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To investigate the effect of forced even pacing through virtual pacing assistance and an opponent in a competitive setting on end‐spurt behaviour in freestyle swimmers, including related physiological underpinnings. Twenty‐seven competitive swimmers and triathletes were recruited. There were four 1500 m freestyle trials: (i) familiarisation time trial, (ii) self‐paced time trial (STT), (iii) head‐to‐head competition time trial (CTT) and (iv) forced even pacing through virtual pacing assistance time trial (FET). Eventually, 12 swimmers met the criteria for the CTT and FET to be included in the analysis. Changes in end‐spurt behaviour, finishing time and physiological parameters (lactate, cortisol, noradrenaline and heart rate) were analysed using a linear mixed model with fixed effects for trials and a random effect for swimmer identity. A separate linear model was computed for competition outcome. The end‐spurt for each race was determined by means of an end‐spurt indicator (ESI; ESI > 0 greater end‐spurt). Swimmers demonstrated a significantly greater ESI in FET (+2.6; p < 0.001) and CTT (+1.4; p = 0.022) compared to STT. Blood lactate concentration in FET (+1.0 mmol L−1; p < 0.001) and CTT (+1.6 mmol L−1; p < 0.001) was significantly higher than in STT. Winners had a significantly greater ESI than losers in CTT (+1.6 and p = 0.005). Swimmers utilised a greater end‐spurt through metabolically optimal forced even pacing by virtual pacing assistance and in a head‐to‐head competition due a larger mobilisation of anaerobic reserves as indicated by greater blood lactate concentrations. Winners had a significantly greater end‐spurt than losers despite similar metabolic disturbances. Highlights: Compared to a self‐paced time trial, swimmers in a forced even pacing trial by virtual pacing assistance and in a head‐to‐head competition execute a greater end‐spurt.The larger end‐spurt is associated with larger mobilisation of anaerobic reserves as indicated by greater blood lactate concentrations.Winners had a significantly greater end‐spurt than losers despite similar metabolic disturbances. [ABSTRACT FROM AUTHOR]

Citrulline malate (CM) is purported to be an ergogenic aid during various types of exercise performance. However, the effects of CM on repeated sprint performance (RSP) are under‐explored. In a placebo‐controlled, double‐blind, counterbalanced cross‐over design, male university‐level team sport athletes (n = 13) performed two familiarization trials, after which CM or placebo (PLA) (8 × 1 g tablets each day) were taken on the 2 days prior to, and with breakfast on the morning of, each main experimental trial. The main experimental trials employed a RSP protocol consisting of 10 repetitions of 40 m maximal shuttle run test (MST) with a 30 s interval between the start of each sprint. Sprint times and heart rate were recorded throughout the MST, and blood lactate concentrations were measured before, immediately after, and 5 min after completing the MST. CM resulted in better RSP compared to PLA, as indicated by a lower sprint performance decrement (Sdec: CM, 4.68% ± 1.82% vs. PLA, 6.10% ± 1.83%; p = 0.03; ES = 0.77), which was possibly influenced by the fastest sprint time being faster in CM (CM, 8.16 ± 0.34 s vs. PLA, 8.29 ± 0.39 s; p = 0.011; ES = 0.34). There were no differences between CM and PLA in average sprint time (p = 0.54), slowest sprint time (p = 0.48), blood lactate concentrations (p = 0.73) or heart rate (p = 0.18), nor was there a condition × time interaction effect across the 10 sprints (p = 0.166). Three days of CM supplementation (8 g daily) attenuated the sprint performance decrement during short‐duration high‐intensity exercise in the form of running RSP in male university‐level team sport athletes. Highlights: This study addresses a knowledge gap around the ergogenic potential of citrulline malate (CM) in repeated sprint running performance.Three days of CM supplementation (8 g daily) was observed to improve short‐duration (5 min) high‐intensity exercise performance in male university‐level team sport athletes when measured by the sprint performance decrement in a 10 repetition 40 m maximal shuttle run test.The attenuation in the sprint performance decrement was not associated with any differences compared to the placebo condition in heart rate or blood lactate concentrations.The outcomes of this study suggest that short‐term CM supplementation could be beneficial for team sport athletes who perform short‐duration high‐intensity efforts, such as soccer, Gaelic games, field hockey, and rugby. [ABSTRACT FROM AUTHOR]

We investigated the effect of ischemic preconditioning (IPC) with and without caffeine supplementation on mean power output (MPO) during a 4‐min cycling time‐trial (TT). In a double‐blinded, randomized, crossover‐design, 11 trained men performed a TT on 4 days separated by ∼1 week. One hour before TT, participants ingested either caffeine (3 mg kg bw−1) or placebo pills, after which femoral blood‐flow was either restricted with occlusion cuffs inflated to ∼180 mmHg (IPC), or sham‐restricted (0–10 mmHg; Sham) during 3 × 2‐min low‐intensity cycling (10% of incremental peak power output). Then, participants performed a standardized warm‐up followed by the TT. Plasma lactate and K+ concentrations and ratings of perceived exertion (RPE) were measured throughout trials. TT MPO was 382 ± 17 W in Placebo + Sham and not different from Placebo + IPC (−1 W; 95% CI: −9 to 7; p = 0.848; d: 0.06), whereas MPO was higher with Caffeine + Sham (+6W; 95% CI: −2 to 14; p = 0.115; d: 0.49) and Caffeine + IPC (+8 W; 95% CI: 2–13; p = 0.019; d: 0.79) versus Placebo + Sham. MPO differences were attributed to caffeine (caffeine main‐effect: +7 W; 95% CI: 2–13; p = 0.015; d: 0.54. IPC main‐effect: 0 W; 95% CI: −6 to 7; p = 0.891; d: 0.03; caffeine × IPC interaction‐effect: p = 0.580; d: 0.17). TT RPE and plasma variables were not different between treatments. In conlcusion, IPC with co‐ingestion of placebo does not improve short‐term high‐intensity performance in trained men versus a double‐placebo control (Placebo + Sham) and does not additively enhance performance with caffeine. These data do not support IPC as a useful strategy for athletes prior to competition but confirms caffeine's performance‐enhancing effect. Highlights: Active ischemic preconditioning (IPC) prior to exercise has been proposed as a strategy to enhance short‐term exercise performance.However, the effect of combined IPC and caffeine ingestion on short‐term high‐intensity exercise performance in trained individuals remains unclear.Active IPC with co‐ingestion of placebo pills did not improve short‐term high‐intensity exercise performance in trained men and its use cannot be recommended over caffeine to improve subsequent short‐term maximal performanceIngestion of caffeine (3 mg kg bw−1) prior to short‐term high‐intensity exercise is an effective ergogenic strategy which athletes may benefit from. [ABSTRACT FROM AUTHOR]

In this paper, we consider a singular nonlinear differential system that characterizes the intricate dynamics of brain lactate kinetics between cells and capillaries, as described by System (1.1) below. We begin by establishing the existence and uniqueness of nonnegative solutions for our system through the application of Schauder's fixed-point theorem. Subsequently, we explore the behavior of these solutions as the viscosity term approaches zero, shedding light on the system's dynamic evolution in such scenarios. To provide empirical validation for our theoretical findings, we offer a series of numerical simulations. These simulations not only confirm the results we have obtained but also reinforce prior research, underscoring the model's efficiency in capturing the complexities of the brain's lactate kinetics. Our work contributes not only to the theoretical underpinning of this field but also to its practical implications, making it a valuable resource for both researchers and practitioners seeking to comprehend and manipulate these vital biological processes. [ABSTRACT FROM AUTHOR]

Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30–70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation–inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5′- triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation. [ABSTRACT FROM AUTHOR]

