Physical exercise is recognized as an effective intervention to improve mood, physical performance, and general well-being. It achieves these benefits through cellular and molecular mechanisms that promote the release of neuroprotective factors. Interestingly, reduced levels of physical exercise have been implicated in several central nervous system diseases, including ocular disorders. Emerging evidence has suggested that physical exercise levels are significantly lower in individuals with ocular diseases such as glaucoma, age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy. Physical exercise may have a neuroprotective effect on the retina. Therefore, the association between reduced physical exercise and ocular diseases may involve a bidirectional causal relationship whereby visual impairment leads to reduced physical exercise and decreased exercise exacerbates the development of ocular disease. In this review, we summarize the evidence linking physical exercise to eye disease and identify potential mediators of physical exercise-induced retinal neuroprotection. Finally, we discuss future directions for preclinical and clinical research in exercise and eye health.

Initially, molecular hydrogen was considered a physiologically inert and non-functional gas. However, experimental and clinical studies have shown that molecular hydrogen has anti-inflammatory, anti-apoptotic, and strong selective antioxidant effects. This study aimed to evaluate the effects of 60 minutes of molecular hydrogen inhalation on respiratory gas analysis parameters using a randomized, double-blind, placebo-controlled, crossover design. The study was conducted at Faculty of Physical Culture, Palacký University Olomouc from September 2022 to March 2023. Twenty, physically active female participants aged 22.1 ± 1.6 years who inhaled either molecular hydrogen or ambient air through a nasal cannula (300 mL/min) for 60 minutes while resting were included in this study. Metabolic response was measured using indirect calorimetry. Breath-by-breath data were averaged over four 15-minute intervals. Compared with placebo (ambient air), molecular hydrogen inhalation significantly decreased respiratory exchange ratio and ventilation across all intervals. Furthermore, the change in respiratory exchange ratio was negatively correlated with body fat percentage from 30 minutes onwards. In conclusion, 60 minutes of resting molecular hydrogen inhalation significantly increased resting fat oxidation, as evidenced by decreased respiratory exchange ratio, particularly in individuals with higher body fat percentages.

Lactate, a byproduct of pyruvate in the glycolytic pathway, has been recognized as a signaling molecule and a regulator of gene expression. In skeletal muscles, lactate is dynamically regulated during exercise and influences muscular function, including myogenic differentiation and metabolism. The effects of lactate vary depending on lactate levels, which are influenced by exercise intensity, type, and duration. Furthermore, the effects of lactate on cellular signaling are different during the stages of myogenic differentiation. However, the distribution of lactate signaling in terms of lactate concentration, signaling types, and myogenesis has not been fully elucidated. In this study, we investigated the dual effects of lactate on myogenic differentiation and viability using C2C12 cells and C57BL/6 mice. Low levels of lactate treatment promoted myogenesis in the early stage of C2C12 differentiation, while high lactate concentrations or treatment with 3,5-DHBA, a GPR81 agonist, impaired cell viability during late myogenic differentiation. Transcriptomic analysis and knockdown experiments revealed that lactate promotes myogenesis and muscular metabolic functions through the induction of Ranbp3l and Nfat5 expressions. On the other hand, the detrimental effects of lactate on cell survival are mediated by the GPR81-induced PI3K-Akt/ERK-Atf4 axis. GPR81 signaling also feeds forward the expression of Hcar1 via Akt and ERK. These dual actions of lactate on skeletal muscle were also observed in vivo through lactate or 3,5-DHBA injections and exercise training models. Our study concludes that maintaining a balance in lactate signaling is crucial for regulating skeletal muscle phenotypes in response to exercise and lactate treatments.

The study examined the effect of aerobic and sprint sets sequence on physiological responses and perceived exertion during concurrent training sessions. Twelve male highly trained swimmers performed four sessions in randomized order, using combinations of the following training sets: (a) lactate threshold training (8 × 200-m at a speed corresponding to lactate threshold with 30-s recovery; LT), (b) high-intensity aerobic training (8 × 100-m at the maximal aerobic speed with 30-s recovery; MAS) and (c) repeated-sprints training (8 × 25-m repeated sprints with 2-min recovery; SPR). The four combinations used were as follows: LT-SPR, SPR-LT, MAS-SPR, SPR-MAS. Blood lactate (BL), pH, base excess (BE), bicarbonate, heart rate (HR), HR variability, objective [training impulse (iTRIMP)] and subjective training load [session's rating of perceived exertion (sRPE)] were measured. Between session pH and BE were no different, but mean BL was higher in sessions starting with repeated sprints compared with the reverse order (SPR-LT: 6.3 ± 3.6, LT-SPR: 5.3 ± 3.7 mmol·L-1, p = 0.03; SPR-MAS: 7.2 ± 3.9, MAS-SPR: 6.0 ± 3.7 mmol·L-1, p = 0.05). Bicarbonate in SPR-LT was lower compared with LT-SPR (p = 0.03). sRPE, but not iTRIMP, was higher in sessions starting with SPR compared with the reverse order (p = 0.02). Anaerobic-aerobic set sequence, compared with the reverse order, augments BL response and increases perceived training load but not the training impulse.

