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

Objective: Head trauma, a cause of serious morbidity and mortality in general, is among the most common causes of emergency department visits in geriatric patients. In this context, this study investigated the factors affecting prognosis and mortality in geriatric patients presenting with head trauma at the emergency department. Methods: This retrospective cohort study included 842 patients aged 65 years and above who presented with head trauma to the emergency department between January 1, 2019, and December 31, 2019. Demographic and clinical data of the 622 patients included in the study were analyzed. Results: A total of 622 geriatric patients with head trauma were included in this study. Of these, 54.2% (337/622) were men, and 45.8% (285/622) were women. The mean age of the patients was 75.3 ± 7.5 years. Antihypertensives were the most common medications taken by the patients. Subdural hematoma is the most frequently observed cranial pathology. A simple fall is the most observed mechanism for trauma. A total of 17.5% (109/622) of the patients were admitted to the hospital. Of these patients, 8.4% (52/622) were transferred to the intensive care unit and 2.6% (16/622) of the patients died. Conclusion: Mortality would be expected to be higher in elderly patients with head trauma, hypotension, or high lactate levels. The need for intensive care unit transfer was higher in patients with coronary artery disease. The mortality rate of the patients increased with an increasing length of hospital stay. Head trauma, a cause of serious morbidity and mortality in general, is among the most common causes of emergency department visits in geriatric patients. Of the 622 patients, 54.2% (337/622) were men, and 45.8% (285/622) were women. A simple fall is the most observed mechanism for trauma. Mortality would be expected to be higher in elderly patients with head trauma, hypotension, or high lactate levels. [ABSTRACT FROM AUTHOR]

Background: Myocardial lactate production in the coronary circulation during acetylcholine (ACh)-provocation test (abbreviated as lactate production) provides supporting evidence for coronary spasm-induced myocardial ischemia. The purpose of this study was to examine the clinical features, predictive factors, and prognosis of patients with coronary vasospastic angina (VSA) and lactate production., Methods and Results: We examined all 712 patients who underwent both myocardial lactate measurement during ACh-provocation test in the left coronary artery and genetic screening test of a -786T/C polymorphism in the 5'-flanking region of the endothelial nitric oxide synthase (eNOS) gene between January 1991 and December 2010. Lactate production was observed in 252 of the 712 patients and in 219 of 356 VSA patients diagnosed by ACh-provocation test. Compared with lactate production-negative VSA patients, the lactate production-positive counterparts were more likely to be nonsmoker female diabetics with -786T/C eNOS polymorphism (61% vs 31%, P<0.001, 62% vs 34%, P<0.001, 24% vs 14%, P=0.016, and 25% vs 15%, P=0.018, respectively). Multivariable logistic regression analysis identified female sex, diabetes mellitus, and -786T/C eNOS polymorphism to correlate with lactate production (odds ratio 3.51, 95% CI 2.16 to 5.70, P<0.001; odds ratio 2.53, 95% CI 1.38 to 4.65, P=0.003; and odds ratio 1.85, 95% CI 1.02 to 3.35, P=0.044, respectively). Kaplan-Meier survival curve showed no difference in 5-year survival rate free from major adverse cardiac events between lactate production-positive and -negative VSA patients (P=0.319)., Conclusions: The results indicated that female sex, diabetes, and mutation in -786T/C eNOS gene correlate with ACh-provoked myocardial ischemia in patients with coronary spasm., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

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: Sepsis and septic shock cause significant mortality worldwide, with no targeted molecular therapies available. Metformin has pleomorphic effects that may be beneficial in sepsis, but at present, the impact of metformin exposure on sepsis remains controversial. Metformin might alter lactate metabolism, but little is known about its influence on lactate kinetics. We therefore investigated the impact of preadmission metformin use on lactate kinetics, acute kidney injury (AKI) and mortality in sepsis. Materials and Methods: We retrospectively analysed all ICU admissions with sepsis and septic shock between January 2013 and September 2020, identifying 77 users and 390 nonusers (subdivided in diabetics, n = 48 and nondiabetics, n = 342). Results: (Sub)groups did not differ in illness severity or sepsis aetiology. Admission lactate levels were similar, but evolution in lactate over the first 24 h showed a larger decrease in users vs nonusers (median − 53% vs. −36%, p =.010). No difference in AKI or renal replacement therapy was found. Mortality was lower in users vs nonusers in case of septic shock (21.9% (n = 7) vs. 42.7% (n = 61) for 90d mortality, p =.029, OR 0.38 [95% CI: 0.15–0.93]), but showed no significant differences in the combined sepsis and septic shock population. Conclusions: In our data, preadmission metformin use is associated with a significantly larger decrease in lactate after admission with sepsis or septic shock and with reduced mortality in septic shock. This underscores the need for further studies investigating the interplay between metformin, lactate and sepsis, thereby exploring the potential use of metformin or its pathways in sepsis. [ABSTRACT FROM AUTHOR]

