Antiproliferative effects of glucosamine, a glucose derivative with a similar structure to glucose, have been discovered, but the molecular mechanisms are not yet fully understood. Since glucosamine and glucose not only have similar structures but also are catalyzed by the same enzyme, hexokinase (HK), the present study delved into determining whether the antiproliferative effect of glucosamine involved the inhibition of glycolysis by competition with glucose. Whole‑genome screening analysis showed that a number of the gene pathways controlled by glucosamine were directly and indirectly involved in glycolysis. In vitro experiments revealed that as more glucose was added, the antiproliferative effect of glucosamine decreased. Also, it was found that glucosamine was transported into cells mainly through glucose transporter (GLUT) 2 which was responsible for the antiproliferative effects of glucosamine. In addition, the present study found that cancer cell lines with low expression level of HKII show high sensitivity to glucosamine and a HK inhibitor, 3‑bromopyruvate, enhanced the antiproliferative effect of glucosamine. Under hypoxic conditions, activated hypoxia‑inducible factor 1α (HIF‑1α) inducing glucose uptake and glycolysis hampered glucosamine‑induced cell death and HIF1A knockdown or HK inhibitors restored the antiproliferative effects of glucosamine. These findings demonstrated that glucosamine is an efficient glycolysis inhibitor and that GLUT2 and HKII play important roles as biomarkers for determining sensitivity to glucosamine. Moreover, the results suggested that the antiproliferative effect of glucosamine may be more efficient when administered in combination with other glycolytic agents or inhibitors targeting HIF‑1α.

Hypoxia serves as a critical determinant in the advancement of various intractable pathological conditions including oncological disorders and hypovascular wounds, which may profoundly attenuate the efficacy of pharmacological interventions and substantially inhibit the physiological recovery processes. Consequently, in an effort to mitigate the inherent constraints of conventional methodologies (e.g., exogenous oxygen delivery systems), a self-powered triboelectric nanogenerator (TENG)-based algae-integrated pliable and enveloped device (TAPED) operates as a wearable system to sustain oxygen generation. The TAPED system harnesses biomechanical energy generated through natural bodily movements to energize an integrated luminescent source, enabling controlled photosynthesis for sustained, on-demand oxygen production. The incorporation of TENG technology renders TAPED self-sufficient, eliminating the necessity for external recharging, reducing device mass, and improving convenience for continuous oxygen delivery. Additionally, its body-attachable design circumvents risks associated with direct algal implantation, such as immunogenic reactions and infections. Specifically, experimental application of TAPED has exhibited significant therapeutic efficacy in diverse pathological conditions, including diabetic chronic infected wounds, breast carcinoma tumors, and lactic acid accumulation consequent to strenuous exercise-induced fatigue. Collectively, the TAPED represents an advanced therapeutic approach, which holds substantial potential for translational application within clinical contexts, particularly for enhancing patient prognosis in hypoxic diseases such as oncology and wound management.

Mitochondrial ribosomal proteins (MRPs) are essential components of mitochondrial ribosomes, responsible for translating proteins encoded by mitochondrial DNA and maintaining mitochondrial energy metabolism and function. Emerging evidence suggests that MRPs exhibit significant expression changes in multiple cancer types, profoundly affecting tumor biology through modulating oxidative stress levels, inducing metabolic reprogramming, disrupting cell cycle regulation, inhibiting apoptosis, promoting mitophagy, and remodeling the tumor microenvironment. Specifically, MRPs have been implicated in tumor cell proliferation, migration, invasion, and apoptosis, highlighting their potential as therapeutic targets. This review summarizes the multifaceted roles of MRPs in cancer, focusing on their impact on the tumor microenvironment and their potential as prognostic biomarkers and therapeutic targets. We also explore the implications of MRPs in precision oncology, particularly in patient stratification and the design of metabolic targeted therapies, offering new insights and research directions for the precise prevention and treatment of cancer.

Unlike differentiated somatic cells, which possess elongated mitochondria, undifferentiated cells, such as those of preimplantation embryos, possess round, immature mitochondria. Mitochondrial morphology changes dynamically during cell differentiation in a process called mitochondrial maturation. The significance of the alignment between cell differentiation and mitochondrial maturity in preimplantation development remains unclear. In this study, we analyzed mouse embryos into which liver-derived somatic mitochondria were introduced (SM-embryos). Most SM-embryos were arrested at the two-cell stage. Some of the introduced somatic mitochondria became round, while others remained elongated and large. RNA-sequencing revealed a disruption of both minor and major zygotic gene activation (ZGA) in SM-embryos. Minor ZGA did not terminate before major ZGA, and the onset of major ZGA was inhibited, as shown by histone modification analyses of histone H3 lysine 4 trimethylation and histone H3 lysine 27 acetylation. Further analysis of metabolites involved in histone modification regulation in SM-embryos showed a significantly lower NAD+/NADH ratio in SM-embryos than in control embryos. Additionally, the mitochondrial membrane potential, an indicator of mitochondrial function, was lower in SM-embryos than in control embryos. Our results demonstrated that introducing somatic mitochondria into an embryo induces mitochondrial dysfunction, thereby disrupting metabolite production, leading to a disruption in ZGA and inducing developmental arrest. Our findings reveal that the alignment between cell differentiation and mitochondrial maturity is essential for early embryonic development.

