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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]

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]

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]

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]

Cardiovascular disease (CVD) is the leading cause of death worldwide. Physical activity interventions improve almost all modifiable CVD risk factors, but the effect of physical activity on low density lipoprotein cholesterol (LDL‐C) is uncertain. This may be due to lack of research on the feeding status in which the physical activity is performed. The aim of this study is to investigate the effect of fasted versus fed exercise on LDL‐C concentrations in males and females. One hundred healthy participants, equal males and females, aged between 25 and 60 years will be recruited and will undergo a home‐based 12‐week exercise intervention. After baseline testing, participants will be randomized to a fasted exercise (exercise after an 8‐h fast) or fed exercise (exercise 90–180 min after ingestion of 1 g kg−1 CHO) group and will perform 50 min of moderate intensity exercise (e.g., 95% heart rate of lactate threshold 1) three times a week either before or after a high carbohydrate (1 g kg−1) meal. Participants will visit the laboratory again at week 4 and week 12 and measurements will be taken for body composition, resting blood pressure, fasting blood glucose, lipid profiles and systemic inflammation, lactate threshold, and 14‐day blood glucose control. [ABSTRACT FROM AUTHOR]

Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material‐engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material‐enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin‐like catalysts of the encapsulated Gd‐doped CeO2, syrosingopine, and lactate oxidase are used in ZIF‐8 (USL, where U, S, and L represent the urchin‐like Gd‐doped CeO2@ZIF‐8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ‐generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1‐polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material‐interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

Lactate is a metabolic product of glycolysis and has recently been shown to act as a signaling molecule that induces adaptations in oxidative metabolism. In this study, we investigated whether lactate administration enhanced muscle hypertrophy and protein synthesis responses during resistance exercise in animal models. We used male ICR mice (7–8 weeks old) were used for chronic (mechanical overload induced by synergist ablation: [OL]) and acute (high‐intensity muscle contraction by electrical stimulation: [ES]) resistance exercise models. The animals were intraperitoneally administrated a single dose of sodium lactate (1 g/kg of body weight) in the ES study, and once a day for 14 consecutive days in the OL study. Two weeks of mechanical overload increased plantaris muscle wet weight (main effect of OL: p < 0.05) and fiber cross‐sectional area (main effect of OL: p < 0.05), but those were not affected by lactate administration. Following the acute resistance exercise by ES, protein synthesis and phosphorylation of p70 S6 kinase and ribosomal protein S6, which are downstream molecules in the anabolic signaling cascade, were increased (main effect of ES: p < 0.05), but lactate administration had no effect. This study demonstrated that exogenous lactate administration has little effect on the muscle hypertrophic response during resistance exercise using acute ES and chronic OL models. Our results do not support the hypothesis that elevated blood lactate concentration induces protein synthesis responses in skeletal muscle. [ABSTRACT FROM AUTHOR]

After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell‐cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology. [ABSTRACT FROM AUTHOR]

It is useful to investigate various physiological responses induced by fatigue in athletes. Moreover, wearable noninvasive sensors, including sweat sensors, are compatible with fatigue evaluation because of their ease of use, and ability to measure repeatedly and continual data. This cross‐sectional study aimed to clarify how sweat lactate elimination curves obtained during constant workload exercise changed following fatigue. Seventeen recreationally trained males (average age, 20.6 ± 0.8 years) completed two consecutive constant workload exercise tests (at 25% peak power) with rest intervals; the participants were encouraged to perform Test 1 until exhaustion and Test 2 only for 10 min. Subjective fatigue (numerical rating scale with face rating scale), sweat lactate, and sweat rate were measured for 10 min in each test. Subjective fatigue was compared using the Wilcoxon signed‐rank test and time to each constant value between Tests 1 and 2 was compared using paired t‐test. Subjective fatigue significantly increased during Test 2 compared with that during Test 1. After Test 1, the sweat lactate elimination curve demonstrated a leftward shift, as proved by the significantly sooner observation of the peak and constant values of sweat lactate (2, 3, and 4 μA) (p < 0.01). Our preliminary results suggest that the sweat lactate elimination curve is different in the fatigue state. Further research may provide insight in the application of this curve to the evaluation for fatigue. To evaluate the changes in sLA after fatigue using a wearable sLA sensor, comparing the sweat lactate elimination curve during constant workload exercise between in fatigued state and notfatigued in twenty healthy recreationally trained males was performed. As a results, a leftward shifted curve was detected, which suggest the possibility of taking insight in the application of this curve to the evaluation for fatigue by further research. [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]

Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole of glucose. Instead, in mosttumours the Warburg effect is an essential part of a 'selfish' metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) hypoxia‐inducible factor‐1 (HIF‐1) overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), activated (PI3K–Akt–mTORC1, Ras–Raf–MEK–ERK–cMyc, Jak–Stat3) or deactivated (LKB1–AMPK) signalling pathways, components of the tumour microenvironment, and HIF‐1 cooperation with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerable acceleration of glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non‐essential amino acids, lipids and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate, which stimulates tumour growth and suppression of anti‐tumour immunity – in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies; (f) cytosolic lactate being mainly exported through upregulated lactate–proton symporters (MCT4), working together with other H+ transporters, and carbonic anhydrases (CAII, CAIX), which hydrate CO2 from oxidative metabolism to form H+ and bicarbonate; (g) these proton export mechanisms, in concert with poor vascular drainage, being responsible for extracellular acidification, driving malignant progression and resistance to conventional therapies; (h) maintenance of the cellular redox homeostasis and low reactive oxygen species (ROS) formation; and (i) HIF‐1 overexpression, mutant p53 and mutant PTEN, which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e. aerobic glycolysis in the presence of oxygen and – in principle – functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a minority of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction. [ABSTRACT FROM AUTHOR]