Lactate, a small organic acid related to short-chain fatty acids, is emerging as a key energy metabolite, although much remains unknown about its actions in the gut. In the current study, we specifically tested how oral and parenteral (IV) lactate affects lactoylation of amino acids in humans and whether these clinical results could be reproduced in a perfused rat intestine model. Furthermore, using targeted and untargeted metabolomics, we globally investigated how oral and IV lactate impacts the circulating metabolome to delineate potential circulating messengers and obtain additional mechanistic insights into how oral lactate may potentially induce glucagon-like peptide-1 secretion as well as alternative metabolites correlated to human health. Our findings provide a better understanding of the general effects of lactate in the gut and how it potentially signals to increase satiety in humans.NEW & NOTEWORTHY By investigating the effects of oral versus IV lactate administration, we find that oral lactate elevates plasma l-lactate and strongly increases circulating l-Lac-Phe and l-Lac-Val, potentially via an alternative mechanism than exercise-induced formation. Furthermore, we find that GLP-1 secretion is not directly induced by lactate but may be mediated via increased bile acids and SCFAs in the gut.

Research on physical activity (PA) and health has a fundamental concern with dose-response relationships. The variables of (1) Frequency, (2) Intensity, (3) Time, and (4) Type (i.e., the FITT principle) have traditionally been used to operationalize the dosage of PA. We consider some limitations of FITT and propose that it can be complemented by the additional variable density (from the German exercise and training variable Belastungsdichte), which can be defined as the timing of successive work bouts within a single PA bout as well as the timing between successive PA bouts within a specific time period; it does so by quantifying the temporal intervals between successive work or PA bouts (i.e., time spent at a lower PA intensity or resting such as in napping/sleeping or sedentary behaviors). Using the field of PA and brain health as an example, we discuss the opportunities and challenges for further research employing the variable density and consider its potential to improve the understanding of dose-response relationships between PA and health outcomes.

Cell organelles compartmentalize metabolic reactions and require inter-organelle communications to coordinate metabolic activities in fluctuating nutrient environments. While membrane contacts enable this communication by facilitating metabolite exchange, the functional organization of organelles through these contacts remains underexplored. Here, we show that excess lactate induces severe metabolic stress under nutrient deprivation in the budding yeast Saccharomyces cerevisiae, necessitating a rapid life cycle of lipid droplets (LDs) for cellular adaptation. This process uncovers a previously uncharacterized subcellular architecture-an organelle triad-comprising the vacuole, LDs, and the nuclear endoplasmic reticulum (ER). The vacuole undergoes expansion and deformation, enveloping the entire nucleus that is encircled by an orbit of LDs. Formation of this organelle triad depends on the timely and abundant expression of membrane-tethering proteins that mediate vacuole-LD contact sites and nuclear ER-vacuole junctions. This dynamic and reversible subcellular organization ensures efficient LD metabolism to support cell survival under nutrient stress.

Lactate plays a central role in controlling the utilization of energy substrates and the selection of metabolic pathways. This review aims to determine how lactate participates in energy supply and elaborate on how lactate is involved in the fat metabolism and regulation of white adipose and skeletal muscle tissues during exercise, thereby helping the human body achieve precise matching with different exercise intensities and a dynamic balance in energy supply.Numerous studies have confirmed that lactate, through multiple pathways such as the GPR81 receptor and MCT1, regulates the cAMP/PKA signaling pathway, adrenaline concentration, and mitochondrial biogenesis and antioxidant function during exercise, participating in the fatty acid metabolism process of a single bout of exercise and exhibiting different effects in white adipose tissue and skeletal muscle, thereby effectively regulating lipid metabolism. This regulatory process is dependent on lactate concentration and exercise duration. Furthermore, lactate plays a crucial role in the restructuring of lipid metabolism induced by long-term exercise, particularly in promoting the browning of white adipose tissue and enhancing mitochondrial function. However, the bridging role of lactate in the transition of energy supply mechanisms and its deeper mechanisms in lipid metabolism regulation remain at the forefront of metabolic scientific research. In the future, there is an urgent need to delve into the regulatory network of lactate under different exercise intensities, reveal its potential applications in the treatment of metabolic diseases, provide a theoretical basis for the development of new treatment strategies, and promote the formulation of personalized exercise prescriptions to optimize metabolic health and disease management.

This study investigated the effects of lactate levels in broiler breast on protein lactylation modification, meat quality, and their correlation. High lactate injections led to increased lactate levels in both serum and breast muscle, and significantly reduced the values of pH0, pH45min and pH24h. Additionally, the lactylation levels in breast muscle were increased both post-slaughter and post-mortem. Protein lactylation in breast muscle occurred through enzymatic and non-enzymatic pathways at these stages, with the underlying mechanisms varying according to lactate levels and the muscle aging process. Correlation analysis revealed that post-slaughter lactylation contributed to breast muscle morphometry, whereas post-mortem lactylation was associated with meat quality and texture profile. These findings could demonstrate the presence and dynamic patterns of protein lactylation in broiler breast muscles, offering new insights into the role of lactate accumulation in meat quality variation.

