this review aims to explore the role of the HIF-α signaling pathway in the development of AML.

Infection generates localized hypoxia in affected tissue, inducing cellular survival responses and modulating inflammatory processes. Consideration of oxygen status as a parameter in in vitro infection research is therefore vital to the generation of physiologically relevant data within the 3R context. In this study, we characterize the culture morphology and oxygenation of liquid-liquid interface (LLI) permanent bronchial epithelial (Calu-3), classical air-liquid interface (cALI) Calu-3, and cALI human primary bronchial epithelial cell (hBEC) models under the normoxic conditions within standard incubators, commonly employed in in vitro work. We compare the normoxic state of these models to their hypoxic state to assess changes in the airway epithelial environment in response to oxygen deprivation, and the extent to which select hypoxia responses can be observed at the molecular level. Additional juxtapositions are drawn between Calu-3 LLI and cALI models and Calu-3 conventional monolayer (CM) and inverted air-liquid interface (iALI) models, due to their relevance for basic and specialized research, respectively. Epithelial complexity was observed to vary amongst the filter-based models, and all models were found to exhibit characteristic extracellular oxygen depletion patterns under normoxia. Importantly, the extracellular oxygen contents of Calu-3 LLI, cALI, and CM models significantly decreased during normoxic incubation. Specific hypoxia responses through stabilization of HIF-1α, HIF-2α, and/or HIF-3α and alteration of ACE2 protein levels differed in response to both culture format and cell type. Therefore, while all models examined provide valuable opportunities for in vitro exploration, variation in their morphological, physiological, and molecular characteristics necessitates careful consideration during experimental design.

Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

Oxygen shortage, known as hypoxia, occurs commonly in both physiological and pathological conditions. Transcriptional regulation by hypoxia-inducible factors is a dominant regulatory mechanism controlling hypoxia-responsive genes during acute hypoxia; however, recent studies suggest that post-transcriptional regulation, including RNA degradation, also involves hypoxia-induced gene expression during the chronic hypoxia. In this study, we developed a method to quantify the contributions of RNA synthesis and degradation to differential gene expression, and identified 102 genes mainly regulated via RNA degradation under chronic hypoxia in HCT116 cells. Bioinformatics analysis showed that the genes mainly regulated by RNA degradation were involved in glycolysis. We examined changes in the RNA-binding ability of RNA-binding proteins by RNA interactome capture and statistical analysis using public databases. We identified fragile X messenger ribonucleoprotein 1 (FMRP) as an RNA-binding protein involved in the chronic hypoxia-induced increase in mRNAs encoding rate-limiting enzymes. This study emphasizes the importance of post-transcriptional gene regulation under chronic hypoxia in HCT116 cells.

Multiomics analysis at the single-cell level is essential for both fundamental research and clinical applications, with proteomics and metabolomics being particularly crucial for providing insights into cellular states and functions. The state of the art flow cytometry has shown great potential in identifying cellular proteins, while emerging metabolite mass spectrometry cytometry techniques address metabolite detection. Herein, we propose a tandem platform that integrates fluorescence flow cytometry with electrospray ionization mass spectrometry for one-step single-cell analysis of protein and metabolites. An algorithm was established to correlate multidimensional information in individual cells, with additional data processing modules designed to ensure accuracy and facilitate further analysis. The tandem cytometry platform demonstrated efficacy in profiling breast cancer cells, particularly under hypoxic conditions, revealing metabolic shifts with decreased glutathione and increased l-glutamine levels, indicative of hypoxia-inducible factor activity. This platform introduces a powerful analytical capability that promises to elevate the precision of cell-based diagnostics and therapeutic strategies.