Isotopic assays of brain glucose utilization rates have been used for more than four decades to establish relationships between energetics, functional activity, and neurotransmitter cycling. Limitations of these methods include the relatively long time (1–60 min) for the determination of labeled metabolite levels and the lack of cellular resolution. Identification and quantification of fuels for neurons and astrocytes that support activation and higher brain functions are a major, unresolved issues. Glycolysis is preferentially up-regulated during activation even though oxygen level and supply are adequate, causing lactate concentrations to quickly rise during alerting, sensory processing, cognitive tasks, and memory consolidation. However, the fate of lactate (rapid release from brain or cell–cell shuttling coupled with local oxidation) is long disputed. Genetically encoded biosensors can determine intracellular metabolite concentrations and report real-time lactate level responses to sensory, behavioral, and biochemical challenges at the cellular level. Kinetics and time courses of cellular lactate concentration changes are informative, but accurate biosensor calibration is required for quantitative comparisons of lactate levels in astrocytes and neurons. An in vivo calibration procedure for the Laconic lactate biosensor involves intracellular lactate depletion by intravenous pyruvate-mediated trans-acceleration of lactate efflux followed by sensor saturation by intravenous infusion of high doses of lactate plus ammonium chloride. In the present paper, the validity of this procedure is questioned because rapid lactate–pyruvate interconversion in blood, preferential neuronal oxidation of both monocarboxylates, on-going glycolytic metabolism, and cellular volumes were not taken into account. Calibration pitfalls for the Laconic lactate biosensor also apply to other metabolite biosensors that are standardized in vivo by infusion of substrates that can be metabolized in peripheral tissues. We discuss how technical shortcomings negate the conclusion that Laconic sensor calibrations support the existence of an in vivo astrocyte–neuron lactate concentration gradient linked to lactate shuttling from astrocytes to neurons to fuel neuronal activity. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is one of the most common gynecological cancers. Accumulated evidence shows that long non‐coding RNAs (lncRNAs) play essential roles in cervical cancer occurrence and progression, but their specific functions and mechanisms remain to be further explored. Methods: The RT‐qPCR assay was used to detect the expression of NEAT1 in cervical cancer tissues and cell lines. CCK‐8, colony formation, flow cytometry, western blotting, and Transwell assays were used to evaluate the impact of NEAT1 on the malignant behavior of cervical cancer cells. Glucose consumption, lactate production, ATP levels, ROS levels, MMP levels, and the mRNA expressions of glycolysis‐related genes and tricarboxylic acid cycle‐related genes were detected to analyze the effect of NEAT1 on metabolism reprograming in cervical cancer cells. The expressions of PDK1, β‐catenin and downstream molecules of the WNT/β‐catenin signaling pathway in cervical cancer cells and tissues were detected by western blotting, RT‐qPCR, immunofluorescence and immunohistochemistry assays. Results: This study investigated the role and possible molecular mechanism of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in cervical cancer. Our results showed that NEAT1 was highly expressed in cervical cancer tissues and cell lines. Downregulation of NEAT1 inhibited the proliferation, migration, invasion and glycolysis of cervical cancer cells, while overexpression of NEAT1 led to the opposite effects. Mechanistically, NEAT1 upregulated pyruvate dehydrogenase kinase (PDK1) through the WNT/β‐catenin signaling pathway, which enhanced glycolysis and then facilitated cervical cancer metastasis. Furthermore, NEAT1 maintained the protein stability of β‐catenin but did not affect its mRNA level. We also excluded the direct binding of NEAT1 to the β‐catenin protein via RNA pull‐down assay. The suppressive impact of NEAT1 knockdown on cell proliferation, invasion, and migration was rescued by β‐catenin overexpression. The WNT inhibitor iCRT3 attenuated the carcinogenic effect induced by NEAT1 overexpression. Conclusion: In summary, these findings indicated that NEAT1 may contribute to the progression of cervical cancer by activating the WNT/β‐catenin/PDK1 signaling axis. [ABSTRACT FROM AUTHOR]

The human gut hosts numerous ecological niches for microbe–microbe and host–microbe interactions. Gut lactate homeostasis in humans is crucial and relies on various bacteria. Veillonella spp., gut lactate‐utilizing bacteria, and lactate‐producing bacteria were frequently co‐isolated. A recent clinical trial has revealed that lactate‐producing bacteria in humans cross‐feed lactate to Veillonella spp.; however, their interspecies interaction mechanisms remain unclear. Veillonella dispar, an obligate anaerobe commonly found in the human gut and oral cavity, ferments lactate into acetate and propionate. In our study, we investigated the interaction between V. dispar ATCC 17748T and three representative phylogenetically distant strains of lactic acid bacteria, Lactobacillus acidophilus ATCC 4356T, Lacticaseibacillus paracasei subsp. paracasei ATCC 27216T, and Lactiplantibacillus plantarum ATCC 10241. Bacterial growth, viability, metabolism and gene level adaptations during bacterial interaction were examined. V. dispar exhibited the highest degree of mutualism with L. acidophilus. During co‐culture of V. dispar with L. acidophilus, both bacteria exhibited enhanced growth and increased viability. V. dispar demonstrated an upregulation of amino acid biosynthesis pathways and the aspartate catabolic pathway. L. acidophilus also showed a considerable number of upregulated genes related to growth and lactate fermentation. Our results support that V. dispar is able to enhance the fermentative capability of L. acidophilus by presumably consuming the produced lactate, and that L. acidophilus cross‐feed not only lactate, but also glutamate, to V. dispar during co‐culture. The cross‐fed glutamate enters the central carbon metabolism in V. dispar. These findings highlight an intricate metabolic relationship characterized by cross‐feeding of lactate and glutamate in parallel with considerable gene regulation within both L. acidophilus (lactate‐producing) and V. dispar (lactate‐utilizing). The mechanisms of mutualistic interactions between a traditional probiotic bacterium and a potential next‐generation probiotic bacterium were elucidated in the production of short‐chain fatty acids. [ABSTRACT FROM AUTHOR]

During prolonged running at moderate‐to‐high intensity, running economy (RE) deteriorates and attainable maximal oxygen consumption (VO2max) decreases. Whether these changes appear similarly in trained and untrained runners exercising at the same relative intensity is not clear. We recruited 10 trained runners (TR) and 10 active adults (AA), and compared RE and attainable VO2max before and after 1 h of running at 70% of VO2max. Submaximal VO2 increased more (p = 0.019) in AA (0.20 ± 0.13 L min−1) than in TR (0.07 ± 0.05 L min−1). Attainable VO2max decreased in AA (−0.21 ± 0.15 L min−1, p = 0.002), but remained unchanged in TR (−0.05 ± 0.10 L min−1, p = 0.18). Relative intensity (i.e., VO2/attainable VO2max), increased more (p = 0.001) in AA (8.3 ± 4.4%) than in TR (2.6 ± 1.9%). These results demonstrate that the ability to resist changes in RE and VO2max following prolonged running is superior in trained versus untrained runners, when exercising at the same relative intensity. [ABSTRACT FROM AUTHOR]

Chronic wound monitoring can provide personalized pathophysiological information for wound management and treatment. Continuously monitoring the wound milieu via the holographic pH sensor can reflect the wound healing processes. However, the integration with wearable devices is hindered by its inherently restricted interrogation angle dependency within 5°. Herein, a ball bearing‐based double photopolymerization method is developed to fabricate holographic pH sensors with a broader interrogation angle range of 15°–60° in wound exudates. The fabricated holographic pH sensor is then integrated with the flexible ultrathin polyurethane substrate, which replays a total Bragg peak shift of approximately 150 nm with physiological pH changes from 7.00 to 8.75. The conformable holographic pH sensing bandages demonstrate the ability to quantify the pH value under various bending manipulations, simulating the mounting on the body surface. The reversibility in artificial wound exudate demonstrates the durability and capability of real‐time pH monitoring in the wound milieu with minimal effect on the replay wavelength. The addition of electrolytes, albumin, urea, uric acid, lactate, and glucose does not interfere with the readout over the physiological pH range of wound exudates. The obtained conformable holographic sensing bandage benefits the wound healing process monitoring through colorimetric interrogation at point‐of‐care (POC) settings. [ABSTRACT FROM AUTHOR]

Lactate is now considered an additional fuel or signaling molecule in the brain. In this study, using an oxygen–glucose deprivation (OGD) model, we found that treatment with lactate inhibited the global increase in intracellular calcium ion concentration ([Ca2+]) in neurons and astrocytes, decreased the percentage of dying cells, and caused a metabolic shift in astrocytes and neurons toward aerobic oxidation of substrates. OGD resulted in proinflammatory changes and increased expression of cytokines and chemokines, whereas incubation with lactate reduced these changes. Pure astrocyte cultures were less sensitive than neuroglia cultures during OGD. Astrocytes exposed to lipopolysaccharide (LPS) also showed pro‐inflammatory changes that were reduced by incubation with lactate. Our study suggests that lactate may have neuroprotective effects under ischemic and inflammatory conditions. [ABSTRACT FROM AUTHOR]

