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Introduction: Severe trauma-induced blood loss can lead to metabolic acidosis, shock, and death. Identification of abnormalities in the bicarbonate and serum markers may be seen before frank changes in vital signs in the hemorrhaging trauma patient, allowing for earlier lifesaving interventions. In this study the author aimed to evaluate the usefulness of serum bicarbonate and other lab markers as predictors of mortality in trauma patients within 30 days after injury.Methods: This retrospective, propensity-matched cohort study used the TriNetX database, covering approximately 92 million patients from 55 healthcare organizations in the United States, including 3.8 million trauma patients in the last two decades. Trauma patients were included if they had lab measurements available the day of the event. The analysis focused on mortality within 30 days post-trauma in comparison to measured lab markers. Cohorts were formed based on ranges of bicarbonate, lactate, and base excess levels.Results: Before propensity score matching, a total of 1,275,363 trauma patients with same-day bicarbonate, lactate, or base excess labs were identified. A significant difference in mortality was found across various serum bicarbonate lab ranges compared to the standard range of 21–27 milliequivalents per liter (mEq/L), post-propensity score matching. The relative risk of death was 6.806 for bicarbonate ≤5 mEq/L; 8.651 for 6–10; 6.746 for 11–15; 2.822 for 16–20; and 1.015 for bicarbonate ≥28. Serum lactate also displayed significant mortality outcomes when compared to a normal level of ≤2 millimoles per liter. Base excess showed similar significant correlation at different values compared to a normal base excessof −2 to 2 mEq/L.Conclusion: This study, approximately 100 times larger than prior studies, associated lower bicarbonate levels with increased mortality in the trauma patient. While lactate and base excess offer prognostic value, lower bicarbonate values have a higher relative risk of death. The greater predictive value of bicarbonate and accessibility during resuscitations suggests that it may be the superior prognostic marker in trauma.

This study investigated the effects of an acute dose (900 mg) of New Zealand Blackcurrant (NZBC) extract on 5-km running performance, alongside associated physiological and metabolic responses. Sixteen trained male runners (age 26 ± 5 years, stature 173.4 ± 7.3 cm, body mass 73.7 ± 6.9 kg, maximal oxygen consumption [ V ˙ O 2 max ] 55.4 ± 6.1 ml·kg−1·min−1) ingested either capsules containing NZBC extract (3 × 300 mg CurraNZ, 315 mg anthocyanins) or a matched placebo (3 × 300 mg gluten-free flour) 2 hr before exercise in a double-blind, randomized, crossover design. Performance time, physiological, and metabolic responses were assessed in a 5-km time trial, preceded by 10-min exercise at the lactate threshold on a treadmill. NZBC extract did not alter the physiological or metabolic responses to exercise at the lactate threshold (oxygen uptake, respiratory exchange ratio, minute ventilation, carbohydrate oxidation, fat oxidation, heart rate, blood lactate, or rating of perceived exertion, p >.05). The 5-km time trial was completed in a faster time in the NZBC extract condition compared with placebo (NZBC: 1,308.96 ± 122.36 s, placebo: 1,346.33 ± 124.44, p =.001, d = −0.23, confidence interval range = [−0.46, 0.00 s]). No differences in physiological or metabolic responses were apparent between conditions for the 5-km time trial (p >.05). Ingesting 900 mg of NZBC extract as an acute dose improves performance in trained male runners without altering physiological or metabolic responses to exercise. Further research is needed to assess a wider range of possible mechanisms (e.g., cardiovascular function, metabolite profiles) to advance insight into improved performance following supplementation. [ABSTRACT FROM AUTHOR]

Forages and concentrates have consistently distinct patterns of fermentation in the rumen, with forages producing more methane (CH4) per unit of digested organic matter (OM) and higher acetate to propionate ratio than concentrates. A mechanism based on the Monod function of microbial growth has been proposed to explain the distinct fermentation pattern of forages and concentrates, where greater dilution rates and lower pH associated with concentrate feeding increase dihydrogen (H2) concentration through increasing methanogens growth rate and decreasing methanogens theoretically maximal growth rate, respectively. Increased H2 concentration would in turn inhibit H2 production, decreasing methanogenesis, inhibit H2-producing pathways such as acetate production via pyruvate oxidative decarboxylation, and stimulate H2-incorporating pathways such as propionate production. We examined the hypothesis that equalizing dilution rates in serial rumen cultures would result in a similar fermentation profile of a high forage and a high concentrate substrate. Under a 2 × 3 factorial arrangement, a high forage and a high concentrate substrate were incubated at dilution rates of 0.14, 0.28, or 0.56 h-1 in eight transfers of serial rumen cultures. Each treatment was replicated thrice, and the experiment repeated in two different months. The high concentrate substrate accumulated considerably more H2 and formate and produced less CH4 than the high forage substrate. Methanogens were nearly washed-out with high concentrate and increased their initial numbers with high forage. The effect of dilution rate was minor in comparison to the effect of the type of substrate. Accumulation of H2 and formate with high concentrate inhibited acetate and probably H2 and formate production, and stimulated butyrate, rather than propionate, as an electron sink alternative to CH4. All three dilution rates are considered high and selected for rapidly growing bacteria. The archaeal community composition varied widely and inconsistently. Lactate accumulated with both substrates, likely favored by microbial growth kinetics rather than by H2 accumulation thermodynamically stimulating electron disposal from NADH into pyruvate reduction. In this study, the type of substrate had a major effect on rumen fermentation largely independent of dilution rate and pH.

Pyruvate and lactate are the final metabolites of the glycolytic system that are formed under oxygen-rich and anaerobic conditions, respectively. They play an important role in energy metabolism. Obtaining a tissue distribution image of pyruvate and lactate holds great significance in molecular biology because the glycolytic system plays an essential role in diseases, such as tumors and diabetes; microbial activities, such as alcohol production and lactic acid fermentation; and maintaining homeostasis in the gut environment. However, it is difficult to obtain images of the distribution of in vivo metabolites because of the low detection sensitivities of current methods. In this study, a novel derivatization method for pyruvate and lactate was developed using matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) to detect pyruvate and lactate in vivo and obtain biodistribution images. We investigated derivatization methods using readily available 3-nitrophenylhydrazine (3NPH), the addition of which improves the sensitivity of pyruvate detection, and the distribution of pyruvate in mouse testes was successfully visualized. Furthermore, the distribution of lactate in the mouse testes could be visualized, and improved detection sensitivity for the main metabolites of the tricarboxylic acid cycle was demonstrated. This derivatization method can be used to detect carboxyl-containing metabolites, including pyruvate, via MALDI-MSI. Furthermore, 3NPH forms amide bonds with carbonyl, phosphate, and carboxyl groups, suggesting the possibility of visualizing its distribution in many metabolites. [ABSTRACT FROM AUTHOR]