Advancements in tumor research have highlighted the potential of epigenetic therapies as a targeted approach to cancer treatment. However, the application of these therapies has faced challenges due to the issue of substrate availability since the discovery of epigenetic modifications. Interestingly, metabolic changes are closely associated with epigenetic changes, and notably, certain metabolic enzymes exhibit nuclear localization within epigenetically active cellular contexts. This suggests that nuclear localization of metabolic enzymes may provide a mechanistic foundation for addressing substrate availability issues in epigenetic regulation. To date, there has been limited progress in synthesizing this information systematically. In this study, we provide an overview of the interplay between metabolic enzymes and epigenetic mechanisms, highlighting their critical roles. Subsequently, we summarize recent advances regarding the nuclear localization of metabolic enzymes, shedding light on their emerging roles in epigenetic regulation and oncogenesis.

Lactate dehydrogenase A (LDHA) plays a crucial role in regulating lactate synthesis in various biological processes. Lactate, a byproduct of glycometabolism, has been recognized as a unique molecule with implications in both metabolism and immunity. Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), is a highly contagious and severe infectious disease that primarily affects pigs. Prior research has shown that CSFV infection disrupts the normal glycolytic process, leading to an accumulation of lactate within the host. Nevertheless, it remains unclear whether there is mutual regulation between the CSFV and LDHA-lactate axis. Here, we have found that CSFV infection increases LDHA expression in vivo and in vitro, which may be attributed to attenuated ISGylation of LDHA. Furthermore, CSFV infection induces L-lactate production via LDHA dependence in vitro. The cellular biology research on LDHA has revealed that LDHA not only localizes to the mitochondria but also inhibits PINK1-Parkin-mediated mitophagy. Through various experimental techniques such as western blot to detect mitophagy marker proteins, laser confocal microscopy to observe the flow of mitophagy, and transmission electron microscopy to assess changes in the number of mitochondria enclosed within autophagosome-like vesicles, it has been discovered that the addition of exogenous lactate can inhibit PINK1-Parkin-mediated mitophagy. Importantly, we have observed that lactate activates the JAK1-STAT1-ISG15 network and suppresses CSFV replication by antagonizing CCCP-induced mitophagy. These results represent the first report on the mechanisms through which the LDHA-lactate axis regulates mitophagy, the JAK-STAT pathway, and CSFV replication. This study provides novel insights into the roles of the LDHA-lactate axis in glycometabolism and viral replication.

This research unveils how CSFV interacts with cellular metabolism through LDHA. By revealing LDHA's dual role and how lactate influences cellular processes during CSFV infection, this study uncovers new pathways for viral replication. These findings not only deepen our understanding of viral-host interactions but also open doors for innovative antiviral strategies centered around manipulating cellular metabolism.

During farm-to-consumer transport, a live supply chain can aid in maintaining the quality of whiteleg shrimp (Penaeus vannamei). However, the changes in muscle quality and gut microbiota of shrimp in the live supply chain and their interactions are poorly understood. Here, we investigated the dynamics of cumulative survival, muscle quality, and gut microbiota in the key phases of the live shrimp supply chain: post-harvest, post-transport, post-respite, and simulated sales [ambient temperature (AT; 29 °C ± 0.3 °C); low temperature (LT; 23 °C ± 0.3 °C)]. The results suggest that among the various stages, the highest mortality (12%) occurred after transport, while the respite process was associated with enhanced gut-mediated stress resilience. Notably, the transport, 24 h sales, and 40 h sales stages were identified as three potential critical control points. Furthermore, the LT group exhibited an 8% higher survival rate, better quality parameters (34.9% higher hardness), increased abundance of Bacteroidetes (from 3.63% to 7.39%), and a reduced F: B ratio. Correlation analysis identified Xanthomonadales and Oscillospirales as potential biomarkers for maintaining quality, positively linked to survival, muscle hardness, and brightness. Our findings provide valuable insights into optimizing control strategies and microbial biomarkers for enhancing muscle quality in live supply chains and aquaculture.

Liver diseases pose a significant threat to human health. Lactate, a byproduct of glycolysis, serves various biological functions, including acting as an energy source, a signaling molecule, and a substrate for lactylation. Lactylation is a novel lactate-dependent post-translational modification that plays a role in tumor proliferation, the regulation of immune cell function, and the modulation of gene expression. In this paper, we summarize the roles of lactate and lactylation in energy metabolism, inflammatory immunity, and the tumor microenvironment, while also elucidating recent research advancements regarding lactate and lactylation in the context of hepatic fibrosis, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, lactate and lactylation are proposed as promising new targets for the treatment of liver diseases.

Pathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease-associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage-specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry-based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.

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.

Hexavalent chromium [Cr (VI)] is a known environmental pollutant, which promotes tumorigenesis. Hypoxia-inducible factor-1α (HIF-1α) is crucial for cancer development. Here, we found that Cr (VI) treatment promoted lactate utilization by increasing monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4) expression, while increasing the expression of HIF-1α in A549 cells but reducing HIF-1α and MCT1 in HELF cells. CoCl2, an HIF-1α inducer, increased MCT1, while the HIF-1α inhibitor YC-1 and MCT1 inhibitor AZD3965 suppressed Cr (VI)-induced lactate utilization and cell growth. Chromatin immunoprecipitation (ChIP) assay revealed HIF-1α bound to the MCT1 promoter to enhance its transcription. Using Reactivating p53 and Inducing Tumor Apoptosis (RITA), which can increase the protein level of p53, we discovered that the low level of p53 protein in A549 cells determined the effect of Cr (VI)-induced HIF-1α. These findings highlighted the role of p53 protein level in the effects of Cr (VI) on HIF-1α/MCT1 to induce lactate utilization and cell growth. Targeting the p53/HIF-1α/MCT1 pathway could inhibit Cr (VI)-mediated tumorigenesis.