Aim: To evaluate umbilical arterial lactate concentrations after spontaneous vaginal delivery and after elective Cesarean delivery, and to study the simultaneous effects of maternal and obstetric variables in high lactate levels in vaginally delivered healthy term singletons. Methods: The birth register study included information about the umbilical artery lactate values and clinical perinatal data from 7723 women and their singleton newborns (7301 spontaneous vaginal and 422 elective cesareans) from Kuopio University Hospital, Finland. High lactate levels were evaluated more extensively among healthy term neonates (N = 6541), to evaluate high levels after normal vaginal labors. Results: The mean lactate level was significantly lower after elective cesarean compared to vaginal delivery (2.42 [0.94] vs. 3.56 [1.62] mmol/l; p < 0.0001). Consequently, the 90th percentile limit values were 3.60 and 5.80 mmol/L. Among healthy term newborns born vaginally, higher lactate values (≥5.80 mmol/L) were independently associated with a longer duration of the active second stage of labor (ORs 1.91–10.97) and duration of ruptured fetal membranes (ORs 1.36–2.46), higher gestational age at birth (ORs 1.41–1.86), null parity (OR 2.17), maternal infection (OR 1.81) and short maternal stature (OR 1.45). We report 90th/95th limits for umbilical arterial lactate values in relation to the various durations of labors for term newborns who are delivered by the vaginal route. Conclusions: Even though the high umbilical lactate levels may indicate serious birth asphyxia, levels after vaginal birth reflect the physiological stress and subclinical transient asphyxia frequently seen in normal vaginal deliveries. [ABSTRACT FROM AUTHOR]

Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis. Synopsis: Inflammation alters skin tissue metabolism, however, the consequences for immune cell effector function remain unclear. Here, in vivo work in mice uncovers a ROS/HIF-1α-induced metabolic crosstalk between epidermal cells and macrophages during sterile inflammation, which aggravates disease progression. Induced skin inflammation shifts metabolic preferences to glycolysis and the TCA cycle in the epidermis and in macrophages, respectively. Inflammation-induced metabolic compartmentalisation is bridged by lactate secreted from the epidermis. Inhibition of lactate transport leads to reduced macrophage-mediated ECM degradation and in turn, inflammation. Inhibition of lactate transfer attenuates psoriasis symptoms in a imiquimod-induced mouse model. Lactate produced via glycolysis in epidermal cells activates NF-κB signaling and M2-like pro-remodeling phenotypes in dermal macrophages. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is a common malignancy which threatens the health of women. Circular RNAs (circRNAs) are critical factors in multiple cancers, including BC. The aim of this experiment was to investigate the molecular mechanisms of circRNA Septin 9 (circSEPT9) in the progression of BC. Methods: CircSEPT9, microRNA-625-5p (miR-625-5p) and polypyrimidine tractbinding protein 3 (PTBP3) levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to detect the protein levels of PTBP3, E-cadherin and vimentin. Cell counting kit-8 assay (CCK8) and thymidine analog 5-ethynyl-20-deoxyuridine (EDU) was utilized for proliferation examination. Flow cytometry was conducted to measure apoptosis. Transwell assay and wound healing assay to investigate the migration of BC cells. Glucose uptake and lactate production were determined by specific kits. Additionally, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were utilized to verify the interaction. A murine xenograft model was established to investigate the function of circSEPT9 in BC in vivo. Results: Overexpression of circSEPT9 was found in BC tissues and cells. Silencing circSEPT9 impeded BC cell proliferation, migration, epithelial-mesenchymal transition (EMT) and glycolytic metabolism but facilitated cell apoptosis in vitro. Meanwhile, circSEPT9 knockdown constrained tumor growth in vivo. MiR-625-5p was targeted by circSEPT9. The influence of silencing circSEPT9 on BC cell function was regained by miR-625-5p inhibitor. Furthermore, miR-625-5p regulated BC cell malignant phenotypes via downregulating PTBP3. Conclusion: circSEPT9 contributed to the malignant progression of BC by upregulating PTBP3 via sponging miR-625-5p. [ABSTRACT FROM AUTHOR]

The incorporation of isolated Sn (IV) and Zr (IV) ions into silica frameworks is attracting widespread attention, which exhibits remarkable catalytic performance (conversion, selectivity, and stability) in a broad range of reactions, especially in the field of biomass catalytic conversion. As a representative example, the conversion route of carbohydrates into valuable platform and commodity chemicals such as lactic acid and alkyl lactates, has already been established. The zeotype materials also possess water‐tolerant ability and are capable to be served as promising heterogeneous catalysts for aqueous reactions. Therefore, dozens of Sn‐ and Zr‐containing silica materials with various channel systems have been prepared successfully in the past decades, containing 8 membered rings (MR) small pore CHA zeolite, 10‐MR medium pore zeolites (FER, MCM‐56, MEL, MFI, MWW), 12‐MR large pore zeolites (Beta, BEC, FAU, MOR, MSE, MTW), and 14‐MR extra‐large pore UTL zeolite. This review about Sn‐ and Zr‐containing metallosilicate materials focuses on their synthesis strategy, catalytic applications for diverse reactions, and the effect of zeolite characteristics on their catalytic performances. [ABSTRACT FROM AUTHOR]

The development of effective and stable non‐precious catalysts for hydrogenation of ester to diols remains a challenge. Herein, the catalytic hydrogenation of ethyl lactate (EL) to 1,2‐propanediol (1,2‐PDO) with supported Co catalysts derived from layered double hydroxides (LDHs) is investigated. Catalytic tests reveal that LDH‐derived Co catalysts exhibit the best catalytic performance with 98 % of EL conversion and >99 % of 1,2‐PDO selectivity at mild conditions, compared with other Co catalysts (supported on Al2O3, and TiO2) and LDH‐derived Cu catalysts. Due to the strong interaction among Co and Al matrix, the main composition is metallic Co0 and CoO after reduction at 600 °C. Besides, the catalyst shows good recyclability in the liquid phase hydrogenation. The superior catalytic performance can be attributed to the synergistic effect between Co0 and CoO, in which H2 molecule is activated on Co0 and EL is strongly adsorbed on CoO via hydroxyl groups. [ABSTRACT FROM AUTHOR]

Objective: Tumor cells can acquire a large amount of energy and structural components by reprogramming energy metabolism; moreover, metabolic profiles slightly differ according to cancer type. This study compared and assessed the metabolic profile of head and neck squamous cell carcinoma (HNSCC) and normal tissues, which were collected from patients without cancer. Subjects and Methods: Overall, 23 patients with HNSCC and 6 patients without cancer were included in the analysis. Metabolomic profiles were analyzed using capillary electrophoresis‐mass spectrometry. Gene expression was evaluated using real‐time reverse transcription‐polymerase chain reaction. Results: Glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, and glutamine metabolism were upregulated in HNSCC tissues based on gene expression analysis. HNSCC could then have enhanced energy production and structural component. The levels of lactate, succinate, glutathione, 2‐hydroxyglutarate, and S‐adenosylmethionine, considered as oncometabolites, increased and these had accumulated in HNSCC tissues. Conclusions: The level of metabolites and the expression of enzymes differ between HNSCC and normal tissues. Reprogramming metabolism in HNSCC provides an energy source as well as structural components, creating a system that offers rapid proliferation, progression, and is less likely to be eliminated. [ABSTRACT FROM AUTHOR]

Introduction: Delayed graft function (DGF) is a frequent complication following kidney transplant. This study aimed to assess the association between early post‐operative lactate variation and DGF. Methods: This was a single center, retrospective cohort study between February 2021 and December 2022 in Saint–Louis Hospital (APHP, France). Venous lactate levels were measured immediately (H0) and 4 h (H4) after kidney transplant. The primary outcome was the occurrence of DGF (need for renal replacement therapy between transplantation and day 7). Secondary outcome was the occurrence of complications (i.e., death, vascular thrombosis, hemorrhagic shock, urological complications (hematoma, urinoma), local or systemic infection) between transplant and day 7. Results: Two hundred 12 patients were included, and 38 (17.9%) developed DGF. Venous lactate variation between H0 and H4 was higher in patients who developed DGF (−30 (IQR −83, −6)% vs. −15 (IQR −62, −11)%, p =.037), but the variation of level was more often positive (corresponding to an increased lactate production over time between H0 and H4) in patients who developed DGF ((28(85%) vs. 94(62%), p =.011). In multivariate logistic regression, positive venous lactate level variation between H0 and H4 was strongly associated with a reduced risk of developing DGF (OR.30 [.09–.79], p =.024). We did not find any association between post‐operative hyperlactatemia and occurrence of complications between transplant and day 7. Discussion: DGF is a frequent complication following kidney transplantation. Its early prediction could help physicians optimize treatment and protect the kidney. Early venous lactate variation after kidney transplant could help to predict the occurrence of DGF. [ABSTRACT FROM AUTHOR]

