Search Results (987)

Differences in metabolic traits between traditional and modern pig breeds may influence their physiological responses to stress hormones. This study evaluated the in vivo metabolic effects of an acute adrenaline challenge in Iberian (obese, slow-growing) and Landrace (lean, fast-growing) pigs (Sus scrofa domesticus). Four Iberian and five Landrace barrows (≈50 kg body weight; BW) fitted with a carotid catheter received an injection of adrenaline (3 µg/kg BW), and serial blood samples were collected for 105 min. Adrenaline transiently increased plasma glucose (p < 0.001) and lactate (p < 0.001) concentrations, both peaking at 5 min post-injection. Iberian pigs showed higher plasma lactate (1.26 vs. 1.03 mM; p = 0.002), triglycerides (0.34 vs. 0.27 mM; p < 0.001), and non-esterified fatty acids (NEFA; 0.38 vs. 0.29 mM; p = 0.021), but lower glucose (4.80 vs. 5.03 mM; p = 0.010) than Landrace pigs, while cholesterol remained unaffected (p > 0.10). No breed × time interaction was detected for any metabolite. The relative increase in glucose reached +47% in Iberian and +27% in Landrace pigs, whereas lactate rose +140% and +113%, respectively, indicating stronger glycolytic activation in Iberian pigs. Despite the limited sample size, the results provide physiologically relevant evidence supporting increased metabolic flexibility in Iberian pigs, characterized by a heightened sensitivity to adrenergic stimulation and associated with enhanced lipolytic and glycolytic responses; however, these conclusions should be interpreted within the specific experimental conditions under which the study was conducted. These findings demonstrate that Iberian pigs have higher metabolic sensitivity to adrenergic stimulation, with enhanced lipolytic and glycolytic activity. In conclusion, breed-dependent differences in stress-related metabolism suggest that Iberian pigs are furnished with increased metabolic flexibility to face short-term stress. Full article

Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor–stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas–Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1α. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1/hypoxia-inducible factor-1α (HIF-1α) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target. Full article

Slow-growing and locally invasive, chordoma is a rare malignant bone tumor, with a reported annual worldwide incidence of 0.08 per 100,000 cases. It accounts for about 3 percent of all bone tumors and about 20 percent of primary spinal tumors. The incidence rates vary between countries and races, with white/Caucasian males in the 5th or 6th decade of life having a higher prevalence. Chordoma poses significant challenges because of its high recurrence rate and resistance to several standard treatment techniques. All cancers, including chordomas, have altered energy metabolism processes that contribute to their unchecked growth and survival. The significance of non-coding RNAs, particularly circular RNAs (circRNAs), as key regulators at the intersection of cellular metabolism and immune function has been highlighted by recent discoveries. By focusing on important glycolytic enzymes in tumor cells and altering metabolic reprogramming pathways, CircRNAs can influence cancer metabolic adaptability. Furthermore, via influencing immune cell functions as immunological checkpoint signaling and macrophage polarization, circRNAs influence immune evasion in the tumor microenvironment. These frequently happen via regulating important pathway signals, like PI3K/AKT/mTOR and NRF2, or by processes like miRNA sponging, creating a tumor microenvironment that is immunosuppressive and metabolically friendly. The translational pathway of circRNA-targeted therapeutics is promoted as a developing pharmacological entity in this review, which also highlights recent information on the control of circRNA-mediated immunometabolism in chordoma and examines numerous important molecular axes. There are promising opportunities to develop novel precision treatments for chordoma by considering circRNAs as dual regulators of immunological and metabolic networks. 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