Electrical stimulation (ES) has been established as a reliable and beneficial approach in therapeutic rehabilitation, exhibiting negligible side effects. Nevertheless, research focusing on the application of ES for cardiac hypertrophy remains limited, as it fails to provide an enduring remedy for chronic diseases. In this investigation, vagal ES, characterized by its wireless, battery-free, and fully implantable nature, was utilized to treat cardiac hypertrophy. The vagus nerve at the stimulation site was carefully embedded within an envelope, sealed securely using multiple bioabsorbable sutures. Subsequently, a cardiac hypertrophy model was induced in rats via abdominal aortic coarctation for four weeks. The findings of this investigation demonstrated that ES markedly attenuated cardiac hypertrophy. Metabolomic analysis revealed a notable reduction in lactate levels within myocardial tissue following ES. Proteomic analysis of myocardial tissues indicated a substantial decrease in the expression of autophagy and mitophagy-related proteins after ES. Additionally, ChIP-seq result revealed a specific binding interaction between H3K18 lactylation (H3K18la) and BCL2 interacting protein 3 (Bnip3), while luciferase reporter assays demonstrated that H3K18la directly governed Bnip3 transcriptional activation, exploring its role in modulating mitophagy. Mechanistically, it was shown that ES reduced lactate accumulation through the upregulation of monocarboxylate transporter 4 (MCT4) by decreasing norepinephrine (NE) levels. Furthermore, ES reversed cardiac hypertrophy by diminishing H3K18la levels, thus inhibiting Bnip3 protein expression. This pathway assists in diminishing cardiac hypertrophy, emphasizing the critical involvement of the afferent vagal pathway in regulating cardiac hypertrophy.

Lactate is a classical byproduct of glucose metabolism, and the main lactate production pathway depends on glycolysis. Lactate stabilized HIF1α by inhibiting PHD activity, leading to hypoxic stress response and exacerbating glycolysis in multiple tissues. However, the redox induction mechanism of lactate in mammary gland has not been understood yet. Herein, we describe a lactate-responsive HIF1α/circadian control mechanism in oxidative stress in the mammary glands of dairy cows.

The in vivo study showed that dairy cows with high lactate concentrations are associated with reduced milk yield and more ROS accumulation in mammary gland. Western blot results in MAC-T cells showed positive correlation between lactate concentrations, expression of HIF1α and oxidative stress indicators, but not circadian core components. To test how lactate-mediated HIF1α dysfunction leads to cell protection process, we investigated altered expression of circadian core related genes following HIF1α stabilization. We found that stabilized HIF1α by lactate inhibited stimulated expression of circadian core components due to the similarity of HRE and E-box transcription elements. Furthermore, we found that lactate treatment strengthened the binding of HIF1α with BMAL1, HMOX1 and FOXO3 in MAC-T cells. Moreover, HIF1α knockdown altered expression of circadian rhythm related genes and reduced oxidative stress state.

In summary, our study highlights the central role of competitive transcriptional element occupancy in lactate-mediated oxidative stress of mammary gland, which is caused by HIF1α stabilization and circadian rhythm dysfunction. Our findings introduce a novel nutritional strategy with potential applications in dairy farming for optimizing milk production and maintaining mammary gland health.

In regenerative medicine, the therapeutic potential of mesenchymal stem cells (MSC), such as stem cells from human apical papilla (SCAP), is well-documented and largely attributed to their secretome. However, their poor survival post-transplantation limits their efficacy. This study hypothesized that combining SCAP spheroids with nanomedicines loaded with NecroX-5 (an anti-necrotic drug) and rapamycin (an immunosuppressive agent) would enhance SCAP survival in vivo. The approach aimed to reduce oxidative stress-related cell death and suppress immune reactions towards xeno-/allogenic cells. Two types of nanocarriers, polymeric nanoparticles (NP) and lipid nanocapsules (LNC), were compared to encapsulate NecroX-5 and rapamycin. A magnetic-dependent method was employed to associate SCAP with nanomedicines, involving co-encapsulation of drugs and Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) in the nanocarriers and cell magnetization using Nanoshuttle™. In vivo, SCAP hybrid spheroids expressing Luciferase, when injected subcutaneously into immunocompetent mice, showed increased bioluminescence signals compared to regular spheroids. These results provide proof-of-concept that magnetic-driven association of cells and nanomedicines into hybrid spheroids is feasible and suggest that delivering SCAP as hybrid spheroids can enhance their survival.

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites-lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)-linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64-0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

Head and neck squamous cell carcinoma (HNSCC) treatment faces significant clinical challenges. Lactate metabolism plays a crucial role in the initiation of many cancers and the tumor microenvironment (TME). However, the prognostic significance of lactate metabolism-related genes (LMRGs) and the role of TME in HNSCC require further elucidation.

