Search

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

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]

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

S‐nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumor suppressor role, although the mechanisms responsible are still largely unclear. In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR‐low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8+ T cells. Notably, GSNOR‐low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR‐Cas9‐mediated generation of GSNOR gene knockout (KO) CRC cells confirmed in vitro and in vivo that GSNOR‐deficiency conferred higher tumorigenic and tumor‐initiating capacities. Moreover, GSNOR‐KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR‐KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2‐deoxyglucose (2DG), and a fragmented mitochondrial network. Real‐time metabolic analysis revealed that GSNOR‐KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient‐derived xenografts and organoids from clinical GSNOR‐low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

This article, published in Equine Veterinary Education, discusses the presence of increased peritoneal fluid lactate (PFL) in colic cases that were treated medically and survived to discharge. The study evaluated case records from horses with colic admitted to two veterinary hospitals in South Africa and the United Kingdom. The results showed that horses with severely increased PFL were able to survive with medical therapy alone, suggesting that the decision to recommend surgery for colic patients should not solely rely on PFL levels. However, it is important to note that this study has limitations, including a small sample size and variations in breeds, age, and sex of the horses. [Extracted from the article]

Currently available point‐of‐care systems for body fluid collection exhibit poor integration with sensors. Herein, the design of a disposable device for interstitial fluid (ISF) extraction as well as glucose, lactate, and potassium ion (K+) monitoring is reported on. It is minimally invasive and appropriate for single use, minimizing the risk of infection to the user. This microscale device contains a 3D‐printed cap‐like structure with a four‐by‐four microneedle (MN) array, bioreceptor‐modified carbon fiber (CF)‐sensing surface, and negative pressure convection technology. These features are incorporated within a compact, self‐contained, and manually operated microscale device, which is capable of withdrawing ≈3.0 μL of ISF from the skin. MN arrays applied with an upward driving force may increase the ISF flow rate. Moreover, functionalized CF working electrodes (WE1, WE2, WE3) are shown to selectively detect lactate, glucose, and K+ with high sensitivities of 0.258, 0.549, and 0.657 μA μm−1 cm−2 and low detection limits of 0.01, 0.080, 0.05 μm, respectively. Ex vivo testing on porcine skin is used to detect the ISF levels of the biomarkers. The microscale device can be a replacement for current point‐of‐care diagnostic approaches. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to explore whether hexokinase 1 (HK1) is involved in the inhibition of inflammation mediated by nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) signalling pathway in the development of apical periodontitis (AP). Methodology: Human AP tissues and normal control tissues were collected in the clinic. First, the levels of glucose, pyruvate, lactate and hexokinase activity were examined in human AP tissues. ECAR and OCR were further measured to detect the level of glycolysis in vitro model of inflammation, which established with lipopolysaccharide (LPS)‐stimulated RAW264.7 cell line. Secondly, the expression of HK1, NLRP3, caspase‐1 and interleukin (IL)‐1β were measured by Western blot, immunohistochemistry or RT–qPCR. Finally, lentiviral short hairpin RNA (shRNA) silencing technique or the inhibitor 2‐deoxy‐d‐glucose (2‐DG) were used to further detect the relationship between HK1‐mediated glycolysis and NLRP3‐mediated inflammation in the development of AP in vitro. Results: Initially, the level of glycolysis was significantly increased in human AP tissues. Subsequently, the expression of HK1, NLRP3, caspase‐1 and IL‐1β were upregulated significantly in human AP tissues. Furthermore, in the model of AP in vitro, a high level of glycolysis and the high expression of HK1, NLRP3, caspase‐1 and IL‐1β was observed. Finally, the expression of NLRP3, caspase‐1 and IL‐1β mediated by LPS stimulation was significantly reduced via HK1 knockdown or 2‐DG treatment in vitro. Conclusions: Our data support that HK1‐mediated glycolysis plays a crucial role in the development of AP via upregulating the NLRP3 signalling pathway. Moreover, targeting HK1 may contribute to prevent the progression of AP, which has a potential clinical translation. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) remains an incurable haematological malignancy despite substantial advances in therapy. Hypoxic bone marrow induces metabolic rewiring in MM cells contributing to survival and drug resistance. Therefore, targeting metabolic pathways may offer an alternative treatment option. In this study, we repurpose two FDA‐approved drugs, syrosingopine and metformin. Syrosingopine was used as a dual inhibitor of monocarboxylate transporter 1 and 4 (MCT1/4) and metformin as an inhibitor for oxidative phosphorylation (OXPHOS). Anti‐tumour effects were evaluated for single agents and in combination therapy. Survival and expression data for MCT1/MCT4 were obtained from the Total Therapy 2, Mulligan, and Multiple Myeloma Research Foundation cohorts. Cell death, viability, and proliferation were measured using Annexin V/7‐AAD, CellTiterGlo, and BrdU, respectively. Metabolic effects were assessed using Seahorse Glycolytic Rate assays and LactateGlo assays. Differential protein expression was determined using western blotting, and the SUnSET method was implemented to quantify protein synthesis. Finally, the syngeneic 5T33MMvv model was used for in vivo analysis. High‐level expression of MCT1 and MCT4 both correlated with a significantly lower overall survival of patients. Lactate production as well as MCT1/MCT4 expression were significantly upregulated in hypoxia, confirming the Warburg effect in MM. Dual inhibition of MCT1/4 with syrosingopine resulted in intracellular lactate accumulation and reduced cell viability and proliferation. However, only at higher doses (>10 μm) was syrosingopine able to induce cell death. By contrast, combination treatment of syrosingopine with metformin was highly cytotoxic for MM cell lines and primary patient samples and resulted in a suppression of both glycolysis and OXPHOS. Moreover, pathway analysis revealed an upregulation of the energy sensor p‐AMPKα and more downstream a reduction in protein synthesis. Finally, the combination treatment resulted in a significant reduction in tumour burden in vivo. This study proposes an alternative combination treatment for MM and provides insight into intracellular effects. © 2023 The Pathological Society of Great Britain and Ireland. [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: Periodontal ligament cells (PDLCs), as mesenchymal cells in the oral cavity, are closely linked to periodontal tissue regeneration. However, the effect of local glucose deficiency on periodontal tissue regeneration, such as immediately post‐surgery, remains unknown. Objective: In the present study, we investigated the effect of a low‐glucose environment on the proliferation and osteogenic differentiation of PDLCs. Materials and Methods: We used media with five glucose concentrations (100, 75, 50, 25, and 0 mg/dL) and focused on the effects of a low‐glucose environment on the proliferation, osteogenic differentiation, and autophagy of PDLCs. Additionally, we focused on changes in lactate production in a low‐glucose environment and investigated the involvement of lactate with AZD3965, a monocarboxylate transporter‐1 (MCT‐1) inhibitor. Results: The low‐glucose environment inhibited PDLCs proliferation, migration, and osteogenic differentiation, and induced the expression of the autophagy‐related factors LC3 and p62. Lactate and ATP production were decreased under low‐glucose conditions. The addition of AZD3965 (MCT‐1 inhibitor) in normal glucose conditions caused a similar trend as in low‐glucose conditions on PDLCs. Conclusion: Our results suggest lactate production through glucose metabolism in the osteogenic differentiation of PDLCs. A low‐glucose environment decreased lactate production, inhibiting cell proliferation, migration, and osteogenic differentiation and inducing autophagy in PDLCs. [ABSTRACT FROM AUTHOR]