Introduction: Cardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false-positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus. Our aim was to establish proof of concept in an animal model using a microdialysis probe to monitor lactate subcutaneously.Material and Methods: We performed an in vivo study in adult male wild-type Wistar rats. We modified electrodes used for CTG monitoring in human fetuses to incorporate a microdialysis membrane. Optimum flow rates for microdialysis were determined in vitro. For the in vivo experiment, a microdialysis probe was inserted into the skin on the back of the animal. De-oxygenation and acidosis were induced by lowering the inspiratory oxygen pressure. Oxygenation and heart rate were monitored. A jugular vein cannula was inserted to draw blood samples for analysis of lactate, pH, pco2 , and saturation. Lactate levels in dialysate were compared with plasma lactate levels.Results: Baseline blood lactate levels were around 1 mmol/L. Upon de-oxygenation, oxygen saturation fell to below 40% for 1 h and blood lactate levels increased 2.5-fold. Correlation of dialysate lactate levels with plasma lactate levels was 0.89 resulting in an R2 of .78 in the corresponding linear regression.Conclusions: In this animal model, lactate levels in subcutaneous fluid collected by microdialysis closely reflected blood lactate levels upon transient de-oxygenation, indicating that our device is suitable for subcutaneous measurement of lactate. Microdialysis probe technology allows the measurement of multiple compounds in the dialysate, such as glucose, albumin, or inflammatory mediators, so this technique may offer the unique possibility to shed light on fetal physiology during the intrapartum period. [ABSTRACT FROM AUTHOR]

METTL3 is an RNA methyltransferase implicated in the control of cell differentiation and proliferation in embryonic development and cancer. The current study was aimed to explore the function and underlying mechanism of METTL3 in hepatocellular carcinoma (HCC). We evaluated the expression and prognostic significance of METTL3 in 100 HCC cases and TCGA dataset. In HCC cases, both the RNA and protein expression of METTL3 were significantly upregulated and associated with poor prognosis. Gene set enrichment analysis of transcriptional profiles in HCC specimens revealed that METTL3 expression was associated with impaired glucose metabolism and mTOR signal pathway. In Huh‐7 and SMMC‐7721 HCC cells, downregulation of METTL3 by siRNA interference inhibited glycolytic capacity, which was proved by the decreased intracellular glucose uptake and lactate production. In terms of mechanism, we found mTORC1 activity was impaired by downregulation of METTL3, additional silencing of METTL3 cannot further decrease the phosphorylation level of mTORC1 and glycolysis activity in Rapamycin‐treated HCC cells. At last, we observed that downregulation of METTL3 synergizes with the glycolysis inhibitor 2‐deoxyglucose (2‐DG) to inhibit tumor growth in vitro. Our study provided evidence that METTL3 is involved in the regulation of glycolysis activity in HCC, suggesting that suppression of glycolysis via METTL3 inhibition was a potential treating strategy against HCC. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?What is the contribution of the main acidic compounds accumulated during contractions, namely H+, lactic acid and inorganic phosphate, to evoke the metabolic component of the exercise pressor reflex?What is the main finding and its importance?We found that the pressor response to acidic stimuli is driven by the concentration of hydrogen ions and that lactate and inorganic phosphate act as potentiating agents. H+ ions, lactate and inorganic phosphate are produced by contracting skeletal muscles and evoke, in part, the metabolic component of the exercise pressor reflex. Owing to their disparate dissociation constants (i.e. pKa), the contribution of each acid to the muscle metaboreflex is unclear. This lack of information prompted us to determine the reflex pressor responses to injection of acidic saline, lactate (24 mm) and inorganic phosphate (86 mm) at various values of pH (from 2.66 to 7.5), alone or in combination, into the arterial supply of hindlimb skeletal muscle of decerebrate rats. In particular, we tested the hypothesis that the pressor response to an injection of a combination of lactate and phosphate at an acidic pH is greater than that evoked by injection of either phosphate or lactate alone at the same pH. We found that injection of acidic saline produced a pressor response only at a pH of 2.66 (7 ± 4 mmHg), an effect that was potentiated when the solution contained lactate (50 ± 20 mmHg). At a pH of 6.0, however, this effect was lost. At a pH of 6.0, only the injection of inorganic phosphate produced a significant pressor response (23 ± 12 mmHg). A large potentiating effect was found when lactate was added to the inorganic phosphate solution (39 ± 18 mmHg), an effect that was lost at a pH >7.0. Our findings led to the conclusion that the pressor response to injection of acidic solutions was driven by H+ ions and that inorganic phosphate and lactate functioned as sensitizing agents. [ABSTRACT FROM AUTHOR]

Fatty acid (FA)‐derived lipid products generated by cytochrome P450 (CYP), lipoxygenase (LOX), and cyclo‐oxygenase (COX) influence cardiovascular function. However, plasma measurements invariably ignore 40% of the blood specimen, namely the erythrocytes. These red blood cells (RBCs) represent a cell mass of about 3 kg. RBCs are a potential reservoir for epoxy fatty acids, which on release could regulate vascular capacity. We tested the hypothesis that maximal physical activity would influence the epoxy fatty acid status in RBCs. We used a standardized maximal treadmill exercise according to Bruce to ensure a robust hemodynamic and metabolic response. Central hemodynamic monitoring was performed using blood pressure and heart rate measurements and maximal workload was assessed in metabolic equivalents (METs). We used tandem mass spectrometry (LC‐MS/MS) to measure epoxides derived from CYP monooxygenase, as well as metabolites derived from LOX, COX, and CYP hydroxylase pathways. Venous blood was obtained for RBC lipidomics. With the incremental exercise test, increases in the levels of various CYP epoxy‐mediators in RBCs, including epoxyoctadecenoic acids (9,10‐EpOME, 12,13‐EpOME), epoxyeicosatrienoic acids (5,6‐EET, 11,12‐EET, 14,15‐EET), and epoxydocosapentaenoic acids (16,17‐EDP, 19,20‐EDP) occurred, as heart rate, systolic blood pressure, and plasma lactate concentrations increased. Maximal (13.5 METs) exercise intensity had no effect on diols and various LOX, COX, and hydroxylase mediators. Our findings suggest that CYP epoxy‐metabolites could contribute to the cardiovascular response to maximal exercise. [ABSTRACT FROM AUTHOR]