We built a prognostic multigene signature with LMRGs and systematically correlated the risk signature with immunological characteristics and immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize lactate metabolism in TME. Finally, single-cell sequencing analysis, immunofluorescence analyses, and a series of in vitro experiments were used to explore the role of PYGL in HNSCC. Potential drugs targeting PYGL were screened using AutoDock 4.2.

A prognostic multigene signature based on LMRGs was developed, which effectively stratified patients into high- and low-risk groups, with significant differences in overall survival (OS) and progression-free survival (PFS). Patients in the low-risk group exhibited reduced lactate metabolism, higher CD8 + T cell infiltration, and improved response to immunotherapy. Single-cell sequencing revealed that tumor cells had the most active lactate metabolism compared to other cells in the TME. PYGL, identified as the most critical prognostic gene, was highly expressed in tumor-associated macrophages and played a role in inhibiting M1 macrophage polarization. Knockdown of PYGL led to reduced lactate levels, and its expression was inversely correlated with CD8 + T cell infiltration. Furthermore, PYGL was involved in copper-dependent cell death, highlighting its potential as a therapeutic target. Drug screening identified elesclomol, which showed promising results in PYGL-knockdown cells.

The study established a robust LMRGs-based prognostic model that not only predicts patient survival but also correlates with the immune microenvironment in HNSCC. PYGL emerged as a key biomarker with significant implications for both prognosis and therapeutic intervention. Its role in regulating lactate metabolism and immune suppression suggests that targeting PYGL could enhance the efficacy of immunotherapies. This research provides a foundation for future clinical strategies aimed at improving outcomes in HNSCC by modulating the tumor's metabolic and immune landscapes.

Skin wound healing represents a dynamic and intricate biological process involving the coordinated efforts of various cellular and molecular components to restore tissue integrity and functionality. Among the myriads of cellular events orchestrating wound closure, fibroblast migration and the regulation of fibrosis play pivotal roles in determining the outcome of wound healing. In recent years, probiotic therapy has emerged as a promising strategy for modulating wound healing and fibrosis. Here, we aim to investigate the effect of bacterial probiotics on cell migration and anti-fibrotic response of human dermal fibroblast (HDFs).

Probiotic mixture BioK was co-cultured with HDFs in vitro to assess its impact on fibroblast migration, gene expression, and protein production associated with important processes in wound healing. Gene expression was investigated by transcriptomic analysis and confirmed by RT-qPCR. Protein levels of the identified genes were evaluated by ELISA. The role of lactic acid, produced by BioK, in mediating pH-related effects on fibroblast activity was further examined.

We observed that BioK effectively promoted HDFs migration in vitro, which was found to be related to the up-regulation of genes involved in the phosphoinositide 3-kinase (PI3K) signaling pathways such as Paxillin, PI3K, PKC and ITG-β1. Interestingly, we also found that BioK down-regulated the expression of Nox-4, α-SMA and Col-I in TGF-Smad signaling pathways, which are involved in the differentiation of fibroblasts to myofibroblasts, and extracellular matrix type I collagen production, demonstrating its potential in reducing formation of fibrosis and scars. One of the acting factors for such down-regulation was identified to be BioK-produced lactic acid, which is known to lower the surrounding pH and to play a major role in fibroblast activity and wound healing.

This study demonstrates BioK's beneficial effects on fibroblast migration and its potential to mitigate fibrosis through pH modulation and pathway-specific gene regulation. These findings enhance our understanding of probiotic action on wound healing and offer promising therapeutic insights for the reduction of scar formation.

Not applicable.

  V ˙ L a max estimates an athlete's maximal-glycolytic rate. This study aimed to determine the relationships between the   V ˙ L a max and cycle ergometry efforts with a high-glycolytic energy contribution and the influence of   V ˙ L a max and VO 2 max on respiratory compensation point. Eleven national-international endurance cyclists (VO 2 max  = 70.7 ± 5.9 ml·kg-1·min-1) completed a 15-s isokinetic-test with pre- and postlactate measurements to determine   V ˙ L a max , a 1-min maximal effort, and a ramp test to exhaustion in a single test session. The main findings showed strong relationships between   V ˙ L a max and the mean absolute (r = 0.83, p = .002) and relative (r = 0.88, p = .0004) power during the lactic interval of the 15-s isokinetic-test. This relationship weakened when comparing   V ˙ L a max with mean absolute (r = 0.52, p = .098) and relative (r = 0.29, p = .393) power during a 1-min maximal effort. Combining the   V ˙ L a max and   V ˙ O 2 max data through multiple regression resulted in a positive effect on the estimation of respiratory compensation point. It was concluded that the   V ˙ L a max is a relevant indicator of maximal glycolytic rate. However, this metric currently lacks scientific validation as an accurate estimate of glycolytic rate and provides minimal extra information over using the power output from the isokinetic test alone. Practitioners may simply measure power over glycolytically demanding efforts to understand the maximal glycolytic rate of their athletes.

Cardiometabolic health is declining in the U.S. and anticipated to worsen over the next 30 years. Measurements of cardiometabolic health include blood metabolite profiles. One such metabolite is blood lactate. Lactate assessment is common in critical care and performance settings but less frequently used for the general population. The delayed onset of lactate accumulation during exercise may be an indicator of cardiometabolic health. Assessing lactate during a submaximal exercise test may assist in describing cardiometabolic health status in terms of metabolic fitness and metabolic flexibility.