Aims: Sepsis progression is marked by a complex immune response, where the involvement of hypoxia-inducible factors (HIFs) plays an uncertain role. The study aims to elucidate the involvement of HIF-1α in monocyte function during sepsis and its potential as a prognostic indicator. Methods and Results: Transcriptomic data from healthy individuals and septic patients in datasets GSE54514, GSE167363, and GSE46955 were analyzed. Additionally, human monocytes were employed to elucidate how HIF regulates immune responses in the context of sepsis. Septic nonsurvivors exhibited sustained upregulation of HIF-1α expression alongside compromised inflammatory response and antigen presentation, with downregulation of NF-κB and HLADRB1 genes associated with poor sepsis prognosis. Conversely, septic survivors displayed an increased proportion of classical monocytes and enhanced inflammation and expression of antigen presentation-related genes. During the recovery phase of sepsis, monocytes continued to demonstrate elevated HIF-1α expression. In cultured THP1 cells and septic CD14 + monocytes, HIF hindered inflammatory responses and antigen presentation, while also suppressing the proportion of classical monocytes after LPS stimulation. Mechanistically, HIF significantly attenuated LPS-induced immune responses in monocytes by inhibiting the phosphorylation of IKK. Conclusions: HIF in monocytes acts as a suppressor of immune-inflammatory responses and antigen presentation, and may serve as a negative molecular marker for sepsis development.

Hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular adaptation to hypoxia, drives colorectal cancer (CRC) progression by fueling angiogenesis, metastasis, and therapy resistance. Emerging evidence delineates intricate crosstalk between non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, and circular RNAs-and HIF-1α, forming bidirectional regulatory networks that orchestrate CRC pathogenesis. By interacting with HIF-1α, these non-coding RNAs contribute to the orchestration of the aggressive hypoxic tumor microenvironment. Recent studies have evaluated the clinical potential of lncRNAs and miRNAs in the realms of non-invasive liquid biopsies and RNA-targeted therapies. This review offers a comprehensive synthesis of recent investigations into the mechanisms by which lncRNAs and miRNAs interact with HIF-1α to modulate CRC progression. Additionally, we further explore the clinical implications of ncRNA/HIF-1α crosstalk, emphasizing their potential as diagnostic biomarkers and therapeutic targets, while also spotlighting intriguing and promising areas of ncRNA research. Methods: In this study, our search strategy employed in databases such as PubMed, Web of Science, and EMBASE is as follows: we will specify search terms, including combinations of "non-coding RNA", "HIF-1α", and "colorectal cancer", along with a date range for the literature search (for example, from 2000 to 2025) to capture the most relevant and up-to-date research.

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge due to its late diagnosis and intrinsic treatment resistance, exacerbates by its development from chronic inflammation to cancer transition (ICT). Here, this investigation aims to develop and evaluate ABSi-148, a novel near-infrared (NIR) agent targeting hypoxic carbonic anhydrase IX (CA IX), for its potential applications in ICT imaging and even PDAC treatment. ABSi-148 is synthesized from 4-(2-Aminoethyl) benzene sulfonamide (ABS), a sulfonamide derivative, conjugating with MHI-148 dye with merits of exceptional NIR-emitting traits, high biocompatibility, and deep tissue penetration imaging capability. It selectively accumulates in CoCl2-induced pancreatic stellate cells and pancreatic cancer cells via binding with transmembrane CA IX in vitro. Meanwhile, ABSi-148 effectively visualizes the early pancreatic lesion, and its long-term administration inhibits the progression of hypoxia-related fibrosis involved in pancreatic intraepithelial neoplasias (PanINs), and even PDAC progression in vivo. Besides, ABSi-148 monitors treatment efficacy and localizes hypoxic tumor regions, enhancing survival in tamoxifen combined with caerulein-induced KPC mice. Overall, ABSi-148 emerges as a theranostic NIR agent for precise diagnosis and targeted therapy in ICT of PDAC, promising to alleviate tumor progression and enhancing outcomes.

Hematopoietic stem cell (HSC) mobilization is often difficult to achieve in patients suffering from multiple myeloma and non-Hodgkin's lymphoma. Granulocyte-colony stimulating factor (G-CSF) therapy alone has often not led to the desired outcomes. Herein, we describe the discovery of 7-cyclohexyl-4-hydroxy-8-oxo-N-(pyridazin-4-ylmethyl)-7,8-dihydro-2,7-naphthyridine-3-carboxamide 13, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which was discovered by focusing on drug-like properties. Building on a previous discovery that HIF-PH inhibitors can enhance HSC mobilization in combination with G-CSF, we optimized 13 to exhibit high PHD2 potency, improved solubility, and an optimized PK profile. 13 was effective at enhancing G-CSF-induced HSC mobilization in mice at a dose of 2 mg/kg.

