Search Results (332)

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease characterized by progressive cartilage destruction, and chondrocyte apoptosis plays a critical role in TMJOA progression. As chondrocytes reside in an avascular microenvironment inside the cartilage matrix, energy production via glycolysis is crucial for their survival. This study investigated the role of the key glycolytic enzyme Hexokinase 2 (HK2) in TMJOA pathogenesis and the therapeutic potential of dental pulp stem cell-derived extracellular vesicles (DPSC-EVs). In a rat experimental TMJOA model induced by monosodium iodoacetate (MIA) intra-articular injection, we observed a significantly decreased expression of HK2 along with cartilage matrix degradation. In the in vitro study, MIA induced chondrocyte apoptosis with caspase-3 activation, accompanied by impaired glycolytic function. Intervention with DPSC-EVs effectively rescued the expression of HK2 within chondrocytes, leading to a notable restoration of cellular glycolysis. Consequently, DPSC-EV treatment markedly attenuated the progression of TMJOA by reducing chondrocyte apoptosis and improved cartilage integrity. Our findings demonstrated that DPSC-EVs represent a promising cell-free therapeutic strategy for TMJOA, exerting their protective effects by targeting HK2, thereby preserving chondrocyte viability and attenuating osteoarthritis development. Full article

Background/Objectives: To evaluate the immunohistochemical expression of hexokinase-2 (HK2), glutaminase-1 (GLS1), and fatty acid synthase (FASN) and its prognostic significance in diffuse gastric adenocarcinoma. Materials and Methods: Formalin-fixed paraffin-embedded tissue samples from 92 patients with diffuse gastric adenocarcinoma were analyzed. Immunohistochemistry (IHC) was performed to assess the expression of HK2, GLS1 and FASN. Expression levels were evaluated semi-quantitatively based on staining intensity and the percentage of positive cells. Associations between enzyme expression and clinicopathological features were assessed using the Chi-square test. Kaplan–Meier survival analysis was employed to evaluate progression-free survival (PFS) and overall survival (OS) and the log-rank test and Cox proportional hazards models were used for statistical analysis. Results: HK2 and FASN were overexpressed in 20.7% and 22.8% of patients, respectively, and were significantly associated with advanced tumor stage. In contrast, GLS1 expression, found in 30.4% of patients, did not independently correlate with clinicopathological characteristics. Furthermore, HK2 expression and co-expression of HK2/FASN (10.9%) and HK2/GLS1/FASN (8.7%) were associated with progressive disease. In the univariate analysis, stage, HK2 overexpression, and co-expression of HK2/FASN and HK2/GLS1/FASN were associated with shorter survival. However, only stage retained prognostic value in the multivariate analysis. Conclusions: Co-expression of these key metabolic enzymes remains a promising candidate as prognostic markers and therapeutic targets. Concurrent targeting of these metabolic pathways may offer novel therapeutic opportunities for patients with advanced-stage gastric cancer. Full article

The metabolic control analysis (MCA) was applied to several subsystems selected from the model of human erythrocyte energy metabolism. These subsystems represent varying degrees of simplification of energy metabolism, from the simplest subsystem of the first three glycolytic reactions that determine the steady-state rate of glycolysis, to an expanded subsystem that includes all glycolytic reactions plus passive and active ion transport across the cell membrane. The control coefficients of enzyme activities for the rate of glycolysis are found to be very different in different subsystems. However, no specific trend is observed in changes in control coefficients as the subsystem becomes more complex. Thus, in subsystems containing only glycolysis, the control coefficients of hexokinase (HK) and phosphofructokinase (PFK) together amount to 0.99. When ATPases are added, this value decreases to 0.18 and below, and the maximum control coefficient goes to ATPase (0.82–1.00). It would seem that there is a natural decrease in the contribution of HK and PFK to the regulation of the rate of glycolysis as the dimension of the system increases. However, disabling the allosteric regulation of PFK by AMP completely changes the picture. In a subsystem containing only glycolysis, disabling this regulation does not affect the control coefficients. After adding ATPase to such a subsystem, the HK and PFK control coefficients increase, and the control coefficient of ATPase takes on a negative value. Thus, we found that in extended subsystems involving glycolysis and ATPase or transmembrane ion transport, information on the initial regulation of glycolysis may not be revealed in the MCA results. It appears that the MCA alone cannot reveal regulatory mechanisms of metabolic systems in the presence of strong allosteric and feedback regulation. Full article