Background: Whole blood (WB) reigns superior to component therapy for the treatment of hemorrhagic shock on the battlefield. Though cold storage of WB offers a shelf life of 21 to 35 days, storage lesions and the potential for blood wastage remain. Storing WB in an additive solution (AS) containing apoptotic inhibitors may help preserve blood cell viability and improve blood quality over extended cold storage. Study Design and Methods: Non‐leukoreduced WB was obtained from healthy individuals and dosed with: AS, AS+Necrostatin‐1 (AS+N1), AS+Boc‐D‐fmk (AS+B; apoptosis inhibitor), AS+Q‐VD‐OPh (AS+Q; apoptosis inhibitor), and Control (0.9% saline). Blood bags were kept refrigerated (1°–6°C) for 21 days. Bags were tested on days 0, 7, 14, and 21 for complete blood count, metabolism, clot formation, aggregation function, platelet activation, and red blood cell quality. Results: Platelet count was better preserved in all AS‐containing samples. All groups displayed increased glucose consumption and lactate production with storage. Furthermore, all groups displayed a similar decline in clot strength (max amplitude) over the 21‐day storage period. Bags that received AS displayed greater preservation of GPIIb expression and lower phosphatidylserine exposure. P‐selectin expression was increased in all AS groups. Discussion: Treatment of hemorrhagic shock with WB transfusion is logistically simpler than component therapy. Results from our study suggest that refrigerated WB stored with an AS containing apoptotic and necrotic inhibitors helps better preserve platelet count but does not improve platelet function. The future development of WB ASs is warranted to optimize both platelet quality and hemostatic function. [ABSTRACT FROM AUTHOR]

Background: The Trichosporonaceae family comprises a large number of basidiomycetes widely distributed in nature. Some of its members, especially Trichosporon asahii, have the ability to cause human infections. This ability is related to a series of virulence factors, which include lytic enzymes production, biofilm formation, resistance to oxidising agents, melanin and glucuronoxylomannan in the cell wall, metabolic plasticity and phenotypic switching. The last two are poorly addressed within human pathogenic Trichosporonaceae. Objective: These factors were herein studied to contribute with the knowledge of these emerging pathogens and to uncover mechanisms that would explain the higher frequency of T. asahii in human infections. Methods: We included 79 clinical isolates phenotypically identified as Trichosporon spp. and performed their molecular identification. Lactate and N‐acetyl glucosamine were the carbon sources of metabolic plasticity studies. Morphologically altered colonies after subcultures and incubation at 37°C indicated phenotypic switching. Results and Conclusion: The predominant species was T. asahii (n = 65), followed by Trichosporon inkin (n = 4), Apiotrichum montevideense (n = 3), Trichosporon japonicum (n = 2), Trichosporon faecale (n = 2), Cutaneotrichosporon debeurmannianum (n = 1), Trichosporon ovoides (n = 1) and Cutaneotrichosporon arboriforme (n = 1). T. asahii isolates had statistically higher growth on lactate and N‐acetylglucosamine and on glucose during the first 72 h of culture. T. asahii, T. inkin and T. japonicum isolates were able to perform phenotypic switching. These results expand the virulence knowledge of Trichosporonaceae members and point for a role for metabolic plasticity and phenotypic switching on the trichosporonosis pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of inhaling a beta-agonist (salbutamol) compared to placebo on skiing and cycling performance in well-trained elite athletes. Methods: Three different exercise protocols were used, all with a cross-over double blind placebo-controlled design. Participants inhaled 800 µg salbutamol or a placebo prior to the test, which was repeated on a following day with the participants inhaling the other substance. Fifteen junior elite skiers performed four free-style high intensity sprints (1100 m/work time 3.5–4.5 min). Twelve elite cyclists carried out a short cycling protocol, starting with two 5 min submaximal workloads followed by a maximal intermittent performance test to exhaustion. Another 12 elite cyclists performed the maximal intermittent performance test to exhaustion after a 150 min long submaximal cycling protocol. Results: Group mean time for the ski sprints increased, with no difference between treatment groups. In the short cycling protocol time to exhaustion was 9.1% (95% CI 52–161) lower after inhaling salbutamol compared to placebo and in the long cycling protocol time to exhaustion was 9.1% (95% CI – 121–267) lower after inhaling salbutamol compared to placebo. Blood lactate, heart rate and ventilation increased during submaximal exercise with salbutamol compared to placebo in the short cycling protocol (p <.05). Conclusion: This study could not confirm any positive performance effects from inhaling 800 µg salbutamol compared to placebo in skiing and high-intensity intermittent cycling performance. Instead, time to exhaustion in the maximal intermittent performance test was lower in both cycling protocols. Highlights There was no difference in performance time between salbutamol and placebo treatment in real-life applicable repeated ski sprints. Time to exhaustion in the maximal intermittent performance test was 9.1% lower after inhaling salbutamol compared to placebo, both when performed after 10 and 150 min of submaximal cycling. [ABSTRACT FROM AUTHOR]