Metabolic changes of malignant plasma cells (PCs) and adaptation to tumour microenvironment represent one of the hallmarks of multiple myeloma (MM). We previously showed that MM mesenchymal stromal cells are more glycolytic and produce more lactate than healthy counterpart. Hence, we aimed to explore the impact of high lactate concentration on metabolism of tumour PCs and its impact on the efficacy of proteasome inhibitors (PIs). Lactate concentration was performed by colorimetric assay on MM patient's sera. The metabolism of MM cell treated with lactate was assessed by seahorse and real time Polymerase Chain Reaction (PCR). Cytometry was used to evaluate mitochondrial reactive oxygen species (mROS), apoptosis and mitochondrial depolarization. Lactate concentration resulted increased in MM patient's sera. Therefore, PCs were treated with lactate and we observed an increase of oxidative phosphorylation‐related genes, mROS and oxygen consumption rate. Lactate supplementation exhibited a significant reduction in cell proliferation and less responsive to PIs. These data were confirmed by pharmacological inhibition of monocarboxylate transporter 1 (MCT1) by AZD3965 which was able to overcame metabolic protective effect of lactate against PIs. Consistently, high levels of circulating lactate caused expansion of Treg and monocytic myeloid derived suppressor cells and such effect was significantly reduced by AZD3965. Overall, these findings showed that targeting lactate trafficking in TME inhibits metabolic rewiring of tumour PCs, lactate‐dependent immune evasion and thus improving therapy efficacy. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer is a malignant tumor with a poor prognosis and high incidence. Circular RNAs (circRNAs) have been shown to be involved in the pathogenesis of cancers, including esophageal cancer. Here, we explored the precise role of circ_0003340 in esophageal cancer development. Methods: The expression levels of circ_0003340, miR‐874‐3p and enabled homolog (ENAH) were detected by quantitative real‐time polymerase chain reaction and western blot. Subcellular localization and RNase R assays were used to characterize circ_0003340. Cell Counting Kit 8, flow cytometry, transwell assays were used to analyze cell proliferation, apoptosis, migration and invasion. The effect of circ_0003340 on tumor growth was assessed by tumor experiments in vivo. Dual‐luciferase reporter assay was used to analyze the relationship between miR‐874‐3p and circ_0003340 or ENAH. Results: Circ_0003340 was mainly located in the cytoplasm and was upregulated in esophageal cancer tissues and cells. Circ_0003340 knockdown inhibited cell proliferation, migration, invasion, glucose consumption, and lactate production and induced cell apoptosis in esophageal cancer cells. Moreover, circ_0003340 knockdown suppressed tumor growth in vivo. MiR‐874‐3p was reduced in esophageal cancer tissues and cells, and it was a molecular mediator of circ_0003340 function in esophageal cancer cells. ENAH was identified as a direct and functional target of miR‐874‐3p in esophageal cancer cells. The promotion effect of circ_0003340 on ENAH was ameliorated by miR‐874‐3p. Conclusion: The data demonstrated that circ_0003340 promoted the progression of esophageal cancer through miR‐874‐3p/ENAH axis, which might provide novel therapeutic targets for esophageal cancer intervention. [ABSTRACT FROM AUTHOR]

Undernutrition is continued to be significant public health problem worldwide. The extra calories and nutrients required to support breastfeeding make lactating mothers at higher risk of malnutrition than general population. Undernourished lactating mothers have also been found to influence both the quantity and quality of breast milk and then the nutritional and health status of their offspring. Different evidence showed that undernutrition among lactating mothers is a serious public health problem in Ethiopia in which one of every four lactate mothers are undernourished. Despite this fact, the prevalence of undernutrition among lactating women in Ethiopian was not well investigated and very limited number of studies are conducted. This study aims to assess the prevalence of undernutrition and associated factors among lactating mothers in rural Yilmana Densa District, Northwest Ethiopia. A community‐based cross‐sectional study was conducted among 428 lactating mothers. The data were collected by using interviewers administered structured questionnaire; and also, anthropometric measurements were taken from the study participants. Binary logistic regression model was undertaken to identify significantly associated factors with undernutrition. The prevalence of undernutrition among lactating mothers was 22.6%. Household income, food security status, dietary diversity score, number of meals, potable water source, and latrine facility were found to be significantly associated with undernourishment of lactating mothers. A significant proportion of lactating mothers in the district suffered from undernutrition and hence, to improve nutritional status of lactating mothers, strategies should focus on nutrition counseling, advancing diversified production and consumption, improvement of access to potable water and latrine, as well as effective household food security interventions. [ABSTRACT FROM AUTHOR]

Endometriosis is a gynaecological condition characterized by the growth of endometrium‐like tissues within and outside of the pelvic cavity. Recent studies have demonstrated that aberrant infiltration of M2 macrophages is mainly responsible for the establishment of endometriotic lesions. A growing body of evidence shows that glycolysis and lactate accumulation have great impact on the regulation of immunomicroenvironment. However, the communication signal between glycolysis and macrophages is poorly defined in endometriosis. Hereby, we investigate the correlation between glycolysis and M2 macrophage infiltration in endometriosis. Next, we confirm that lactate is pivotal factor that drives macrophage M2‐polarization to promote endometriotic stromal cells invasion in vitro and in vivo. In addition, we also identify that the activation of Mettl3 and its target gene Trib1 promote M2 macrophage polarization. Moreover, we also demonstrate that Trib1 induce M2 macrophage polarization via the activation of ERK/STAT3 signalling pathway. Finally, by injecting 2‐DG into endometriosis mice model, we show that the restrain of glycolysis significantly reduces the progression of endometriosis, which provides evidence for lactate as a potential therapeutic strategy for the prevention and treatment of endometriosis. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the most common malignancy in the world and a growing number of researches have focused on its metabolic characteristics. Studies have shown that the long non‐coding RNA (lncRNA) HOXA11‐AS is aberrantly expressed in many tumors. However, the role of HOXA11‐AS in lung adenocarcinoma (LUAD) glycolysis and other energy metabolism pathways has not been characterized. Method: The mRNA levels of HOXA11‐AS, microRNA‐148b‐3p (miR‐148b‐3p), and pyruvate kinase M2 (PKM2) were detected using qRT‐PCR. The expression levels of proteins were measured using immunohistochemistry and western blot. The CCK‐8, EdU, and colony formation assays were used to assess proliferation. Glycolytic changes were assessed by measuring lactate production, ATP production, and 18F‐FDG uptake. Bioinformatics analysis and dual‐luciferase reporter assays were used to characterize the relationship between HOXA11‐AS, miR‐148b‐3p, and PKM2. Proliferation and glycolytic changes were analyzed in xenograft tumor experiments using Micro‐PET imaging after downregulation of HOXA11‐AS in vivo. Results: The expression of HOXA11‐AS was markedly increased in LUAD, and was strongly associated with a poor prognosis. In addition, HOXA11‐AS promoted proliferation and glycolysis in LUAD, and miR‐148b‐3p inhibited proliferation and glycolysis in LUAD. Mechanistically, HOXA11‐AS positively regulated PKM2 expression by binding to miR‐148b‐3p, thereby promoting LUAD proliferation and glycolysis. In addition, HOXA11‐AS inhibited LUAD xenograft growth and glycolysis via upregulation of miR‐148b‐3p expression and downregulation of PKM2 expression in vivo. Conclusions: These results showed that HOXA11‐AS enhanced LUAD proliferation and glycolysis via the miR‐148b‐3p/PKM2 axis. The findings in this paper expanded our understanding of the molecular mechanisms of LUAD tumorigenesis and glycolysis and showed that HOXA11‐AS could be useful as a diagnostic and prognostic marker for LUAD. 18F‐FDG PET/CT can be used to visually evaluate the therapeutic effect of targeting HOXA11‐AS. [ABSTRACT FROM AUTHOR]