To introduce the MetFlex Index™ (MFI), a novel, scalable exercise-based and marker of cardiometabolic health, and to characterize its associations with routinely assessed cardiometabolic health risk factors.

Participants completed a submaximal test on a commercial stationary cycle following assessments of body composition, anthropometrics, vital signs, and a blood draw. Lactate was collected at each stage and the 1st and 2nd lactate thresholds were described. The MFI was calculated by using the power, in Watts, attained at the 1st lactate threshold relative to the participant's Body Mass Index (BMI).

Data were collected on 827 participants (43 ± 13 years, 67% male, 72% overweight or obese). MFI peaked in the 30-39 year old cohort and decreased in subsequent decades. MFI was negatively associated with most markers of anthropometry, body composition, blood pressure, and was not associated with most blood metabolites.

The MetFlex Index™ is a novel exercise-based approach using blood lactate to characterize skeletal muscle metabolism and is associated with several cardiometabolic health indices.

Protein lactylation is a novel post-translational modification that has rarely been investigated in rheumatoid arthritis (RA). This study aimed to explore lactylation proteomics in RA patients and validate sorted candidate lactylation sites. Synovial tissues from ten RA and six osteoarthritis (OA) patients were subjected to lactylation proteomics via affinity enrichment and LC-MS/MS. Four candidate lactylated modification sites were validated by immunoprecipitation. Totally, 566 sites and 250 proteins with lactylated modifications in RA patients and 548 sites and 220 proteins with lactylated modifications in OA patients were identified. By comparison, 24 upregulated but 2 downregulated lactylated modification sites and 18 upregulated but 1 downregulated lactylated modification protein were discovered in RA patients versus OA patients. The dysregulated lactylated proteins were mainly enriched in biological processes such as positive regulation of plasma membrane repair by GO analysis; pathways such as neutrophil extracellular trap formation by KEGG analysis; and two metabolism-related items by COG/KOG analysis. Immunoprecipitation confirmed that FTH1-K69la (P = 0007) and PKM2-K166la (P = 0.003), but not ANXA2-K115la (P = 0.127) or ANXA5-K76la (P = 0.361), were more abundant in RA patients versus OA patients. Moreover, FTH1-K69la was positively correlated with erythrocyte sedimentation rate (ESR) in RA patients (P = 0.037). Conclusively, this study describes a general landscape of lactylation proteomics in the RA.

As a major energy source in the metabolism of early embryos, lactate also participates in regulating zygotic gene expression and subsequently contributes to preimplantation embryonic development. Nevertheless, the influence of lactate on embryonic development in bovine cloned embryos remains elusive. For this reason, this research explored the differences in metabolic pathways between in vitro fertilization (IVF) embryos and somatic cell nuclear transfer (SCNT) embryos during zygotic genome activation (ZGA) using Smart-seq and observed changes in SCNT embryo development in response to lactate supplementation. Weighted gene coexpression network analysis (WGCNA) revealed that LDHA functions as a hub gene that significantly influences the gene expression profile of 8-cell SCNT embryos. Compared with those of IVF embryos, SCNT embryos showed lower LDHA levels and lactate contents. Lactate supplementation was found to increase the developmental potential and blastocyst quality of SCNT embryos. Furthermore, the addition of lactate significantly increased the immunofluorescence intensity of both Pan Kla and H3K18la as well as the expression levels of the zygotic genes ZSCAN5B and SUPT4H1 in SCNT embryos. These results indicate that lactate deficiency leading to the downregulation of histone lactylation may be an important factor affecting the in vitro development of SCNT embryos.

During the development and progression of lung cancer, cell metabolism function is altered. Thus, cells rely on aerobic glycolysis and abnormal lipid and amino acid metabolism to obtain energy and nutrients for growth, proliferation and drug resistance. Circular RNAs (circRNAs), a class of non-coding RNAs, serve important biological roles in the growth and development of tumors. Functionally, circRNAs act as molecular sponges that absorb microRNAs (miRNAs) and RNA-binding proteins and as protein scaffolds that regulate gene transcription and translation through the maintenance of mRNA stability. In addition, circRNAs are important regulators of tumor metabolism and promote tumor progression through mediating tumor cell proliferation, metastasis and the induction of chemoresistance. Results of previous studies reveal that circRNAs may serve a key role in regulating tumor metabolic processes in lung cancer, through miRNA sponging and alternative mechanisms. Thus, circRNAs demonstrate potential as therapeutic targets for lung cancer. The present study aimed to review the effects of circRNAs on lung cancer cell metabolism and provide novel insights into the clinical treatment of lung cancer. The present review may also provide a novel theoretical basis for the development of lung cancer drug targets.

Lactate and digit ratio (2D:4D) have been linked to sports performance, cardiovascular disease, and some cancers. 2D:4D is strongly and positively associated with lactate during exercise across a range of running speeds in men. This study aimed to consider the relationship between 2D:4D and lactate in women during an incremental cardiopulmonary exercise test.