Summary: Bacterial nutrition is an essential aspect of host–pathogen interaction. For the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans, fatty acids derived from lipid droplets are considered the major carbon source. However, many other soluble nutrients are available inside host cells and may be used as alternative carbon sources. Lactate and pyruvate are abundant in human cells and fluids, particularly during inflammation. In this work, we study Mtb metabolism of lactate and pyruvate combining classic microbial physiology with a 'multi‐omics' approach consisting of transposon‐directed insertion site sequencing (TraDIS), RNA‐seq transcriptomics, proteomics and stable isotopic labelling coupled with mass spectrometry‐based metabolomics. We discovered that Mtb is well adapted to use both lactate and pyruvate and that their metabolism requires gluconeogenesis, valine metabolism, the Krebs cycle, the GABA shunt, the glyoxylate shunt and the methylcitrate cycle. The last two pathways are traditionally associated with fatty acid metabolism and, unexpectedly, we found that in Mtb the methylcitrate cycle operates in reverse, to allow optimal metabolism of lactate and pyruvate. Our findings reveal a novel function for the methylcitrate cycle as a direct route for the biosynthesis of propionyl‐CoA, the essential precursor for the biosynthesis of the odd‐chain fatty acids. [ABSTRACT FROM AUTHOR]

Electron‐transferring flavoproteins (ETFs) have been found in all kingdoms of life, mostly assisting in shuttling electrons to the respiratory chain for ATP production. While the human (h) ETF has been studied in great detail, very little is known about the biochemical properties of the homologous protein in the model organism Saccharomyces cerevisiae (yETF). In view of the absence of client dehydrogenases, for example, the acyl‐CoA dehydrogenases involved in the β‐oxidation of fatty acids, d‐lactate dehydrogenase 2 (Dld2) appeared to be the only relevant enzyme that is serviced by yETF for electron transfer to the mitochondrial electron transport chain. However, this hypothesis was never tested experimentally. Here, we report the biochemical properties of yETF and Dld2 as well as the electron transfer reaction between the two proteins. Our study revealed that Dld2 oxidizes d‐α‐hydroxyglutarate more efficiently than d‐lactate exhibiting kcatapp/KMapp values of 1200 ± 300 m−1·s−1 and 11 ± 2 m−1·s−1, respectively. As expected, substrate‐reduced Dld2 very slowly reacted with oxygen or the artificial electron acceptor 2,6‐dichlorophenol indophenol. However, photoreduced Dld2 was rapidly reoxidized by oxygen, suggesting that the reaction products, that is, α‐ketoglutarate and pyruvate, 'lock' the reduced enzyme in an unreactive state. Interestingly, however, we could demonstrate that substrate‐reduced Dld2 rapidly transfers electrons to yETF. Therefore, we conclude that the formation of a product‐reduced Dld2 complex suppresses electron transfer to dioxygen but favors the rapid reduction in yETF, thus preventing the loss of electrons and the generation of reactive oxygen species. [ABSTRACT FROM AUTHOR]

Subsequently, electrochemical devices were developed in which the lactate in the blood sample reacts with the enzyme lactate oxidase and produces an electrical voltage measured by an embedded sensor, from which the lactate concentration can be derived from previous calibrations. The initial methodology of POC lactate measurement was colorimetric, where an enzymatic reaction linked the end product of the reaction to a color, and the change of color was proportional to the lactate concentration. In recent years there has been increasing interest in the measurement of lactate as one component in the assessment of metabolic status. [Extracted from the article]

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]

Fructose metabolism is generally held to occur essentially in cells of the small bowel, the liver, and the kidneys expressing fructolytic enzymes (fructokinase, aldolase B and a triokinase). In these cells, fructose uptake and fructolysis are unregulated processes, resulting in the generation of intracellular triose phosphates proportionate to fructose intake. Triose phosphates are then processed into lactate, glucose and fatty acids to serve as metabolic substrates in other cells of the body. With small oral loads, fructose is mainly metabolized in the small bowel, while with larger loads fructose reaches the portal circulation and is largely extracted by the liver. A small portion, however, escapes liver extraction and is metabolized either in the kidneys or in other tissues through yet unspecified pathways. In sedentary subjects, consumption of a fructose‐rich diet for several days stimulates hepatic de novo lipogenesis, increases intrahepatic fat and blood triglyceride concentrations, and impairs insulin effects on hepatic glucose production. All these effects can be prevented when high fructose intake is associated with increased levels of physical activity. There is also evidence that, during exercise, fructose carbons are efficiently transferred to skeletal muscle as glucose and lactate to be used for energy production. Glucose and lactate formed from fructose can also contribute to the re‐synthesis of muscle glycogen after exercise. We therefore propose that the deleterious health effects of fructose are tightly related to an imbalance between fructose energy intake on one hand, and whole‐body energy output related to a low physical activity on the other hand. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools. [ABSTRACT FROM AUTHOR]

Key points: Synapses have high energy demands which increase during intense activity. We show that presynaptic terminals can utilise extracellular glucose or lactate to generate energy to maintain synaptic transmission. Reducing energy substrates induces a metabolic stress: presynaptic ATP depletion impaired synaptic transmission through a reduction in the number of functional synaptic vesicle release sites and a slowing of vesicle pool replenishment, without a consistent change in release probability. Metabolic function is compromised in many pathological conditions (e.g. stroke, traumatic brain injury and neurodegeneration). Knowledge of how synaptic transmission is constrained by metabolic stress, especially during intense brain activity, will provide insights to improve cognition following pathological insults. Abstract: The synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 m m) as the extracellular substrates while inducing metabolic stress. High‐frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage‐clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCTs). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high‐intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low. [ABSTRACT FROM AUTHOR]