This review delves into the pivotal role and intricate mechanisms of aerobic glycolysis in nasopharyngeal carcinoma (NPC). NPC, a malignancy originating from the nasopharyngeal epithelium, displays distinct geographical and clinical features. The article emphasizes the significance of aerobic glycolysis, a pivotal metabolic alteration in cancer cells, in NPC progression. Key enzymes such as hexokinase 2, lactate dehydrogenase A, phosphofructokinase 1, and pyruvate kinase M2 are discussed for their regulatory functions in NPC glycolysis through signaling pathways like PI3K/Akt and mTOR. Further, the article explores how oncogenic signaling pathways and transcription factors like c-Myc and HIF-1α modulate aerobic glycolysis, thereby affecting NPC's proliferation, invasion, metastasis, angiogenesis, and immune evasion. By elucidating these mechanisms, the review aims to advance research and clinical practice in NPC, informing the development of targeted therapeutic strategies that enhance treatment precision and reduce side effects. Overall, this review offers a broad understanding of the multifaceted role of aerobic glycolysis in NPC and its potential impact on therapeutic outcomes.

Developing a catalytic nanoenzyme activated by the tumor microenvironment (TME) shows excellent potential for in situ cancer treatment. However, the rational design of a cascade procedure to achieve high therapeutic efficiency remains challenging. In this study, the colorectal TME-responsive multifunctional cascade nanoenzyme Cu2-xO@MnO2@glucose oxidase (GOx)@hyaluronic acid (HA) was developed to target in situ cancer starvation/chemodynamic therapy (CDT)/photothermal therapy (PTT). First, the MnO2 nanolayer specifically decomposes within the acidic TME to generate Mn2+ and oxygen (O2), thereby alleviating the hypoxic TME. Subsequently, Cu2-xO can be vulcanized into Cu2-xS by overexpressing sulfuretted hydrogen (H2S) gas in the colorectal tumor for a second near-infrared (NIR-II) light-triggered deep tissue PTT. Cu2-xS nanoparticles can react with hydrogen peroxide (H2O2) to generate hydroxyl radical (OH) for the CDT. In addition, GOx catalyzes the conversion of glucose into H2O2 for starvation therapy and enhances the CDT efficiency by self-supplying H2O2. Interestingly, the generated reactive oxygen species (ROS) induce immunogenic cell death (ICD), which further activates adaptive cancer immunity for anti-tumor immunotherapy. Finally, therapeutic efficiency was greatly improved after coating with tumor-targeted HA. Collectively, these TME-responsive cascade nanoenzymes can realize PTT, CDT starvation therapy, and immunotherapy, paving the way for the design of TME-responsive cascade nanoenzymes for synergistically enhanced tumor-specific therapy.

Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.

Despite apparently curative treatment, many patients with colorectal cancer develop subsequent metastatic disease. Current prognostic models are criticised because they are based on standard staging and omit novel biomarkers. Improved prognostication is an unmet need.

To improve prognostication for colorectal cancer by developing a baseline multivariable model of standard clinicopathological predictors, and to then improve prediction via addition of promising novel imaging, genetic and immunohistochemical biomarkers.

Prospective multicentre cohort.

Thirteen National Health Service hospitals.

Consecutive adult patients with colorectal cancer.

Collection of prespecified standard clinicopathological variables and more novel imaging, genetic and immunohistochemical biomarkers, followed by 3-year follow-up to identify postoperative metastasis.

Best multivariable prognostic model including perfusion computed tomography compared with tumour/node staging. Secondary outcomes: Additive benefit of perfusion computed tomography and other biomarkers to best baseline model comprising standard clinicopathological predictors; measurement variability between local and central review; biological relationships between perfusion computed tomography and pathology variables.

Between 2011 and 2016, 448 participants were recruited; 122 (27%) were withdrawn, leaving 326 (226 male, 100 female; mean ± standard deviation 66 ± 10.7 years); 183 (56%) had rectal cancer. Most cancers were locally advanced [≥ T3 stage, 227 (70%)]; 151 (46%) were node-positive (≥ N1 stage); 306 (94%) had surgery; 79 (24%) had neoadjuvant therapy. The resection margin was positive in 15 (5%); 93 (28%) had venous invasion; 125 (38%) had postoperative adjuvant chemotherapy; 81 (25%, 57 male) developed recurrent disease. Prediction of recurrent disease by the baseline clinicopathological time-to-event Weibull multivariable model (age, sex, tumour/node stage, tumour size and location, treatment, venous invasion) was superior to tumour/node staging: sensitivity: 0.57 (95% confidence interval 0.45 to 0.68), specificity 0.74 (95% confidence interval 0.68 to 0.79) versus sensitivity 0.56 (95% confidence interval 0.44 to 0.67), specificity 0.58 (95% confidence interval 0.51 to 0.64), respectively. Addition of perfusion computed tomography variables did not improve prediction significantly: c-statistic: 0.77 (95% confidence interval 0.71 to 0.83) versus 0.76 (95% confidence interval 0.70 to 0.82). Perfusion computed tomography parameters did not differ significantly between patients with and without recurrence (e.g. mean ± standard deviation blood flow of 60.3 ± 24.2 vs. 61.7 ± 34.2 ml/minute/100 ml). Furthermore, baseline model prediction was not improved significantly by the addition of any novel genetic or immunohistochemical biomarkers. We observed variation between local and central computed tomography measurements but neither improved model prediction significantly. We found no clear association between perfusion computed tomography variables and any immunohistochemical measurement or genetic expression.