Key points The neurogenic potential of the brain decreases during ageing, whereas the risk of neurodegenerative diseases and stroke rises. This creates a mismatch between the rate of neuron loss and the brain's capacity for replacement. Adult neurogenesis primarily occurs in the subgranular zone (SGZ) and the ventricular‐subventricular zone (V‐SVZ). Exercise enhances SGZ neurogenesis, and we previously showed that V‐SVZ neurogenesis is induced by exercise via activation of the lactate receptor HCA1. Here, we investigated how high‐intensity interval training (HIIT) and medium‐intensity interval training (MIIT) affect neurogenesis in these niches. Wild‐type (WT) and HCA1 knockout (KO) mice were randomized to sedentary, HIIT or MIIT (n = 5–8 per group) for 3 weeks. In the SGZ, HIIT increased the density of doublecortin (DCX)‐positive cells in WT mice by 85% (5.77±1.76 vs. 3.12±1.54 cells/100 µm, P = 0.013) and KO mice (67% increase; 7.91±2.92 vs. 4.73±1.63 cells/100 µm, P = 0.004). MIIT did not alter the density of DCX‐positive cells in either genotype. HIIT increased the density of Ki‐67‐positive cells only in KO mice (P = 0.038), whereas no differences in nestin‐positive cells were observed. In the V‐SVZ, HIIT increased the density of DCX‐positive cells in WT mice by 155% (117.79±39.72 vs. 46.25±19.96 cells/100 µm, P < 0.001) and MIIT increased the density of DCX‐positive cells by 80% (83.26±39.48 vs. 46.25±19.96 cells/100µm, P = 0.027). No exercise‐induced changes were observed in KO mice. Similar patterns were noted for Ki‐67 positive and DCX/Ki‐67 double‐positive cells in the V‐SVZ. These findings suggest that HIIT enhances neurogenesis more robustly than MIIT in both niches, with HCA1 playing a crucial role in V‐SVZ neurogenesis. The neurogenic potential of the brain decreases with age, whereas the risk of neurodegenerative diseases and stroke increases, highlighting a mismatch between neuronal loss and replacement capacity. Exercise enhances neurogenesis in both the subgranular zone and the ventricular‐subventricular zone. High‐intensity interval exercise is more effective than medium‐intensity interval exercise at promoting neurogenesis in both the subgranular zone and the ventricular‐subventricular zone of wild‐type mice. The enhancement of neurogenesis in the ventricular‐subventricular zone is dependent on the activation of the HCA1 receptor, as evidenced by the ability of medium‐ and high‐intensity interval exercise to induce neurogenesis in wild‐type mice and the lack of this effect in HCA1 knockout mice. By contrast, neurogenesis in the subgranular zone is independent on the activation of the HCA1 receptor, highlighting that neurogenesis in the two major neurogenic niches are regulated differently. [ABSTRACT FROM AUTHOR]

Key points We investigated acute effects of the Na+,K+‐ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K+] ([K+]a) and fatigue with intense exercise. In a randomised, crossover, double‐blind design, 10 healthy adults ingested 0.50 mg digoxin (DIG) or placebo (CON) 60 min before cycling for 1 min at 60% V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ then at 95% V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ until fatigue. Pre‐ and post‐exercise muscle biopsies were analysed for [3H]‐ouabain binding site content without (OB‐Fab) and after incubation in digoxin antibody (OB+Fab) and NKA α1‐2 and β1‐2 isoform proteins. In DIG, pre‐exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA–digoxin occupancy was 8.2%. Muscle OB‐Fab did not differ between trials, whereas OB+Fab was higher in DIG than CON (8.1%, treatment main effect, P = 0.001), whilst muscle NKA α1‐2 and β1‐2 abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [−7.7%, 2.90 (0.77) vs. 3.14 (0.86) min, respectively; P = 0.037]. [K+]a increased during exercise until 1 min post‐exercise (P = 0.001), and fell below baseline at 3–10 (P = 0.001) and 20 min post‐exercise (P = 0.022, time main effect). In DIG, [K+]a (P = 0.035, treatment effect) and [K+]a rise pre‐fatigue were greater [1.64 (0.73) vs. 1.55 (0.73), P = 0.016], with lesser post‐exercise [K+]a decline than CON [−2.55 (0.71) vs. −2.74 (0.62) mM, respectively, P = 0.003]. Preserved muscle OB‐Fab with digoxin, yet increased OB+Fab with unchanged NKA isoforms, suggests a rapid regulatory assembly of existing NKA α and β subunits exists to preserve muscle NKA capacity. Nonetheless, functional protection against digoxin was incomplete, with earlier fatigue and perturbed [K+]a with exercise. Intense exercise causes marked potassium (K+) shifts out of contracting muscle cells, which may contribute to muscle fatigue. Muscle and systemic K+ perturbations with exercise are largely regulated by increased activity of Na+,K+‐ATPase in muscle, which can be specifically inhibited by the cardiac glycoside, digoxin. We found that acute oral digoxin in healthy adults reduced time to fatigue during intense exercise, elevated the rise in arterial plasma K+ concentration during exercise and slowed K+ concentration decline post‐exercise. Muscle functional Na+,K+‐ATPase content was not reduced by acute digoxin, despite an 8.2% digoxin occupancy, and was unchanged at fatigue. Muscle Na+,K+‐ATPase isoform protein abundances were unchanged by digoxin or fatigue. These suggest possible rapid assembly of existing subunits into functional pumps. Thus, acute digoxin impaired performance and exacerbated plasma K+ disturbances with intense, fatiguing exercise in healthy participants. These occurred despite the preservation of functional Na+,K+‐ATPase in muscle. [ABSTRACT FROM AUTHOR]

In mammals, early embryonic gastrulation process is high energy demanding. Previous studies showed that, unlike endoderm and mesoderm cells, neuroectoderm differentiated from human embryonic stem cells relied on aerobic glycolysis as the major energy metabolic process, which generates lactate as the final product. Here we explored the function of intracellular lactate during neuroectoderm differentiation. Our results revealed that the intracellular lactate level was elevated in neuroectoderm and exogenous lactate could further promote hESCs differentiation towards neuroectoderm. Changing intracellular lactate levels by sodium lactate or LDHA inhibitors had no obvious effect on BMP or WNT/β-catenin signaling during neuroectoderm differentiation. Notably, histone lactylation, especially H3K18 lactylation was significant upregulated during this process. We further performed CUT&Tag experiments and the results showed that H3K18la is highly enriched at gene promoter regions. By analyzing data from CUT&Tag and RNA-seq experiments, we further identified that four genes, including PAX6, were transcriptionally upregulated by lactate during neuroectoderm differentiation. A H3K18la modification site at PAX6 promoter was verified and exogenous lactate could also rescue the level of PAX6 after shPAX6 inhibition. [ABSTRACT FROM AUTHOR]

Micro-environmental acidity is a common feature of the tumor. One of the causes behind tumor acidity is lactate production by hypoxic cells of the tumor. Hypoxia is a direct result of the establishment of oxygen gradients. It is commonly observed in the tumor in an in vitro experimental setup and also in vivo situation. Here, we propose a mathematical model to analyze the production of lactate by hypoxic cells, and it is used as an alternative fuel by normoxic cells in tumor tissue in vitro and in vivo conditions. Also, we study the effects of unequal oxygen concentrations at the tumor boundaries on lactate status in the tumor. The effects of necrotic core on lactate accumulation is examined. The results are in good agreement with experimental data and are in align with the theoretical findings of previous studies. The analytical results show that lactate levels are elevated in an in vivo tumor compared to that in an in vitro tumor. Also, during the onset of necrotic core formation, the effects of necrotic core on lactate levels are noticed. Knowledge of the lactate status in a patient’s tumor may be helpful in choosing the appropriate and effective medicines for cancer treatment. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion In the setting of trauma and suspected critical bleeding, indications to commence blood transfusions remain unclear, with high rates of potentially avoidable transfusions. Prehospital blood lactate measurements could help predict the need for blood transfusions. The aim of this study was to compare measurements detected by a point‐of‐care (POC) lactate device with laboratory measured lactate levels.This was a cross‐sectional study conducted in the emergency department. Eligible patients were those with suspected major trauma and critical bleeding. Venous or arterial blood samples were collected. POC measurements of lactate levels were conducted using a StatStrip Xpress® lactate meter and compared with laboratory values.Among 70 patients, the mean difference between the POC and laboratory lactate results was −0.19 mmol/L, with limits of agreement at −1.9 and 1.5. Most measurements (n = 66; 94.3%) were within the limits of agreement. A POC lactate level of >3.3 mmol/L had >90% specificity for transfusion, whereas a level <1.4 mmol/L had 90% sensitivity to rule out a transfusion.The level of agreement of POC lactate with the laboratory lactate was high. Research on clinical decision rules for pre‐hospital transfusion that incorporate POC lactate measures is therefore feasible. [ABSTRACT FROM AUTHOR]