Abstract: The shift from lactate production to consumption in CHO cell metabolism is a key event during cell culture cultivations and is connected to increased culture longevity and final product titers. However, the mechanisms controlling this metabolic shift are not yet fully understood. Variations in lactate metabolism have been mainly reported to be induced by process pH and availability of substrates like glucose and glutamine. The aim of this study was to investigate the effects of elevated pCO2 concentrations on the lactate metabolic shift phenomena in CHO cell culture processes. In this publication, we show that at elevated pCO2 in batch and fed‐batch cultures, the lactate metabolic shift was absent in comparison to control cultures at lower pCO2 values. Furthermore, through metabolic flux analysis we found a link between the lactate metabolic shift and the ratio of NADH producing and regenerating intracellular pathways. This ratio was mainly affected by a reduced oxidative capacity of cultures at elevated pCO2. The presented results are especially interesting for large‐scale and perfusion processes where increased pCO2 concentrations are likely to occur. Our results suggest, that so far unexplained metabolic changes may be connected to increased pCO2 accumulation in larger scale fermentations. Finally, we propose several mechanisms through which increased pCO2 might affect the cell metabolism and briefly discuss methods to enable the lactate metabolic shift during cell cultivations. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Pneumonia is an inflammatory disease caused by micro‐organisms. The pneumonia severity index (PSI) and CURB_65 scores are widely used to predict the mortality risk. We wanted to calculate the value of lactic acid level in predicting the mortality risk. Materials and methods: This prospective cross‐sectional study performed in a third level education and research hospital. The pneumonia diagnosis was determined by symptoms, physical examination findings, and radiological findings. Results: The mean age of the patients was 71.0 ± 16.5. The overall mortality rate was 21.8%. The mean lactate level was 3.53 ± 3.59. Lactate is significantly higher in patients who were died. The PSI and CURB_65 scores were higher in patients who died. The cutoff value of lactate level for mortality is 3.35 mmol/mm3. The cutoff point of PSI for mortality was 148.5 points; equal or over this point the mortality rate is 90.9%. Discussion: The early prediction of the mortality risk is important to determine the high risk patients to hospitalize in intensive care unit and close follow up. The lactate level, PSI score and CURB_65 scores are good predictors for mortality. We can use them in emergency departments for risk stratification. [ABSTRACT FROM AUTHOR]

Keywords: chemoreceptor; exercise; metabolism; oxygen; respiration; ventilation EN chemoreceptor exercise metabolism oxygen respiration ventilation 2813 2814 2 06/03/22 20220601 NES 220601 It was a pleasure to read Brooks and colleagues' review on lactate in contemporary biology (Brooks et al., 2022). Further support stems from glomus cells treated with rotenone, a mitochondrial complex I inhibitor, which abolished additional effects on hypoxia but did not prevent lactate-induced glomus cell depolarization. [Extracted from the article]

Objective Clinical neurological assessment is challenging for severe traumatic brain injury ( TBI) patients in the acute setting. Waves of neurochemical abnormalities that follow TBI may serve as fluid biomarkers of neurological status. We assessed the cerebrospinal fluid ( CSF) levels of glutamate, lactate, BDNF, and GDNF, to identify potential prognostic biomarkers of neurological outcome. Methods This cross-sectional study was carried out in a total of 20 consecutive patients (mean [ SD] age, 29 [13] years; M/F, 9:1) with severe TBI Glasgow Coma Scale ≤ 8 and abnormal computed tomography scan on admission. Patients were submitted to ventricular drainage and had CSF collected between 2 and 4 h after hospital admission. Patients were then stratified according to two clinical outcomes: deterioration to brain death (nonsurvival, n = 6) or survival (survival, n = 14), within 3 days after hospital admission. CSF levels of brain-derived substances were compared between nonsurvival and survival groups. Clinical and neurological parameters were also assessed. Results Glutamate and lactate are significantly increased in nonsurvival relative to survival patients. We tested the accuracy of both biomarkers to discriminate patient outcome. Setting a cutoff of >57.75, glutamate provides 80.0% of sensitivity and 84.62% of specificity ( AUC: 0.8214, 95% CL: 54.55-98.08%; and a cutoff of >4.65, lactate has 100% of sensitivity and 85.71% of specificity ( AUC: 0.8810, 95% CL: 54.55-98.08%). BDNF and GDNF did not discriminate poor outcome. Interpretation This early study suggests that glutamate and lactate concentrations at hospital admission accurately predict death within 3 days after severe TBI. [ABSTRACT FROM AUTHOR]

The article offers information on the "Fructose in physiology: friend or foe" title of a Symposium delivered at Europhysiology 2018 in London and supported by the Journal of Physiology. Topics include the physiology of fructose metabolism in health and disease, mechanisms by which fructose may exert metabolic effects within specific populations, and sex-specific effects of fructose intake on metabolism and health.

Key points The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection., In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices., Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner., Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328., Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change., Abstract A rise in lactate concentration and the leak potassium channel TREK1 have been independently associated with cerebral ischaemia. Recent literature suggests lactate to be neuroprotective and TREK1 knockout mice show an increased sensitivity to brain and spinal cord ischaemia; however, the connecting link between the two is missing. Therefore we hypothesized that lactate might interact with TREK1 channels. In the present study, we show that lactate at ischaemic concentrations (15-30 m m) at pH 7.4 increases TREK1 current in CA1 stratum radiatum astrocytes and causes membrane hyperpolarization. We confirm the intracellular action of lactate on TREK1 in hippocampal slices using monocarboxylate transporter blockers and at single channel level in cell-free inside-out membrane patches. The intracellular effect of lactate on TREK1 is specific since other monocarboxylates such as pyruvate and acetate at pH 7.4 failed to increase TREK1 current. Deletion and point mutation experiments suggest that lactate decreases the longer close dwell time incrementally with increase in lactate concentration by interacting with the histidine residue at position 328 (H328) in the carboxy terminal domain of the TREK1 channel. The interaction of lactate with H328 is dependent on the charge on the histidine residue since isosteric mutation of H328 to glutamine did not show an increase in TREK1 channel activity with lactate. This is the first demonstration of a direct effect of lactate on ion channel activity. The action of lactate on the TREK1 channel signifies a separate neuroprotective mechanism in ischaemia since it was found to be independent of the effect of acidic pH on channel activity. [ABSTRACT FROM AUTHOR]