The main aim of this study was to examine the influence of ischemic preconditioning (IPC) on maximal accumulated oxygen deficit (MAOD). We conducted a three-arm and assessor-blinded randomized, controlled crossover study. Sixteen 400-meter running male athletes (19.9 ± 1.3 years; 1.78 ± 0.05 m; 67.9 ± 5.5 kg) completed three supramaximal intensity tests separated with Control, Local (legs), and Remote (arms) IPC interventions. IPC was induced on the limbs on both sides (4×5 min alternating unilateral occlusion 220 mmHg and reperfusion; arms or thighs; right side first) before participants performed the supramaximal intensity test on a treadmill at 110% VO2max intensity to exhaustion. During each test, indices of respiratory gas exchange, blood lactate, and heart rate were determined. The MAOD was calculated as the difference between the theoretical VO2 demand and the actual VO2 during the supramaximal intensity test. Differences from three trials were analyzed using ANOVA with repeated measures. IPC increased MAOD (RIPC, 59 ± 17 ml/kg/min, p = 0.018; LIPC, 57 ± 15 ml/kg/min, p = 0.037; p < 0.05) compared with Control (49 ± 9 ml/kg/min). Time to exhaustion was enhanced after IPC (Control: 257.2 ± 69.5 s, RIPC, 292.3 ± 66.6 s, p = 0.048; LIPC, 291.6 ± 79.2 s, p = 0.042; p < 0.05). In contrast, the enhancements of RIPC and LIPC trials were similar (p = 1.000). Blood lactate concentrations were similar across the three intervention conditions (p > 0.05). Acute IPC improved MAOD and supramaximal intensity exercise capacity in 400-meter running athletes. The increased MAOD indicated greater anaerobic capacity, which can be the potential mediator for improvement in exhaustion time. Highlights Ischemic preconditioning may improve the exhaustion time of supramaximal intensity running in well-trained 400-meter middle distance athletes. Acute IPC may be beneficial to anaerobic exercise capacity as the maximal accumulated oxygen deficit increases after IPC. Acute IPC occlusion on the upper arms or thighs may improve anaerobic capacity. [ABSTRACT FROM AUTHOR]

Patients admitted to intensive care after cardiac arrest are at risk of circulatory shock and early mortality due to cardiovascular failure. The aim of this study was to evaluate the ability of the veno‐arterial pCO2 difference (∆pCO2; central venous CO2 – arterial CO2) and lactate to predict early mortality in postcardiac arrest patients. This was a pre‐planned prospective observational sub‐study of the target temperature management 2 trial. The sub‐study patients were included at five Swedish sites. Repeated measurements of ∆pCO2 and lactate were conducted at 4, 8, 12, 16, 24, 48, and 72 h after randomization. We assessed the association between each marker and 96‐h mortality and their prognostic value for 96‐h mortality. One hundred sixty‐three patients were included in the analysis. Mortality at 96 h was 17%. During the initial 24 h, there was no difference in ∆pCO2 levels between 96‐h survivors and non‐survivors. ∆pCO2 measured at 4 h was associated with an increased risk of death within 96 h (adjusted odds ratio: 1.15; 95% confidence interval [CI]: 1.02–1.29; p =.018). Lactate levels were associated with poor outcome over multiple measurements. The area under the receiving operating curve to predict death within 96 h was 0.59 (95% CI: 0.48–0.74) and 0.82 (95% CI: 0.72–0.92) for ∆pCO2 and lactate, respectively. Our results do not support the use of ∆pCO2 to identify patients with early mortality in the postresuscitation phase. In contrast, non‐survivors demonstrated higher lactate levels in the initial phase and lactate identified patients with early mortality with moderate accuracy. [ABSTRACT FROM AUTHOR]