Prostate cancer progression involves metabolic reprogramming that supports sustained proliferation and survival, highlighting metabolic pathways as potential targets for intervention. While genistein (GEN) and butein (BTN) are naturally occurring polyphenolic compounds with reported anticancer activities, their combined effects on prostate cancer cell metabolism and apoptotic signaling remain unclear. Here, we investigated the effects of GEN and BTN, administered individually and in combination, on human PC-3 prostate cancer cells, with normal human prostate epithelial cells (HPrEC) used for comparison. Cell viability was assessed using MTT and trypan blue exclusion assays. Glycolytic metabolism was evaluated by measuring glucose consumption, lactate production, hexokinase and pyruvate dehydrogenase activity, and intracellular ATP levels, while apoptotic and survival signaling pathways were analyzed by means of Annexin V staining and Western blotting. GEN/BTN co-treatment selectively reduced PC-3 cell viability, producing greater inhibitory effects than either compound alone. This enhanced response was accompanied by suppression of glycolytic metabolism, ATP depletion, attenuation of AKT and ERK phosphorylation, and activation of apoptotic signaling, as evidenced by increased cleavage of caspase-3 and PARP. Collectively, these findings indicate that GEN/BTN co-treatment cooperatively disrupts glycolytic metabolism while activating apoptotic signaling in prostate cancer cells. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV) infection relies on glycolytic reprogramming to support replication, but the mechanisms driving this metabolic shift remain poorly understood. The stimulator of interferon genes (STING), an innate immune adaptor, recently emerged as a metabolic regulator by directly binding and inhibiting hexokinase-2 (HK₂), a key rate-limiting enzyme in glycolysis. Whether PRRSV exploits the STING-HK₂ axis to unleash glycolysis for its own replication is unknown. Here we demonstrate that PRRSV infection induced STING degradation and promoted HK₂ suppression, activating glycolysis for viral replication. In PRRSV-infected Marc-145 cells, lactate production (a glycolysis marker) and HK₂ expression increased time-dependently, peaking at 48 h post-infection (hpi). Conversely, STING protein levels decreased significantly at 36 hpi and further at 48 hpi, suggesting a correlation between STING downregulation and glycolytic activation. The HK₂ inhibitor 2-deoxy-D-glucose reduced lactate production and viral load, while the glycolysis activator PS48 enhanced both. STING knockdown via siRNA increased HK₂ expression, lactate secretion, and PRRSV nucleocapsid protein levels, whereas STING overexpression suppressed these phenotypes. Co-immunoprecipitation and confocal microscopy demonstrated direct STING-HK₂ interaction and cytoplasmic co-localization, maintained during PRRSV infection. HK₂ overexpression promoted viral replication without altering STING levels, confirming HK₂ as a downstream effector. In conclusion, PRRSV-triggered degradation of STING enhances HK₂ expression, promoting lactate accumulation and accelerating viral replication. These findings suggest that the STING-HK₂ axis can act as a critical viral metabolic checkpoint and highlight targeting metabolic–immune crosstalk as a potential anti-viral strategy. Full article

Targeting the Warburg effect (aerobic glycolysis) in tumor cells represents a promising metabolic therapeutic strategy in cancer research. This review analyzes the regulatory mechanisms and therapeutic potential of key glycolysis pathway components, including glucose transporters (GLUTs) and glycolytic enzymes such as hexokinase 2 (HK2), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA). We evaluate the molecular mechanisms of various inhibitors and the current clinical development landscape, noting that limitations of monotherapy stem not only from tumor metabolic plasticity but also largely from the unacceptable toxicity of many inhibitors due to the essential role of glycolysis in normal cell metabolism. Furthermore, we explore the molecular basis of synergistic interactions between glycolysis inhibitors and chemotherapy, radiotherapy, immunotherapy, photothermal therapy, and targeted therapy, proposing that rational combination strategies may help overcome resistance and improve therapeutic efficacy. Finally, the review outlines future challenges and directions, emphasizing that the primary obstacle in metabolic treatments is achieving selective inhibition of glycolytic enzymes in cancer cells while sparing normal cells. To address this challenge, the development of high-selectivity agents, cancer-specific nanodelivery systems, precise biomarker identification, and innovative combination regimens based on metabolic-immune regulation is crucial for advancing glycolysis-targeted therapy toward clinical translation. Full article