The number of patients developing metastasis was lower than expected from historical data. Our findings should not be overinterpreted. While the baseline model was superior to tumour/node staging, any clinical utility needs definition in daily practice.

A prognostic model of standard clinicopathological variables outperformed tumour/node staging, but novel biomarkers did not improve prediction significantly. Biomarkers that appear promising in small single-centre studies may contribute nothing substantial to prognostication when evaluated rigorously.

It would be desirable for other researchers to externally evaluate the baseline model.

This trial is registered as ISRCTN95037515.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/22/49) and is published in full in Health Technology Assessment; Vol. 29, No. 8. See the NIHR Funding and Awards website for further award information.

Tumor tissues generally exist in a relatively hypovascular state, and cancer cells must adapt to severe tissue conditions with a limited molecular oxygen and nutrient supply for their survival. Lipid metabolism serves a role in this adaptation. Lipids are supplied not only through the bloodstream but also through autonomous synthesis by cancer cells, and they function as sources of adenosine triphosphate and cell components. Although cancer‑associated lipid metabolism has been widely reviewed, how this metabolism responds to the tumor environment with poor molecular oxygen and nutrient supply remains to be fully discussed. The main aim of the present review was to summarize the findings on this issue and to provide insights into how cancer cells adapt to better cope with metabolic stresses within tumors. It may be suggested that diverse types of lipid metabolism have a role in enabling cancer cells to adapt to both hypoxia and nutrient‑poor conditions. Gaining a deeper understanding of these molecular mechanisms may reveal novel possibilities of exploration for cancer treatment.

Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H2O2)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H2O2 and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.

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.

Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.

The role of extracellular vesicles (EVs) in mediating chemoresistance has gained significant attention due to their ability to transfer bioactive molecules between drug-resistant and drug-sensitive cells. In particular, they have been demonstrated to play an active part in breast cancer chemoresistance by the horizontal transfer of genetic and protein material. This review highlights the role of EVs, particularly their miRNA cargo, in driving drug resistance in breast cancer. EVs derived from chemoresistant cells carry miRNAs and lncRNAs, which are known to modulate gene networks involved in cell proliferation and survival. These cargo molecules suppress apoptosis by targeting pro-apoptotic genes like PTEN and BIM, promote epithelial-mesenchymal transition (EMT) through the regulation of pathways such as TGF-β and Wnt/b-catenin, and contribute to tumor growth and resistance by enhancing angiogenesis and modulating the tumor microenvironment. Beyond RNA-mediated effects, EVs also transfer functional proteins, including P-glycoprotein and Hsp70, which impact cellular metabolism and survival pathways. Our findings underscore the significance of EVs in breast cancer chemoresistance, suggesting their potential involvement as possible prognostic factors to predict therapy response and as therapeutic targets in combination with usual therapy.

Mint3 enhances aerobic ATP production with subsequent nuclear translocation of hypoxia-inducible factor-1 (HIF-1) and activation of angiogenesis-related genes. It remains unclear if and when Mint3 is activated and whether it is involved in hepatocarcinogenesis. We explored the expression of Mint3 in surgically resected hepatocellular carcinoma (HCC) tissues. We evaluated the effects of Mint3 knockdown on spheroid formation capacity and subcutaneous tumor growth in immune-deficient mice. We used Mint3 knockout mice to evaluate the effects of chemically induced HCC development. Mint3 was overexpressed in well-differentiated HCC with the activation of HIF-1 target genes irrespective of the absence of hypervascularization. Mint3 knockdown ameliorated the expression of HIF-1 target genes in patient-derived HCC cell lines and suppressed spheroid formation. Mint3 knockdown further inhibited subcutaneous tumor formation in vivo in immune-deficient mice. Chemical HCC development induced by N-nitrosodiethylamine (DEN) or DEN/CCl4 was dramatically suppressed in Mint3 knockout mice compared to control mice. Mint3 plays a crucial role in early-stage HCC development before hypervascularization by activating HIF-1 target genes before the tumor becomes hypoxic. Mint3 is a molecular target that prevents HCC development in the early stages.

Dendritic cells (DCs) are specialized antigen-presenting cells crucial for initiating and regulating adaptive immune responses, making them promising candidates for therapeutic interventions in various immune-mediated diseases. Increasing evidence suggests that the microenvironment in which cells are cultured, as well as the milieu in which they perform their functions, significantly impact their immunomodulatory properties. Among these environmental factors, the role of oxygen in DC biology and its significance for both their in vitro generation and in vivo therapeutic application require investigation. Unlike the atmospheric oxygen level of 21 % commonly used in in vitro assays, physiological oxygen levels are much lower (3-9 %), and hypoxia (<1.3 %) is a prevalent condition of both healthy tissues and disease states. This mismatch between laboratory and physiological conditions underscores the critical need to culture and evaluate therapeutic cells under physiologically relevant oxygen levels to improve their translational relevance and clinical outcomes. This review explores the characteristic hallmarks of human DCs that are influenced by oxygen-dependent pathways, including metabolism, phenotype, cytokine secretion, and migration. Furthermore, we discuss the potential of manipulating oxygen levels to refine the generation and functionality of DCs for therapeutic purposes.