The brain possesses intricate mechanisms for monitoring sodium (Na) levels in body fluids. During prolonged dehydration, the brain detects variations in body fluids and produces sensations of thirst and aversions to salty tastes. At the core of these processes Nax, the brain's Na sensor, exists. Specialized neural nuclei, namely the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which lack the blood--brain barrier, play pivotal roles. Within the glia enveloping the neurons in these regions, Nax collaborates with Na+/K+-ATPase and glycolytic enzymes to drive glycolysis in response to elevated Na levels. Lactate released from these glia cells activates nearby inhibitory neurons. The SFO hosts distinct types of angiotensin II- sensitive neurons encoding thirst and salt appetite, respectively. During dehydration, Nax-activated inhibitory neurons suppress salt-appetite neuron's activity, whereas salt deficiency reduces thirst neuron's activity through cholecystokinin. Prolonged dehydration increases the Na sensitivity of Nax via increased endothelin expression in the SFO. So far, patients with essential hypernatremia have been reported to lose thirst and antidiuretic hormone release due to Naxtargeting autoantibodies. Inflammation in the SFO underlies the symptoms. Furthermore, Nax activation in the OVLT, driven by Na retention, stimulates the sympathetic nervous system via acid-sensing ion channels, contributing to a blood pressure elevation. [ABSTRACT FROM AUTHOR]

The perception regarding lactate has changed over the past decades, and some of its physiological roles have gradually been revealed. However, the effects of exogenous lactate on skeletal muscle synthesis remain unclear. This study aimed to confirm the effects of a 5‐week lactate administration and post‐exercise lactate administration on skeletal muscle synthesis. Thirty‐two Institute of Cancer Research mice were randomly assigned to non‐trained + placebo, non‐trained + lactate, trained + placebo, and trained + lactate groups. Furthermore, 3 g/kg of lactate or an equivalent volume of saline was immediately administered after exercise training (maximum oxygen uptake: 70%). Lactate administration and/or exercise training was performed 5 days/week for 5 weeks. After the experimental period, it was observed that lactate administration tended to elevate skeletal muscle weight, increased protein kinase B (p < 0.05) and mammalian target of rapamycin (p < 0.05) mRNA levels, and decreased muscle ring‐finger protein‐1 expression (p < 0.05). Lactate administration after exercise training significantly enhanced plantaris muscle weight; however, it had no additional effects on most signaling factors. This study demonstrated that a 5‐week lactate administration could stimulate skeletal muscle synthesis, and lactate administration after exercise training may provide additional effects, such as increasing skeletal muscle. [ABSTRACT FROM AUTHOR]

Background: Equine spermatozoa appear to differ from spermatozoa of other species in using oxidative phosphorylation preferentially over glycolysis. However, there is little information regarding effects of different energy sources on measured parameters in equine spermatozoa. Objective: To determine the effect of three individual energy substrates, glucose, pyruvate, and lactate, on motion characteristics, membrane integrity, and acrosomal status of stallion spermatozoa. Materials and methods: Freshly ejaculated stallion spermatozoa were incubated with combinations of glucose (5 mm), pyruvate (10 mm), and lactate (10 mm) for 0.5 to 4 h. Response to calcium ionophore A23187 (5 μm) was used to evaluate capacitation status. Motility was evaluated using computer‐assisted sperm analysis, and plasma membrane and acrosomal integrity were evaluated by flow cytometry. Results: Incubation with lactate alone for 2 h increased acrosomal sensitivity to A23187. Notably, incubation with lactate alone for 4 h induced a significant spontaneous increase in acrosome‐reacted, membrane‐intact (viable) spermatozoa, to approximately 50% of the live population, whereas no increase was seen with incubation in glucose or pyruvate alone. This acrosomal effect was observed in spermatozoa incubated at physiological pH as well as under alkaline conditions (medium pH approximately 8.5). Sperm motility declined concomitantly with the increase in acrosome‐reacted spermatozoa. Sperm motility was significantly higher in pyruvate‐only medium than in glucose or lactate. The addition of pyruvate to lactate‐containing medium increased sperm motility but reduced the proportion of live acrosome‐reacted spermatozoa in a dose‐dependent fashion. Discussion: This is the first study to demonstrate that incubation with a specific energy substrate, lactate, is associated with spontaneous acrosome reaction in spermatozoa. The proportion of live, acrosome‐reacted spermatozoa obtained is among the highest reported for equine spermatozoa. Conclusion: These findings highlight the delicate control of key sperm functions, and may serve as a basis to increase our understanding of stallion sperm physiology. [ABSTRACT FROM AUTHOR]

Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen‐sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species‐related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field. [ABSTRACT FROM AUTHOR]

Background: The association between the lactate/albumin ratio (L/A) as a diagnostic indicator and unfavourable clinical outcomes has been established in patients with community‐acquired pneumonia, sepsis and heart failure, but the connection between L/A and all‐cause mortality in patients with acute myocardial infarction (AMI) has yet to be fully understood. Methods: This was a retrospective cohort study using MIMIC‐IV (v2.2) data, with 2816 patients enrolled and all‐cause mortality during hospitalization as the primary outcome. Kaplan–Meier (KM) analysis was used to compare the all‐cause mortality between high‐level and low‐level L/A groups. Receiver operating characteristic (ROC) curve, Restricted cubic splines (RCS) and Cox proportional hazards analysis were performed to investigate the relationship between L/A ratio and in‐hospital all‐cause mortality. Results: L/A values were significantly higher in the non‐survivor groups than the survival groups (1.14 [.20] vs..60 [.36], p <.05), and area under the ROC curve [.734 (95% confidence interval,.694–.775)] was better than other indicators. Data of COX regression analysis showed that higher L/A value supposed to be an independent risk factor for in‐hospital mortality. RCS analysis showed evidence of an increasing trend and a non‐linear relationship between L/A and in‐hospital mortality (p‐value was non‐linear <.05). KM survival curves were significantly lower in the high L/A group than the low L/A group (p <.001), and the former group had an increased risk of in‐hospital mortality compared with the latter one (Log Rank p <.001). Conclusions: L/A demonstrates significant independent predictive power for elevated all‐cause mortality during hospitalization in patients diagnosed with AMI. [ABSTRACT FROM AUTHOR]

Introduction: Male elite cyclists (average VO2‐max: 71 mL/min/kg, n = 18) completed 7 weeks of high‐intensity interval training (HIT) (3×/week; 4‐min and 30‐s intervals) during the competitive part of the season. The influence of a maintained or lowered total training volume combined with HIT was evaluated in a two‐group design. Weekly moderate‐intensity training was lowered by ~33% (~5 h) (LOW, n = 8) or maintained at normal volume (NOR, n = 10). Endurance performance and fatigue resistance were evaluated via 400 kcal time‐trials (~20 min) commenced either with or without prior completion of a 120‐min preload (including repeated 20‐s sprints to simulate physiologic demands during road races). Results: Time‐trial performance without preload was improved after the intervention (p = 0.006) with a 3% increase in LOW (p = 0.04) and a 2% increase in NOR (p = 0.07). Preloaded time‐trial was not significantly improved (p = 0.19). In the preload, average power during repeated sprinting increased by 6% in LOW (p < 0.01) and fatigue resistance in sprinting (start vs end of preload) was improved (p < 0.05) in both groups. Blood lactate during the preload was lowered (p < 0.001) solely in NOR. Measures of oxidative enzyme activity remained unchanged, whereas the glycolytic enzyme PFK increased by 22% for LOW (p = 0.02). Conclusion: The present study demonstrates that elite cyclists can benefit from intensified training during the competitive season both with maintained and lowered training volume at moderate intensity. In addition to benchmarking the effects of such training in ecological elite settings, the results also indicate how some performance and physiological parameters may interact with training volume. [ABSTRACT FROM AUTHOR]