Alzheimer’s disease (AD) is regarded as a disease of the brain. Cumulative evidence increasingly supports a full-body view on this disorder, with the liver and kidneys playing an important role in amyloid clearance. The latter is likely potentiated by caloric restriction (CR), whose impact on the metabolism of amyloid-handling tissues is poorly understood. We studied the sex-specific effects of amyloidosis and CR on oxidative and metabolic processes in APPPS1 mice that express amyloidogenic proteins. Wild-type (WT) and APPPS1 mice were either fed ad libitum (AL) or received 70% of their AL caloric intake (CR). Compared to age-matched WT controls, the brain, liver, and kidney of 9-month-old AL APPPS1 mice exhibited higher levels of oxidative stress markers, higher superoxide dismutase, and lower catalase activities. These differences were sex- and tissue-specific, with kidneys showing the largest AD-induced differences between sexes. In addition, APPPS1 mice possessed higher pyruvate kinase activity than WT mice in all organs and higher hexokinase and phosphofructokinase activities in the brain, with stronger effects in males. CR intensified the accumulation of lipid peroxides in the liver and the female brain but decreased it in the female kidney. CR potentiated glycolysis, predominantly in females and modulated glutathione-dependent enzymes, in a sex-dependent manner. Full article

Background: Honeybees sustain vital ecological roles through foraging behavior, which provides pollination services and is likely regulated by dopamine signaling coupled to brain energy metabolism. However, the genetic and metabolic mechanisms underlying this regulation remain unclear. Methods: We treated honeybee workers with the dopamine receptor agonist bromocriptine and employed an integrative approach, combining liquid chromatography–mass spectrometry (LC–MS) metabolomics with single-nucleus RNA sequencing (snRNA-seq). Results: Metabolomics revealed increased levels of N6-carboxymethyllysine (CML) and a coordinated shift in central carbon metabolites, including higher glucose, pyruvate, and lactate within glycolysis, and ribose-5-phosphate in the pentose phosphate pathway (PPP). Integration with transcriptomics showed heterogeneous responses: glial cells exhibited higher glycolysis pathway scores and upregulated hexokinase expression compared to neurons, whereas major PPP enzymes were upregulated in both glial and neuronal subsets. Conclusions: These findings suggest that dopamine receptor activation is associated with altered whole-brain metabolic profiles and concurrent, cell-type-specific upregulation of glycolytic and PPP enzyme genes, particularly in glia. This study characterizes these neuro-metabolic associations, offering insights into the cellular and metabolic basis of foraging behavior in worker bees. Full article

Wheat is one of the most important crops contributing to global food and nutritional security. However, the gradual increase in soil salt content significantly impairs wheat growth and development, ultimately resulting in reduced yields. Therefore, enhancing the salt tolerance of wheat is of significant importance. Salt stress commonly induces oxidative stress in plants, and nucleoredoxin (NRX) has been shown to effectively maintain redox homeostasis under stress conditions. However, the functional role and molecular mechanism of the NRX gene in regulating salt tolerance in wheat remain to be elucidated. The results of this study demonstrated that TaNRX1-2D homologous overexpression (OE) lines exhibited significantly enhanced tolerance to salt stress. The survival rate and antioxidant enzyme activities (including superoxide dismutase and catalase) in the OE lines were higher than those in the wild type (WT). In contrast, the levels of superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and malondialdehyde (MDA) in the OE lines were markedly lower than those in the WT. Conversely, the RNA interference (RNAi) lines displayed opposing trends. The results of yeast one-hybrid (Y1H) and dual luciferase assays (D-LUC) demonstrated that the TaERD15L-3B transcription factor positively regulated the expression of the TaNRX1-2D gene by binding to the ABRERATCAL cis-acting element in the TaNRX1-2D promoter. Through luciferase complementation assay (LCA), bimolecular fluorescence complementation (BiFC) assay, and a “mutation capture strategy”, it was found that TaNRX1-2D (C54, 327S) interacted with TaCAT2-B, indicating that TaCAT2-B was the target protein of TaNRX1-2D. The results of data-independent acquisition (DIA) proteomics analysis indicated that TaNRX1-2D may mediate salt tolerance in wheat through the positive regulation of nsLTP protein abundance and the negative regulation of hexokinase protein abundance. In general, the TaERD15L-3B/TaNRX1-2D regulatory module played a crucial role in conferring salt tolerance in wheat. This study provided an important theoretical basis and identified a potential gene target for developing salt-tolerant wheat varieties through molecular breeding approaches. Full article