Death from mechanical asphyxia (DMA) refers to death from acute respiratory disorder caused by mechanical violence. Due to the absence of characteristic signs in corpses, it has been rather challenging to achieve the precise authentication of DMA. In this research, human pulmonary samples were collected and grouped according to different causes of death in search of potential biomarkers of DMA. Hydroxyacyl-CoA dehydrogenase (HADH) was identified significantly up-regulated in DMA group. Cell experiments were conducted to figure out the mechanism of the up-regulation of HADH. According to the results, we assumed acute and severe hypoxia caused by mechanical asphyxia contributed to the expression change of HADH, which could be a self-saving reaction of cells that are forced to adjust energy metabolism. Generally, HADH can be biomarker of DMA and help the precise authentication of DMA.

Hypoxic pulmonary hypertension (HPH) develops in association with diseases characterized by low oxygen levels leading to pulmonary artery (PA) narrowing and death. Hypoxia has been linked to increased PA collagen and changes in PA adventitial fibroblast (PAAF) metabolism. However, the mechanisms by which hypoxia regulates PAAF function are unknown. Hypoxia-inducible factor-1α (HIF-1α) is a subunit of a transcription factor that is degraded in normoxia but stabilized in hypoxia and is involved in extracellular matrix remodeling by fibroblasts. We examined the role of hypoxia and HIF-1α in regulating PAAF function. Human PAAF (HPAAF) were cultured in normoxic and hypoxic conditions. Cells were further treated with HIF1-α inhibitor or no drug. Protein expression, mRNA expression, enzyme activity, and metabolite concentration were examined. Male C57BL6/J mice were exposed to 0 or 10 days of hypoxia after which right ventricular hemodynamics and tissue metabolism were assessed. Hypoxia led to an increase in collagen content and decrease in matrix metalloproteinase-2 (MMP2) activity. HIF-1α inhibition limited collagen accumulation and restored MMP2 activity. HPAAF demonstrated elevated lactic acid concentration and decreased ATP in hypoxia. HIF-1α inhibition blunted these effects. Mice exposed to hypoxia developed significant elevation in right ventricle systolic pressures and had decreased ATP levels in pulmonary tissue. This study investigated the mechanisms by which hypoxia drives HPAAF-mediated collagen accumulation and metabolic changes. We identify the key role of HIF-1α in regulating changes. These findings provide important insights into understanding HPAAF-mediated PA remodeling and help identify possible novel therapeutic targets.

Glioblastoma (GBM) is highly malignant and grows rapidly, and there is currently a lack of effective treatments. Metabolism provides the basis for the occurrence and development of GBM. Pyruvate dehydrogenase A1 (PDHA1) is a key component in both the tricarboxylic acid cycle and glycolysis, playing an important role in the metabolic processes related to cancer, but its role in GBM remains unclear. Glioma associated mesenchymal stem cells (GaMSC) play a significant role in the development of glioma. This study aims to explore the relationship between GaMSC derived exosomes (GAMSC-EXO) and PDHA1, as well as the effects and mechanisms on GBM glucose metabolism. In this study, human GaMSC-derived exosomes were isolated and identified. The role of GAMSC-EXO in GBM proliferation, migration, invasion and glucose metabolism was investigated. The upstream miRNA of PDHA1 was predicted and the relationship between miR-21-5p and PDHA1 in GAMSC-EXO and its effect on GBM glucose metabolism was investigated. We found that GAMSCs promote GBM cell proliferation, migration, invasion and glycolysis by releasing exosomes. After inhibiting GBM glycolysis, GBM proliferation, migration and invasion abilities were weakened. MiR-21-5p in exosomes was identified as the miRNA that affects the above biological behaviors. Mechanismly, miR-21-5p directly binds to the mRNA of PDHA1 and downregulates its transcription, thereby promoting GBM glycolysis. Together, this study demonstrated that exosomal miR-21-5p from GAMSC promoted GBM proliferation, migration, invasion, and glycolysis by targeting PDHA1, which provided novel insights into the metabolic interactions between GAMSCs and GBM cells, emphasizing the importance of exosome-mediated communication in tumor progression.

Objective. For the effective growth of malignant tumors, including glioblastoma, the necessary factors involve endoplasmic reticulum (ER) stress, hypoxia, and the availability of nutrients, particularly glucose. The ER degradation enhancing alpha-mannosidase like protein 1 (EDEM1) is involved in ER-associated degradation (ERAD) targeting misfolded glycoproteins for degradation in an N-glycan-independent manner. EDEM1 was also identified as a new modulator of insulin synthesis and secretion. The present study aims to investigate the regulation of the EDEM1 gene expression in U87MG glioblastoma cells by hypoxia and glucose or glutamine deprivations depending on the knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1) with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in tumorigenesis. Methods. The U87MG glioblastoma cells (transfected by an empty vector; control) and ERN1 knockdown cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Hypoxia was introduced by dimethyloxalylglycine (4 h). For glucose and glutamine deprivations, the cells were exposed to DMEM medium without glucose and glutamine, respectively, for 16 h. The expression level of the EDEM1 gene was studied by quantitative RT-PCR and normalized to the ACTB mRNA. Results. It was found that inhibition of endoribonuclease and protein kinase activities of ERN1 led to down-regulation of EDEM1 gene expression in glioblastoma cells. Moreover, the expression of this gene was also decreased after silencing ERN1 in glioblastoma cells. At the same time, the expression of EDEM1 gene did not significantly change in cells with inhibited ERN1 endoribonuclease only. The expression of the EDEM1 gene was increased under hypoxia in control U87MG cells, but resistant to hypoxia in cells with ERN1 knockdown. Furthermore, the expression of this gene was up-regulated under glucose and glutamine deprivations in control glioblastoma cells. However, the ERN1 knockdown increased the sensitivity of EDEM1 gene expression to glucose and decreased to glutamine deprivations. Conclusion. The results of the present study demonstrate that inhibition of ERN1 down-regulated the expression of the EDEM1 gene through protein kinase activity of ERN1 and that the regulation of this gene expression by hypoxia and nutrient supply, especially glucose, is differently controlled by ERN1 in glioblastoma cells.