In a clinical setting, ex vivo perfusions are routinely used to maintain and assess organ viability prior to transplants. Organ perfusions are also a model system to examine metabolic flux while retaining the local physiological structure, with significant success using hyperpolarized (HP) 13C NMR in this context. We use a novel exocrine pancreas perfusion technique via the common bile duct to assess acinar cell metabolism with HP [1‐13C]pyruvate. The exocrine component of the pancreas produces digestive enzymes through the ductal system and is often neglected in research on the pancreas. Real‐time production of [1‐13C]lactate, [1‐13C]alanine, [1‐13C]malate, [4‐13C]malate, [1‐13C]aspartate, and H13CO3− was detected. The appearance of these resonances indicates flux through both pyruvate dehydrogenase and pyruvate carboxylase. We studied excised pancreata from C57BL/6J mice and NOD.Rag1−/−.AI4α/β mice, a commonly used model of Type 1 Diabetes (T1D). Pancreata from the T1D mice displayed increased lactate to alanine ratio without changes in oxygen consumption, signifying increased cytosolic NADH levels. The mass isotopologue analysis of the extracted pancreas tissue using gas chromatography–mass spectrometry revealed confirmatory 13C enrichment in multiple TCA cycle metabolites that are products of pyruvate carboxylation. The methodology presented here has the potential to provide insight into mechanisms underlying several pancreatic diseases, such as diabetes, pancreatitis, and pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Abelson tyrosine kinase (c‐Abl) is frequently mutated and highly expressed, and promotes non‐small‐cell lung cancer (NSCLC) survival, metastasis and tumorigenesis. c‐Abl could also be modified through ubiquitination, but the underlying mechanism is not well understood. Methods: Mass spectrometry assays were performed to search c‐Abl deubiquitination enzymes. The molecular mechanism was determined using Co‐IP assays, pull‐down assays, Western blotting upon gene knockdown or overexpression. Cell lines and animal models were used to investigate the role of c‐Abl and USP7 in NSCLC. EdU staining assay and Transwell assay were performed to evaluate the proliferation and migration ability of NSCLC cells, respectively. Results: Ubiquitin‐specific protease 7 (USP7) is found to upregulate c‐Abl via the deubiquitinase screen. USP7 interacts with c‐Abl and decreases its K48‐linked polyubiquitination, thereby increasing the stability of c‐Abl. In addition to the wild‐type one, c‐Abl mutants can also be deubiquitinated and stabilized by USP7. Moreover, USP7 promotes c‐Abl accumulation in cytoplasm by increasing its binding to 14‐3‐3α/β and activates the oncogenic c‐Abl signalling pathway. Furthermore, the USP7/c‐Abl axis promotes NSCLC cell glycolysis by direct phosphorylating and stabilizing hexokinase‐2 (HK2). Knockdown of USP7 or c‐Abl suppresses NSCLC cell glycolysis and reduces lactate production. Further studies revealed that overexpression of USP7 facilitates NSCLC cell growth and metastasis as well as xenograft growth in nude mice, while these activities are suppressed with USP7 or c‐Abl being knocked down. Conclusions: USP7 is a deubiquitinase of c‐Abl and upregulates its oncogenic activity. USP7 promotes NSCLC cell metabolism by activating c‐Abl and HK2. Targeting the USP7/c‐Abl/HK2 axis might be a potential strategy to the precision therapy of NSCLC. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is the most common type of gynecological tumor, presenting poor prognosis at diagnosis and with recurrences being frequently observed. Reactive species generated by physical plasma and transferred into liquids have shown promising results in cancer therapy. Recently, Ringer's lactate solution was exposed to plasma showing selective anticancer activity on EOC cells. In this work, we compared the effect of plasma treatment, using the kINPen plasma jet, on Ringer's saline and Ringer's lactate solution. These two plasma‐treated liquids were analyzed chemically by quantifying reactive species and the extent of lactate oxidation. The biological efficiency of the plasma‐treated liquids was explored in EOC cells. The results show that lactate is affected by plasma treatment, displaying a reduction of cytotoxic potential. [ABSTRACT FROM AUTHOR]

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)‐specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC‐specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2‐deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels. [ABSTRACT FROM AUTHOR]

Background: Compelling evidence implicates diabetes‐associated hyperglycemia as a promoter of tumor progression in oral potentially malignant disorders (OPMD). Yet, information on hyperglycemia‐induced cell signaling networks in oral oncology remains limited. Our group recently reported that glucose‐rich conditions significantly enhance oral dysplastic keratinocyte viability and migration through epidermal growth factor receptor (EGFR) activation, a pathway strongly linked to oral carcinogenesis. Here, we investigated the basal metabolic phenotype in these cells and whether specific glucose‐responsive EGFR ligands mediate these responses. Methods: Cell energy phenotype and lactate concentration were evaluated via commercially available assays. EGFR ligands in response to normal (5 mM) or high (20 mM) glucose were analyzed by quantitative real‐time PCR, ELISA, and western blotting. Cell viability and migration assays were performed in the presence of pharmacological inhibitors or RNA interference. Results: When compared to normal keratinocytes, basal glycolysis in oral dysplastic keratinocytes was significantly elevated. In highly glycolytic cells, high glucose‐activated EGFR increasing viability and migration. Notably, we identified amphiregulin (AREG) as the predominant glucose‐induced EGFR ligand. Indeed, enhanced cell migration in response to high glucose was blunted by EGFR inhibitor cetuximab and AREG siRNA. Conversely, AREG treatment under normal glucose conditions significantly increased cell viability, migration, lactate levels, and expression of glycolytic marker pyruvate kinase M2. Conclusion: These novel findings point to AREG as a potential high glucose‐induced EGFR activating ligand in highly glycolytic oral dysplastic keratinocytes. Future studies are warranted to gain more insight into the role of AREG in hyperglycemia‐associated OPMD tumor progression. [ABSTRACT FROM AUTHOR]

The high incidence, low healing rate and huge economic burden of wounds (especially chronic wounds) worldwide remain a great challenge for clinical staff and patients. The various stages of wound healing are regulated by paracrine or autocrine cytokines and growth factors, and the study of their intrinsic mechanisms is a prerequisite for better wound treatment. Lactate, the end product of glycolysis, plays a role in all stages of wound healing, and recent studies have identified lactate as an epigenetic regulator that regulates gene expression through histone lysine lactylation and stimulates posttranslational modifications to regulate related gene expression, thereby causing a series of biological functional changes. This article reviews the progress of research on lactate and lactylation during wound healing or in related diseases, including its involvement in immune regulation, inflammation control, and proliferative remodeling, and finally describes the prospects for lactate therapy regarding wound healing. [ABSTRACT FROM AUTHOR]

Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the ‘lactate shuttle’ moving between cells and transmitting signals. The glycolytic-dependent metabolism found in tumours and fast-growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate-induced lactylation moves even further on pro-tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone. [ABSTRACT FROM AUTHOR]

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post‐translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip‐mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri‐methylation promotes tumor glycolysis and M2‐like polarization of tumor‐associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri‐methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Background: The post‐operative course after Liver Transplantation (LT) can be complicated by early allograft dysfunction (EAD), primary nonfunction (PNF) and death. A lactate concentration at the end of transplant of ≥5 mmol/L was recently proposed as a predictive marker of PNF, EAD, and mortality; this study aimed to validate these previous reports in a large single center cohort. Methods: This retrospective cohort study included adult liver transplant recipients who received grafts from deceased donors at our center between June 2012 and May 2021. Receiver operating characteristic (ROC) curves for the lactate concentration at the end of transplantation were computed to determine the AUC for PNF, EAD and mortality at 90 days. Results: In our cohort of 1137 cases, the AUCs for lactate to predict EAD, PNF and mortality were respectively.56 (95% confidence interval [CI]:.53–.60),.69 (95% CI:.52–.85), and.74 (95% CI:.63–.84). Conclusion: The clinical value of lactate concentration at the end of transplantation to predict PNF, EAD and mortality at 90 days was, at best, modest, as shown by the relatively low AUCs. Our findings cannot validate previous reports that the lactate level alone is a good predictor of poor outcomes after liver transplantation. [ABSTRACT FROM AUTHOR]