Purpose: Accumulating evidence has highlighted the critical roles of circular RNAs (circRNAs) in non‐small‐cell lung cancer (NSCLC). This study aims to unveil the roles of circRARS (circular RARS) (hsa_circ_0001551) in NSCLC. Methods: Quantitative real‐time PCR was used to determine the expression of circRARS in NSCLC tissues and cells. Kaplan–Meier analysis was used to determine the prognostic value of circRARS expression. CCK8, transwell, and wound healing assays were used to assess the proliferation, invasion, and migration abilities of NSCLC cells. RNA pull‐down, cell fraction, glucose consumption, lactate production, and lactate dehydrogenase activity assays were conducted to explore the potential mechanisms of circRARS in NSCLC. Results: circRARS is upregulated in NSCLC tissues and positively correlated with smoking status, lymph node metastasis, and higher tumor stages. NSCLC patients with high expression of circRARS have poor overall survival. Functional assays demonstrated that circRARS accelerated the proliferation, invasion, and migration of NSCLC cells in vitro. The cell fraction suggested that circRARS mainly accumulated in cytoplasm and the RNA pull‐down assay showed lactate dehydrogenase (LDHA) could bind with circRARS. Furthermore, circRARS positively regulates LDHA activity and LDHA expression at the transcription level. Moreover, downregulated circRARS decreases glucose consumption and lactate production and compromises aerobic glycolysis in NSCLC cells. Finally, rescue assays showed circRARS could promote NSCLC cell proliferation by regulating LDHA activity. Conclusion: This study shows that circRARS can promote glycolysis and tumor progression in NSCLC by regulating LDHA. [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]

Aerobic glycolysis is a well-known hallmark of hepatocellular carcinoma (HCC). Hence, targeting the key enzymes of this pathway is considered a novel approach to HCC treatment. The effects of sodium butyrate (NaBu), a sodium salt of the short-chain fatty acid butyrate, on aerobic glycolysis in HCC cells and the underlying mechanism are unknown. In the present study, data obtained from cell lines with mouse xenograft model revealed that NaBu inhibited aerobic glycolysis in the HCC cells in vivo and in vitro. NaBu induced apoptosis while inhibiting the proliferation of the HCC cells in vivo and in vitro. Furthermore, the compound inhibited the release of lactate and glucose consumption in the HCC cells in vitro and inhibited the production of lactate in vivo. The modulatory effects of NaBu on glycolysis, proliferation and apoptosis were related to its modulation of hexokinase 2 (HK2). NaBu downregulated HK2 expression via c-myc signalling. The upregulation of glycolysis in the HCC cells induced by sorafenib was impeded by NaBu, thereby enhancing the anti-HCC effect of sorafenib in vitro and in vivo. Thus, NaBu inhibits the expression of HK2 to downregulate aerobic glycolysis and the proliferation of HCC cells and induces their apoptosis via the c-myc pathway., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

This study aimed to determine the physiological features and rumen microbial composition associated with the non‐glucogenic‐to‐glucogenic short‐chain fatty acids ratio (NGR). Holstein cows were housed in a free‐stall barn with an automatic milking system and fed a partially mixed ration. Physiological and microbial analyses were performed on 66 datasets collected from 66 cows (50–250 days in milk). NGR was positively correlated with ruminal pH, relative abundances of protozoa and fungi, methane conversion factor, methane intensity, plasma lipids, parity, and milk fat, and negatively correlated with total short‐chain fatty acids. To highlight the differences in bacterial and archaeal compositions between NGRs, low‐NGR cows (N = 22) were compared with medium‐NGR (N = 22) and high‐NGR (N = 22) cows. The low‐NGR group was characterized by a lower abundance of Methanobrevibacter and a higher abundance of operational taxonomic units belonging to the lactate‐producing, such as Intestinibaculum, Kandleria, and Dialister, and the succinate‐producing Prevotella. Our findings indicate that NGR affects the methane conversion factor, methane intensity, and blood and milk compositions. Low NGR is associated with a higher abundance of lactate‐ and succinate‐producing bacteria and lower abundances of protozoa, fungi, and Methanobrevibacter. [ABSTRACT FROM AUTHOR]