Objective. Endoplasmic reticulum (ER) stress and hypoxia are key factors for the effective growth of malignant tumors, including glioblastoma. The phosphoserine aminotransferase 1 (PSAT1) is an ER stress-responsive enzyme responsible for serine synthesis and necessary for tumor cell proliferation. The present study aims to investigate the regulation of the PSAT1 gene expression in U87MG glioblastoma cells and normal human astrocytes by ER stress and hypoxia depending on hydrocortisone, a native stress hormone used for co-treatment of glioblastoma and other malignant tumors. Methods. The U87MG glioblastoma cells and normal human astrocytes were used. Hypoxia was introduced by dimethyloxalylglycine. Tunicamycin was used for the induction of ER stress. Further, the cells were treated with hydrocortisone. RNA was extracted from cells after 4 h exposure to hydrocortisone, tunicamycin, and hypoxia. The expression level of the PSAT1 gene was studied by quantitative RT-PCR and normalized to ACTB mRNA. Results. We found that treatment of normal human astrocytes with hydrocortisone resulted in a decreased expression of the PSAT1 gene, but its expression in glioblastoma cells was resistant to this hormone action. However, hypoxia did not significantly change the expression of the PSAT1 gene in normal astrocytes, but strongly modified the effect of hydrocortisone on this gene expression. At the same time, hypoxia increased the expression of the PSAT1 gene in glioblastoma cells independently of hydrocortisone. Tunicamycin decreased the expression of this gene in normal astrocytes, but increased it in glioblastoma cells. In addition, the impact of tunicamycin on PSAT1 gene expression was suppressed by hypoxia in both normal astrocytes and glioblastoma cells and by hydrocortisone only in normal astrocytes. At the same time, the combined effect of hypoxia and hydrocortisone greatly enhanced the expression of the PSAT1 gene in tunicamycin-treated normal astrocytes and especially glioblastoma cells. Conclusion. The results of this study showed that hydrocortisone differentially controls the regulation of PSAT1 gene expression by ER stress and hypoxia in normal astrocytes and glioblastoma cells and that the combined effect of hydrocortisone and hypoxia greatly enhanced PSAT1 gene expression in tunicamycin-treated cells.

Acute liver failure (ALF) is a fulminant clinical syndrome that usually leads to multiple organ failure and high mortality. Macrophages play a crucial role in the initiation, development, and recovery of ALF. Targeting macrophages through immunotherapy holds significant promise as a therapeutic strategy. These cells exhibit remarkable plasticity, enabling them to differentiate into various subtypes based on changes in their surrounding microenvironment. M1-type macrophages are associated with a pro-inflammatory phenotype and primarily rely predominantly on glycolysis. In contrast, M2-type macrophages, which are characterized by anti-inflammatory phenotype, predominantly obtain their energy from oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Shifting macrophage metabolism from glycolysis to OXPHOS inhibits M1 macrophage activation and promotes M2 macrophage activation, thereby exerting anti-inflammatory and reparative effects. This study elucidates the relationship between macrophage activation and glucose metabolism reprograming from an immunometabolism perspective. A comprehensive literature review revealed that several signaling pathways may regulate macrophage polarization through energy metabolism, including phosphatidyl-inositol 3-kinase/protein kinase B (PI3K/AKT), mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α), nuclear factor-κB (NF-κB), and AMP-activated protein kinase (AMPK), which exhibit crosstalk with one another. Additionally, we systematically reviewed several traditional Chinese medicine (TCM) monomers that can modulate glucose metabolism reprograming and influence the polarization states of M1 and M2 macrophages. This review aimed to provide valuable insights that could contribute to the development of new therapies or drugs for ALF.

Radiation therapy is widely recognized as an efficacious modality for treating neoplasms located within the craniofacial region. Nevertheless, this approach is not devoid of risks, predominantly concerning potential harm to the neural structures. Adverse effects may encompass focal cerebral necrosis, cognitive function compromise, cerebrovascular pathology, spinal cord injury, and detriment to the neural fibers constituting the brachial plexus. With increasing survival rates among oncology patients, evaluating post-treatment quality of life has become crucial in assessing the benefits of radiation therapy. Consequently, it is imperative to investigate therapeutic strategies to mitigate cerebral complications from radiation exposure. Current management of radiation-induced cerebral damage involves corticosteroids and bevacizumab, with preclinical research on antioxidants and thalidomide. Despite these efforts, an optimal treatment remains elusive. Recent studies suggest the gut microbiota's involvement in neurologic pathologies. This review aims to discuss the causes and existing treatments for radiation-induced cerebral injury and explore gut microbiota modulation as a potential therapeutic strategy.