Cell competition is an evolutionarily conserved quality control process that eliminates suboptimal or potentially dangerous cells. Although differential metabolic states act as direct drivers of competition, how these are measured across tissues is not understood. Here, we demonstrate that vesicular glutamate transporter (VGlut) and autocrine glutamate signaling are required for cell competition and Myc -driven super-competition in the Drosophila epithelia. We find that the loss of glutamate-stimulated VGlut>NMDAR>CaMKII>CrebB signaling triggers loser status and cell death under competitive settings via the autocrine induction of TNF. This in turn drives TNFR>JNK activation, triggering loser cell elimination and PDK/LDH-dependent metabolic reprogramming. Inhibiting caspases or preventing loser cells from transferring lactate to their neighbors nullifies cell competition. Further, in a Drosophila model for premalignancy, Myc -overexpressing clones co-opt this signaling circuit to acquire super-competitor status. Targeting glutamate signaling converts Myc "super-competitor" clones into "losers," highlighting new therapeutic opportunities to restrict the evolution of fitter clones. [Display omitted] • Glutamate signaling surveys epithelial fitness through cell competition • Loss of glutamate signaling results in autocrine TNF-induced loser elimination • Loser cells undergo metabolic reprogramming and transfer lactate to winners • Mychigh cells promote and depend on glutamate signaling to outcompete neighbors Soares et al. show that differential levels of VGlut>NMDAR>CaMKII-mediated glutamate signaling regulate epithelial fitness, in which loser cells undergo TNF-induced elimination and donate their carbon fuel to winners. Targeting this signaling axis converts Myc super-competitors into losers. [ABSTRACT FROM AUTHOR]

The study aimed to establish the test-retest reliability of detrended fluctuation analysis of heart rate variability (DFA-α1) based exercise intensity thresholds, assess its agreement with ventilatory- and lactate-derived thresholds and the moderating effect of sex and cardiorespiratory fitness (CRF) on the agreement. Intensity thresholds for thirty-seven participants (17 females) based on blood lactate (LT1/LT2), gas-exchange (VT1/VT2) and DFA-α1 (αTh1/αTh2) were assessed. Heart rate (HR) at αTh1 and αTh2 showed good test-retest reliability (coefficient of variation [CV] < 6%), and moderate to high agreement with LTs (r = 0.40 – 0.57) and VTs (r = 0.61 – 0.66) respectively. Mixed effects models indicated bias magnitude depended on CRF, with DFA-α1 overestimating thresholds versus VTs for lower fitness levels (speed at VT1 <8.5 km⋅hr−1), while underestimating for higher fitness levels (speed at VT2 >15 km⋅hr−1; VO2max >55 mL·kg−1·min−1). Controlling for CRF, sex significantly affected bias magnitude only at first threshold, with males having higher mean bias (+2.41 bpm) than females (−1.26 bpm). DFA-α1 thresholds are practical and reliable intensity measures, however it is unclear if they accurately represent LTs/VTs from the observed limits of agreement and unexplained variance. To optimise DFA-α1 threshold estimation across different populations, bias should be corrected based on sex and CRF. [ABSTRACT FROM AUTHOR]

Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival. C. Libert & colleagues provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and of their activities in the context of sepsis. They further discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival. [ABSTRACT FROM AUTHOR]

Introduction: Strength training (ST) is a strategy to enhance quality of life through increased strength, muscle hypertrophy, and functional capacity. Training systems are associated with manipulation of volume and intensity, generating different stimuli, such as Rest-Pause (RP) and Sarcoplasmic Stimulating Training (SST). These systems induce greater mechanical and physiological stress, leading to increased strength and muscle hypertrophy. However, the metabolic and psycho-affective effects of advanced systems in experienced practitioners remain inconclusive. The purpose of the study is to analyze the acute effects of RP, SST, and Traditional (TMS) systems on metabolic and psycho-affective responses in adult men. Methods: This experimental crossover study assessed 15 subjects (30.38 ± 2.06 years; 88.40 ± 6.50 kg; 1.74 ± 0.07 cm) experienced in ST, evaluated under TMS, RP, and SST during flat bench press and leg press 45° exercises. Body composition, muscular strength via 1-RM testing, lactate concentration (LAC), and psycho-affective measures (Rating of Perceived Exertion-RPE; Visual Analog Scale-VAS; Feeling Scale-FS) were determined. Statistical analysis was performed using the Minitab software, with p ≤ 0.05, IC-95%). Results: The finals results showed SST exhibited a 38.10% lower LAC concentration post-training session compared to TMS, while RP showed 37.20% lower LAC concentration than TMS post-session. Average RPE values for RP and SST were higher (8.50 ± 1.10 and 8.60 ± 0.90, respectively) than TMS (6.00 ± 1.10). VAS displayed higher average values for RP and SST (8.00 ± 2.00 and 8.00 ± 1.00, respectively) compared to TMS (5.00 ± 1.00), with affective ratings indicating positive values for TMS and values between 0 and −5 for RP (40%) and SST (60%) post-training sessions, suggesting that RP and SST induced less affective response than TMS. Discussion: The results lead to the conclusion that manipulation of training volume and intensity led to higher RPE and pain (VAS). The data suggest that inappropriate prescription of these systems could lead to greater displeasure, leading us to hypothesize that a higher likelihood of discontinuation from strength training programs would occur, suggesting that greater repetition volumes (RP and SST) should be targeted at individuals with a higher training level. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is a chronic, progressive lung disease characterized by fibroblast proliferation, extensive extracellular matrix and collagen deposition, accompanied by inflammatory damage, ultimately leading to death due to respiratory failure. Endoplasmic reticulum (ER) stress in pulmonary fibrotic tissue is indeed recognized as a significant factor exacerbating PF development. Emerging evidences indicated a potential association between ER stress induced by lactate and cellular apoptosis in PF. However, the mechanisms in this process need further elucidation. In this paper, pulmonary fibrosis model was induced by bleomycin (BLM) intratracheally in mice. In the cellular model, type II epithelial cells were treated by lactate and TGF-β to detect ER stress and apoptosis markers. Lactate could promote ER stress response and apoptosis. Mechanically, lactate activated Caspase-12 via ATF4-Chop axis to induce cell apoptosis and promote fibrosis. ER stress inhibitor could effectively suppress alveolar epithelial cells apoptosis and pulmonary fibrosis. We concluded that pro-fibrotic properties of lactate are associated with alveolar epithelial cells apoptosis by causing ER stress and thus provide new potential therapeutic targets for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