The participants were professional female football players. The treadmill test began at a speed of 6 km/h and was increased by 2 km/h every 3.15 min, with measurements at 6, 8, 10, 12, and 14 km/h.

There were 25 Caucasian and 3 Black participants; 2D:4D and lactate levels were lower in the latter, but the sample size was too small for meaningful comparisons. Lactate levels increased with running speed. The 2D:4D was not associated with lactate at 6 to 12 km/h. At 14 km/h, lactate was positively associated with right and left 2D:4D (stronger for the former) and negatively with height and digit lengths. These correlations were significant for the total sample and Caucasians only. Multiple regressions for the Caucasian sample showed that right 2D:4D was positively related to lactate at 14 km/h, and height was negatively associated with lactate at all speeds.

During exercise, the effect sizes for relationships between 2D:4D and lactate in women are positive but smaller than those reported for men and restricted to higher running speeds. Unlike men, women show a negative relationship between height and lactate. It is suggested that prenatal and pubertal sex steroid effects may explain these sex differences.

Post‑translational modifications (PTMs) of proteins influence their functionality by altering the structure of precursor proteins. These modifications are closely linked to tumor progression through the regulation of processes such as cell proliferation, apoptosis, angiogenesis and invasion. Tumors produce large amounts of lactic acid through aerobic glycolysis. Lactic acid not only serves an important role in cell metabolism, but also serves an important role in cell communication. Lactylation, a PTM involving lactate and lysine residues as substrates, serves as an epigenetic regulator that modulates intracellular signaling, gene expression and protein function, thereby serving a crucial role in tumorigenesis and progression. The identification of lactylation provides a key breakthrough in elucidating the interaction between tumor metabolic reprogramming and epigenetic modification. The present review primarily summarizes the occurrence of lactylation, its effect on tumor progression, drug resistance, the tumor microenvironment and gut microbiota, and its potential as a therapeutic target for cancer. The aim of the present review was to provide novel strategies for potential cancer therapies.

Histone lysine lactylation (Kla) has recently been reported to participate in various biological processes, regulating transcription, inflammation, and immune-related diseases. However, the mechanism of histone Kla in innate immunity and viral infection remains largely unknown. Here, we observed fluorescent Kla signals in all four histones (H2A, H2B, H3, and H4) in PK-15 cells. Immunoprecipitation analysis showed prominent histone Kla protein bands, with H2B being the most abundant. We generated the H2B K16R mutant plasmid and identified K16 as one of the Kla modification sites in H2B. Further exploration revealed increased global H2B Kla and H2BK16la levels upon classical swine fever virus (CSFV) infection. By employing the Kla agonist (L-lactate), inhibitor (oxamate), or siLDHA, we demonstrated that H2BK16la and pan Kla in PK-15 cells rely on the LDHA-lactate axis, which is also crucial for CSFV-induced H2BK16la and pan Kla levels. Moreover, our data proved the interaction between H2B and CSFV NS4A protein. Notably, H2B Kla can modulate CSFV proliferation. Mechanistically, H2BK16la and pan Kla activate the nuclear factor kappa B (NF-κB) pathway by mediating p65 nuclear translocation via karyopherin α2 (KPNA2), thereby inducing type III interferon (IFN-λ) expression and inhibiting CSFV replication. In conclusion, our study unveils the role of H2B Kla in regulating the NF-κB pathway during viral infection, presenting a novel mechanism. These findings significantly contribute to understanding the pathogenic mechanisms during viral infection and hold promise for the development of viral therapeutic strategies.

Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate receptor or GPR81, is a class A G-protein-coupled receptor with key roles in regulating lipid metabolism, neuroprotection, angiogenesis, cardiovascular function, and inflammatory response in humans. HCAR1 is highly expressed in numerous types of cancer cells, where it participates in controlling cancer cell metabolism and defense mechanisms, rendering it an appealing target for cancer therapy. However, the molecular basis of HCAR1-mediated signaling remains poorly understood. Here, we report four cryo-EM structures of human HCAR1 and HCAR2 in complex with the Gi1 protein, in which HCAR1 binds to the subtype-specific agonist CHBA (3.16 Å) and apo form (3.36 Å), and HCAR2 binds to the subtype-specific agonists MK-1903 (2.68 Å) and SCH900271 (3.06 Å). Combined with mutagenesis and cellular functional assays, we elucidate the mechanisms underlying ligand recognition, receptor activation, and G protein coupling of HCAR1. More importantly, the key residues that determine ligand selectivity between HCAR1 and HCAR2 are clarified. On this basis, we further summarize the structural features of agonists that match the orthosteric pockets of HCAR1 and HCAR2. These structural insights are anticipated to greatly accelerate the development of novel HCAR1-targeted drugs, offering a promising avenue for the treatment of various diseases.