Summary: In this case report, we present a rare case of life‐threatening gastrointestinal haemorrhage associated with deranged coagulation due to supratherapeutic levels of dabigatran. Dabigatran is a potent, synthetic, reversible non‐peptide thrombin inhibitor which is increasingly used for stroke prevention in patients with non‐valvular atrial fibrillation. It is generally accepted that dabigatran dosing does not require titration or the monitoring of plasma levels due to its predictable pharmacokinetics and pharmacodynamics. However, this case report challenges this viewpoint while identifying an important knowledge gap in relation to the effect of altered gastrointestinal motility on the absorption of direct oral anticoagulants. Furthermore, it demonstrates the successful use of high‐dose idarucizumab in a critical care setting. Idarucizumab is a monoclonal antibody fragment that binds specifically to dabigatran and its metabolites, thereby reversing the anticoagulant effect. [ABSTRACT FROM AUTHOR]

Candida albicans is a normal resident of humans and also a prevalent fungal pathogen. Lactate, a nonfermentative carbon source available in numerous anatomical niches, can be used by C. albicans as a carbon source. However, the key regulator(s) involved in this process remain unknown. Here, through a genetic screen, we report the identification of a transcription factor Zcf24 that is specifically required for lactate utilization in C. albicans. Zcf24 is responsible for the induction of CYB2, a gene encoding lactate dehydrogenase that is essential for lactate catabolism, in response to lactate. Chromatin immunoprecipitation showed a significantly higher signal of Zcf24 on the CYB2 promoter in lactate‐grown cells than that in glucose‐grown cells. Genome‐wide transcription profiling indicates that, in addition to CYB2, Zcf24 regulates genes involved in the β‐oxidation of fatty acids, iron transport, and drug transport. Surprisingly, deleting ZCF24 confers enhanced commensal fitness. This could be attributed to Crz1‐activated β‐glucan masking in the zcf24 mutant. The orthologs of Zcf24 are distributed in species most closely to C. albicans and some filamentous fungal species. Altogether, Zcf24 is the first transcription factor identified to date that regulates lactate catabolism in C. albicans and it is also involved in the regulation of commensalism. [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]

New Findings: What is the central question of this study?What is the effect of an elevated carboxyhaemoglobin (COHb) concentration following carbon monoxide inhalation on the maximal lactate steady state (MLSS) in humans and is this effect dependent on aerobic fitness?What is the main finding and its importance?An elevated COHb concentration intensified physiological responses to exercise at the MLSS – including heart rate, ventilation and peripheral fatigue – in general and reduced the MLSS (i.e., destabilized the blood lactate concentration) in trained but not untrained males and females. This study investigated whether a lower effective [Hb], induced by carbon monoxide (CO) inhalation, reduces the peak oxygen uptake (V̇O2peak${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$) and the maximal lactate steady state (MLSS) and whether training status explains individual variation in these impairments. Healthy young participants completed two ramp incremental tests (n = 20, 10 female) and two trials at MLSS (n = 16, eight female) following CO rebreathe tests and sham procedures (SHAM) in random orders. All fitness variables were normalized to fat‐free mass (FFM) to account for sex‐related differences in body composition, and males and females were matched for aerobic fitness. The V̇O2peak${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (mean (SD): −4.2 (3.7)%), peak power output (PPO) (−3.3 (2.2)%) and respiratory compensation point (RCP) (−6.3 (4.5)%) were reduced in CO compared with SHAM (P < 0.001 for all), but the gas exchange threshold (−3.3 (7.1)%) was not (P = 0.077). Decreases in V̇O2peak${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (r = −0.45; P = 0.047) and PPO (r = −0.49; P = 0.029) in CO were correlated with baseline aerobic fitness. Compared to SHAM, physiological and perceptual indicators of exercise‐related stress were exacerbated by CO while cycling at MLSS. Notably, the mean blood lactate concentration ([La]) increased (i.e., Δ[La] >1.0 mM) between 10 min (5.5 (1.4) mM) and 30 min (6.8 (1.3) mM; P = 0.026) in CO, with 9/16 participants classified as unstable. These unstable participants had a higher V̇O2peak${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (66.2 (8.5) vs. 56.4 (8.8) ml kg FFM−1 min−1, P = 0.042) and V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ at MLSS (55.8 (7.0) vs. 44.3 (7.0) ml kg FFM−1 min−1, P = 0.006) compared to the stable group. In conclusion, a reduced O2‐carrying capacity decreased maximal and submaximal exercise performance, with higher aerobic fitness associated with greater impairments in both. [ABSTRACT FROM AUTHOR]

Funazushi is a Japanese traditional fermented fish made with boiled rice without the addition of microbial starter cultures. Isolates from various commercial funazushi products, as identified by 16S rDNA sequences, suggested that Lentilactobacillus buchneri strains are major lactic acid bacteria. Based on an analysis of the putative CRISPR (clustered regularly interspaced short palindromic repeat) region, the genetic diversity of L. buchneri strains was examined. The data suggested that the diversity of L. buchneri strains depended on the factories at which funazushi was produced. An analysis of samples during fermentation indicated that the transition of microbes occurred, and L. buchneri was the dominant species. To determine the factors associated with domination, bacteriocin production and environmental stress tolerance, including NaCl and organic acid (lactate and acetate) tolerance, were evaluated. L. buchneri isolates did not produce bacteriocin. Although the isolates did not exhibit NaCl tolerance, they displayed higher lactate tolerance than other lactic acid bacteria isolated during funazushi fermentation. Based on reports that L. buchneri can convert lactate to acetate, the previous and present results suggested that lactate tolerance and lactate conversion in L. buchneri could explain its domination in funazushi. Our study presented a model for the domination mechanisms of specific microbes in fermented foods by spontaneous fermentation. [ABSTRACT FROM AUTHOR]