Reproductive-stage drought arrests silk elongation, causing a greater anthesis-silking interval and subsequent kernel loss in maize. Exogenous brassinolide (BR) is known to increase drought tolerance; however, its influence on silk growth under water deficit remains unresolved. Here, we subjected maize to drought before tassel emergence (V13) and then applied foliar BR at concentrations of 0, 0.1, 0.5, or 1 mg mL⁻¹, with distilled water-sprayed plants serving as controls. Silk elongation under water-deficit stress was partially restored by 0.1 and 0.5 mg mL⁻¹ BR but suppressed by 1 mg mL⁻¹, with 0.5 mg mL⁻¹ increasing silk length by 2.9-fold compared to the stress control, recovering it to 26.5% of the well-watered level. This protection was underpinned by elevated antioxidant capacity (POD, SOD, and CAT by 31–77%, 12–46%, and 20–33%, respectively) and a 25–76% rise in proline relative to the distilled water-sprayed, which collectively curtailed oxidative damage, as evidenced by 36–67% reductions in O₂⁻ and H₂O₂ levels and a 24% decrease in MDA content. Critically, BR reprogrammed sugar metabolism: sucrose phosphate synthase (SPS) activity declined, while sucrose synthase (SS-I) and vacuolar invertase (VIN) activities surged, thereby shifting carbon partitioning from sucrose toward hexoses to sustain energy supply for silk growth. Genome-wide RNA-seq identified 6171 upregulated and 3295 downregulated genes, significantly enriched in 20 pathways, including starch/sucrose metabolism, glycolysis/gluconeogenesis, and phenylpropanoid biosynthesis. The expression of key genes, including sucrose invertase (INV) and hexokinase (HK), was significantly upregulated by 2.4- to 8.7-fold and 2.3- to 4.0-fold, respectively, compared to the distilled water-sprayed control. This multi-level analysis demonstrates that BR mitigates drought-induced silk growth arrest by orchestrating antioxidant defense, osmotic regulation, and metabolic reprogramming into a coordinated network, providing mechanistic insights into brassinosteroid-mediated reproductive stress adaptation in maize. Full article

Diabetes is a chronic metabolic disorder that poses a growing global health challenge, currently affecting nearly 500 million people. Over the past four decades, the rising prevalence of diabetes has highlighted the urgent need for innovations in monitoring and management. Traditional enzymatic methods, including those using glucose oxidase, glucose dehydrogenase, and hexokinase, are widely adopted due to their specificity and relative ease of use. However, they are hindered by issues of instability, environmental sensitivity, and interference from other biomolecules. Non-enzymatic sensors, which employ metals and nanomaterials for the direct oxidation of glucose, offer an attractive alternative. These platforms demonstrate higher sensitivity and cost-effectiveness, though they remain under refinement for routine use. Non-invasive glucose detection represents a futuristic leap in diabetes care. By leveraging alternative biofluids such as saliva, tears, sweat, and breath, these methods promise enhanced patient comfort and compliance. Nonetheless, their limited sensitivity continues to challenge widespread adoption. Looking forward, the integration of nanotechnology, wearable biosensors, and artificial intelligence paves the way for personalized, affordable, and patient-centered diabetes management, marking a transformative era in healthcare. This review explores the evolution of glucose monitoring, from early chemical assays to advanced state-of-the-art nanotechnology-based approaches. Full article

Soluble sugars are key determinants of fruit quality, directly influencing sensory attributes such as sweetness and flavor, as well as nutritional value and texture. Their content and composition are precisely regulated by sugar-metabolizing enzymes. Key enzymes, including invertase (INV), sucrose phosphate synthase (SPS), sucrose synthase (SUS), fructokinase (FRK), and hexokinase (HXK), play pivotal roles in these processes. However, a systematic and in-depth analysis of their regulatory mechanisms is currently lacking, which hinders a comprehensive understanding of the regulatory network governing fruit sugar metabolism. This review employs bibliometric analysis to systematically examine research trends in fruit sugar metabolism. Furthermore, it synthesizes recent advances in the coordinated regulatory mechanisms from the perspectives of transcriptional regulation, epigenetic modifications, and signal transduction, aiming to provide a clearer framework for future research. At the transcriptional level, transcription factor families such as MYB, WRKY, NAC, and MADS-box achieve precise regulation of sugar metabolism-related genes by specifically binding to the promoters of their target genes. Regarding epigenetic regulation, mechanisms including histone modifications, non-coding RNAs, and DNA methylation influence the expression of sugar-metabolizing enzymes at the post-transcriptional level by modulating chromatin accessibility or mRNA stability. Signaling pathways integrate hormonal signals (e.g., ABA, ethylene), environmental signals (e.g., temperature, light), and sugar-derived signals into the regulatory network, forming complex feedback mechanisms. These regulatory mechanisms not only directly affect sugar accumulation in fruits but also participate in fruit quality formation by modulating processes such as cell turgor pressure and carbon allocation. By integrating recent findings on transcriptional regulation, epigenetics, and signaling pathways, this review provides a theoretical foundation for fruit quality improvement and targeted breeding. Full article