BackgroundAimMethodsResultsConclusionsLactate is a by-product of thiamine-deficient cellular metabolism, and hyperlactataemia can indicate severe illness. However, little is known about the clinical significance of hyperlactataemia in thiamine deficiency disorders.To describe the relationship between whole-blood lactate level and thiamine-responsive disorders (TRDs) in children with signs/symptoms of thiamine deficiency in a high-risk region.This is a secondary analysis of data from the Lao Thiamine study, a prospective cohort study which enrolled hospitalised infants and children (aged 21 days to <18 months) who had at least one sign or symptom suggestive of thiamine deficiency in Lao PDR. Therapeutic thiamine was administered, and clinical evaluations were completed at several time-points over the next 72 h. Three paediatricians reviewed individual case reports to evaluate clinical response to thiamine and assigned TRD status. Data from 402 children were analysed by logistic regression and predictive modelling to examine the relationship between hyperlactataemia and TRDs.Baseline hyperlactataemia (lactate >4.0 mmol/L) was associated with an increased odds of clinical improvement after thiamine administration [OR (95% CI) 2.32 (1.28–4.45), p = 0.007]. Baseline hyperlactataemia was a significant predictor of thiamine deficiency (thiamine diphosphate <40 nmol/L) [area under the receiver operating curve (95% CI) 0.76 (0.67–0.84), p < 0.001], and increased odds of mortality [OR (95% CI) 3.51 (1.38–8.94), p = 0.009].In children with signs/symptoms of thiamine deficiency, hyperlactataemia is associated with a favourable clinical response to thiamine, biochemical thiamine deficiency, and increased odds of mortality. Lactate may be useful in identifying children who might benefit from therapeutic thiamine. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the relationship between serum lactate levels at admission to the intensive care unit (ICU) and the clinical outcomes of children with sepsis. Methods: We used the Pediatric Intensive Care (PIC) database to identify 288 pediatric patients with sepsis. We analyzed the relationship between lactate levels and hospital and ICU mortality in sepsis by establishing a segmented multivariable Cox regression model. We also conducted subgroup analysis as well as analyzed the restricted cubic spline curves. Results: After adjusting for all potential confounding factors, an increase of 1 mmol/L in lactate levels was found to be associated with an 17% rise in the 28-day hospital mortality risk among sepsis patients (HR: 1.17, 95% CI: 1.08–1.27, P = 0.0002). When considering lactate as a categorical variable, the mortality risk of patients with lactate levels ≥ 2.2 mmol/L was significantly increased (HR: 3.61, 95% CI: 1.24–10.54, P = 0.0189). The restricted cubic spline curve analysis revealed a nonlinear correlation between lactate and 28-day mortality, with an inflection point at 2.2 mmol/L. Similar findings were also observed in the assessment of secondary outcomes. Conclusions: Our study demonstrates a non-linear correlation between lactate levels and 28-day mortality in pediatric sepsis, with a critical threshold of 2.2mmol/l for lactate levels in septic patients. Early assessment of lactate levels is recommended for children with sepsis to facilitate prompt intervention and mitigate the risk of fatality. [ABSTRACT FROM AUTHOR]

Lactylation, a novel discovered posttranslational modification, is a vital component of lactate function and is prevalent in a wide range of cells, interacting with both histone and non-histone proteins. Recent studies have confirmed that lactylation as a new contributor to epigenetic landscape is involved in multiple pathological processes. Accumulating evidence reveals that lactylation exists in different pathophysiological states and leads to inflammation and cancer; however, few mechanisms of lactylation have been elaborated. This review summarizes the biological processes and pathophysiological roles of lactylation in cancer, as well as discusses the relevant mechanisms and potential therapeutic targets, aiming to provide new insights for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores Warburg's paradox, whereby cancer cells use both glucose and oxygen to survive, even though glucose is converted to lactate instead of being oxidized. By systematically investigating cellular metabolism during each phase of cell division and comparing the metabolic profiles of lymphoma cells and non-malignant lymphocytes, we discovered that pyruvate, the end-product of glucose metabolism, is converted into alanine. This conversion directs glutamine carbon, rather than glucose, into the TCA cycle. Furthermore, using fludarabine to selectively inhibit lymphoma cell proliferation, we showed that blocking the conversion of pyruvate to alanine disrupts the TCA cycle and interferes with the supply of nucleotides and the energy necessary for cancer cell growth. Our findings suggest that with the suppression of glucose oxidation, the conversion of pyruvate to alanine is the crucial metabolic link that connects glucose and oxygen metabolism and serves as a key component of Warburg's paradox. Background/Objectives: Warburg's metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg's paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6, 15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg's paradox and lymphomagenesis. [ABSTRACT FROM AUTHOR]

Independent risk factors for sepsis‐associated acute kidney injury (S‐AKI) patients include elevated lactate levels, but the specific mechanism remains unclear. Recently, An et al. discovered that excessive acetylation and inactivation of PDHA1 lead to overproduction of lactate, resulting in mitochondrial fragmentation, ATP depletion, excessive mtROS production, and mitochondrial apoptosis, thereby exacerbating AKI in sepsis. Therefore, understanding the pathophysiological processes of mitochondrial function and lactate generation in SAKI is essential and can aid in the development of novel therapeutic strategies. This review elucidates the pathological mechanisms of mitochondrial autophagy and dynamics in AKI. We also discuss the sources of lactate in SAKI and some consequences of lactonization, which may provide new strategies for improving renal injury and delaying the progression of these diseases. [ABSTRACT FROM AUTHOR]

Nutrition is largely affected in bipolar disorder (BD), however, there is a lack of understanding on the relationship between dietary categories, BD, and the prevalence of metabolic syndrome. The objective of this study is to examine dietary trends in BD and it is hypothesized that diets with increased consumption of seafood and high-fiber carbohydrates will be correlated to improved patient outcomes, and a lower frequency of metabolic syndrome. This retrospective cohort study includes two French cohorts. The primary cohort, FACE-BD, includes 268 stable BD patients. The second cohort, I-GIVE, includes healthy controls, both stable and acute BD and schizophrenia patients. Four dietary categories were assessed: meat, seafood, low-fiber and high-fiber carbohydrates. Dietary data from two food frequency questionnaires were normalized using min-max scaling and assessed using various statistical analyses. In our primary cohort, the increased high-fiber carbohydrate consumption was correlated to lower prevalence of metabolic syndrome and improved mood. Low-fiber carbohydrate consumption is associated with higher BMI, while higher seafood consumption was correlated to improved mood and delayed age of onset. Results were not replicated in our secondary cohort. Limitations: Our populations were small and two different dietary questionnaires were used; thus, results were used to examine similarities in trends. Overall, various dietary trends were associated with metabolic syndrome, BMI, lactate, mood and age of onset. Improving our understanding of nutrition in BD can provide mechanistic insight, clinically relevant nutritional guidelines for precision medicine and ultimately improve the quality of lives for those with BD. • Food frequency questionnaires evaluated in 2 French cohorts of Bipolar patients. • Various statistical analyses utilized to assess dietary trends in bipolar disorder. • Seafood consumption was associated with mood and age of disease onset. • High fiber carbohydrates consumption decreases prevalence of metabolic syndrome. • Low-fiber carbohydrate consumption was associated with higher Body Mass Index. [ABSTRACT FROM AUTHOR]

Bone malunion or nonunion leads to functional and esthetic problems and is a major healthcare burden. Activation of bone marrow mesenchymal stem cells (BMSCs) and subsequent induction of osteogenic differentiation by local metabolites are crucial steps for bone healing, which has not yet been completely investigated. Here, we found that lactate levels are rapidly increased at the local injury site during the early phase of bone defect healing, which facilitates the healing process by enhancing BMSCs regenerative capacity. Mechanistically, lactate serves as a ligand for the Olfr1440 olfactory receptor, to trigger an intracellular calcium influx that in turn activates osteogenic phenotype transition of BMSCs. Conversely, ablation of Olfr1440 delays skeletal repair and remodelling, as evidenced by thinner cortical bone and less woven bone formation in vivo. Administration of lactate in the defect area enhanced bone regeneration. These findings thus revealed the key roles of lactate in the osteogenic differentiation of BMSCs, which deepened our understanding of the bone healing process, as well as provided cues for a potential therapeutic option that might greatly improve bone defect treatment. [ABSTRACT FROM AUTHOR]