Radiotherapy is one of the primary modalities for oncologic treatment and has been utilized at least once in over half of newly diagnosed cancer patients. Cranial radiotherapy has significantly enhanced the long-term survival rates of patients with brain tumors. However, radiation-induced brain injury, particularly hippocampal neuronal damage along with impairment of neurogenesis, inflammation, and gliosis, adversely affects the quality of life for these patients. Astrocytes, a type of glial cell that are abundant in the brain, play essential roles in maintaining brain homeostasis and function. Despite their importance, the pathophysiological changes in astrocytes induced by radiation have not been thoroughly investigated, and no systematic or comprehensive review addressing the effects of radiation on astrocytes and related diseases has been conducted. In this paper, we review current studies on the neurophysiological roles of astrocytes following radiation exposure. We describe the pathophysiological changes in astrocytes, including astrogliosis, astrosenescence, and the associated cellular and molecular mechanisms. Additionally, we summarize the roles of astrocytes in radiation-induced impairments of neurogenesis and the blood-brain barrier (BBB). Based on current research, we propose that brain astrocytes may serve as potential therapeutic targets for treating radiation-induced brain injury (RIBI) and subsequent neurological and neuropsychiatric disorders.

Epitranscriptomics, the study of RNA modifications such as N6-methyladenosine (m6A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m6A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance.

This review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m6A writers, readers, and erasers. HIF-1 modulates the expression of key m6A components, while its own mRNA is regulated by m6A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m6A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation.

The intricate interplay between m6A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.

Ascorbic acid, the reduced form of vitamin C, is a ubiquitous small carbohydrate. Despite decades of focused research, new metabolic functions of this universal electron donor are still being discovered and add to the complexity of our view of vitamin C in human health. Although praised as an unsurpassed water-soluble antioxidant in plasma and cells, the most interesting functions of vitamin C seem to be its roles as specific electron donor in numerous biological reactions ranging from the well-known hydroxylation of proline to cofactor for the epigenetic master regulators ten-eleven translocation enzymes and Jumonji domain-containing histone-lysine demethylases. Some of these functions may have important implications for disease prevention and treatment and have spiked renewed interest in, eg, vitamin C's potential in cancer therapy. Moreover, some fundamental pharmacokinetic properties of vitamin C remain to be established including if other mechanisms than passive diffusion governs the efflux of ascorbate anions from the cell. Taken together, there still seems to be much to learn about the pharmacology of vitamin C and its role in health and disease. This review explores new avenues of vitamin C and integrates our present knowledge of its pharmacology. SIGNIFICANCE STATEMENT: Vitamin C is involved in multiple biological reactions of which most are essential to human health. Hundreds of millions of people are considered deficient in vitamin C according to accepted guidelines, but little is known about the long-term consequences. Although the complexity of vitamin C's physiology and pharmacology has been widely disregarded in clinical studies for decades, it seems clear that a deeper understanding of particularly its pharmacology holds the key to unravel and possibly exploit the potential of vitamin C in disease prevention and therapy.

Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated HIF-1 and HIF-2 levels with an aggressive tumor phenotype and poor patient outcome. Despite extensive validation as a target in cancer, pharmaceutical targeting of HIFs, particularly the interaction between α and βsubunits that forms the active transcription factor, has proved challenging. Nonetheless, many indirect inhibitors of HIFs have been identified, targeting diverse parts of this pathway. Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.

Many oncogenic transcription factors (TFs) are considered to be undruggable because of their reliance on large protein-protein and protein-DNA interfaces. TFs such as hypoxia-inducible factors (HIFs) and X-box-binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to unfolded protein response element (UPRE) and hypoxia-induced response element (HRE) motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the basic leucine zipper domain of XBP1 and recognize UPRE and HRE motifs. A lead molecule, STR22, binds UPRE and HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1α binding to HRE-containing promoters and enhancers, inhibits hypoxia-induced gene expression and blocks protumorigenic phenotypes in triple-negative breast cancer (TNBC) cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF-DNA binding.

Joint tissues affected by inflammatory arthritis (IA) create hypoxic microenvironments that sustain the inflammatory response. Although targeting molecules in hypoxia-induced pathways has provided valuable insights into potential novel therapies for various types of IA, progress remains preclinical, and no clinical trials have been conducted for IA.

A literature search was conducted to create a narrative review exploring the role of hypoxia and its signaling pathways in IA pathogenesis, as well as the potential and future directions for IA therapies that target hypoxia-induced molecules before moving forward to clinical applications.