Objective: Status epilepticus (SE) requires rapid intervention to prevent cerebral injury and mortality. The ketogenic diet, which bypasses glycolysis, is a promising remedy for patients with refractory SE. We tested the role of glycolytic lactate production in sustaining SE. Methods: Extracellular lactate and glucose concentration during a seizure and SE in vivo was measured using lactate and glucose biosensors. A lactate dehydrogenase inhibitor, oxamate, blocked pyruvate to lactate conversion during SE. Video‐EEG recordings evaluated seizure duration, severity, and immunohistochemistry was used to determine neuronal loss. Genetically encoded calcium indicator GCaMP7 was used to study the effect of oxamate on CA1 pyramidal neurons in vitro. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from CA1 neurons to study oxamate's impact on neurotransmission. Results: The extracellular glucose concentration dropped rapidly during seizures, and lactate accumulated in the extracellular space. Inhibition of pyruvate to lactate conversion with oxamate terminated SE in mice. There was less neuronal loss in treated compared to control mice. Oxamate perfusion decreased tonic and phasic neuronal activity of GCaMP7‐expressing CA1 pyramidal neurons in vitro. Oxamate application reduced the frequency, but not amplitude of sEPSCs recorded from CA1 neurons, suggesting an effect on the presynaptic glutamatergic neurotransmission. Interpretation: A single seizure and SE stimulate lactate production. Diminishing pyruvate to lactate conversion with oxamate terminated SE and reduced associated neuronal death. Oxamate reduced neuronal excitability and excitatory neurotransmission at the presynaptic terminal. Glycolytic lactate production sustains SE and is an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

An effective systemic mechanism regulates tumor development and progression; thus, a rational design in a one‐stone‐two‐birds strategy is meant for cancer treatment. Herein, a hollow Fe3O4 catalytic nanozyme carrier co‐loading lactate oxidase (LOD) and a clinically‐used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self‐replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti‐tumor immune microenvironment. The synergetic bio‐effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co‐delivered LOD and intracellular acidification enabled the augmented self‐replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti‐tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1‐polarize tumor‐associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof‐of‐concept study represents a promising candidate nanoplatform for synergetic cancer treatment. [ABSTRACT FROM AUTHOR]

Imatinib is the frontline treatment option in treating chronic myelogenous leukemia (CML). Hitherto, some patients relapse following treatment. Biochemical analysis of a panel of clonally derived imatinib‐resistant cells revealed enhanced glucose uptake and ATP production, suggesting increased rates of glycolysis. Interestingly, increased lactate export was also observed in imatinib‐resistant cell lines. Here, we show that metformin inhibits the growth of imatinib‐resistant cell lines as well as peripheral blood mononuclear cells isolated from patients who relapsed following imatinib treatment. Metformin exerted these antiproliferative effects by inhibiting MCT1 and MCT4, leading to the inhibition of lactate export. Furthermore, glucose uptake and ATP production were also inhibited following metformin treatment due to the inhibition of GLUT1 and HK‐II in an AMPK‐dependent manner. Our results also confirmed that metformin‐mediated inhibition of lactate export and glucose uptake occurs through the regulation of mTORC1 and HIF‐1α. These results delineate the molecular mechanisms underlying metabolic reprogramming leading to secondary imatinib resistance and the potential of metformin as a therapeutic option in CML. [ABSTRACT FROM AUTHOR]

A wrist‐watch type biosensing system for real‐time sweat lactic acid (LA) monitoring was fabricated and tested. The system consists of a microfluidic LA biosensor, a carrier‐flow supplying device, and a sampling device for transporting whole secretions at the skin surface to the biosensor by continuous flow of phosphate‐buffered saline (PBS). The perfusion test of PBS onto the skin surface by using the sampling device resulted in less than 1% leakage frequency at the collection site. The carrier‐flow supplying device was able to feed PBS regardless of the body angle. When the subject wearing the device performed resistance training (lateral raise, 20 repetitions, 12.5 kg dumbbells), the LA secretion increased from 2 µg/cm2/min to 16 µg/cm2/min in response to the exercise, and then recovered to the baseline. The setup time for the measurement was less than 60 s. This indicates that the wrist‐watch device can readily measure LA dynamics on the skin surface under conditions of the subject. [ABSTRACT FROM AUTHOR]

The purpose of the study was to compare the degree of intersubject variability in the cardiorespiratory, metabolic, and perceptual responses to high‐intensity interval training (HIIT) prescribed based on the relative anaerobic speed reserve (ASR) or maximal aerobic speed (MAS) and to identify the optimal % ASR for execution of such HIIT. Seventeen male physical education students (age: 23.6 ± 1.1 years, height: 180.2 ± 5.9, body mass: 78.3 ± 8.1 kg; % body fat: 14.3 ± 2.7%) volunteered to execute three randomly scheduled 10‐min HIIT exercises at 110% vVO2max, Δ15% ASR, or Δ25% ASR. Analysis of variance for repeated measures and the least significant difference post‐hoc test were used to compare the physiological responses and the mean of individual residuals between the training sessions. The coefficients of variation (CV) of time spent ≥90% of maximal oxygen uptake (VO2max) and maximal heart rate (HRmax), peak VO2, mean VO2, peak HR, mean HR, blood lactate [La], and rating of perceived exertion (RPE) were 48.7%, 35.9%, 9.3%, 7%, 3.5%, 4.8%, 32%, and 16.9% during 110% vVO2max, 47.2%, 31%, 7.5%, 6.7%, 3.9%, 4.6%, 24.2%, and 14.6% during Δ15% ASR, and 48.1%, 31.5%, 7.6%, 8.4%, 3.6%, 4.1%, 20.2%, and 3.4% during Δ25% ASR session, respectively. Only the residuals in RPE were significantly (p < 0.001) higher in 110% vVO2max and Δ15% ASR in comparison to Δ25% ASR. Time spent ≥90% HRmax/VO2max was maximized during Δ15% ASR session, albeit this was not significantly different from other sessions. The ASR‐based method leads to reduced CVs of physiological and perceptual responses during 10‐min HIIT; however, only reductions in [La] and RPE may be considered practically meaningful. Practitioners can use vVO2max for prescription of 10‐min HIIT session comprised of 15‐s work and passive recovery intervals. [ABSTRACT FROM AUTHOR]

Background: Cancer stem cells are pivotal in cancer progression and therapy, including lung adenocarcinoma (LUAD). High NCAPG level is implicated in malignant tumorigenesis, but investigations on NCAPG and LUAD stem cells are warranted. Hence, projecting the impact of NCAPG on cell stemness and the targeted therapy for LUAD is of the essence. Methods: Bioinformatics analyzed NCAPG expression in LUAD tissues. qRT‐PCR assayed NCAPG expression in LUAD cells. CCK‐8 assessed cell viability and cell sphere‐forming assay measured sphere‐forming ability. Western blot assessed expression of stem cell‐related markers (CD133, CD44, Oct‐4) and specific genes (HK2, PKM2, LDHA) related to glycolysis metabolism pathway. Cellular glycolytic capacity was assayed by glycolytic metabolites pyruvic acid, lactate, citrate, and malate assay kits, and extracellular acidification rate and oxygen consumption rate analyzers. Results: NCAPG was upregulated in LUAD and enriched in the aerobic glycolysis pathway, and its expression was positively correlated with that of glycolytic marker genes. Cell function assays revealed that NCAPG stimulated proliferation, stemness, and glycolytic activity of LUAD cells. Rescue experiments unveiled that 2‐DG (glycolysis inhibitor) was able to reverse the stimulative impact of NCAPG overexpression on proliferation, stemness, and glycolytic activity of LUAD cells. Conclusion: NCAPG stimulated LUAD cell stemness through activation of glycolysis pathway. NCAPG may be possible biomarker for diagnosis and target for treatment of LUAD. [ABSTRACT FROM AUTHOR]