Developing nanozymes for cancer therapy has attracted great attention from researchers. However, enzymes-loaded magnetic particles triggered by both a low-frequency vibrating magnetic field (VMF) and laser for inhibiting tumor growth have never been reported. Herein, we developed a magnetic nanozyme with 3D flower-like nanostructures for cancer therapy. Specifically, the flower-like nanozymes exposed to a VMF could efficiently damage the mitochondrial membrane and cell structure, and inhibit tumor growth through magneto-mechanical force. In parallel, magnetic nanozymes in a weak acid environment containing glucose could generate abundant hydrogen peroxide through glucose oxidase-catalyzed oxidation of glucose, and further significantly promote the Fenton reaction. Interestingly, both glucose oxidase- and Fenton-based catalytic reactions were significantly promoted by the VMF exposure. Flower-like magnetic nanospheres upon a near-infrared laser irradiation could also damage cancer cells and tumor tissues through photothermal effect. The cell-killing efficiency of magnetic nanozymes triggered by the VMF or laser significantly increased in comparison with that of nanozymes without exposures. Mouse tumors grown after injection with magnetic nanozymes was inhibited in a significant way or the tumors disappeared after exposure to a VMF and laser due to the synergistic effect of four major stimuli, viz., magneto-mechanical force, photothermal conversion, improved Fenton reaction, and intratumoral glucose consumption-based starvation effect. This is a great platform that may be suitable for treating many solid tumors.

Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.

The pyruvate dehydrogenase kinase-3 (PDK3) plays an important role in the regulation of a variety of cancers, including lung, by inhibiting the pyruvate dehydrogenase complex (PDC), shifting energy production towards glycolysis necessary for cancer metabolism. In this study, we aimed to identify potential PDK3 inhibitors using a computer-based drug design approach. Virtual screening of the FDA-approved library of 3839 compounds was carried out, from which Bagrosin and Dehydrocholic acid appeared best due to their strong binding affinity, specific interactions, and potential biological characteristics, and thus were selected for further investigations. Both compounds show strong interactions with functionally important residues of the PDK3 with a binding affinity of - 10.6 and - 10.5 kcal/mol for Bagrosin and Dehydrocholic acid, respectively. MD simulation studies for 100 ns suggest the formation of stable complexes, which is evident from RMSD, RMSF, Rg, and SASA parameters. The PCA and FEL analysis suggested admirable global energy minima for the bagrosin-PDK3 and dehydrocholic acid-PDK3 complexes. Finally, we identified FDA-approved drugs, Bagrosin and Dehydrocholic acid, that offer valuable resources and potential therapeutic molecules for targeting lung cancer. Further clinical investigations are required to validate the clinical utility of selected molecules.

Hypoxia is one of the main hallmarks of hepatocellular carcinoma (HCC) resulting from improper oxygenation and insufficient nourishment of the HCC microenvironment. The effect of hypoxia is mediated by hypoxia-inducible factor-1A (HIF-1A) via targeting various downstream pathways, including glycolysis, angiogenesis, and survival signaling. However, HCC cell lines in a 2-dimensional (2D) setting do not resemble the metabolic signature of HCC. Here we aim to overcome these limitations by developing an HCC organoid that recapitulates the HIF-1A metabolic shift. The enrichment analysis of the RNA-Seq data revealed that HIF-1A-driven glycolytic shift is of the significant pathways. The established organoid model, using xeno-free plasma-derived extracellular matrix (ECM) as a scaffold and nutritive biomatrix, maintained its structural integrity and viability for up to 14 days; the comparative analysis of the cobalt (II) chloride (CoCl2)-treated organoids to the untreated ones unveiled reduced size and proliferative capacity. Interestingly, our organoid model showed an elevated expression of HIF-1A and glycolysis enzymes compared to their counterparts in the CoCl2-treated organoids. HIF-1A molecular expression-translated biochemical signature is further assessed in our spontaneously growing organoids showing an increase in glucose uptake, intracellular pyruvate, extracellular lactate dehydrogenase expression, and extracellular lactate production, while hydrogen peroxide (H2O2), a marker for oxidative metabolism, is reduced. Our data confirmed the potency of the established organoid model to mimic the molecular and biochemical HIF-1A-driven metabolism, which validates its potential use as an in vitro HCC model. Our model naturally simulates hypoxic conditions and simultaneous HIF-1A-dependent glycolysis within HCC rather than using of CoCl2-induced hypoxic conditions.

Prostate cancer (PCa) is a high prevalence disease, per 10000 habitants, that tends to increase with age. This pathology is difficult to detect at an early stage due to the absence of symptoms, hence the importance of monitoring signs for early detection. This disease can be detected by various methods, including plasmatic levels of prostate-specific antigen (PSA) and rectal touch, with biopsy being necessary to confirm the diagnosis. Patients affected by prostate cancer can have localized or advanced disease. There are conventional approaches that have been used as a reference in localized cancer, such as active surveillance, surgery, or radiotherapy. However, the adverse effects might vary and, sometimes, they can be permanent. An overview about the innovative therapeutic approaches to improve outcomes in terms of both tumor remission and side effects for localized PCa is presented. In case of emerging light-based treatment strategies, they aimed at ablating tumor tissue by inducing an external light are non-invasive, localized and, considerably, they are able to reduce lesions in peripheral tissues. One is photodynamic therapy (PDT) and it involves the photooxidation of molecules culminating in the formation of reactive oxygen species (ROS), inducing cell death. On the other hand, photothermal therapy (PTT) is based on inducing hyperthermia in cancer cells by irradiating them with beams of light at a specific wavelength. To improve the heat generated, gold nanoparticles (AuNPs) have those desirable characteristics that have drawn attention to PTT. Various studies point to AuNPs as efficient nanomaterials in PTT for the treatment of tumors, including prostate cancer. This review includes the most representative advances in this research field, dated from 1998 to 2023. It is noticed that several advances have been made and the way to find the effective treatment without impacting adverse side effects is shorter.

Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.

Senecavirus A (SVA) induced porcine idiopathic vesicular disease (PIVD) has been spread worldwide due to persistent infection, causing economic losses in swine industry. Host factors play an important role in replication of SVA, while, the interaction of migration inhibitory factor (MIF) and the virus has not been verified. Here, MIF facilitates the replication of SVA by enhancing the glycolysis via hypoxia-inducible factor alpha (HIF-1α) was reported. SVA infection up-regulates the expression of MIF in 3D4/21 cells, and infection experiment of cells with overexpression and interference expression of MIF showed that MIF facilitates the replication of SVA. MIF promoted the glycolysis in SVA infection to facilitate its replication by enhancing the accumulation of lactate and decreasing the production of adenosine triphosphate (ATP) and inhibiting the expression of retinoic acid-inducible gene I (RIG-I), mitochondrial antiviral-signaling protein (MAVS), interferon regulatory factor 3 (IRF3), interferon-beta (IFN-β), IFN-α, interferon-stimulating gene 15 (ISG15), and ISG56. Meanwhile, specific inhibitor verified MIF facilitates the replication of SVA by enhancing glycolysis. Further results showed MIF induces the increased expression of HIF-1α, which enhances MIF-induced glycolysis. These results provide new data on host factors in replication of SVA, as well as better understanding the role of MIF in virus infection.

It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also retard cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.

This review explores the regenerative capacity of Xenopus laevis, focusing on tail regeneration, as a model to uncover cellular, molecular, and developmental mechanisms underlying tissue repair. X. laevis tadpoles provide unique insights into regenerative biology due to their regeneration-competent and -incompetent stages and ability to regrow complex structures in the tail, including the spinal cord, muscle, and skin, after amputation. The review delves into the roles of key signaling pathways, such as those involving reactive oxygen species (ROS) and signaling molecules like BMPs and FGFs, in orchestrating cellular responses during regeneration. It also examines how mechanotransduction, epigenetic regulation, and metabolic shifts influence tissue restoration. Comparisons of regenerative capacity with other species shed light on the evolutionary loss of regenerative abilities and underscore X. laevis as an invaluable model for understanding the constraints of tissue repair in higher organisms. This comprehensive review synthesizes recent findings, suggesting future directions for exploring regeneration mechanisms, with potential implications for advancing regenerative medicine.

The significance of the tumor microenvironment (TME) in tumor initiation and progression is increasingly acknowledged. Conventional therapeutic approaches face limitations within the complex TME, including the restrictions imposed by hypoxia on photodynamic therapy (PDT) and the deficiency of endogenous H₂O₂ affecting chemodynamic therapy (CDT). In response to the TME's characteristics of high metabolism, hypoxia, and weak acidity, a multifunctional nanosystem MNPs/GOD@CS/IR820, which synergistically integrates CDT and PDT, has been developed. This system can actively accumulate at tumor sites under an external magnetic field and release active components in response to the weakly acidic TME. It mitigates the limitations imposed by hypoxia and endogenous H₂O₂ deficiency on PDT and CDT, respectively, thereby enabling synergistic treatment. Additionally, the system's multimodal imaging capabilities facilitate precise tumor localization and real-time, non-invasive in vivo assessment via fluorescence imaging and MRI. In vitro and in vivo evaluations demonstrate significant antitumor efficacy, effectively inhibiting tumor growth and improving survival rates. By comprehensively addressing the challenges posed by the complex TME and enhancing real-time monitoring capabilities, our nanosystem paves the way for personalized and precise cancer treatment. STATEMENT OF SIGNIFICANCE: This study introduces an innovative MNPs/GOD@CS/IR820 nanosystem that represents a significant advancement in cancer nanomedicine by addressing critical limitations of conventional photodynamic therapy (PDT), particularly in hypoxic tumor microenvironments. By synergistically integrating chemodynamic therapy (CDT) with PDT and incorporating MRI and fluorescence dual-modal imaging capabilities, this multifunctional platform offers enhanced therapeutic efficacy and real-time monitoring. The system's ability to generate oxygen in situ overcomes hypoxia-induced limitations, while its multimodal mechanism of action induces tumor cell apoptosis through multiple pathways. In vitro and in vivo studies demonstrate remarkable antitumor efficacy across diverse cancer types, significantly inhibiting tumor growth and improving survival rates. This comprehensive approach to cancer diagnosis and treatment not only advances precision medicine for targeted, multimodal cancer management but also provides a promising foundation for future clinical applications, potentially transforming cancer treatment strategies and improving patient outcomes.

Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking.

Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth.

Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy.

UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Cognitive dysfunction is not only a common symptom of major depressive disorder, but also a more common residual symptom after antidepressant treatment and a risk factor for chronic and recurrent disease. The disruption of hypocretin regulation is known to be associated with depression, however, their exact correlation is remains to be elucidated. Hypocretin-1 levels are increased in the plasma and hypothalamus from chronic unpredictable mild stress (CUMS) model mice. Excessive hypocretin-1 conducted with hypocretin receptor 1 (HCRTR1) reduced lactate production and brain-derived neurotrophic factor (BDNF) expression by hypoxia-inducible factor-1α (HIF-1α), thus impairing adult hippocampal neuroplasticity, and cognitive impairment in CUMS model. Subsequently, it is found that HCRTR1 antagonists can reverse these changes. The direct effect of hypocretin-1 on hippocampal lactate production and cognitive behavior is further confirmed by intraventricular injection of hypocretin-1 and microPET-CT in rats. In addition, these mechanisms are further validated in astrocytes and neurons in vitro. Moreover, these phenotypes and changes in molecules of lactate transport pathway can be duplicated by specifically knockdown of HCRTR1 in hippocampal astrocytes. In summary, the results provide molecular and functional insights for involvement of hypocretin-1-HCRTR1 in altered cognitive function in depression.

In recent years, metabolic reprogramming in liver fibrosis has become a research hotspot in the field of liver fibrosis at home and abroad. Liver fibrosis is a pathological change caused by chronic liver injury from a variety of causes. Liver fibrosis is a common pathological feature of many chronic liver diseases such as chronic hepatitis B, non-alcoholic steatohepatitis, and autoimmune hepatitis, as well as the pathogenesis of the disease. The development of chronic liver disease into cirrhosis must go through the pathological process of liver fibrosis, in which hepatic stellate cells (HSC) play an important role. Following liver injury, HSC are activated and transdifferentiated into scar-forming myofibroblasts, which drive the trauma healing response and which rely on the deposition of collagen-rich extracellular matrix to maintain tissue integrity. This reaction will continue without strict control, which will lead to excessive accumulation of matrix and liver fibrosis. The mechanisms and clinical studies of liver fibrosis have been the focus of research in liver diseases. In recent years, several studies have revealed the mechanism of HSC metabolic reprogramming and the impact of this process on liver fibrosis, in which glucose metabolic reprogramming plays an important role in the activation of HSC, and it mainly meets the energy demand of HSC activation by upregulating glycolysis. Glycolysis is the process by which one molecule of glucose is broken down into two molecules of pyruvate and produces energy and lactate under anaerobic conditions. Various factors have been found to be involved in regulating the glycolytic process of HSC, including glucose transport, intracellular processing of glucose, exosome secretion, and lactate production, etc. Inhibition of the glycolytic process of HSC can be an effective strategy against liver fibrosis. Currently, the combined action of multiple targets and links of Chinese medicine such as turmeric, comfrey, rhubarb and scutellaria baicalensis against the mechanism of liver fibrosis can effectively improve or even reverse liver fibrosis. This paper summarizes that turmeric extract curcumin, comfrey extract comfreyin, rhubarb, Subtle yang yu yin granules, Scutellaria baicalensis extract oroxylin A and cardamom extract cardamomin affect liver fibrosis by regulating gluconeogenic reprogramming. Therefore, studying the mechanism of action of TCM in regulating liver fibrosis through reprogramming of glucose metabolism is promising to explore new methods and approaches for Chinese Medicine modernization research.

A canonical view of the primary physiological function of myoglobin (Mb) is that it is an oxygen (O2) storage protein supporting mitochondrial oxidative phosphorylation, especially as the tissue O2 partial pressure (Po2) drops and Mb off-loads O2. Besides O2 storage/transport, recent findings support functions for Mb in lipid trafficking and sequestration, interacting with cellular glycolytic metabolites such as lactate (LAC) and pyruvate (PYR), and "ectopic" expression in some types of cancer cells and in brown adipose tissue (BAT). Data from Mb knockout (Mb-/-) mice and biochemical models suggest additional metabolic roles for Mb, especially regulation of nitric oxide (NO) pools, modulation of BAT bioenergetics, thermogenesis, and lipid storage phenotypes. From these and other findings in the literature over many decades, Mb's function is not confined to delivering O2 in support of oxidative phosphorylation but may serve as an O2 sensor that modulates intracellular Po2- and NO-responsive molecular signaling pathways. This paradigm reflects a fundamental change in how oxidative metabolism and cell regulation are viewed in Mb-expressing cells such as skeletal muscle, heart, brown adipocytes, and select cancer cells. Here, we review historic and emerging views related to the physiological roles for Mb and present working models illustrating the possible importance of interactions between Mb, gases, and small-molecule metabolites in regulation of cell signaling and bioenergetics.

Regions of hypoxia occur in most solid tumours and are known to significantly impact therapy response and patient prognosis. Ag5 is a recently reported silver molecular cluster which inhibits both glutathione and thioredoxin signalling therefore limiting cellular antioxidant capacity. Ag5 treatment significantly reduces cell viability in a range of cancer cell lines with little to no impact on non-transformed cells. Characterisation of redox homeostasis in hypoxia demonstrated an increase in reactive oxygen species and glutathione albeit with different kinetics. Significant Ag5-mediated loss of viability was observed in a range of hypoxic conditions which mimic the tumour microenvironment however, this effect was reduced compared to normoxic conditions. Reduced sensitivity to Ag5 in hypoxia was attributed to HIF-1 mediated signalling to reduce PDH via PDK1/3 activity and changes in mitochondrial oxygen availability. Importantly, the addition of Ag5 significantly increased radiation-induced cell death in hypoxic conditions associated with radioresistance. Together, these data demonstrate Ag5 is a potent and cancer specific agent which could be used effectively in combination with radiotherapy.