Background: Cigarette smoking disrupts cellular energy metabolism and remains a major global health problem. The Mediterranean diet, characterized by antioxidant and anti-inflammatory properties, has been implicated in the regulation of metabolic pathways. Objective: This study aimed to examine the association between adherence to the Mediterranean diet and the expression of energy metabolism-related genes in smokers aged 18–55 years. Methods: Smokers were classified according to their Mediterranean Diet Adherence Screener (MEDAS) scores into an adhering group (n = 24) and a non-adhering group (n = 24). Participant characteristics were recorded, blood samples were collected, and total RNA was isolated. Gene expression analysis was performed using a custom RT-qPCR array targeting energy metabolism-related genes. Pathway enrichment analysis was conducted using EnrichR Reactome 2024, and gene–metabolite relationships were explored using MetaboAnalyst 6.0 to support pathway-level interpretation. Results: Smoking was associated with coordinated upregulation of genes involved in glycolysis, glucose transport, lipid metabolism, amino acid metabolism, the pentose phosphate pathway, and redox regulation, consistent with a metabolically stressed state. In contrast, adherence to the Mediterranean diet was associated with lower expression of genes related to glycolytic flux, lipid β-oxidation, and amino acid turnover, alongside relatively higher engagement of tricarboxylic acid cycle-related pathways and reduced activation of redox-associated processes. Conclusions: Adherence to the Mediterranean diet was associated with differences in the expression of genes involved in cellular energy metabolism among smokers, suggesting a potential modulatory role of dietary patterns in smoking-related metabolic alterations. Full article

This study aimed to modify metabolite synthesis in Saccharomyces cerevisiae (S. cerevisiae) under simulated wine fermentation conditions by regulating the glycerol metabolic pathway. We systematically analyzed the effects of overexpressing the aquaporin gene AQY1 and co-expressing AQY1 with the glycerol-3-phosphate dehydrogenase gene GPD1 on the metabolism of ethanol, higher alcohols, and esters. Our results indicate that AQY1 overexpression increased glycerol yield by 6.58%, reduced higher alcohol content by 14.60%, and elevated ester content by 7.15%. The downregulation of related amino acid metabolism genes correlated with the observed decrease in higher alcohol levels. Notably, co-expression of AQY1 and GPD1 further enhanced glycerol yield by 10.66% while decreasing ethanol content by 6.32%. By analyzing changes in gene expression alongside metabolic mechanisms, we hypothesize that the redistribution of carbon flux and NADH toward the glycerol pathway not only decreases the precursors for ethanol synthesis but also directly inhibits the activity of aldehyde dehydrogenase (ALD2/3/4/6), thereby constraining ethanol production. In comparison to AQY1 overexpression alone, the co-expression strategy did not significantly alter glycerol accumulation; however, it reduced both ethanol and ester content by 8.38% and 8.40%, respectively, while markedly increasing higher alcohol content by 22.30%. This increase may result from enhanced glycolytic flux and pyruvate accumulation, which promote metabolic flow toward amino acid synthesis pathways. In summary, this study effectively remodeled the central carbon metabolism network by targeting glycerol metabolism, achieving diverse metabolic product synthesis and providing important references for the selection and breeding of industrial S. cerevisiae strains. Full article

The lactoperoxidase system (LpoS) is an enzymatic antimicrobial mechanism of saliva that oxidizes (pseudo)halide substrates to reactive compounds capable of limiting microbial growth. This study evaluated how different LpoS variants—utilizing iodide (LpoS-I⁻), thiocyanate (LpoS-SCN⁻), selenocyanate (LpoS-SeCN⁻), and a thiocyanate–iodide mixture (LpoS-SCN⁻ + I⁻)—affect virulence, metabolism, and biofilm structure in Streptococcus mutans. Using qRT-PCR, pyruvate assays, MTT reduction, and confocal microscopy, we found that LpoS-I⁻ most effectively reduced atpD and ldh expression, impaired acid tolerance, and decreased lactate and pyruvate production. LpoS-SCN⁻ and LpoS-SeCN⁻ also downregulated atpD and gtfB, although LpoS-SeCN⁻ upregulated ldh. Despite minimal structural biofilm disruption, LpoS-I⁻ markedly inhibited intracellular and extracellular pyruvate accumulation, suggesting altered glycolytic flux. These findings indicate that iodide-based LPO systems modulate key metabolic and regulatory pathways in S. mutans and may hold potential for inclusion in anticaries oral formulations. Full article