Among α-hydroxy acid-oxidizing flavoenzymes l-lactate oxidase ( LOX) is unique in featuring a second-sphere tyrosine (Tyr191 in Aerococcus viridans LOX; av LOX) at the binding site for the substrate's carboxylate group. Y191F, Y191L and Y191A variants of av LOX were constructed to affect a hydrogen-bond network connecting Tyr191 to the carboxylate of the bound ligand via the conserved Tyr40 and to examine consequent effects on enzymatic reactivity. Kinetic studies at 20 °C and pH 6.5 revealed that release of pyruvate product was decreased 4.7-fold (Y191F), 19-fold (Y191L) and 28-fold (Y191A) compared with wild-type enzyme (~ 141 s−1) and thus became mainly rate limiting for l-lactate oxidation by the variants at a steady-state under air-saturated conditions. In the Y191L and the Y191A variants, but not in the Y191F variant, l-lactate binding was also affected strongly by the site-directed substitution. Reduction of the flavin cofactor by l-lactate and its reoxidation by molecular oxygen were, however, comparatively weakly affected by the replacements of Tyr191. Unlike the related lactate monooxygenase, which prevents the fast dissociation of pyruvate to promote its oxidative decarboxylation by H2O2 into acetate, CO2 and water as final reaction products, all av LOX variants retained their native oxidase activity where catalytic turnover results in the equivalent formation of H2O2. The 1.9 Å crystal structure of the Y191F variant bound with FMN and pyruvate revealed a strictly locally disruptive effect of the site-directed substitution. Product off-rates appear to be dictated by partitioning of residues including Tyr191 from an active-site lid loop into bulk solvent and modulation of the hydrogen bond strength that links Tyr40 with the pyruvate's carboxylate group. Overall, this study emphasizes the possibly high importance of contributions from second-sphere substrate-binding residues to the fine-tuning of reactivity in α-hydroxy acid-oxidizing flavoenzymes, requiring that the catalytic steps of flavin reduction and oxidation are properly timed with the physical step of α-keto acid product release. Database The structure of Y191F variant of A. viridans l-lactate oxidase was deposited in the ww PDB under the accession code . [ABSTRACT FROM AUTHOR]

Key points Lactate is increased in myometrial capillary blood from women in slow or non-progressive labour (dystocia), suggesting that it is detrimental to uterine contractions., There are no studies of the effect of lactate on the myometrium. In the present study, we have investigated its effects and mechanism of action on myometrial strips from term pregnant rats., We show that lactate significantly decreased spontaneous contractility. Lactatedecreased pHi and inhibited Ca2+ transients. Nulling the decrease in pHi abolished the effects of lactate effects. If Ca2+ entry was enhanced, the effects of lactate were abolished., The present study suggests that the accumulation of extracellular lactate could contribute to labour dystocia., Abstract Lactate is increased in myometrial capillary blood from women in slow or non-progressive labour (dystocia), suggesting that it is detrimental to uterine contractions. There are, however, no studies of the effect of lactate on the myometrium. We therefore investigated its effects and mechanism of action on myometrial strips from term pregnant rats. The effects on spontaneous and oxytocin-induced contractility in response to sodium lactate and other weak acids (1-20 mM) were studied. In some experiments, simultaneous force and intracellular Ca2+ or pH (pHi) were measured with Indo-1 or Carboxy-SNARF, respectively. Statistical differences were tested using non-parametric tests. Lactate significantly decreased spontaneous contractility with an EC50 of 3.9 mM. Propionate, butyrate and pyruvate also reduced contractions with similar potency. The effects of lactate were reduced in the presence of oxytocin but remained significant. Lactate decreased pHi and nulling the decrease in pHi abolished its effects. We also show that lactate inhibited Ca2+ transients, with these changes mirroring those produced on force. If Ca2+ entry was enhanced by depolarization (high KCl) or applying the Ca2+ channel agonist, Bay K 4644, the effects of lactate were abolished. Taken together, these data show that lactate in the physiological range potently decreases myometrial contractility as a result of its inhibition of Ca2+ transients, which can be attributed to the induced acidification. The present study suggests that the accumulation of extracellular lactate will reduce myometrial contractions and could therefore contribute to labour dystocia. [ABSTRACT FROM AUTHOR]

Neuropeptide Ys (NPYs) contribute to sympathetic‐adreno stimulation: NPY1‐36 potentiates the effects of catecholamines (CATs), whereas NPY3‐36 inhibits CAT release. We sought to investigate whether inhibiting dipeptidyl‐peptidase‐4 (DPP4), cleaving NPY1‐36 into NPY3‐36, leads to increased NPY1‐36 potentiating effects and reduced NPY3‐36 inhibitory effects on CATs, thereby improving endurance performance. Seven male participants (age 27 ± 3 years, BMI 23.1 ± 2.4 kg/m2) performed time‐to‐exhaustion cycling exercise at 95% of peak power output with either placebo, or saxagliptin, a DPP4 inhibitor. Oxygen consumption (V̇O2), heart rate variability, NPY1‐36, NPY3‐36, catecholamines, and lactate were measured at several time points before, during, and after exercise. With saxagliptin, DPP4 activity (12.7 ± 1.6 vs. 0.2 ± 0.3 U/L, p = 0.001; d = 10.7) was decreased at rest, while NPY3‐36 (1.94 ± 0.88 vs. 0.73 ± 0.22 pm; p < 0.001; d = 2.04) decreased and NPY1‐36 increased during exercise (2.64 ± 2.22 vs. 4.59 ± 2.98 pm; p < 0.01; d = 0.19). CATs were unchanged. Time‐to‐exhaustion was 32% higher with saxagliptin. The difference in time‐to‐exhaustion between placebo and saxagliptin was correlated with NPY1‐36 differences (R = 0.78, p < 0.05). Peak V̇O2 and other cardio‐respiratory values were not different, whereas peak NPY concentrations were higher with saxagliptin. DPP4 blockade improved performance, increased NPY1‐36, and decreased NPY3‐36 concentrations which may have potentiating effects on the influences of CATs. However, DPP4 is involved in many different actions, thus NPYs are one group of factors that may underly its performance‐enhancing effects; further studies are required to determine the exact mechanisms. [ABSTRACT FROM AUTHOR]

Deregulated metabolism is a well‐known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone‐like molecules by activating cell surface G‐protein‐coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis‐derived and β‐oxidation‐derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite‐sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets. [ABSTRACT FROM AUTHOR]