Emerging evidence supports the involvement of N6-Methyladenosine (m6A) modification in the etiology and progression of lung adenocarcinoma (LUAD), highlighting its potential as a therapeutic target. RNA-binding protein 15 (RBM15) is a well-known m6A writer protein that enhances global m6A methylation levels by associating with the METTL3-WTAP complex. Previous studies have demonstrated that RBM15 is upregulated and exerts an oncogenic role in LUAD by promoting the N6-methyladenosine-mediated mRNA stability. However, the regulatory mechanisms of RBM15 remain elusive. In this study, we observed that L-lactate upregulates RBM15 protein levels in non-small-cell lung cancer cell lines A549 and H23 in a time- and dosage-dependent manner. Furthermore, we discovered that lactate uptake mediated by Monocarboxylate transporter 1 (MCT1) is essential for RBM15 induction. Subsequent investigations revealed that L-lactate promotes lactylation of RBM15 majorly at Lys850 (K850), while histone deacetylase 3 (HDAC3) acts as the delactylase for RBM15. Importantly, lactylation of RBM15 stabilizes itself by inhibiting proteasome-mediated ubiquitin degradation. Mutation of the lactylation site K850R disrupts the association between RBM15 and METTL3, leading to a reduction in global m6A levels. Moreover, K850R significantly abrogated RBM15-mediated cell proliferation and migration in LUAD cells. Collectively, these findings unveil lactylation as a novel regulatory mechanism affecting both stability and m6A methylation activity of RBM15 in LUAD cells.

Metabolic syndrome (MetS) is a combination of risk factors that contribute to the development of many of today's chronic diseases. Rates of MetS continue to increase and it is now considered a worldwide epidemic. As with many chronic diseases it may take years for symptoms and the effects of MetS to manifest into severe health problems. Therefore, early detection is paramount A recently proposed method for the early detection of MetS is the assessment of an individual's metabolic flexibility during exercise. Metabolic flexibility is defined as the ability of the body to switch between energy substrates, primarily fats and carbohydrates, to produce energy and meet metabolic demand. This provides an indication of mitochondrial health, the possible beginning point of early insulin resistance and the development of MetS.Although there is widespread use of exercise and expired gas analysis to determine metabolic flexibility, there is no consensus on the appropriate guidelines, protocol, or interpretation of the subsequent data. Studies have used a variety of different protocols involving maximal and submaximal tests with step protocols ranging from 2 to 10 min, differences in data averaging, analysis, and stoichiometric equations, as well as variations in nutritional status of participants, and mode of exercise. This has led to considerable variation in reported results. Although the use of exercise to determine metabolic flexibility and act as a possible marker of early mitochondrial dysfunction holds significant promise, more work is required to determine the optimal protocol for clinical and research purposes.

Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.

Background: The impact of histone lactylation modification (HLM) on glioblastoma (GBM) progression is not well understood. This study aimed to identify HLM-associated prognostic genes in GBM and explore their mechanisms of action. Methods: The presence and role of lactylation in glioma clinical tissue samples and its correlation with GBM progression were analysed through immunohistochemical staining and Western blotting. Sequencing data for GBM were obtained from publicly available databases. An initial correlation analysis was performed between global HLM levels and GBM. Differentially expressed HLM-related genes (HLMRGs) in GBM were identified by intersecting differentially expressed genes (DEGs) from the TCGA-GBM dataset, key module genes derived from weighted gene coexpression network analysis (WGCNA), and previously reported HLMRGs. Prognostic genes were subsequently identified through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses, which formed the basis for constructing a risk prediction model. Associations between HLMRGs and GBM were further evaluated via single-cell RNA sequencing (scRNA-seq) datasets. Complementary analyses, including functional enrichment, immune infiltration, somatic mutation, and nomogram-based survival prediction, were conducted alongside in vitro experiments. Additionally, drug sensitivity and Chinese medicine prediction analyses were performed to identify potential therapeutic agents for GBM. Results: We detected a significant increase in global lactylation levels in GBM, which correlated with patient survival. We identified 227 differentially expressed HLMRGs from the intersection of 3,343 differentially expressed genes and 948 key module genes, indicating strong prognostic potential. Notably, genes such as SNCAIP, TMEM100, NLRP11, HOXC11, and HOXD10 were highly expressed in GBM. Functional analysis suggested that HLMRGs are involved primarily in pathways related to cytokine‒cytokine receptor interactions, cell cycle regulation, and cellular interactions, including microglial differentiation states. Further connections were established between HLMRGs and infiltrating immune cells, particularly type 1 T helper (Th1) cells, as well as mutations in genes such as PTEN. The potential therapeutic agents identified included ATRA and Can Sha. Conclusion: The HLM-related gene risk prediction model shows substantial promise for improving patient management in GBM, providing crucial insights for clinical prognostic evaluations and immunotherapeutic approaches in GBM.

Patients with advanced cancer frequently endure severe pain, which substantially diminishes their quality of life and can adversely impact survival. Analgesia, a critical modality for alleviating such pain, is now under scrutiny for its potential role in cancer progression, a relationship whose underlying mechanisms remain obscure. Emerging evidence suggests that lactate, once considered a metabolic byproduct, actively participates in the malignant progression of cancer by modulating both metabolic and immunological pathways within the tumor microenvironment. Furthermore, lactate is implicated in the modulation of cancer-related pain, exerting effects through direct and indirect mechanisms. This review synthesizes current understanding of lactate's production, transport, and functional roles in tumor cells, encompassing the regulation of tumor metabolism, immunity, and progression. Additionally, we dissect the complex, bidirectional relationship between lactate and pain, and assess the impact of anesthetics on pain relief, lactate homeostasis, and tumorigenesis.