Conjunctival melanoma (CoM) is a rare but potentially lethal cancer of the eye, with limited therapeutic option for metastases. A better understanding how primary CoM disseminate to form metastases is urgently needed in order to develop novel therapies. Previous studies indicated that primary CoM tumors express Vascular Endothelial Growth Factor (VEGF) and may recruit pro-tumorigenic M2-like macrophages. However, due to a lack of proper models, the expected role of angiogenesis in the metastatic dissemination of CoM is still unknown. We show that cells derived from two CoM cell lines induce a strong angiogenic response when xenografted in zebrafish larvae. CoM cells are highly glycolytic and secrete lactate, which recruits and polarizes human and zebrafish macrophages towards a M2-like phenotype. These macrophages elevate the levels of proangiogenic factors such as VEGF, TGF-β, and IL-10 in the tumor microenvironment to induce an angiogenic response towards the engrafted CoM cells in vivo. Chemical ablation of zebrafish macrophages or inhibition of glycolysis in CoM cells terminates this response, suggesting that attraction of lactate-dependent macrophages into engrafted CoM cells drives angiogenesis and serves as a possible dissemination mechanism for glycolytic CoM cells. [ABSTRACT FROM AUTHOR]

Background: Lactate is a commonly used biomarker for sepsis, although it has limitations in certain cases, suggesting the need for novel biomarkers. We evaluated the diagnostic accuracy of plasma renin concentration and renin activity for mortality and kidney outcomes in patients with sepsis with hypoperfusion or hypotension. Methods: This was a multicenter, prospective, observational study of 117 patients with septic shock treated at three tertiary emergency departments between September 2021 and October 2022. The accuracy of renin activity, renin, and lactate concentrations in predicting 28-day mortality, acute kidney injury (AKI), and renal replacement requirement was assessed using the area under the ROC curve (AUC) analysis. Results: The AUCs of initial renin activity, renin, and lactate concentrations for predicting 28-day mortality were 0.66 (95% confidence interval [CI], 0.55–0.77), 0.63 (95% CI, 0.52–0.75), and 0.65 (95% CI, 0.53–0.77), respectively, and those at 24 hrs were 0.74 (95% CI, 0.62–0.86), 0.70 (95% CI, 0.56–0.83), and 0.67 (95% CI, 0.54–0.79). Renin concentrations and renin activity outperformed initial lactate concentrations in predicting AKI within 14 days. The AUCs of renin and lactate concentrations were 0.71 (95% CI, 0.61–0.80) and 0.57 (95% CI, 0.46–0.67), respectively (P =0.030). The AUC of renin activity (0.70; 95% CI, 0.60–0.80) was also higher than that of lactate concentration (P =0.044). Conclusions: Renin concentration and renin activity show comparable performance to lactate concentration in predicting 28-day mortality in patients with septic shock but superior performance in predicting AKI. [ABSTRACT FROM AUTHOR]

Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Metabolic rewiring of cancer cells is one of the hallmarks of cancer. As a consequence, the metabolic landscape of the tumour microenvironment (TME) differs compared to correspondent healthy tissues. Indeed, due to the accumulation of acid metabolites, such as lactate, the pH of the TME is generally acidic with a pH drop that can be as low as 5.6. Disruptions in the acid-base balance and elevated lactate levels can drive malignant progression not only through cell-intrinsic mechanisms but also by impacting the immune response. Generally, acidity and lactate dampen the anti-tumour response of both innate and adaptive immune cells favouring tumour progression and reducing the response to immunotherapy. In this review, we summarize the current knowledge on the functional, metabolic and epigenetic effects of acidity and lactate on the cells of the immune system. In particular, we focus on the role of monocarboxylate transporters (MCTs) and other solute carrier transporters (SLCs) that, by mediating the exchange of lactate (among other metabolites) and bicarbonate, participate in pH regulation and lactate transport in the cancer context. Finally, we discuss advanced approaches to target pH or lactate in the TME to enhance the anti-tumour immune response. [ABSTRACT FROM AUTHOR]

Introduction: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been established as an effective treatment for peritoneal cancer (PC). However, this kind of combination therapy is associated with a high lactate level. Moreover, studies have suggested that the rate of complications early after surgery directly increased with elevated lactate levels. Glucose-insulin-potassium (GIP), a potent cardioprotective intervention, has been demonstrated to adjust blood glucose (BG) levels and reduce lactate levels. However, the insulin-glucose ratio should be adjusted according to the surgery performed. Here, we aimed to evaluate the advantages of using modified GIP during CRS/HIPEC to reduce the lactate level at the end of surgery and further reduce the incidence of early postoperative complications. Methods and analysis: The modified GIP versus conventional management during surgery study is a single-center, randomized, single-blinded outcome assessment clinical trial of 80 patients with PC who are between 18 and 64 years old and undergoing CRS/HIPEC. Participants will be randomly allocated to receive modified GIP or conventional treatment (1:1). The primary outcome will be the plasma lactate level at the end of surgery. The secondary outcomes will include the highest levels and fluctuation ranges of lactate and BG during surgery, extubation time, APACHE-II score 24 h after surgery, postoperative defecation and exhaust time, postoperative lactate clearance time, postoperative liver and kidney function, incidence of complications within 7 days after surgery, length of intensive care unit stay (LIS), length of hospital stay (LHS), and total cost of hospitalization. Ethics and dissemination: The trial protocol was approved by the Scientific Research Ethics Committee of Beijing Shijitan Hospital Affiliated with Capital Medical University, approval number sjtky11-1x-2022(118). The results will be published in international peer-reviewed journals. Trial registration: ChiCTR2200057258. Registered on March 5, 2022. [ABSTRACT FROM AUTHOR]

Introduction: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor. Methods: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors. Results: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs. Conclusions: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma. [ABSTRACT FROM AUTHOR]

During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting. [ABSTRACT FROM AUTHOR]

Hyperlactatemia is common during tumor craniotomy, but the underlying pathophysiology is unclear. This study measured simultaneous arterial and jugular‐bulb lactate concentrations in patients undergoing brain tumor craniotomy to investigate the hypothesis that hyperlactatemia was associated with a net cerebrovascular lactate input. In 20 patients, arterial and jugular‐bulb blood was collected hourly from the start of surgery to 6 h postoperatively for measurement of lactate, glucose, and oxygen concentration. For each marker, data were analyzed using a linear mixed‐effects model with jugular‐bulb concentration as dependent variable, arterial concentration as fixed effect, and patient as random effect. Furthermore, we generated regression lines between arterial and jugular‐bulb concentrations. The slope of the regression line between arterial and jugular‐bulb lactate was 0.95 (95% CI 0.93–0.97, R2 = 0.98), indicating that increasing arterial lactate levels were associated with an increasingly positive net cerebrovascular balance (net input). The line crossed the identity line at 2.86 (95% CI 0.57–5.16) mmol/L, indicating that lower levels of lactate were associated with a negative net cerebrovascular balance (net output). This suggests a switch from net lactate output during normolactatemia towards net input during hyperlactatemia. Hyperlactatemia in tumor‐craniotomy patients probably does not originate from the brain. [ABSTRACT FROM AUTHOR]