Hypoxia is a prevalent feature of the IA synovial microenvironment and contributes to disease progression. Various studies and preclinical models demonstrate how hypoxia-inducible factors, vascular endothelial growth factors, and matrix metalloproteinases, among other molecules, influence rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Despite these findings, drug development targeting these molecules in IA has been limited due to challenges in delineating the mechanistic pathways of hypoxia, the distinct roles of hypoxia-induced molecules depending on anatomical sites, and concerns regarding pharmacokinetics and patient safety. However, given that hypoxia-induced molecule-targeting therapies have been successfully approved for treating cancers and cardiovascular diseases, further research is needed to advance the application of similar medications in IA.

Given the pathogenic effects of hypoxic microenvironments in IA, it is imperative to continue gathering compelling evidence to advance hypoxia-induced therapies. Furthermore, elucidating the safety and efficacy of such drugs in various preclinical models, in collaboration with chemists and the pharmaceutical industry, is crucial for accelerating the development of novel, optimized treatment methods.

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species are defined by their genomes, and differences between individuals within a given species directly result from variations in their genetic codes. While genetic alterations can give rise to disease-causing acquisitions of distinct cell identities, it is now well-established that biochemical imbalances within a cell can also lead to cellular dysfunction and diseases. Specifically, nongenetic chemical events orchestrate cell metabolism and transcriptional programs that govern functional cell identity. Thus, imbalances in cell signaling, which broadly defines the conversion of extracellular signals into intracellular biochemical changes, can also contribute to the acquisition of diseased cell states. Metal ions exhibit unique chemical properties that can be exploited by the cell. For instance, metal ions maintain the ionic balance within the cell, coordinate amino acid residues or nucleobases altering folding and function of biomolecules, or directly catalyze specific chemical reactions. Thus, metals are essential cell signaling effectors in normal physiology and disease. Deciphering metal ion signaling is a challenging endeavor that can illuminate pathways to be targeted for therapeutic intervention. Here, we review key cellular processes where metal ions play essential roles and describe how targeting metal ion signaling pathways has been instrumental to dissecting the biochemistry of the cell and how this has led to the development of effective therapeutic strategies.

Hypoxia, or a state of low tissue oxygenation, has been characterized as an important feature of solid tumors that is related to aggressive phenotypes. The cellular response to hypoxia is controlled by Hypoxia-inducible factors (HIFs), a family of transcription factors. HIFs promote the transcription of gene products that play a role in tumor progression including proliferation, angiogenesis, metastasis, and drug resistance. HIF-1 and HIF-2 are well known and widely described. Although these proteins share a high degree of homology, HIF-1 and HIF-2 have non-redundant roles in cancer. In this review, we summarize the similarities and differences between HIF-1α and HIF-2α in their structure, expression, and DNA binding. We also discuss the canonical and non-canonical regulation of HIF-1α and HIF-2α under hypoxic and normal conditions. Finally, we outline recent strategies aimed at targeting HIF-1α and/or HIF-2α.

MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs that target messenger RNAs, leading to their repression or decay. Interestingly, miRNAs play a role in the cellular response to low oxygen levels, known as hypoxia, which is associated with reactive oxygen species and oxidative stress. However, the physiological implications of hypoxia-induced miRNAs ("hypoxamiRs") remain largely unclear. Here, we investigate the role of miR-210 in brown adipocyte differentiation and thermogenesis. We treated the cells under sympathetic stimulation with hypoxia, CoCl2, or IOX2. To manipulate miR-210, we performed reverse transfection with antagomiRs. Adipocyte markers expression, lipid accumulation, lipolysis, and oxygen consumption were measured. Hypoxia hindered BAT differentiation and suppressed sympathetic stimulation. Hypoxia-induced HIF-1α stabilization increased miR-210 in brown adipocytes. Interestingly, miR-210-5p enhanced differentiation under normoxic conditions but was insufficient to rescue the inhibition of brown adipocyte differentiation under hypoxic conditions. Although adrenergic stimulation activated HIF-1α signaling and upregulated miR-210 expression, inhibition of miR-210-5p did not significantly influence UCP1 expression or oxygen consumption. In summary, hypoxia and adrenergic stimulation upregulated miR-210, which impacted brown adipocyte differentiation and thermogenesis. These findings offer new insights for the physiological role of hypoxamiRs in brown adipose tissue, which could aid in understanding oxidative stress and treatment of metabolic disorders.