The concept of lactate shuttle is widely accepted in exercise physiology. Lactate transport is mediated by monocarboxylate transporters (MCT), which enable cells to take up and release lactate. However, the role of lactate during exercise has not yet been fully elucidated. In this study, we investigated the effects of lactate transport inhibition on exercise capacity and metabolism in mice. Here, we demonstrated that MCT1 inhibition by α‐cyano‐4‐hydroxycinnamate administration (4‐CIN, 200 mg/g of body weight) reduced the treadmill running duration at 20 m/min. The administration of 4‐CIN increased the blood lactate concentration immediately after exercise. With matched exercise duration, the muscle lactate concentration was higher while muscle glycogen content was lower in 4‐CIN‐administered mice. Further, we showed that MCT4 inhibition by bindarit administration (50 mg/kg of body weight) reduced the treadmill running duration at 40 m/min. Bindarit administration increased the muscle lactate but did not alter the blood lactate and glucose concentrations, as well as muscle glycogen content, immediately after exercise. A negative correlation was observed between exercise duration at 40 m/min and muscle lactate concentration immediately after exercise. Our results suggest that lactate transport via MCT1 and MCT4 plays a pivotal role in sustaining exercise. [ABSTRACT FROM AUTHOR]

Background: 0.9% saline commonly used for resuscitation of septic patients might induce biochemical changes leading to detrimental effects. Ringer's lactate being a balanced crystalloid might be beneficial in such a scenario. Objectives: We undertook this study to explore in detail the effect of these fluids in the resuscitation of septic patients, and risks and benefits these two fluids would have on the overall prognosis of patients. Methods: This was an open-label randomized controlled trial undertaken in emergency medical services attached to the department of medicine at a tertiary care teaching hospital. One hundred sixty adult (⩾18 years old) medical patients admitted with the diagnosis of sepsis fulfilling eligibility criteria were included. They were randomly assigned to receive 0.9% saline or ringer's lactate. These fluids were given for the initial 24 h only, and after then, the type of fluid given was based on treating physician discretion. Various biochemical parameters were measured at baseline and various time points during the hospital stay. The primary outcome was to find out the incidence of hyperchloremia at 24 h from the time of randomization and during the hospital stay. The secondary outcomes were incidence of acute kidney injury, need for renal replacement therapy; differences in pH, bicarbonate, serum lactate, coagulation parameters, sequential organ failure assessment scores at various time points; and hospital/30-day mortality. Results: The baseline characteristics in both groups were comparable. At admission, each group had a serum chloride value which was comparable (p value: 0.595); however, at 24 and 48 h, a statistically significant difference was noticed, with 0.9% saline group having a higher mean serum chloride value (113.66 ± 10.04 v/s 108.98 ± 8.04 mEq/L, p value: 0.001 at 24 h) and (114.75 ± 9.51 v/s 111.12 ± 7.84 mEq/L, p value: 0.022 at 48 h). At 24 and 48 h post-randomization, the incidence of hyperchloremia was significantly higher in the 0.9% saline group (at 24 h, 0.9% saline: 75.0% v/s Ringer's lactate: 48.8%, p value: 0.001 and at 48 h, 0.9% saline: 77.2% v/s Ringer's lactate: 60.3%, p value: 0.022), although there was no difference in the incidence of hyperchloremia recorded during the hospital stay. Acute kidney injury incidence at 24 and 48 h post-randomization was significantly higher in the 0.9% saline group (at 24 h, 0.9% saline: 23.8% v/s Ringer's lactate: 10.0%, p value: 0.020 and at 48 h, 0.9% saline: 29.1% v/s Ringer's lactate: 15.4%, p value: 0.039). No significant differences in other secondary outcomes were observed. Conclusion: Higher incidence of hyperchloremia and a higher rate of acute kidney injury at 24 and 48 h after randomization were noted in the 0.9% saline group. [ABSTRACT FROM AUTHOR]

In theory, metformin dose adjustment along with metformin plasma concentration monitoring will ensure that concentrations do not exceed the upper limit of safety in renally impaired patients and may therefore help mitigate the risk of hyperlactatemia and possibly acidosis. Using data extracted from the published literature, we aimed to understand the relationship between plasma metformin and lactate concentrations and to establish the metformin plasma concentration associated with severe hyperlactatemia (lactate >5 mmol/L). [Extracted from the article]

Objective To assess whether the frequency of adverse neonatal outcome at delivery is related to the level of lactate in amniotic fluid and to the use of oxytocin. Design Prospective observational study. Setting Soder Hospital, Stockholm, Sweden. Population Seventy-four women in active labor with a gestational age ≥36 weeks and mixed parity. Methods Levels of lactate in amniotic fluid were analyzed bedside from an intrauterine catheter every 30 min during labor. Deliveries were divided into groups with and without oxytocin. Main outcome measures The frequency of adverse neonatal outcome at delivery. Result Of the deliveries 13.5% (10/74) concluded with an adverse neonatal outcome. The levels of lactate in amniotic fluid increased during labor, more so in deliveries where oxytocin was used. In the group with an adverse neonatal outcome, the level of lactate in amniotic fluid was significantly higher in the final sample before delivery ( p = 0.04). In 18 deliveries, stimulation with oxytocin was temporarily halted for at least 30 min due to overly stimulated labor contractions. A decreasing level of lactate in amniotic fluid was shown within a median 5%/30 min. In the group where the administration of oxytocin was halted, there was no adverse neonatal outcome. Conclusion The frequency of adverse neonatal outcome was associated with the level of lactate in amniotic fluid and with the use of oxytocin. The level of lactate in amniotic fluid may be an additional valuable tool when oxytocin is administered during labor. [ABSTRACT FROM AUTHOR]