Metabolic reprogramming is a fundamental hallmark and a key driver of malignant tumors. By reshaping glucose, lipid, and amino acid metabolism, as well as mitochondrial function, it sustains the abnormal proliferation and survival of tumor cells, making it a crucial target for anti-tumor therapy. Curcumin, a natural multi-target compound, exhibits unique advantages in intervening in tumor metabolic reprogramming due to its low toxicity and broad-spectrum regulatory properties. In various tumor models, it can directly modulate the activity of key glycolytic enzymes, such as hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2, as well as transporters like glucose transporter 1. Furthermore, it inhibits the expression of proteins related to lipid metabolism, including fatty acid synthase and stearoyl-CoA desaturase 1, while also intervening in amino acid metabolic networks, such as glutaminase and branched-chain amino acid transaminase. Additionally, curcumin targets mitochondrial function and reactive oxygen species balance, creating multi-dimensional intervention effects through various pathways, including the induction of ferroptosis by regulating the SLC7A11/GPX4 axis and modulating gut microbiota metabolism. Its mechanism of action involves the synergistic regulation of key signaling pathways, including phosphoinositide 3-kinase/Akt, NF-κB, AMP-activated protein kinase, and hypoxia-inducible factor-1alpha. Furthermore, its specific effect profile demonstrates significant dependency on cell type and tumor model. This article systematically reviews the regulatory effects of curcumin on these critical metabolic processes and pathways in tumor metabolic reprogramming, revealing its molecular mechanisms in disrupting tumor growth and progression by targeting energy and biosynthetic metabolism. These findings provide a significant theoretical foundation and a preclinical research perspective for the development of natural antitumor drugs based on metabolic regulation, as well as for optimizing combination therapy strategies. Full article

A systematic literature review of the PubMed database, filtering for publication dates up to and including October 2025, was conducted to identify relevant studies on glucose metabolism and radiotherapy. Radioresistance poses a major therapeutic challenge, in which tumor-associated glucose metabolic reprogramming, characterized by the Warburg effect, supports cellular energy requirements and contributes to radioresistance by facilitating DNA repair and promoting survival pathways. Targeting pivotal glycolytic enzymes, such as hexokinase (HK) and pyruvate kinase M2 (PKM2), and integrating radiotherapy with metabolic modulators have been shown to improve radiosensitivity. Special emphasis is placed on how these interventions remodel the tumor microenvironment and modulate antitumor immunity—emerging factors that influence therapeutic efficacy. This review highlights mechanistic insights and potential therapeutic targets for the development of effective radiosensitization strategies. Full article

Background: Preeclampsia (PE) and gestational diabetes mellitus (GDM) are complex pregnancy disorders characterized by hypertension, proteinuria, increased blood glucose levels, and metabolic dysfunction. Methods: We investigated lymphocyte proliferation, immune function, key antioxidants, and metabolic and mitochondrial enzyme activities in women with PE and PE with GDM compared to normotensive pregnant (NP) controls. Lymphocyte proliferation was assessed following phytohemagglutinin (PHA) stimulation at varying concentrations (0.5, 2.5, and 5 µg/mL). Activities of key antioxidant enzymes, metabolic enzymes, and mitochondrial enzymes were measured. Other stress markers, including nitric oxide (NO) production and lipid peroxidation (TBARS), along with acetylcholine esterase (AChE) activity, and proinflammatory cytokine assays (IL-6 and TNF-α) were also evaluated from the PHA-induced lymphocytes. Results: Lymphocyte proliferation in response to PHA was significantly increased in PE and PE with GDM groups compared to NP, although low-dose PHA (0.5 and 2.5 µg/mL) moderately enhanced proliferation in NP. IL-6 and TNF-α levels were notably elevated in both disease groups. Antioxidant activities of SOD, GST, GPx and AChE, Citrate synthase, Cytochrome c oxidase, and NO production were significantly reduced in PE and PE with GDM, while hexokinase activity involved in glycolysis was elevated in both groups. Further, TBARS levels were elevated in the disease groups, particularly in PE with GDM. Conclusions: The findings arise from a clinical cross-sectional study and highlight significant immune alterations, oxidative stress, and mitochondrial impairment in PE and PE with GDM. The observed elevation in proinflammatory cytokines further underscore the role of immune activation in the pathogenesis of these complications, emphasizing the integrated immunometabolic shifts identified in this study, as potential molecular indicators for early intervention. Full article