Introduction: This study endeavored to investigate the role of DOCK8 in modulating the immune function triggered by sepsis. Methods: Expression of DOCK8 in the whole blood of sepsis patients and its enrichment pathways were assayed by bioinformatics. Pearson analysis was used to predict the relationship between glycolytic signaling pathway and its relevance to neutrophil function in sepsis. A sepsis mouse model was then built by performing cecal ligation and puncture treatment on male mice. Neutrophils were isolated, and their purity was tested by flow cytometry. Neutrophils were then stimulated by lipopolysaccharide to build a sepsis cell model. Next, quantitative reverse transcription polymerase chain reaction and CCK‐8 were applied to test the expression of DOCK8 and cell viability, western blot to assay the expression of HK‐2, PKM2, and LDHA proteins, ELISA to measure the concentrations of TNF‐α, IL‐1β, and IL‐6, Transwell to detect the chemotaxis of neutrophils and flow cytometry to detect the phagocytic activity of neutrophils. Finally, in different treatment groups, we used Seahorse XF 96 to analyze the extracellular acidification rate (ECAR) of sepsis cells and used enzyme‐linked immunosorbent assay to detect the contents of pyruvic acid, lactic acid, and ATP in sepsis cells. Results: DOCK8 was downregulated in sepsis blood and activated neutrophils. Aerobic glycolysis was positively correlated with sepsis. Activated neutrophils promoted the expression of inflammatory factors TNF‐α, IL‐1β, and IL‐6. Low expression of DOCK8 facilitated the proliferation, chemotaxis, and phagocytic activity of sepsis cells and promoted the expression of inflammatory factors. Bioinformatics analysis revealed that DOCK8 was enriched in the glycolytic signaling pathway. Low expression of DOCK8 induced ECAR, promoted the protein expression of HK‐2, PKM2 and LDHA, and favored the increase of pyruvate, lactate, and ATP contents. While 2‐DG treatment could restore these effects. Conclusion: DOCK8 may inhibit sepsis‐induced neutrophil immune function by regulating aerobic glycolysis and causing excessive inflammation, which helps to explore potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Study Objective: Significant practice variation exists when selecting between hydrocortisone and vasopressin as second line agents in patients with septic shock in need of escalating doses of norepinephrine. The goal of this study was to assess differences in clinical outcomes between these two agents. Design: Multicenter, retrospective, observational study. Setting: Ten Ascension Health hospitals. Patients: Adult patients with presumed septic shock receiving norepinephrine prior to study drug initiation between December 2015 and August 2021. Intervention: Vasopressin (0.03–0.04 units/min) or hydrocortisone (200–300 mg/day). Measurements and Main Results: A total of 768 patients were included with a median (interquartile range) SOFA score of 10 (8–13), norepinephrine dose of 0.3 mcg/kg/min (0.1–0.5 mcg/kg/min), and lactate of 3.8 mmol/L (2.4–7.0 mmol/L) at initiation of the study drug. A significant difference in 28‐day mortality was noted favoring hydrocortisone as an adjunct to norepinephrine after controlling for potential confounding factors (OR 0.46 [95% CI, 0.32–0.66]); similar results were seen following propensity score matching. Compared to vasopressin, hydrocortisone initiation was also associated with a higher rate of hemodynamic responsiveness (91.9% vs. 68.2%, p < 0.01), improved resolution of shock (68.8% vs. 31.5%, p < 0.01), and reduced recurrence of shock within 72 h (8.7% vs. 20.7%, p < 0.01). Conclusions: Addition of hydrocortisone to norepinephrine was associated with a lower 28‐day mortality in patients with septic shock, compared to the addition of vasopressin. [ABSTRACT FROM AUTHOR]

Background: Elevated lactate results in an acidic tumor microenvironment (TME), which stimulates the progression of esophageal cancer (EC). Tumor‐associated macrophages (TAMs) are an essential component of the TME. However, the regulatory mechanisms of lactate secreted by EC on TAMs and the effects of EC advancement are unclear. Methods: Proteins and mRNA expression were determined by western blot and RT‐qPCR. Cell metastasis and growth were assessed by scratch assay, transwell and BrdU assays. Lactate in cells was quantified using a lactate kit. A mouse model was constructed for validation in vivo. Results: First, we determined that lactate upgraded the M2‐type polarization marker levels of macrophages. Cell function assays confirmed that lactate‐activated M2 macrophages accelerated EC cell migration and proliferation in vitro. However, the lactate inhibitor – oxamate hampered the level of lactate in TE‐1 cells. Oxamate abolished the facilitation of macrophage polarization by lactate. In addition, we discovered that phosphorylated AKT and phosphorylated ERK was obviously raised in lactate‐stimulated macrophages, and oxamate addition reversed this change, implying that AKT and ERK signaling pathways were involved in macrophage polarization. Response experiments proved that attenuation of AKT/ERK signaling markedly returned the lactate‐induced promotion of EC migration and proliferation by macrophages. Finally, mouse tumor models demonstrated that lactate enhanced EC growth by inducing M2 macrophage polarization. Conclusion: EC‐secreted lactate stimulated macrophage M2 polarization via the AKT/ERK pathway thereby boosting the growth of EC. [ABSTRACT FROM AUTHOR]

Background: The optimal allocation of training time to different intensities in cardiac rehabilitation is still under debate. The objective of this study was to explore whether in a 12‐week cardiac rehabilitation program, replacement of two of four usual continuous endurance training (CET) sessions per week with energy expenditure‐matched high‐intensity interval training (HIIT) affects the trajectories of cardiopulmonary exercise test (CPET) variables such as ventilatory equivalents for O2 (EqO2) and CO2 (EqCO2), and blood lactate (BLa) during CPET. Methods: Eighty‐two male patients undergoing outpatient cardiac rehabilitation after an acute coronary syndrome were randomized to CET (age [mean ± SD] 61.7 ± 9.8 years, body mass index [BMI] 28.1 ± 3.4) or HIIT+CET (60.0 ± 9.4 years, BMI 28.5 ± 3.5). CPET was performed at baseline, after 6 and after 12 weeks. HIIT consisted of ten 60‐s bouts of cycling at an intensity of 100% of the maximal power output (Pmax) achieved in an incremental test to exhaustion, interspersed with 60 s at 20% Pmax. CET was performed at 60% Pmax with equal duration. Training intensities were adjusted after 6 weeks to account for the training‐induced improvement in cardiorespiratory fitness. The entire functions defining the relationship between EqO2, EqCO2, and BLa, with power output were modeled using linear mixed models to assess how these trajectories are affected by HIIT. Results: After 6 and 12 weeks, Pmax increased to 112.9% and 117.5% of baseline after CET, and to 113.9% and 124.7% after HIIT+CET (means). Twelve weeks of HIIT+CET elicited greater reductions of EqO2 and EqCO2 than CET alone (p < 0.0001 each) in a range above 100% baseline Pmax. Specifically, at 100% of baseline Pmax, least squares arithmetic mean EqO2 values of CET and HIIT+CET patients were 36.2 versus 33.5. At 115% and 130% of baseline Pmax, EqO2 values were 41.2 versus 37.1 and 47.2 versus 41.7. Similarly, corresponding EqCO2 values of CET and HIIT+CET patients were 32.4 versus 31.0, 34.3 versus 32.2, and 37.0 versus 34.0. Conversely, mean BLa levels (mM) were not differently affected (p = 0.64). At 100%, 115%, and 130% of baseline Pmax after 12 weeks, BLa levels did not differ to a relevant extent (least squares geometric means, 3.56 vs. 3.63, 5.59 vs. 5.61, 9.27 vs. 9.10). Conclusions: While HIIT+CET reduced ventilatory equivalents more effectively than CET alone, specifically when patients were approaching their maximal performance during CPET, both training strategies were equally effective in reducing BLa levels. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether 4 weeks of normobaric "live high–train low and high" (LHTLH) causes different hematological, cardiorespiratory, and sea‐level performance changes compared to living and training in normoxia during a preparation season. Methods: Nineteen (13 women, 6 men) cross‐country skiers competing at the national or international level completed a 28‐day period (∼18 h day−1) of LHTLH in normobaric hypoxia of ∼2400 m (LHTLH group) including two 1 h low‐intensity training sessions per week in normobaric hypoxia of 2500 m while continuing their normal training program in normoxia. Hemoglobin mass (Hbmass) was assessed using a carbon monoxide rebreathing method. Time to exhaustion (TTE) and maximal oxygen uptake (VO2max) were measured using an incremental treadmill test. Measurements were completed at baseline and within 3 days after LHTLH. The control group skiers (CON) (seven women, eight men) performed the same tests while living and training in normoxia with ∼4 weeks between the tests. Results: Hbmass in LHTLH increased 4.2 ± 1.7% from 772 ± 213 g (11.7 ± 1.4 g kg−1) to 805 ± 226 g (12.5 ± 1.6 g kg−1) (p < 0.001) while it was unchanged in CON (p = 0.21). TTE improved during the study regardless of the group (3.3 ± 3.4% in LHTLH; 4.3 ± 4.8% in CON, p < 0.001). VO2max did not increase in LHTLH (61.2 ± 8.7 mL kg−1 min−1 vs. 62.1 ± 7.6 mL kg−1 min−1, p = 0.36) while a significant increase was detected in CON (61.3 ± 8.0–64.0 ± 8.1 mL kg−1 min−1, p < 0.001). Conclusions: Four‐week normobaric LHTLH was beneficial for increasing Hbmass but did not support the short‐term development of maximal endurance performance and VO2max when compared to the athletes who lived and trained in normoxia. [ABSTRACT FROM AUTHOR]