Today, the intratumoral composition is a relevant factor associated with the progression and aggression of cancer. Although it suggests a metabolic interdependence among the subpopulations inside the tumor, a detailed map of how this interdependence contributes to the malignant phenotype is still lacking. To address this issue, we developed a systems biology approach integrating single-cell RNASeq and genome-scale metabolic reconstruction to map the metabolic cross-feeding among the subpopulations previously identified in the spheroids of MCF7 breast cancer. By calibrating our model with expression profiles and the experimental growth rate, we concluded that the reverse Warburg effect emerges as a mechanism to optimize community growth. Furthermore, through an in silico analysis, we identified lactate, alpha-ketoglutarate, and some amino acids as key metabolites whose disponibility alters the growth rate of the spheroid. Altogether, this work provides a strategy for assessing how space and intratumoral heterogeneity influence the metabolic robustness of cancer, issues suggesting that computational strategies should move toward the design of optimized treatments. [ABSTRACT FROM AUTHOR]

The accumulation and aggregation of beta‐amyloid (Aβ) peptides contributes to neuronal dysfunction and death. These Aβ peptides originate from a transmembrane protein known as amyloid precursor protein (APP), which can be processed via two competing pathways. Alpha‐secretase (ADAM10) cleavage is thought to be neuroprotective while beta‐secretase (BACE1) cleavage results in the production of Aβ. Aerobic exercise reduces BACE1 activity, but the mechanisms involved are unknown though several exercise‐induced mediators such as lactate may be involved. The current study examined whether systemic lactate can alter APP processing and BACE1 and ADAM10 activity. Mice were randomly assigned to one of four groups (n = 10 per group): (1) sedentary; (2) lactate‐injection (1.0 g kg−1 body mass); (3) exercise; and (4) exercise and oxamate (lactate dehydrogenase inhibitor; 750 mg kg−1 body mass). Two hours following intervention, the hippocampus and prefrontal cortex (PFC) were collected. In the PFC lactate‐injection and exercise resulted in higher ADAM10 activity compared to sedentary (exercise P = 0.0215, lactate P = 0.0038), in the hippocampus lactate‐injection was higher compared to sedentary (lactate P = 0.011), and this was absent in the presence of oxamate. Hippocampal BACE1 activity was lower in the lactate group compared to the exercise group (P = 0.01). Oxamate resulted in higher BACE1 protein content compared to sedentary in the PFC (vs. sedentary P = 0.048). These findings suggest that lactate is important for regulating ADAM10 activity and thereby shifts APP processing away from Aβ production. Key points: Exercise is known to alter the processing of amyloid precursor protein by reducing the activity of the rate‐limiting enzyme BACE1 and increasing the activity of ADAM10.It is thought that exercise‐induced factors are responsible for these enzymatic changes.This study examined if lactate accumulation plays a role in this process.Mice were assigned to one of four groups: sedentary, lactate, exercise and exercise + lactate.The findings demonstrate that lactate accumulation alters brain BACE1 and ADAM10 and shifts amyloid precursor protein processing away from beta‐amyloid production. [ABSTRACT FROM AUTHOR]

In cardiogenic shock, biomarkers should ideally help make the diagnosis, choose the right therapeutic options and monitor the patient in addition to clinical and echocardiographic indices. Among "old" biomarkers that have been used for decades, lactate detects, quantifies, and follows anaerobic metabolism, despite its lack of specificity. Renal and liver biomarkers are indispensable for detecting the effect of shock on organ function and are highly predictive of poor outcomes. Direct biomarkers of cardiac damage such as cardiac troponins, B-type natriuretic and N-terminal pro-B-type natriuretic peptides have a good prognostic value, but they lack specificity to detect a cardiogenic cause of shock, as many factors influence their plasma concentrations in critically ill patients. Among the biomarkers that have been more recently described, dipeptidyl peptidase-3 is one of the most interesting. In addition to its prognostic value, it could represent a therapeutic target in cardiogenic shock in the future as a specific antibody inhibits its activity. Adrenomedullin is a small peptide hormone secreted by various tissues, including vascular smooth muscle cells and endothelium, particularly under pathological conditions. It has a vasodilator effect and has prognostic value during cardiogenic shock. An antibody inhibits its activity and so adrenomedullin could represent a therapeutic target in cardiogenic shock. An increasing number of inflammatory biomarkers are also of proven prognostic value in cardiogenic shock, reflecting the inflammatory reaction associated with the syndrome. Some of them are combined to form prognostic proteomic scores. Alongside clinical variables, biomarkers can be used to establish biological "signatures" characteristic of the pathophysiological pathways involved in cardiogenic shock. This helps describe patient subphenotypes, which could in the future be used in clinical trials to define patient populations responding specifically to a treatment. [ABSTRACT FROM AUTHOR]

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

Accurate monitoring tools are necessary for lactate, a critical biomarker linked to anaerobic metabolism and muscular performance. Lactate dehydrogenase (LDH) immobilized on MXene (Ti 3 C 2 T x)-supported CuO nanocomposites (MCNs) modified glassy carbon electrode (LDH/MCN/GCE) is the innovative electrochemical biosensor for lactate detection presented in this work. CuO nanostructure integration onto MXene nanosheets, MCN production, and LDH immobilization were all successfully accomplished, according to structural characterization performed using XRD, SEM, XPS, and FTIR. The best lactate oxidation current was shown by LDH/MCN/GCE, according to electrochemical study. With a low detection limit of 0.25 µM and a high sensitivity of 5.92107 µA/mM, the biosensor exhibited a linear response range of 0.1–121 mM. The remarkable selectivity, stability, and sensitivity were attributed to enhanced LDH immobilization made possible by MCNs and MXene. The promise of LDH/MCN/GCE for bioanalytical applications is highlighted by promising results from practical testing in human blood samples, opening the door for improvements in lactate monitoring and performance optimization techniques. [ABSTRACT FROM AUTHOR]

Sepsis and septic shock remain global healthcare problems associated with high mortality rates despite best therapy efforts. Circulating biomarkers may identify those patients at risk for poor outcomes, however, current biomarkers, most prominently lactate, are non-specific and have an inconsistent impact on prognosis and/or disease management. Activation of the renin-angiotensin- system (RAS) is an early event in sepsis patients and elevated levels of circulating renin are more predictive of worse outcomes than lactate. The precursor protein Angiotensinogen is another key component of the circulating RAS; it is the only known substrate for renin and the ultimate source of the vasopressor Angiotensin II (Ang II). We postulate that lower Angiotensinogen concentrations may reflect a dysfunctional RAS characterized by high renin concentrations but attenuated Ang II generation, which is disproportionate to the high renin response and may compromise adequate support of blood pressure and tissue perfusion in septic patients. The current study compared the association between serum Angiotensinogen with mortality to that of lactate and renin in the VICTAS cohort of sepsis patients at baseline (day 0) by receiver operating characteristic (ROC) and Kaplan–Meier curve analyses. Serum concentration of Angiotensinogen was more strongly associated with 30-day mortality than either the serum concentrations of renin or lactate in sepsis patients. Moreover, the clinical assessment of Angiotensinogen may have distinct advantages over the typical measures of renin. The assessment of intact Angiotensinogen may potentially facilitate more precise therapeutic approaches (including exogenous angiotensin II) to restore a dysfunctional RAS and improve patient outcomes. Additional prospective validation studies are clearly required for this biomarker in the future. [ABSTRACT FROM AUTHOR]