Summary: A 45‐year‐old man attended to a warehouse fire involving burning plastic, without wearing full protective equipment. He subsequently presented to hospital with shortness of breath and his trachea was intubated for airway protection due to initial concerns of inhalational injury. However, a post‐intubation bronchoscopy was normal. The patient's serum lactate level was normal on admission but was increased when measured 14 h after the initial event and accompanied by a metabolic acidosis. Transdermal cyanide poisoning was suspected given this delayed biochemical presentation and the absence of another apparent cause. A handheld chemical detector detected a high level of toxins on the patient's skin. Clinical improvement was not observed after the first dose of intravenous hydroxocobalamin, which was administered before full body decontamination. After decontamination and the administration of a second dose of hydroxocobalamin, the patient's acid–base status rapidly improved and serum lactate level returned to normal. Clinicians should have a high index of suspicion for transdermal cyanide poisoning in patients presenting after exposure to a fire. [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]

The kinetics for hydrolysis of isoamyl DL‐lactate over cation‐exchange resin NKC‐9 was investigated in this paper, which was the prerequisite for a proper design of reactive distillation processes. The effects of mass transfer resistance, temperature, catalyst dosage, and the molar ratio of water to isoamyl DL‐lactate on conversion of isoamyl DL‐lactate were evaluated. The pseudo‐homogeneous (PH), Eley‐Rideal (ER), and Langmuir‐Hinshelwood (LH) models were then utilized to correlate the data obtained from experiments. Activities were used in the kinetics instead of the mole fractions because the reactants and products were not ideal. The activity coefficients were estimated by UNIFAC. It was demonstrated that the PH model was the best one to describe the hydrolysis of isoamyl DL‐lactate. The standard enthalpy was 5.46 kJ · mol−1 and the activation energy was 59.71 kJ · mol−1. Finally, the thermal stability and reusability of NKC‐9 were also tested. [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]

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]

New Findings: What is the topic of this review?Lactate is considered an important substrate for mitochondria in the muscles, heart and brain during exercise and is the main gluconeogenetic precursor in the liver and kidneys. In this light, we review the (patho)physiology of lactate metabolism in sepsis and coronavirus disease 2019 (COVID‐19).What advances does it highlight?Elevated blood lactate is strongly associated with mortality in septic patients. Lactate seems unrelated to tissue hypoxia but is likely to reflect mitochondrial dysfunction and high adrenergic stimulation. Patients with severe COVID‐19 exhibit near‐normal blood lactate, indicating preserved mitochondrial function, despite a systemic hyperinflammatory state similar to sepsis. In critically ill patients, elevated plasma lactate is often interpreted as a sign of organ hypoperfusion and/or tissue hypoxia. This view on lactate is likely to have been influenced by the pioneering exercise physiologists around 1920. August Krogh identified an oxygen deficit at the onset of exercise that was later related to an oxygen 'debt' and lactate accumulation by A. V. Hill. Lactate is considered to be the main gluconeogenetic precursor in the liver and kidneys during submaximal exercise, but hepatic elimination is attenuated by splanchnic vasoconstriction during high‐intensity exercise, causing an exponential increase in blood lactate. With the development of stable isotope tracers, lactate has become established as an important energy source for muscle, brain and heart tissue, where it is used for mitochondrial respiration. Plasma lactate > 4 mM is strongly associated with mortality in septic shock, with no direct link between lactate release and tissue hypoxia. Herein, we provide evidence for mitochondrial dysfunction and adrenergic stimulation as explanations for the sepsis‐induced hyperlactataemia. Despite profound hypoxaemia and intense work of breathing, patients with severe coronavirus disease 2019 (COVID‐19) rarely exhibit hyperlactataemia (> 2.5 mM), while presenting a systemic hyperinflammatory state much like sepsis. However, lactate dehydrogenase, which controls the formation of lactate, is markedly elevated in plasma and strongly associated with mortality in severe COVID‐19. We briefly review the potential mechanisms of the lactate dehydrogenase elevation in COVID‐19 and its relationship to lactate metabolism based on mechanisms established in contracting skeletal muscle and the acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

Summary: There is a lack of evidence regarding the optimal intra‐operative glycaemic level of patients with ornithine transcarbamylase deficiency to prevent cerebral oedema due to protein catabolism and hyperammonemia. We describe a case of a two‐year‐old girl with ornithine transcarbamylase deficiency who underwent cardiac surgery requiring cardiopulmonary bypass. A high‐dose dextrose infusion to prevent protein catabolism was given throughout surgery, which caused uncontrollable hyperglycaemia unresponsive to high‐dose insulin administration. Factors contributing to the hyperglycaemia may have included surgical stress, steroid administration and hypothermia. During invasive surgery, anaesthetists should carefully adjust the rates of dextrose and insulin infusions, guided by close monitoring of blood ammonia, glucose and lactate. [ABSTRACT FROM AUTHOR]

Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium‐derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial–pericyte proximity is required to facilitate the transport of endothelium‐derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter‐1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood–brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood–brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients. Synopsis: The contribution of circulating nutrients and metabolic pathways to crosstalk between endothelial cells and neurovascular pericytes remains ill‐defined. Here, lactate secreted by endothelial cells is identified as a principle source of carbons fueling pericyte metabolism and maintaining blood‐brain barrier integrity. Endothelium‐derived lactate is utilized for energy production and amino acid synthesis by pericytes in the CNS vasculature in mice.Loss of GLUT1 in endothelial cells reduces lactate secretion and pericyte coverage, increasing blood brain barrier permeability.MCT5 and MCT12 are lactate transporters responsible for shuttling lactate between endothelial cells and pericytes. [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]