Hypoxia-inducible factors (HIF) regulate gene transcription, which aids hypoxia adaptation while promoting renal fibrosis. Non-transferrin-bound iron (NTBI) is a catalytic form of iron that can lead to oxidative damage. However, NTBI in cat biofluids has rarely been evaluated.

We assessed cat plasma and urine HIF-1α (pHIF-1α/uHIF-1α) concentrations and urine NTBI (uNTBI) concentrations to investigate their relationship with chronic kidney disease (CKD) severity.

pHIF-1α and uHIF-1α concentrations were measured using commercial ELISA kits, while uNTBI concentrations were detected by inductively coupled plasma mass spectrometry.

Healthy cats (n = 35) and cats with CKD (n = 84) formed the study cohorts. pHIF-1α concentrations increased from 9.48 pg./mL (median) in the healthy cohort to 11.42 pg./mL in early-stage CKD cats but decreased to 8.50 pg./mL in late-stage CKD cats. uHIF-1α concentrations gradually decreased with a significant difference between the control group (44.61 pg./mL) and the late-stage CKD group (36.79 pg./mL, p < 0.001). Cats with proteinuria had significantly higher uNTBI concentrations (35.61 ppb) than non-proteinuric cats (25.13 ppb, p = 0.019). Finally, the concentrations of pHIF-1α and uHIF-1α were positively correlated independent of renal function.

Overall, pHIF-1α and uHIF-1α concentrations are lower in advanced CKD cats, while uNTBI concentrations are significantly higher in proteinuric cats.

Hypoxia Inducible transcription Factors (HIFs) are central to the metazoan oxygen-sensing response. Under low oxygen conditions (hypoxia), HIFs are stabilised and govern an adaptive transcriptional programme to cope with prolonged oxygen starvation. However, when oxygen is present, HIFs are continuously degraded by the proteasome in a process involving prolyl hydroxylation and subsequent ubiquitination by the Von Hippel Lindau (VHL) E3 ligase. The essential nature of VHL in the HIF response is well established but the role of other enzymes involved in ubiquitination is less clear. Deubiquitinating enzymes (DUBs) counteract ubiquitination and provide an important regulatory aspect to many signalling pathways involving ubiquitination. In this review, we look at the complex network of ubiquitination and deubiquitination in controlling HIF signalling in normal and low oxygen tensions. We discuss the relative importance of DUBs in opposing VHL, and explore roles of DUBs more broadly in hypoxia, in both VHL and HIF independent contexts. We also consider the catalytic and non-catalytic roles of DUBs, and elaborate on the potential benefits and challenges of inhibiting these enzymes for therapeutic use.

Fishes are susceptible to hypoxia stress, while the common carp is known for its high tolerance to hypoxia. The hypoxia-inducible factor (HIF) pathway directly regulates the cell's response to hypoxia. Still, it is currently unknown which members of the hif-α genes are present in common carp and their specific functions.

In this study, we found that the hif-1α, hif-2α, and hif-3α genes of common carp all contained twice the number of copies of their orthologs in zebrafish. Common carp has four copies of the hif-1α gene, of which the two hif-1αa genes were expressed at low levels in the vast majority of tissues, while the two hif-1αb genes were expressed at high levels in multiple tissues. We silenced the two hif-1αb genes using chitosan nanoparticles (CSNPs) carrying siRNA and subjected two groups to hypoxic stress. Transcriptome sequencing results show that whether under normoxia or hypoxia, the number of differentially expressed genes (DEGs) caused by silencing the hif-1αb genes in the heart exceeds 1,000, far more than the number of DEGs in the gills or brain. GO enrichment and KEGG enrichment showed that DEGs in the heart were mainly related to immune function and myocardial contraction. DEGs in the gills and brain also enriched many immune-related terms, and some DEGs in the gills were related to iron metabolism and erythropoiesis. Among the paralogs, the two hif-1αa genes were most obviously up-regulated under normoxia, while the hif-3α genes were most obviously up-regulated under hypoxia. We did not find any downstream genes of the HIF pathway that were specifically regulated by the hif-1αb genes.