In recent years, continuous exploration worldwide has revealed that some metabolites produced during cellular and tissue metabolism can act as signalling molecules to exert different effects on the human body. These metabolites may act as cofactors for proteases or as post‐translational modifications linked to proteins. Lactate, a traditional metabolite, is found at high levels in the tumour microenvironment (TME). Many studies have shown that lactate influences tumorigenesis and development via different mechanisms, not only through the metabolic reprogramming of tumours but also through its significant impact on tumour immunity. Previously, tumour cells were reported to use glucose and glutamine to fuel lactate metabolism; however, lactate serves not only as an energy source for tumour cells but also as a precursor substance needed for the post‐translational modification of proteins. Recent studies identified a novel form of epigenetic modification, lactate‐mediated histone lysine lactylation (Kla) and demonstrated that histone lactylation directly stimulates chromatin after gene transcription; consequently, lactylation has become a popular research topic in recent years. This article focuses on the research progress and application prospects of lactylation in the context of tumour immunity. [ABSTRACT FROM AUTHOR]

The reliable monitoring of metabolites in biofluids plays a pivotal role in the diagnosis, treatment, and long-term management of various diseases. Surface-enhanced Raman spectroscopy (SERS) is considered a promising tool for metabolite detection because of its unique advantages for detecting trace amounts of chemical and biological molecules without requiring extensive sample preprocessing. In this study, a SERS sensor is proposed, utilizing silver nanoshells in cooperation with enzymes and 4-mercaptobenzoic acid (4-MBA) as a bifunctional molecule, to monitor two distinct biological metabolites, lactate and cholesterol, at their respective levels. In our method, the enzymatic reactions between oxidases and their specific metabolites initiate a domino reaction, resulting in significant changes in the SERS signal of 4-MBA. Through systematic sensor optimization, the quantification of lactate (1.0 × 10–1 to 1.0 × 10–7 M) and cholesterol (1.0 × 10–2 to 1.0 × 10–6 M) in a buffer solution was successfully achieved using the SERS intensity as an indicator. The limits of detection for lactate and cholesterol were estimated to be 2.7 × 10–7 and 1.0 × 10–8 M, respectively. Our proposed SERS sensor precisely detected lactate concentrations in serum samples, with a high accuracy of over 91%, demonstrating high selectivity for compounds with similar structures and serum constituents. Our SERS sensor platform can be utilized as an efficient and versatile tool for measuring lactate concentrations in serum samples and is expected to have the potential to advance personalized healthcare solutions through rapid point-of-care testing. [ABSTRACT FROM AUTHOR]

Aims Extracts of fermented feed obtained via fermentation of marine animal resources with thermophilic Bacillaceae bacteria increase the fecundity of livestock. The intestinal bacterial profiles in response to long-term administration of this extract to pigs were investigated. Methods and results Half of a swine farm was supplied with potable water containing an extract of fermented feed for more than 2 years, whereas the other half was supplied with potable water without the extract. Feces from 6-month-old pigs rearing in these two areas were collected. 16S rRNA gene sequencing and isolation of lactic acid bacteria revealed an increase in the D/L-lactate-producing bacterium, Lactobacillus amylovorus , and a decrease in several members of Clostridiales following administration of fermented feed. A lactate-utilizing bacterium, Megasphaera elsdenii , was more abundant in the feces of pigs in the fermented feed group. All representative isolates of M. elsdenii showed rapid utilization of D-lactate relative to L-lactate, and butyrate and valerate were the main products. Conclusion The probiotic effect of fermented feed is associated with the modulation of lactate metabolism in the digestive organs of pigs. [ABSTRACT FROM AUTHOR]

Background & Objective: Pre-emptively identifying individuals at risk of developing sepsis and septic shock remains challenging. In septic patients, the Lactate/Albumin Ratio (LAR) and C-reactive protein (CRP)/Albumin ratio (CAR) have been suggested to be promising prognostic indicators for prediction of intensive care unit (ICU) mortality. We compared the prognostic values of CAR and LAR in patients with sepsis and septic shock. Methodology: Eighty adult patients diagnosed with sepsis and admitted to the ICUs of Ain Shams University Hospitals, were included in this observational prospective study. CRP levels, serum lactate, serum albumin, complete blood count (CBC), procalcitonin levels, and SOFA scores were assessed upon admission, with subsequently observing 28-day mortality among the selected patients. Results: CAR values were comparable between the mortality and survival groups (P = 0.807). However, LAR values were significantly elevated in the mortality group vs the survival group (P = 0.044). ROC analysis for mortality indicated that LAR had an AUC of 0.633 at a cutoff value > 0.68, achieving sensitivity and specificity of 89.4% and 21.2%, respectively. In contrast, CAR had an AUC of 0.484 at a cutoff value ≥ 1.54, with sensitivity and specificity values of 63.8% and 57.6%, respectively. Length of ICU stay (P < 0.001), duration of mechanical ventilation (P < 0.001), cardiovascular support (P < 0.001) and the need for renal replacement therapy (P < 0. 039), were increased in the mortality group compared to the survival group. Conclusion: Lactate/albumin ratio is superior and more reliable bio-marker predictor compared to C-reactive protein (CRP)/albumin ratio for ICU mortality. [ABSTRACT FROM AUTHOR]

OBJECTIVES: It is crucial to promptly identify high-mortality patients in emergency departments and initiate their treatment as soon as possible. Although many parameters have been studied to select patients with high mortality, no comprehensive evaluation exists in previous literature on these parameters in critically ill patients, regardless of patient groups. The aim of this study is to evaluate the Glasgow Coma Scale (GCS), quick Sepsis-related Organ Failure Assessment (qSOFA), blood gas base excess (BE), and blood gas lactate in predicting mortality in critically ill patients admitted to the emergency department. METHODS: This prospective observational cohort study included adult patients with Emergency Severity Index 1-2 (critically ill) admitted to the emergency department. All patients were evaluated by the physician within 10 min, and blood gas samples were taken. The data collection forms recorded the patients' GCS and qSOFA scores at the time of first evaluation by the physician. The qSOFA score assessment was performed in all patients with ESI levels 1 and 2, regardless of whether infective pathology was suspected. Blood gas BE and lactate values were also from laboratory test results. Patients or their relatives were contacted by phone at the end of the 1st month to obtain information about the clinical condition (survival or mortality). RESULTS: A total of 868 patients were included, with 163 deaths observed within 30 days. GCS score, qSOFA score, and lactate value were significant in predicting mortality within 30 days. While the BE value was significant for predicting 30-day mortality for values equal to or below the lower limit of -1.5 (P < 0.001), it was not significant for values equal to or above the upper limit of +3 (P > 0.05). The most successful prediction model for predicting 30-day mortality was found to be qSOFA with a cutoff value of ≥1. CONCLUSION: In emergency departments, each of the GCS, qSOFA scores, BE, and lactate values can be used independently as a practical mortality prediction model in critically ill patients. Among these four models, qSOFA is the most successful practical mortality prediction model in critically ill patients. [ABSTRACT FROM AUTHOR]