Background: Breast cancer is widespread in females. The role of circular RNA (circRNA) in breast cancer has aroused much attention. However, the function of several circRNAs remain unclear. The aim of our study was to determine the role of circ_0001955 in breast cancer. Methods: Quantitative real‐time PCR (qPCR) and western blot was employed for expression analysis of circ_0001955, miR‐1299 and glucose transporter 1 (GLUT1). Cell functions including proliferation, apoptosis, migration, invasion and angiogenesis, were assessed using EdU, flow cytometry, transwell and tube formation assays. Glycolysis metabolism was assessed according to glucose consumption, lactate production and ATP content. Dual‐luciferase reporter assay and RIP assay were utilized to validate the binding between miR‐1299 and circ_0001955 or GLUT1. The effects of circ_0001955 in vivo were observed by animal study. Results: Upregulation of circ_0001955 was detected in breast cancer. Knockdown of circ_0001955 inhibited breast cancer cell proliferation, migration, invasion, angiogenesis and glycolysis. MiR‐1299 was a target of circ_0001955, and its repression reversed the effects of circ_0001955 knockdown. Moreover, circ_0001955 targeted miR‐1299 to positively regulate GLUT1 expression. GLUT1 overexpression reversed the effects of miR‐1299 enrichment. GLUT1 knockdown was verified to block tumor growth in vivo. Conclusions: Circ_0001955 was found to promote breast cancer malignant development via targeting of the miR‐1299/GLUT1 pathway, which contributes to our understanding of the pathogenesis of breast cancer. [ABSTRACT FROM AUTHOR]

A kind of organic magnesium salt, water-soluble magnesium lactate, was used as the MgO-precursor in new forms to identify the particular impact of additive dispersity on properties of calcium aluminate cement (CAC)-bonded castables, especially the volume stability. Magnesium lactate could dissolve in water in the mixing process, distribute uniformly, and decompose during heating, providing space for counterbalancing the expansion from in-situ calcium aluminates and MgAl2O4 spinel generation. Hence, in this study, CAC-bonded castables containing 0-1.2 wt% magnesium lactate were prepared. The volume stability and thermo-mechanical strength of castables were tested. Results show that the dissolution of magnesium lactate in water distinctly enhances the volume stability of castables. To understand the underlying mechanism of water-soluble magnesium lactate on the samples, phase compositions and microstructure development of castable matrices were examined. [ABSTRACT FROM AUTHOR]

Lactate ion sensing has emerged as a process that regulates ventilation during metabolic challenges. Most work has focused on peripheral sensing of lactate for the control of breathing. However, lactate also rises in the central nervous system (CNS) during disturbances to blood gas homeostasis and exercise. Using an amphibian model, we recently showed that lactate ions, independently of pH and pyruvate metabolism, act directly in the brainstem to increase respiratory‐related motor outflow. This response had a long washout time and corresponded with potentiated excitatory synaptic strength of respiratory motoneurons. Thus, we tested the hypothesis that lactate ions enhance respiratory output using cellular mechanisms associated with long‐term synaptic plasticity within motoneurons. In this study, we confirm that 2 mM sodium lactate, but not sodium pyruvate, increases respiratory motor output in brainstem‐spinal cord preparations, persisting for 2 h upon the removal of lactate. Lactate also led to prolonged increases in the amplitude of AMPA‐glutamate receptor (AMPAR) currents in individual motoneurons from brainstem slices. Both motor facilitation and AMPAR potentiation by lactate required classic effectors of synaptic plasticity, L‐type Ca2+ channels and NMDA receptors, as part of the transduction process but did not correspond with increased expression of immediate‐early genes often associated with activity‐dependent neuronal plasticity. Altogether these results show that lactate ions enhance respiratory motor output by inducing conserved mechanisms of synaptic plasticity and suggest a new mechanism that may contribute to coupling ventilation to metabolic demands in vertebrates. Key points: Lactate ions, independently of pH and metabolism, induce long‐term increases in respiratory‐related motor outflow in American bullfrogs.Lactate triggers a persistent increase in strength of AMPA‐glutamatergic synapses onto respiratory motor neurons.Long‐term plasticity of motor output and synaptic strength by lactate involves L‐type Ca2+ channels and NMDA‐receptors as part of the transduction process.Enhanced AMPA receptor function in response to lactate in the intact network is causal for motor plasticity.In sum, well‐conserved synaptic plasticity mechanisms couple the brainstem lactate ion concentration to respiratory motor drive in vertebrates. [ABSTRACT FROM AUTHOR]

Background: Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase‐positive non‐small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requires further investigation. Methods: The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis. Results: ALK+ NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK− NSCLC cells. Long‐term exposure to crizotinib could decrease the sensitivity of ALK+ NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases II (HK2). Crizotinib in combination with glycolysis inhibitor 2‐deoxy‐D‐glucose (2DG) synergistically inhibited proliferation, glycolysis, colony formation and invasion ability of ALK+ NSCLC cells. 2DG sensitization crizotinib might be associated with the inhibition of HK2‐mediated glycolysis and P‐ALK/AKT/mTOR signaling pathway in H3122 and H2228 cells. Conclusions: These results indicate that HK2‐mediated glycolysis plays a crucial role in the increased tolerance of ALK+ NSCLC cells to crizotinib. 2DG may sensitize ALK+ NSCLC to crizotinib via suppression of HK2‐mediated glycolysis and the AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Increasing evidence has demonstrated that lactate and adenosine triphosphate (ATP) both play important roles in regulating abnormal metabolism in the tumor microenvironment. Herein, an O2 self‐supplying catalytic nanoagent, based on tannic acid (TA)–Fe(III) coordination complexes‐coated perfluorooctyl bromide (PFOB) nanodroplets with lactate oxidases (LOX) loading (PFOB@TA–Fe(III)–LOX, PTFL), is designed for cascade metabolic‐chemodynamic therapy (CDT) by dual‐depletion of lactate and ATP with hydroxyl •OH radicals generation. Benefiting from the catalytic property of loaded LOX and O2 self‐supplying of PFOB nanodroplets, PTFL nanoparticles (NPs) efficiently deplete tumoral lactate for down‐regulation of vascular endothelial growth factor expression and supplement the insufficient endogenous H2O2. Simultaneously, TA–Fe(III) complexes release Fe(III) ions and TA in response to intracellular up‐regulated ATP in tumor cells followed by TA‐mediated Fe(III)/Fe(II) conversion, leading to the depletion of energy source ATP and the generation of cytotoxic •OH radicals from H2O2. Moreover, TA–Fe(III) complexes provide photoacoustic contrast as imaging guidance to enhance therapeutic accuracy. As a result, PTFL NPs efficiently accumulate in tumors for suppression of tumor growth and show evidence of anti‐angiogenesis and anti‐metastasis effects. This multifunctional nanoagent may provide new insight for targeting abnormal tumor metabolism with the combination of CDT to achieve a synergistic therapeutic effect. [ABSTRACT FROM AUTHOR]