Background/Objectives: Astrocytes are key regulators of brain energy homeostasis, integrating glucose metabolism with antioxidant support for neuronal function. Dysregulation of these processes contributes to neurodegenerative diseases, including Alzheimer’s disease. Andrographolide, a bioactive diterpenoid from Andrographis paniculata, has been reported to exert neuroprotective effects through the modulation of Wnt/β–catenin signaling and neuronal metabolism; however, its actions on astrocytic metabolic pathways remain insufficiently characterized. Methods: Here, we investigated the effects of andrographolide on metabolic and redox parameters in primary mouse cortical astrocytes. Results: Andrographolide increased glucose uptake and antioxidant capacity without affecting AMPK activation or the activity of core glycolytic enzymes. Instead, it selectively enhanced glucose-6-phosphate dehydrogenase activity, promoting glucose flux through the pentose phosphate pathway in a partially Wnt-dependent manner. This metabolic reprogramming was associated with increased NADPH availability and glutathione levels, together with a reduced ATP/ADP ratio, consistent with a shift toward redox maintenance rather than maximal energy production. Conclusions: Collectively, these findings highlight astrocytic metabolic plasticity as a relevant and underexplored target of andrographolide and support the concept that natural compounds can enhance brain resilience by modulating glial redox metabolism. Full article

Background/Objectives: Breast cancer is a prevalent and heterogeneous disease with multiple subtypes, which are defined by characteristics such as molecular biomarkers and metastatic status. This study aimed to profile the metabolic activity of various breast cancer subtypes, both with and without chemotherapy (doxorubicin) application. Methods: Six human breast cell lines were evaluated, two non-tumorigenic controls and four cancerous lines. The cancer lines were clustered as primary-derived, metastasis-derived, triple-negative (TNBC), and strong hormone receptor-positive (ER+/PR+) and analyzed using the Biolog phenotype mammalian microarrays (PM-M1 to PM-M8) to assess metabolic activity via NADH production under a wide array of substrate parameters. Results: Unique metabolic profiles emerged across the subtypes and clusters; the TNBC and metastatic cells demonstrated enhanced utilization of glycolytic and anaerobic substrates consistent with the Warburg effect. The ER+/PR+ cells showed heightened glucose utilization and unique sensitivity to metabolic effectors and doxorubicin. Additionally, significant metabolic differences were observed in nucleoside and amino acid utilization between cancer and control cells, particularly in metastatic and TNBC lines. Conclusions: Our findings reveal the profound metabolic diversity among breast cancer subtypes and highlight distinct substrate dependencies for proliferation. The results additionally provide a framework for developing metabolic biomarkers and targeted therapies for chemotherapy resistance in breast cancer subtypes. Full article

Fast-twitch and slow-twitch muscle fibers not only differ in metabolic characteristics and physiological functions but also significantly influence the texture of livestock meat. RNA editing represents an important post-transcriptional regulatory process that can influence both gene expression and the resulting protein function. However, studies on RNA editing events in yak muscle remain limited. This study systematically identified RNA editing events in yak biceps femoris (BF, n = 3) and obliquus externus abdominis (OEA, n = 3) using transcriptomic data, discovering 17,713 unique editing sites, most located in non-coding regions. Within coding regions, 3350 sites were detected, with 1195 resulting in non-synonymous amino acid substitutions. Further analysis revealed that 785 sites potentially affected miRNA binding sites, suggesting RNA editing may participate in miRNA-mediated gene regulation. Tukey’s post hoc test (p < 0.05) identified 242 sites (involving 170 genes) with significantly different editing levels between BF and OEA. KEGG pathway analysis indicated that genes with differential RNA editing were predominantly associated with pathways involved in muscle fiber type transitions, including the MAPK and calcium signaling pathways. Collectively, this study maps the RNA editing landscape in yak muscle tissue and identifies distinct, fiber-type-specific RNA editing patterns between oxidative and glycolytic muscle fibers, including differences in editing levels and site distributions, supporting a potential association between RNA editing and muscle fiber type transformation. Full article

Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell–cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication—particularly via MIF, CDH5, and MHC-II pathways—highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic–immune mediator and promising therapeutic target. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

Intermittent Hypobaric Storage (IHS) effectively inhibits postharvest deterioration of cassava roots, yet its physiological regulatory mechanisms and associated quality alterations remain poorly understood. This study investigated the regulatory mechanisms of root respiratory physiology under IHS and their impact on quality. Results indicate that IHS reduces root respiration rates and maintains generally low anaerobic respiration enzyme activity, while ATP content remains higher than in the control. This supports efficient energy supply for cellular metabolism, thereby delaying senescence. Transcriptomic analysis revealed that IHS modulates glycolytic genes, suppresses excessive anaerobic respiration, and upregulates pathways associated with ribosome biogenesis and oxygen response. Meanwhile, IHS downregulated ATP-consuming pathways involved in phenylpropanoid biosynthesis. IHS effectively prolongs shelf life and preserves the nutritional quality of cassava roots, maintaining levels comparable to those of fresh roots. These molecular responses collectively support the physiological and biochemical benefits of IHS, providing valuable insights for optimizing its application in cassava postharvest storage. Full article

Dravet Syndrome (DS) is a severe genetic epileptic encephalopathy caused by mutations in the SCN1A gene that encodes the voltage-gated sodium channel (Na_V1.1) subunit alpha. DS is characterized by intractable seizures, progressive developmental delay, cognitive impairment, and high mortality due to sudden unexpected death in epilepsy (SUDEP). SUDEP is mediated by respiratory dysfunction, but the exact molecular underpinnings are unclear. Though hippocampal metabolic alterations have been reported in DS mice, such changes in brain regions controlling breathing have not been studied. We used Scn1a^A1783V/WT DS mice to study temporal alterations in the brain metabolome, including analysis of brainstem and forebrain regions. Glycolytic and pentose phosphate pathway intermediates were significantly elevated in the brainstem of DS mice during the period of enhanced susceptibility to mortality (post-natal days P20–30). In older P40–P50 mice, mitochondrial aconitate and the antioxidant glutathione were significantly elevated in the brainstem. Single-nuclei RNA sequencing (snRNA seq) and proteomic analyses revealed alterations in genes associated with neurotransmission, cellular respiration, and protein translation, as well as reorganization of protein kinase-mediated pathways that are specific to the brainstem. These findings suggest that there are widespread metabolic changes in the brainstem of DS mice. Full article

Background: Neonatal myocytes rely predominantly on glycolytic metabolism for survival during hypoxic conditions. During asphyxia, metabolic pathway dysregulation impairs cardiac myocyte contractility. Co-administration of dextrose and insulin may help restore metabolic homeostasis and improve cardiac function. Methods: Following blinded randomization and instrumentation, near-term lambs (138–140 days gestational age) were asphyxiated by umbilical cord occlusion until complete cardiac arrest, followed by 7 min of continued arrest to model severe asphyxia. Return of spontaneous circulation (ROSC) was defined as heart rate ≥ 100 beats per minute (bpm) and diastolic blood pressure ≥ 20 mmHg. Results: The incidence of ROSC was 3/6 in the control group compared to 5/5 in the experimental group receiving dextrose–insulin therapy, although this difference did not reach statistical significance. Conclusions: In this proof-of-concept study using a near-term ovine model of prolonged asphyxial cardiac arrest, dextrose and insulin co-administered with epinephrine were associated with improved ROSC rates although could be an association. Larger studies are needed to confirm these findings and evaluate clinical translation Full article