Lactate accumulation and macrophage infiltration are pivotal features of both chronic inflammation and cancer. Lactate, once regarded merely as an aftereffect of glucose metabolism, is now gaining recognition for its burgeoning spectrum of biological roles and immunomodulatory significance. Recent studies have evidenced that macrophages display divergent immunophenotypes in different diseases, which play a pivotal role in disease management by modulating macrophage polarization within the disease microenvironment. The specific polarization patterns of macrophages in a high-lactate environment and their contribution to the progression of chronic inflammation and cancer remain contentious. This review presents current evidence on the crosstalk of lactate and macrophage in chronic inflammation and cancer. Additionally, we provide an in-depth exploration of the pivotal yet enigmatic mechanisms through which lactate orchestrates disease pathogenesis, thereby offering novel perspectives to the development of targeted therapeutic interventions for chronic inflammation and cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Low rumen pH is proposed to be a major mechanism for low methane (CH4) emissions from sheep fed forage rape. However, it is difficult to separate this from other in vivo factors, such as rumen passage rate. The objective of this study was to determine the effect of pH alone on CH4 production in vitro using different pH buffers. Ryegrass, white clover and forage rape were incubated in vitro using three different incubation buffers with starting pH values of 5.5, 6.2 and 6.8. RESULTS: Decreasing pH reduced overall in vitro CH4 emission relative to fermented hexoses (CH4/FHex) by up to 54% and overall fermentation by 40%. pH also changed fermentation profiles where the acetate + butyrate to propionate + valerate ratio decreased when pH decreased. Within the three forages, forage rape led to the lowest CH4/FHex, but only in pH 5.5 and 6.2 buffer, and this was enhanced when the pH fell below 6. CONCLUSION: Reducing pH in vitro decreased CH4 production and overall fermentation across all forages. The lower pH reached by forage rape compared to ryegrass and white clover appears to drive the lower CH4 production relative to the extent of fermentation from forage rape compared to the other forages. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the acute metabolic response, neuromuscular activity, and mechanical performance of different set configurations in bench-press (BP). Twenty-two resistance-trained men performed three resistance exercise protocols consisting of 3 x 12 BP repetitions at 60% 1RM, with 4 minutes of rest between sets, but with different set configurations: (a) traditional set (TS), without rest within the set; (b) cluster-6 (CS6), with 30-second intraset rest after the sixth repetition in each set; and (c) cluster-2 (CS2), with 30-second intraset rest every two repetitions. Mean propulsive force (MPF), velocity (MPV), power (MPP), and electromyography (EMG) values were recorded for each repetition. Blood lactate, maximal voluntary isometric BP contraction, and dynamic strength in BP were assessed pre- and post-exercise. The CS2 protocol resulted in greater mechanical performance (i. e. MPF, MPV, and MPP) and lower alterations of EMG parameters (i. e. root mean square and median frequency) during the exercise compared to CS6 and TS (TS

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (T reg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral T reg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nT reg cells, but not iT reg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nT reg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nT reg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nT reg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nT reg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nT reg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nT reg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion. • Acidity enhances T reg cell suppressive functions independent of lactate in vitro and in vivo. • T reg cell oxidative metabolic capacity increases as a result of exposure to acidity. • Treatment with acidity results in T reg cell transcriptional and metabolic changes in one-carbon folate metabolism. • Exposure to acidity ex vivo for 48 hours facilitates increased T reg suppressive functions against T eff cells in the TME and promotes tumor growth in the MC38 colon cancer model. • Treatment of T reg cells with acidity and formate restores suppressive capacity induced by acidity and decreases tumor burden in the MC38 colon cancer model. [ABSTRACT FROM AUTHOR]

Basic biochemical tests are frequently obtained in acutely unwell neonates and children, as well as in some elective situations. Correct interpretation is essential in identifying rare inherited primary metabolic disorders, but secondary causes of hyperammonaemia, elevated blood lactate or acid-base derangement are more common and require appropriate treatment of the underlying cause. Ammonia is the waste product of protein metabolism and is highly toxic. Ammonia should be measured in any sick neonate, and in children with unexplained encephalopathy. Further testing is needed to determine if it is secondary to other factors, or due to a primary metabolic disorder affecting urea cycle function. Specific treatment should be instigated urgently to avoid long term neurological sequelae. Lactate elevation indicates anaerobic respiration and is often secondary to hypoxia or poor tissue perfusion but can indicate a metabolic disorder affecting mitochondrial function or energy metabolism. Blood gas analysis to review acid-base status is a critical test in any sick neonate or child, and correct interpretation will indicate if there is a respiratory or metabolic basis. A metabolic acidosis with elevated anion gap may indicate a primary metabolic disorder. These tests can help identify patients who may have a primary metabolic disorder, and management should be discussed urgently with a specialist metabolic centre. [ABSTRACT FROM AUTHOR]

Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non‐cardiac dyspnoea (NCD), and healthy volunteers. Methods and results: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom‐limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31–73), 150 W (125–175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05–0.11), 0.06 mmol/L/W (0.05–0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03–0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m2 (3.7–5.5) in HFpEF, 5.2 L/min/m2 (4.3–6.2; P < 0.001) in NCD, and 9.1 L/min/m2 (8.0–9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175–1986) vs. 1758 mL/min (1361–2282; P = 0.024) in NCD and 3117 mL/min (2667–3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). Conclusions: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies. [ABSTRACT FROM AUTHOR]

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Background: Chronic diarrhea is a common cause of mortality and morbidity in captive rhesus macaques (Macaca mulatta). The exact etiology of chronic diarrhea in macaques remains unidentified. The occurrence of diarrhea is frequently linked to dysbiosis within the gut microbiome. Research into microbiome signatures correlated with diarrhea in macaques have predominantly been conducted with single sample collections. Our analysis was based on the metagenomic composition of longitudinally acquired fecal samples from rhesus macaques with chronic diarrhea and clinically healthy rhesus macaques that were obtained over the course of two years. We aimed to investigate potential relationships between the macaque gut microbiome, the presence of diarrhea and diet interventions with a selection of commercially available monkey diets. Results: The microbiome signature of macaques with intermittent chronic diarrhea showed a significant increase in lactate producing bacteria e.g. lactobacilli, and an increase in fermenters of lactate and succinate. Strikingly, two lactose free diets were associated with a lower incidence of diarrhea. Conclusion: A lactose intolerance mechanism is suggested in these animals by the bloom of Lactobacillus in the presence of lactose resulting in an overproduction of intermediate fermentation products likely led to osmotically induced diarrhea. This study provides new insights into suspected microbiome-lactose intolerance relationship in rhesus macaques with intermittent chronic diarrhea. The integration of machine learning with metagenomic data analysis holds potential for developing targeted dietary interventions and therapeutic strategies and therefore ensuring a healthier and more resilient primate population. [ABSTRACT FROM AUTHOR]

Regulatory cell death is an important way to eliminate the DNA damage that accompanies the rapid proliferation of neural stem cells during cortical development, including pyroptosis, apoptosis, and so on. Here, the study reports that the absence of GSDMD‐mediated pyroptosis results in defective DNA damage sensor pathways accompanied by aberrant neurogenesis and autism‐like behaviors in adult mice. Furthermore, GSDMD is involved in organizing the mitochondrial electron transport chain by regulating the AMPK/PGC‐1α pathway to target Aifm3. This process promotes a switch from oxidative phosphorylation to glycolysis. The perturbation of metabolic homeostasis in neural progenitor cells increases lactate production which acts as a signaling molecule to regulate the p38MAPK pathway. And activates NF‐휿B transcription to disrupt cortex development. This abnormal proliferation of neural progenitor cells can be rescued by inhibiting glycolysis and lactate production. Taken together, the study proposes a metabolic axis regulated by GSDMD that links pyroptosis with metabolic reprogramming. It provides a flexible perspective for the treatment of neurological disorders caused by genotoxic stress and neurodevelopmental disorders such as autism. [ABSTRACT FROM AUTHOR]