Objective: In rheumatoid arthritis (RA), elevated serum interleukin‐34 (IL‐34) levels are linked with increased disease severity. IL‐34 binds to 2 receptors, macrophage colony‐stimulating factor receptor (M‐CSFR) and syndecan 1, which are coexpressed in RA macrophages. Expression of both IL‐34 and syndecan 1 is strikingly elevated in the RA synovium, yet their mechanisms of action remain undefined. This study was undertaken to investigate the mechanism of action of IL‐34 in RA. Methods: To characterize the significance of IL‐34 in immunometabolism, its mechanism of action was elucidated in joint macrophages, fibroblasts, and T effector cells using RA and preclinical models. Results: Intriguingly, syndecan 1 activated IL‐34–induced M‐CSFR phosphorylation and reprogrammed RA naive cells into distinctive CD14+CD86+GLUT1+ M34 macrophages that expressed elevated levels of IL‐1β, CXCL8, and CCL2. In murine M34 macrophages, the inflammatory phenotype was accompanied by potentiated glycolytic activity, exhibited by transcriptional up‐regulation of GLUT1, c‐Myc, and hypoxia‐inducible factor 1α (HIF‐1α) and amplified pyruvate and l‐lactate secretion. Local expression of IL‐34 provoked arthritis by expanding the glycolytic F4/80‐positive, inducible nitric oxide synthase (iNOS)–positive macrophage population, which in turn attracted fibroblasts and polarized Th1/Th17 cells. The cross‐talk between murine M34 macrophages and Th1/Th17 cells broadened the inflammatory and metabolic phenotypes, resulting in the expansion of IL‐34 pathogenicity. Consequently, IL‐34–instigated joint inflammation was alleviated in RAG−/− mice compared to wild‐type mice. Syndecan 1 deficiency attenuated IL‐34–induced arthritis by interfering with joint glycolytic M34 macrophage and osteoclast remodeling. Similarly, inhibition of glycolysis by 2‐deoxy‐d‐glucose reversed the joint swelling and metabolic rewiring triggered by IL‐34 via HIF‐1α and c‐Myc induction. Conclusion: IL‐34 is a novel endogenous factor that remodels hypermetabolic M34 macrophages and facilitates their cross‐regulation with T effector cells to advance inflammatory bone destruction in RA. [ABSTRACT FROM AUTHOR]

The contribution of glucose absorbed from the small intestine to whole-body glucose metabolism was examined in ewes during late pregnancy and early lactation, using diets based on ground barley or ground maize. Glucose and L-lactate turnover in the whole body and the mesenteric-drained viscera were investigated in these ewes using isotope dilution techniques. The net absorption of glucose by the mesenteric-drained viscera and whole-body glucose turnover were unaffected by diet or reproductive status. Arterial and mesenteric venous blood glucose concentrations, arterial and mesenteric venous L-lactate concentrations and whole-body lactate turnover were all significantly higher in lactation than in pregnancy. The whole-body rates of lactate conversion to glucose and to other products were significantly higher in lactation than in pregnancy. Using a two-pool model of whole-body glucose and lactate metabolism, a relatively high percentage of glucose was converted to lactate (64-84%), accounting for 60-80% of whole-body lactate turnover. A model of glucose and lactate metabolism by the mesenteric-drained viscera was constructed. Both the calculated endogenous glucose production and the visceral conversion of glucose to lactate were greater in lactation than in pregnancy when barley was fed. Calculated total glucose absorption was relatively constant, contributing between 26 and 59% of whole-body glucose turnover. Diet had little effect on glucose and lactate metabolism in either the mesenteric-drained viscera or the whole-body of breeding ewes.

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]

Recent investigations reveal that lactate is not a waste product but a major energy source for cells, especially in the mitochondria, which can support cellular survival under glucose shortage. Accordingly, the new understanding of lactate prompts to target it together with glucose to pursue a more efficient cancer starvation therapy. Herein, zeolitic imidazolate framework‐8 (ZIF‐8) nanoplatforms are used to co‐deliver α‐cyano‐4‐hydroxycinnamate (CHC) and glucose oxidase (GOx) and fulfill the task of simultaneous depriving of lactate and glucose, resulting in a new nanomedicine CHC/GOx@ZIF‐8. The synthesis conditions are carefully optimized in order to yield monodisperse and uniform nanomedicines, which will ensure reliable and steady therapeutic properties. Compared with the strategies aiming at a single carbon source, improved starvation therapy efficacy is observed. Besides, more than boosting the energy shortage, CHC/GOx@ZIF‐8 can block the lactate‐fueled respiration and relieve solid tumor hypoxia, which will enhance GOx catalysis activity, depleting extra glucose, and producing more cytotoxic H2O2. By the synergistically enhanced anti‐tumor effect, both in vitro and in vivo cancer‐killing efficacies of CHC/GOx@ZIF‐8 show twice enhancements than the GOx mediated therapy. The results demonstrate that the dual‐depriving of lactate and glucose is a more advanced strategy for strengthening cancer starvation therapy. [ABSTRACT FROM AUTHOR]