The main effect site of the common carp hif-1αb genes is the heart, and their main functions are to regulate immune response and myocardial contraction. Their functions are partially redundant with the hif-1αa genes and hif-3α genes. When their expressions are inhibited, the expression of hif-1αa genes or hif-3α genes would be up-regulated in specific contexts, thereby compensating for their loss of function. The downstream genes of the HIF pathway in common carp may be generally regulated by multiple hif-α genes.

Anemia and mineral and bone disorder (MBD) are significant complications of chronic kidney disease (CKD). The erythropoietin (Epo) pathway plays a key role in both of these processes in CKD. Another molecule that plays an important role in CKD-MBD is fibroblast growth factor (FGF)-23, whose main role is to maintain serum phosphate levels in the normal range, acting via its co-receptor Klotho; however, its activity may also be related to anemia and inflammation. In this review, the regulation of Epo and FGF-23 and the molecular mechanisms of their action are outlined. Furthermore, the complex interaction between EPO and FGF-23 is discussed, as well as their association with other anemia-related factors and processes such as Klotho, vitamin D, and iron deficiency. Together, these may be part of a "kidney-bone marrow-bone axis" that promotes CKD-MBD.

Individuals who reside at high altitudes for extended periods or those who visit these regions briefly frequently experience high-altitude response, which triggers a series of physiological and pathological changes in the body, ultimately causing altitude sickness. One of the most critical features of high-altitude environments is hypoxia. Recent studies have demonstrated that hypoxia-inducible factor 1 (HIF-1) plays a central role in mediating the body's response to hypoxic conditions at high altitudes. HIF-1, a heterodimeric transcription factor composed of an oxygen-sensitive subunit α (HIF-1α) and a constitutively expressed subunit β (HIF-1β), directly regulates the expression of multiple target genes, thereby modulating various physiological processes essential for cellular adaptation to hypoxia. According to a substantial body of research, aberrant expression of HIF-1 is implicated in the pathogenesis and progression of various diseases, including altitude sickness, cardiovascular disorders, neurological conditions, inflammatory diseases, cognitive impairment, immune dysregulation, and cancer. In this review, we provided an in-depth examination of the structural characteristics and regulatory mechanisms governing HIF-1 expression, discussed its downstream target genes, and highlighted the inhibitors currently under development. Additionally, we summarized the pivotal role and underlying mechanisms of HIF-1 in the development of altitude sickness, particularly its regulatory role in the pathophysiological processes of high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), and high-altitude pulmonary hypertension (HAPH). Through a thorough examination of the role of HIF-1, we aim to provide a theoretical foundation and potential therapeutic targets for the prevention and treatment of altitude sickness.

The major pathological characteristics of Alzheimer's disease (AD) include senile plaques and neurofibrillary tangles (NFTs), which are mainly composed of aggregated amyloid-beta (Aβ) peptide and hyperphosphorylated tau protein, respectively. The excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor critical for tissue adaption to low-oxygen tension. Growing evidence has suggested HIF-1 as a potential therapeutic target for AD; conversely, other experimental findings indicate that HIF-1 induction contributes to AD pathogenesis. These previous findings thus point to the complex, even contradictory, roles of HIF-1 in AD. In this review, we first introduce the general pathogenic mechanisms of AD as well as the potential pathophysiological roles of HIF-1 in cancer, immunity, and oxidative stress. Based on current experimental evidence in the literature, we then discuss the possible beneficial as well as detrimental mechanisms of HIF-1 in AD; these sections also include the summaries of multiple chemical reagents and proteins that have been shown to exert beneficial effects in AD via either the induction or inhibition of HIF-1.

Hypoxic microenvironments induce widespread metabolic changes that have been shown to be critical in regulating innate and adaptive immune responses. Hypoxia-induced changes include the generation of extracellular adenosine followed by subsequent signaling through adenosine receptors on immune cells. This evolutionarily conserved "hypoxia-adenosinergic" pathway of hypoxia → extracellular adenosine → adenosine receptor signaling has been shown to be critical in limiting and redirecting T cell responses including in tumor microenvironments and the gut mucosa. However, the question of whether hypoxic microenvironments are involved in the development of B cell responses has remained unexplored until recently. The discovery that germinal centers (GC), the anatomic site in which B cells undergo secondary diversification and affinity maturation, develop a hypoxic microenvironment has sparked new interest in how this evolutionarily conserved pathway affects antibody responses. In this review we will summarize what is known about hypoxia-adenosinergic microenvironments in lymphocyte development and ongoing immune responses. Specific focus will be placed on new developments regarding the role of the hypoxia-adenosinergic pathway in regulating GC development and humoral immunity.