Limits of thermal tolerance in animal life is dependent on energy supply. Accordingly, the lowered ATP production capacity in ectotherms at high temperatures, which arises from a mismatch between oxygen supply and demand and the consequent switch from aerobic to anaerobic metabolism, affects the thermal resistance of these animals. The anaerobic ATP production capacity depends on the functional properties of the enzymes that reduce pyruvate. Thus, the present study focused on the role of the lactate dehydrogenase (LDH) of two daphnid species for anaerobic energy production at warm temperatures and the implications for their specific heat tolerances. Daphnia magna showed a higher thermal limit (indicated by immobilization time at 37°C) than Daphnia pulex, and in both species, this limit increased with rising acclimation temperature. In contrast to D. pulex, D. magna accumulated significant amounts of lactate at higher ambient temperatures. The intensity of anaerobic metabolism was also affected by acclimation temperature. Studying the functional enzyme properties revealed altered maximal reaction rates and substrate inhibitions of the LDH suites of the two daphnid species. D. magna LDH showed a significantly lower substrate inhibition than D. pulex LDH. The LDH isoform composition and the temperature‐induced changes differed between both species. The detected qualitative modulations of the LDH suites may have resulted from differential isoform expression and different maturation processes. The species‐specific LDH characteristics imply a higher anaerobic energy production at warm temperatures in D. magna, which likely contributes to the higher heat tolerance of this species. Research highlights: Heat tolerance in Daphnia is related tolactate production.Acclimation temperature affects LDH.LDH substrate inhibition prevents high lactate formation.Anaerobic LDH capacity is higher in Daphniamagna than in Daphniapulex.Differentia lLDH isoform expression adds to heat tolerance. [ABSTRACT FROM AUTHOR]

Background: Cardiopulmonary exercise testing with lactate and ammonia samples is used in the diagnostics of metabolic myopathies. As the effect of age and sex on the exercise lactate and ammonia levels are incompletely characterized for clinical associations, our aim was to assess the effects of these factors on healthy subjects to improve the test's interpretation. Methods: Seventy‐three subjects (34 men and 39 women; age < 35 years, n = 26, 35–50 years, n = 23 and >50 years, n = 24) performed cardiopulmonary exercise tests with venous blood gases, plasma lactate and ammonia analyses at rest, during exercise, and 2, 4, 6, 10, 20 and 30 min into recovery. Results: The lactate (p = 0.021–0.044) and ammonia values (p = 0.002–0.038) differed between men and women measured during recovery and between three age groups point‐by‐point in maximal exercise and the recovery phase and also longitudinally, most notably between <35‐ and >50‐year‐groups (lactate p = <0.001–0.040, ammonia p = 0.002–0.03). In the linear model, the yearly reduction of lactate was maximally −0.119 mmol/L and that of ammonia −1.514 µmol/L. The yearly reduction of lactate was greater in women than in men (−0.131 vs.−0.099 2 min into recovery), but for ammonia, the results were not as clear. Conclusions: Plasma lactate and ammonia concentrations measured during cardiopulmonary exercise were lower in older age groups, and their yearly reduction was also influenced by sex. These data give new information on lactate and ammonia levels and the effect of aging on them during exercise and recovery and may help assess cardiopulmonary exercise testing results. [ABSTRACT FROM AUTHOR]

The nucleotide‐binding and oligomerization domain, leucine‐rich repeats, and pyrin domain‐containing protein 3 (NLRP3) inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that the inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC‐0160 or pioglitazone, increased NLRP3 inflammasome activation and IL‐1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP‐associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sens MSDC‐itizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU‐induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3‐related autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to compare performance 5 h after a 90‐min endurance training session when either carbohydrate only or carbohydrate with added whey hydrolysate or whey isolate was ingested during the first 2 h of the recovery period. Methods: Thirteen highly trained competitive male cyclists completed three exercise and diet interventions (double‐blinded, randomized, crossover design) separated by 1 week. The 90‐min morning session (EX1) included a 60 min time‐trial (TT60). Immediately and 1 h after exercise, participants ingested either (1) 1.2 g carbohydrate∙kg−1∙h−1 (CHO), (2) 0.8 g carbohydrate∙kg−1∙h−1 + 0.4 g isolate whey protein∙kg−1∙h−1 (ISO) or (3) 0.8 g carbohydrate∙kg−1∙h−1 + 0.4 g hydrolysate whey protein∙kg−1∙h−1 (HYD). Additional intakes were identical between interventions. After 5 h of recovery, participants completed a time‐trial performance (TTP) during which a specific amount of work was performed. Blood and urine were collected throughout the day. Results: TTP did not differ significantly between dietary interventions (CHO: 43:54 ± 1:36, ISO: 46:55 ± 2:32, HYD: 44:31 ± 2:01 min). Nitrogen balance during CHO was lower than ISO (p < 0.0001) and HYD (p < 0.0001), with no difference between ISO and HYD (p = 0.317). In recovery, the area under the curve for blood glucose was higher in CHO compared to ISO and HYD. HR, VO2, RER, glucose, and lactate during EX2 were similar between interventions. Conclusion: Performance did not differ after 5 h of recovery whether carbohydrate only or isocaloric carbohydrate plus protein was ingested during the first 2 h. Correspondingly, participants were not in negative nitrogen balance in any dietary intervention. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to assess (1) the day‐to‐day variability in, and (2) the magnitude and time‐course of adaptation of physiological parameters (i.e., maximal oxygen uptake [VO2max], heart rate [HR], blood lactate concentration, respiratory exchange ratio [RER], ratings of perceived exertion [RPE], and time‐to‐exhaustion [TTE]) in response to an intervention involving three incremental ramp tests per week for 9 weeks. Methods: Twelve participants (25 ± 4 yrs, VO2max, 47.8 ± 5.2 mL∙min−1∙kg−1 (means ± SD)) completed the entire experimental procedure. The tests comprised a 5‐min constant workload to obtain submaximal parameters followed by an incremental protocol until exhaustion. Results: The mean day‐to‐day variability for the maximal value of VO2 was 2.8%, 1.1% for HR, 18.1% for blood lactate concentration, 2.1% for RER, 1.1% for RPE, and 5.0% for TTE. The values for the corresponding submaximal variables were 3.8% for VO2, 2.1% for HR, 15.6% for blood lactate concentration, 2.6% for RER and 6.0% for RPE. VO2max (+4.7% ± 3.5%), TTE (+17.9% ± 8.6%), and submaximal HR (−3.2 ± 3.5%) improved significantly. Except for RPE (p < 0.01), there were no alterations in the coefficient of variation for any parameter. On the group level, the first changes greater than the day‐to‐day variability in VO2max, TTE, and submaximal HR were observed after 21, 12, and 9 training sessions, respectively. Conclusion: Based on our findings, we recommend that training studies include assessment of the reliability of the measurements, for example, the CVs in the specific laboratory to be able to judge if the changes detected are actually physiological. [ABSTRACT FROM AUTHOR]

Under physiological conditions, the energetic demand of the brain is met by glucose oxidation. However, ample evidence suggests that lactate produced by astrocytes through aerobic glycolysis may also be an oxidative fuel, highlighting the metabolic compartmentalization between neural cells. Herein, we investigate the roles of glucose and lactate in oxidative metabolism in hippocampal slices, a model that preserves neuron–glia interactions. To this purpose, we used high‐resolution respirometry to measure oxygen consumption (O2 flux) at the whole tissue level and amperometric lactate microbiosensors to evaluate the concentration dynamics of extracellular lactate. We found that lactate is produced from glucose and transported to the extracellular space by neural cells in hippocampal tissue. Under resting conditions, endogenous lactate was used by neurons to support oxidative metabolism, which was boosted by exogenously added lactate even in the presence of excess glucose. Depolarization of hippocampal tissue with high K+ significantly increased the rate of oxidative phosphorylation, which was accompanied by a transient decrease in extracellular lactate concentration. Both effects were reverted by inhibition of the neuronal lactate transporter, monocarboxylate transporters 2 (MCT2), supporting the concept of an inward flux of lactate to neurons to fuel oxidative metabolism. We conclude that astrocytes are the main source of extracellular lactate which is used by neurons to fuel oxidative metabolism, both under resting and stimulated conditions. [ABSTRACT FROM AUTHOR]