Lactate is considered to be a signaling molecule that induces mitochondrial adaptation and muscle hypertrophy. The purpose of this study was to examine whether lactate administration attenuates denervation‐induced loss of mitochondrial content and muscle mass. Eight‐week‐old male Institute of Cancer Research mice underwent unilateral sciatic nerve transection surgery. The contralateral hindlimb served as a sham‐operated control. From the day of surgery, mice were injected intraperitoneally with PBS or sodium lactate (equivalent to 1 g·kg−1 body weight) once daily for 9 days. After 10 days of denervation, gastrocnemius muscle weight decreased to a similar extent in both the PBS‐ and lactate‐injected groups. Denervation significantly decreased mitochondrial enzyme activity, protein content, and MCT4 protein content in the gastrocnemius muscle. However, lactate administration did not have any significant effects. The current observations suggest that daily lactate administration for 9 days does not affect denervation‐induced loss of mitochondrial content and muscle mass. [ABSTRACT FROM AUTHOR]

Many metabolic phenotypes in cancer cells are also characteristic of proliferating nontransformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)‐driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched‐chain amino acids to the TCA cycle and lipogenesis increased in the near‐quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF‐stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS‐expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate and provide a model to distinguish the metabolic influences of oncogenic mutations and nononcogenic growth. [ABSTRACT FROM AUTHOR]

Gastric cancer is the fifth most common malignancy and the third most deadly tumor in the world. Zinc finger protein 479 (ZNF479) has been demonstrated to play crucial roles in hepatocellular carcinoma. However, the function of ZNF479 in gastric cancer remains to be clarified. The current study aimed to investigate the role of ZNF479 in gastric cancer progression and elucidate the potential molecular mechanism. In this study, Cell Count Kit‐8 and colony formation assays demonstrated that knockdown of ZNF479 inhibited cell proliferation in AGS and SGC‐7901 cells. Of note, knockdown of ZNF479 hinders tumor growth of xenograft tumor mice. What is more, knockdown of ZNF479 inhibited glucose uptake, lactate production, adenosine triphosphate level, and extracellular acidification ratio; increased oxygen consumption ratio in gastric cancer cells; and decreased the expression of glycolytic proteins both in vitro and in vivo. Furthermore, analysis mechanism suggests that ZNF479 participated in the regulation of gastric cancer progression through affecting the β‐catenin/c‐Myc signaling pathway. Collectively, ZNF479 plays a role as an oncogene through modulating β‐catenin/c‐Myc signaling pathway in the development of gastric cancer, which provides a new research target for future studies. [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.

We have previously reported a novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits cytoprotective activities in vitro. Here, we investigated the effects and underlying mechanisms of DSC on dextran sodium sulphate (DSS)-induced experimental colitis. We found that DSC treatment afforded significant protection against the development of colitis, evidencing by suppressed inflammatory responses and enhanced barrier integrity. Intriguingly, DSC specifically down-regulated DSS-induced colonic NADPH oxidase 4 (Nox4) expression, accompanied by a balanced redox status, suppressed nuclear factor-κB (NF-κB) and NLRP3 inflammasome activation and up-regulated nuclear factor (erythroid-derived 2)-like 2 and haeme oxygenase-1 expression. In vitro study also demonstrated DSC also markedly decreased Nox4 expression and activity associated with inhibiting reactive oxygen species generation, NF-κB activation and NLRP3 inflammasome activation in bone marrow-derived macrophages. Either lentiviral Nox4 shRNA-mediated Nox4 knockdown or Nox4-specific small-interfering RNA mimicked effects of DSC by suppressing NLPR3 inflammasome activation to alleviate experimental colitis or inflammatory macrophage response. Collectively, our results provide the first evidence that DSC ameliorates experimental colitis partly through modulating Nox4-mediated NLRP3 inflammasome activation., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Recent studies have shown perturbed gut microbiota associated with gouty arthritis, a metabolic disease characterized by an imbalance between uric acid production and excretion. To mechanistically investigate altered microbiota metabolism associated with gout disease, 16S rRNA gene amplicon sequence data from stool samples of gout patients and healthy controls were computationally analyzed through bacterial community metabolic models. Patient‐specific community models constructed with the metagenomics modeling pipeline, mgPipe, were used to perform k‐means clustering of samples according to their metabolic capabilities. The clustering analysis generated statistically significant partitioning of samples into a Bacteroides‐dominated, high gout cluster and a Faecalibacterium‐elevated, low gout cluster. The high gout cluster was predicted to allow elevated synthesis of the amino acids D‐alanine and L‐alanine and byproducts of branched‐chain amino acid catabolism, while the low gout cluster allowed higher production of butyrate, the sulfur‐containing amino acids L‐cysteine and L‐methionine, and the L‐cysteine catabolic product H2S. By expanding the capabilities of mgPipe to provide taxa‐level resolution of metabolite exchange rates, acetate, D‐lactate and succinate exchanged from Bacteroides to Faecalibacterium were predicted to enhance butyrate production in the low gout cluster. Model predictions suggested that sulfur‐containing amino acid metabolism generally and H2S more specifically could be novel gout disease markers. [ABSTRACT FROM AUTHOR]