Lactate is one of the major biomarkers to assess the physical fitness of human in clinical or sports medicine. The proper and well‐timed lactate determination can avoid some exigent conditions including hemorrhage, respiratory distress, sepsis, and hypoxia. Therefore, rapid, facile, selective, and reliable detection of lactate have gained appreciation lately. Among the various lactate detection methods, electrochemical method is the most rapid, convenient, and sensitive technique. Specifically, nanomaterial‐based nonenzymatic electrochemical lactate sensors are much desirable to solve the demerits and stability issues of enzymatic lactate sensors. Numerous materials including metal and metal oxide nanoparticles, metal–organic frameworks, molecularly imprinted polymers, and carbons were used as electrocatalysts to achieve highly sensitive lactate sensors. This present review mainly focuses on the recent developments of these materials for enzyme‐free lactate oxidation and the future prospective of electrode modification catalysts for lactate sensors. [ABSTRACT FROM AUTHOR]

Recent studies have shown that activation of the cGAS‐STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX‐2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX‐2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD‐1 expression on tumor‐infiltrating T‐cells and enhanced T‐cell activation in tumor‐draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4+CD25+Foxp3+ regulatory T‐cells, it enhanced the expression of costimulatory molecules and glycolysis‐associated genes in tumor‐infiltrating CD11b+Ly6G+ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN‐γ‐ and TNF‐α‐producing CD8+ T‐cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists. [ABSTRACT FROM AUTHOR]

Amphiphilic boronic acid (BA)‐substituted block copolymers have been utilized in biomedical applications through binding to saccharides, including to glucose whereas binding to the anaerobically produced metabolite lactate is unreported. Glucose requires basic conditions, while lactate binding occurs at neutral physiological conditions. Herein, BA binding to glucose and lactate is used for the first time to convert solvated hydrophobic homopolymer and hydrophobic block copolymers to amphiphilic core‐shell nanoparticle spheres and worms. [ABSTRACT FROM AUTHOR]

Background: The evaluation of performance in endurance athletes and the subsequent individualisation of training is based on the determination of individual physiological thresholds during incremental tests. Gas exchange or blood lactate analysis are usually implemented for this purpose, but these methodologies are expensive and invasive. The short-term scaling exponent alpha 1 of detrended Fluctuation Analysis (DFA-α1) of the Heart Rate Variability (HRV) has been proposed as a non-invasive methodology to detect intensity thresholds. Purpose: The aim of this study is to analyse the validity of DFA-α1 HRV analysis to determine the individual training thresholds in elite cyclists and to compare them against the lactate thresholds. Methodology: 38 male elite cyclists performed a graded exercise test to determine their individual thresholds. HRV and blood lactate were monitored during the test. The first (LT1 and DFA-α1-0.75, for lactate and HRV, respectively) and second (LT2 and DFA-α1-0.5, for lactate and HRV, respectively) training intensity thresholds were calculated. Then, these points were matched to their respective power output (PO) and heart rate (HR). Results: There were no significant differences (p > 0.05) between the DFA-α1-0.75 and LT1 with significant positive correlations in PO (r = 0.85) and HR (r = 0.66). The DFA-α1-0.5 was different against LT2 in PO (p = 0.04) and HR (p = 0.02), but it showed significant positive correlation in PO (r = 0.93) and HR (r = 0.71). Conclusions: The DFA1-a-0.75 can be used to estimate LT1 non-invasively in elite cyclists. Further research should explore the validity of DFA-α1-0.5. Highlights The power and heart rate values derived from the DFA-α1-0.75 threshold showed high levels of validity and agreement when they were compared against the first lactate threshold. The second lactate threshold and the DFA-α1-0.5 were different (p < 0.05) but showed high levels of correlation. The detrended fluctuation analysis is a valid method to estimate the first lactate threshold and more studies are needed to verify its validity with the second lactate threshold. [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]

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]

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]