Background Serial measurement of lactate concentration is utilized for therapeutic and prognostic purposes in human critical care. The prognostic value of serial lactate measurement in equine acute colitis warrants investigation. Hypothesis Serial lactate concentrations are predictive of outcome in horses with colitis. Animals A total of 101 horses with colitis. Methods Retrospective study. Plasma l-lactate concentrations were measured at admission and at 4-8 and 24 hours after admission. Associations between admission, early (4-8 hours) and late (24 hours) lactate concentrations, and survival status were determined. The percent reduction in lactate concentration between admission and the early time point, and between admission and the late time point, was calculated. Using a cutoff value, associations between percent reduction in lactate and survival status and associations between percent reduction in lactate and clinical and clinicopathologic data were determined. Results There was no association between admission plasma lactate concentration and survival status ( P = .26). The 4-8 and 24 hour after admission lactate concentrations were associated with survival status ( P = .023, .013, respectively). Lactate cutoffs of ≤2.3 and ≤1.5 mmol/L had the maximum sensitivity and specificity for predicting survival at the 4-8 and 24 hour time points, respectively. When lactate reduction ≥30% at 4-8 hours and ≥50% at 24 hours after admission were used as the cutoffs, the percent reduction of lactate concentration was significantly associated with survival ( P = .012 and .019, respectively). Conclusion and Clinical Importance The prognostic ability of serial measurement of blood lactate concentration warrants prospective study as a measure of therapeutic response in horses with colitis. [ABSTRACT FROM AUTHOR]

Objective. To study to what extent the fetal scalp blood lactate concentration during labor correlates with fetal scalp pH and base deficit, and metabolic acidosis at birth, and to suggest lactate cut-off values to serve as indicators for either reassurance or immediate intervention. Design. A retrospective observational study. Setting. Labor ward at a university medical center. Sample. Fetal scalp and cord blood samples with acid-base and lactate values from 486 singleton pregnancies beyond 34 weeks' gestation. Methods. The relation between lactate, pH and base deficit (BD) in fetal scalp blood was tested by Spearman's rho correlation coefficient. Lactate cut-off values indicating either reassuring fetal status or immediate intervention were estimated using percentile distribution and compared with pH and BD. Main outcome measures. Metabolic acidosis, defined as umbilical cord artery pH below 7.05 and BD calculated for the blood compartment above 12mmol/l. Results. After 127 (21%) exclusions, 486 cases were available for analysis. Fetal lactate values increased with evolving metabolic acidosis. Lactate concentration correlated with both pH ( r=−0.50, p<0.01) and BD ( r=0.48, p<0.01). Lactate <5.4mmol/l indicated reassuring fetal status, whereas lactate ≥6.6mmol/l indicated metabolic acidosis. Fetal lactate correlated better with either the absence or presence of metabolic acidosis at birth than did fetal pH and BD. Conclusions. In the case of a non-reassuring fetal heart rate, fetal scalp blood lactate provides more accurate information on fetal acid-base status than does pH and/or BD. [ABSTRACT FROM AUTHOR]

Abstract: We examined the effects of lactate on the enzymatic activity of hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) in various mouse tissues. Our results showed that lactate inhibited PFK activity in all the analyzed tissues. This inhibitory effect was observed in skeletal muscle even in the presence of insulin. Lactate directly inhibited the phosphorylation of PFK tyrosine residues in skeletal muscle, an important mechanism of the enzyme activation. Moreover, lactate indirectly inhibited HK activity, which resulted from its cellular redistribution, here attributed to alterations of HK structure. PK activity was not affected by lactate. The activity of HK and PFK is directly related to glucose metabolism. Thus, it is conceivable that lactate exposure can induce inhibition of glucose consumption in tissues. [ABSTRACT FROM AUTHOR]

Abstract: In order to ascertain whether and how mitochondria can produce hydrogen peroxide (H2O2) as a result of l-lactate addition, we monitored H2O2 generation in rat liver mitochondria and in submitochondrial fractions free of peroxisomal and cytosolic contamination. We found that H2O2 is produced independently on the respiratory chain with 1:1 stoichiometry with pyruvate, due to a putative flavine-dependent l-lactate oxidase restricted to the intermembrane space. The l-lactate oxidase reaction shows a hyperbolic dependence on l-lactate concentration and is inhibited by NAD+ in a competitive manner, being the enzyme different from the l-lactate dehydrogenase isoenzymes as shown by their pH profiles. [Copyright &y& Elsevier]

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (∼3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n= 7) or normoxia (NOR group, n= 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training × hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia ( P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise. [ABSTRACT FROM AUTHOR]

Background: Sequential lactate concentration ([LAC]) measurements have prognostic value in that hospitalized humans and neonatal foals that have a delayed return to normolactatemia have greater morbidity and case fatality rate. Hypothesis: Prognosis for survival is decreased in horses with a delayed return to normal [LAC]. Animals: Two hundred and fifty adult horses presented for emergency evaluation excepting horses evaluated because of only ophthalmologic conditions, superficial wounds, and septic synovitis without systemic involvement. Methods: Prospective observational study. [LAC] was measured at admission and then at 6, 12, 24, 48, and 72 hours after admission. The change in [LAC] over time ([LAC]Δ T) was calculated from changes in [LAC] between sampling points. Results: Median [LAC] was significantly ( P < .001) higher at admission in nonsurvivors (4.10 mmol/L [range, 0.60–18.20 mmol/L]) when compared with survivors (1.30 mmol/L [range, 0.30–13.90 mmol/L]) and this difference remained at all subsequent time points. The odds ratio for nonsurvival increased from 1.29 (95% confidence interval 1.17–1.43) at admission to 49.90 (6.47–384) at 72 hours after admission for every 1 mmol/L increase in [LAC]. [LAC]Δ T was initially positive in all horses but became negative and significantly lower in nonsurvivors for the time periods between 24–72 hours (− 0.47, P= .001) and 48–72 hours (− 0.07, P= .032) when compared with survivors (0.00 at both time periods) consistent with lactate accumulation in nonsurvivors. Conclusions and Clinical Importance: These results indicate that lactate metabolism is impaired in critically ill horses and [LAC]Δ T can be a useful prognostic indicator in horses. [ABSTRACT FROM AUTHOR]