The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel-Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

During inflammation, human neutrophils engage β2-integrins to migrate from the blood circulation to inflammatory sites with high cytokine but low oxygen concentrations. We tested the hypothesis that the inhibition of prolyl hydroxylase domain-containing enzymes (PHDs), cytokines, and β2-integrins cooperates in HIF pathway activation in neutrophils. Using either the PHD inhibitor roxadustat (ROX) (pseudohypoxia) or normobaric hypoxia to stabilize HIF, we observed HIF1α protein accumulation in adherent neutrophils. Several inflammatory mediators did not induce HIF1α protein but provided additive or even synergistic signals (e.g., GM-CSF) under pseudohypoxic and hypoxic conditions. Importantly, and in contrast to adherent neutrophils, HIF1α protein expression was not detected in strictly suspended neutrophils despite PHD enzyme inhibition and the presence of inflammatory mediators. Blocking β2-integrins in adherent and activating β2-integrins in suspension neutrophils established the indispensability of β2-integrins for increasing HIF1α protein. Using GM-CSF as an example, increased HIF1α mRNA transcription via JAK2-STAT3 was necessary but not sufficient for HIF1α protein upregulation. Importantly, we found that β2-integrins led to HIF1α mRNA translation through the phosphorylation of the essential translation initiation factors eIF4E and 4EBP1. Finally, pseudohypoxic and hypoxic conditions inducing HIF1α consistently delayed apoptosis in adherent neutrophils on fibronectin under low serum concentrations. Pharmacological HIF1α inhibition reversed delayed apoptosis, supporting the importance of this pathway for neutrophil survival under conditions mimicking extravascular sites. We describe a novel β2-integrin-controlled mechanism of HIF1α stabilization in human neutrophils. Conceivably, this mechanism restricts HIF1α activation in response to hypoxia and pharmacological PHD enzyme inhibitors to neutrophils migrating toward inflammatory sites.

Melanized focal changes (MFCs) in the fillet of farmed Atlantic salmon is a major quality concern. The changes are thought to initially appear as acute red focal changes (RFCs) that progress into chronic MFCs. Recent findings have indicated that hypoxia may be important in their development, possibly leading to necrosis affecting not only myocytes but also adipocytes. Thus, the aim of this study was to investigate possible hypoxic conditions in RFCs and the subsequent inflammatory responses and lesions in the adipose tissue in RFCs and MFCs. A collection of RFCs, MFCs and control muscle samples from several groups of farmed salmon was studied. Using immunohistochemistry, we found induction of the hypoxia-inducible factor 1 pathway in RFCs. Histological investigations of RFCs and MFCs revealed different stages of fat necrosis, including necrotic adipocytes, a myospherulosis-like reaction and the formation of pseudocystic spaces. Accumulations of foamy macrophages were detected in MFCs, indicating degradation and phagocytosis of lipids. Using in situ hybridization, we showed the presence of tyrosinase- and tyrosinase-related protein-1-expressing amelanotic cells in RFCs, which in turn became melanized in MFCs. In conclusion, we propose a sequence of events leading to the formation of MFCs, highlighting the pivotal role of adiposity, hypoxia and fat necrosis.

Vital organ injury is one of the leading causes of global mortality and socio-economic burdens. Current treatments have limited efficacy, and new strategies are needed. Dexmedetomidine (DEX) is a highly selective α2-adrenergic receptor that protects multiple organs by reducing inflammation and preventing cell death. However, its exact mechanism is not yet fully understood. Understanding the underlying molecular mechanisms of its protective effects is crucial as it could provide a basis for designing highly targeted and more effective drugs. Ferroptosis is the primary mode of cell death during organ injury, and recent studies have shown that DEX can protect vital organs from this process. This review provides a detailed analysis of preclinical in vitro and in vivo studies and gains a better understanding of how DEX protects against vital organ injuries by inhibiting ferroptosis. Our findings suggest that DEX can potentially protect vital organs mainly by regulating iron metabolism and the antioxidant defense system. This is the first review that summarizes all evidence of ferroptosis's role in DEX's protective effects against vital organ injuries. Our work aims to provide new insights into organ therapy with DEX and accelerate its translation from the laboratory to clinical settings.