The glyoxalase system, comprising the metalloenzymes glyoxalase I (GLO1) and glyoxalase II (GLO2), is an almost universal metabolic pathway involved in the detoxification of the glycolytic byproduct methylglyoxal tod-lactate. In contrast to the situation with the trypanosomatid parasites Leishmania major and Trypanosoma cruzi, this trypanothione-dependent pathway is less well understood in the African trypanosome, Trypanosoma brucei. Although this organism possesses a functional GLO2, no apparent GLO1 gene could be identified in the T. brucei genome. The absence of GLO1 in T. brucei was confirmed by the lack of GLO1 activity in whole cell extracts, failure to detect a GLO1-like protein on immunoblots of cell lysates, and lack ofd-lactate formation from methylglyoxal as compared to L. major and T. cruzi. T. brucei procyclics were found to be 2.4-fold and 5.7-fold more sensitive to methylglyoxal toxicity than T. cruzi and L. major, respectively. T. brucei also proved to be the least adept of the ‘Tritryp’ parasites in metabolizing methylglyoxal, producingl-lactate rather thand-lactate. Restoration of a functional glyoxalase system by expression of T. cruzi GLO1 in T. brucei resulted in increased resistance to methylglyoxal and increased conversion of methylglyoxal tod-lactate, demonstrating that GLO2 is functional in vivo. Procyclic forms of T. brucei possess NADPH-dependent methylglyoxal reductase and NAD+-dependentl-lactaldehyde dehydrogenase activities sufficient to account for all of the methylglyoxal metabolized by these cells. We propose that the predominant mechanism for methylglyoxal detoxification in the African trypanosome is via the methylglyoxal reductase pathway tol-lactate. [ABSTRACT FROM AUTHOR]

Abstract: Although mitochondria have been the object of intensive study over many decades, some aspects of their metabolism remain to be fully elucidated, including the l-lactate metabolism. We review here the novel insights arisen from investigations on l-lactate metabolism in mammalian, plant and yeast mitochondria. The presence of l-lactate dehydrogenases inside mitochondria, where l-lactate enters in a carrier-mediated fashion, suggests that mitochondria play an important role in l-lactate metabolism. Functional studies have demonstrated the occurrence of several l-lactate carriers. Moreover, immunological investigations have proven the existence of monocarboxylate translocator isoforms in mitochondria. [Copyright &y& Elsevier]

REFERENCES 1 Rafi J. Need updating fetal blood sampling guidelines since lactate levels indicating acidemia are specific to the measuring instrument. We thank Dr Rafi for his interest in our editorial.1 We highlighted that because of the complexity of the analytical process for the measurement of lactate, there is no absolute "gold standard" so each method of measurement ideally requires standardization against neonatal outcome, or at least standardization against another method that has been validated in that way.2 A literature search has not revealed any papers standardizing the ABL90 FLEX PLUS lactate measurements against neonatal outcome. [Extracted from the article]

Objectives. To assess whether there is an association between high lactate concentration in amniotic fluid (AF) and labor dystocia. Design. Prospective observational study. Setting. Labor ward at General South Hospital, Stockholm, Sweden. Population and methods. Women in active labor attending labor ward, having at least two consecutive measurements of lactate concentration in AF, measured 60 minutes apart. Main outcome measure. Dysfunctional labor, defined as instrumental or operative delivery due to dystocia. Results. Among women with spontaneous vaginal deliveries (n=23) the mean lactate concentration in AF during labor was 8.9 mmol/l (range 6.6-10.8), and among women with operative delivery due to labor dystocia (n=31) the corresponding value was 10.9 mmol/l (range 8.0-16.1) (p<0.001). Of 29 women with a high lactate concentration (≥10.1 mmol/l) in at least two consecutive measures collected at least 60 minutes apart, 25 (86%) were delivered instrumentally/operatively due to dystocia. Using this definition of a positive test, the diagnostic accuracy to predict operative delivery due to dystocia was: sensitivity 81% (25/31), specificity 83% (19/23), positive predictive value 86% (25/29), and negative predictive value 76% (19/25). The likelihood ratio was 5.0 for a positive test and 0.2 for a negative test. Conclusions. High lactate concentration (≥10.1mmol/l) in at least two consecutive samples of AF collected during labor 60 minutes apart is strongly associated with dystocia. This method might be useful in clinical management to identify labor dystocia at an early stage of labor. [ABSTRACT FROM AUTHOR]

We investigated the metabolism ofl-lactate in mitochondria isolated from potato tubers grown and saved after harvest in the absence of any chemical agents. Immunologic analysis by western blot using goat polyclonal anti-lactate dehydrogenase showed the existence of a mitochondrial lactate dehydrogenase, the activity of which could be measured photometrically only in mitochondria solubilized with Triton X-100. The addition ofl-lactate to potato tuber mitochondria caused: (a) a minor reduction of intramitochondrial pyridine nucleotides, whose measured rate of change increased in the presence of the inhibitor of the alternative oxidase salicyl hydroxamic acid; (b) oxygen consumption not stimulated by ADP, but inhibited by salicyl hydroxamic acid; and (c) activation of the alternative oxidase as polarographically monitored in a manner prevented by oxamate, anl-lactate dehydrogenase inhibitor. Potato tuber mitochondria were shown to swell in isosmotic solutions of ammoniuml-lactate in a stereospecific manner, thus showing thatl-lactate enters mitochondria by a proton-compensated process. Externally addedl-lactate caused the appearance of pyruvate outside mitochondria, thus contributing to the oxidation of extramitochondrial NADH. The rate of pyruvate efflux showed a sigmoidal dependence onl-lactate concentration and was inhibited by phenylsuccinate. Hence, potato tuber mitochondria possess a non-energy-competentl-lactate/pyruvate shuttle. We maintain, therefore, that mitochondrial metabolism ofl-lactate plays a previously unsuspected role in the response of potato to hypoxic stress. [ABSTRACT FROM AUTHOR]

Keywords: mitochondria; muscle metabolism; nuclear magnetic resonance; 31P MRS EN mitochondria muscle metabolism nuclear magnetic resonance 31P MRS 1797 1798 2 05/18/20 20200515 NES 200515 Four decades after it was first applied to skeletal muscle, phosphorus magnetic resonance spectroscopy ( SP 31 sp P MRS) remains a valuable noninvasive window into metabolism I in vivo i . Bartlett I et al i . did not choose a multimodal approach, but used one of the most conceptually straightforward SP 31 sp P MRS analyses: the initial post-exercise PCr resynthesis rate as a measure of the end-exercise suprabasal oxidative ATP synthesis rate. SP 31 sp P MRS offers a simple way to address ATP cost: the initial PCr depletion rate measures total ATP turnover at the start of exercise, but this obviously cannot be repeated to generate a time-course. [Extracted from the article]