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

Metals play a crucial role in the human body, especially as ions in metalloproteins. Essential metals, such as calcium, iron, and zinc are crucial for various physiological functions, but their interactions within biological networks are complex and not fully understood. Mesenchymal stem/stromal cells (MSCs) are essential for tissue regeneration due to their ability to differentiate into various cell types. This review article addresses the effects of physiological and unphysiological, but not directly toxic, metal ion concentrations, particularly concerning MSCs. Overloading or unbalancing of metal ion concentrations can significantly impair the function and differentiation capacity of MSCs. In addition, excessive or unbalanced metal ion concentrations can lead to oxidative stress, which can affect viability or inflammation. Data on the effects of metal ions on MSC differentiation are limited and often contradictory. Future research should, therefore, aim to clarify the mechanisms by which metal ions affect MSC differentiation, focusing on aspects such as metal ion interactions, ion concentrations, exposure duration, and other environmental conditions. Understanding these interactions could ultimately improve the design of biomaterials and implants to promote MSC-mediated tissue regeneration. It could also lead to the development of innovative therapeutic strategies in regenerative medicine.

Hypoxia, a condition where there is a lack of oxygen, is known to play a role in cancer progression.

This study investigates the correlation between HIF1A gene-altered expression and hypoxia in Bangladeshi breast cancer (BC) cases and TCGA_BC datasets.

This case-control study compares BC cases to healthy controls to understand the relationship between gene changes and cancer.

This study used advanced analysis methods to examine the transcriptional landscape of BC, and quantitatively assessed its correlation using integrated multi-omics analysis.

In Bangladeshi BC cases, the T allele of HIF1A rs1154946 correlates notably (P-value < .001) with BC incidence. ELISA results confirmed a significant association (P-value < .005) between elevated HIF1A expression and BC-related hypoxia. Bioinformatics eQTL analysis validated the correlation between increased HIF1A expression and rs11549465 T allele (P-value < .01). Structural analyses suggested that rs11549465 (P582S) mutation may decrease protein stability (ΔΔG-value: -1.24 kcal/mole), potentially affecting HIF1A function. HIF1A enrichment analysis in BC underscores strong associations with oxygen levels, hypoxia, metabolic processes, apoptosis, and programed cell death (P-value < .001). Transcriptomic data demonstrated a robust correlation (P-value < .0001) between HIF1A expression and copy-number alterations, mutations, and abnormal methylation. Altered HIF1A expression showed strong negative correlations (P-value < .00001) with methylation and the expression of the ER (ESR1), in Whites. Survival analysis revealed marked differences in overall survival linked to high and low HIF1A expression (P-value < .00001). Furthermore, HIF1A expression significantly correlated (P-value < .000001) with hypoxia, TMB, MSI, and immune infiltration by CD8+ T cells, neutrophils, dendritic, and macrophages, providing deeper insights into the BC microenvironment.

Thus, the HIF1A gene could serve as a promising biomarker for breast cancer progression, control, and survival across ethnicities, emphasizing its role in disease development and regulation.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) enzymes regulate adaptive cellular responses to low oxygen concentrations. Inhibition of HIF-P4Hs leads to stabilisation of hypoxia-inducible factors (HIFs) and activation of the HIF pathway affecting multiple biological processes to rescue cells from hypoxia. As evidence from animal models suggests that HIF-P4H inhibitors could be used to treat metabolic disorders associated with insulin resistance, we examined whether roxadustat, an HIF-P4H inhibitor approved for the treatment of renal anaemia, would have an effect on glucose metabolism in primary human myotubes.

Primary skeletal muscle cell cultures, established from biopsies of vastus lateralis muscle from men with normal glucose tolerance (NGT) (n=5) or type 2 diabetes (n=8), were treated with roxadustat. Induction of HIF target gene expression was detected with quantitative real-time PCR. Glucose uptake and glycogen synthesis were investigated with radioactive tracers. Glycolysis and mitochondrial respiration rates were measured with a Seahorse analyser.