BACKGROUND: During high‐cell‐density culture of Lactobacillus fermentum, the optimal pH is often maintained by adding NaOH. During cultivation at controlled pH, L. fermentum experiences osmotic stress due to the continuous accumulation of sodium lactate as a neutralizer product, affecting its survival in subsequent processing. The purpose of this study was to evaluate the nutrient consumption patterns of L. fermentum ATCC 14931 under sodium lactate stress and to screen nutrients that help it resist osmotic stress. RESULTS: The consumption and consumption rates of amino acids, purines, pyrimidines, vitamins, and metal ions were analyzed in chemically defined media containing 0.13, 0.31, or 0.62 mm L−1 sodium lactate. The highest consumption rates were found for arginine, guanine, folic acid, and Mn2+, and the most consumed nutrients were glutamate + glutamine, guanine, ascorbic acid, and Na+. Arginine 2.58 mm L−1, guanine 0.23 mm L−1, and Mn2+ 0.25 mm L−1 were added to the medium at sodium lactate concentrations of 0.13 and 0.62 mm L−1, and arginine 2.58 mm L−1, guanine 0.26 mm L−1, and Mn2+ 0.25 mm L−1 at a sodium lactate concentration of 0.31 mm L−1. The viable cell counts of L. fermentum ATCC 14931 were approximately 1.02‐fold (P < 0.05) of the counts observed in control medium at all three concentrations of sodium lactate. CONCLUSION: The present results suggest that certain nutrients accelerate the growth of L. fermentum under sodium lactate stress and enhance its resistance to this adverse condition. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

L‐lactate is a key metabolite indicative of physiological states, glycolysis pathways, and various diseases such as sepsis, heart attack, lactate acidosis, and cancer. Detection of lactate has been relying on a few enzymes that need additional oxidants. In this work, DNA aptamers for L‐lactate were obtained using a library‐immobilization selection method and the highest affinity aptamer reached a Kd of 0.43 mM as determined using isothermal titration calorimetry. The aptamers showed up to 50‐fold selectivity for L‐lactate over D‐lactate and had little responses to other closely related analogs such as pyruvate or 3‐hydroxybutyrate. A fluorescent biosensor based on the strand displacement method showed a limit of detection of 0.55 mM L‐lactate, and the sensor worked in 90 % serum. Simultaneous detection of L‐lactate and D‐glucose in the same solution was achieved. This work has broadened the scope of aptamers to simple metabolites and provided a useful probe for continuous and multiplexed monitoring. [ABSTRACT FROM AUTHOR]

Impaired respiratory function reduces haemoglobin oxygen affinity in COVID-19 Keywords: COVID-19; haemoglobin-oxygen affinity; haemoglobin P50; oxyhaemoglobins; PaO2 to fraction of inspired oxygen ratio; SARS-CoV-2 EN COVID-19 haemoglobin-oxygen affinity haemoglobin P50 oxyhaemoglobins PaO2 to fraction of inspired oxygen ratio SARS-CoV-2 e44 e47 4 02/21/23 20230301 NES 230301 Using homology modelling and molecular docking algorithms, Liu and Li predicted the existence of interactions between SARS-Cov-2 and haemoglobin (Hb) and suggested that these interactions may change haemoglobin-oxygen (Hb-O SB 2 sb ) affinity.[1] Hb-O SB 2 sb affinity has been extensively studied in intensive care unit (ICU) patients with COVID-19 (usually intubated and mechanically ventilated) showing normal to increased affinity.[[2], [4]] Higher Hb-O SB 2 sb affinity facilitates Hb oxygenation in the lungs while reducing tissue O SB 2 sb unloading; a reduced Hb-O SB 2 sb affinity has the opposite effect. COVID-19, haemoglobin-oxygen affinity, haemoglobin P50, oxyhaemoglobins, PaO2 to fraction of inspired oxygen ratio, SARS-CoV-2. [Extracted from the article]

The aim of this four‐armed parallel group randomized‐controlled trial was to evaluate if plyometric training could have different effects on running performance and physiological adaptations depending on the training intensity distribution (TID) in an 8‐week intervention in endurance athletes. Sixty well‐trained male runners (age: 34 ± 6 years, relative ⩒O2peak: 69 ± 3 ml kg−1 min−1) were recruited and allocated to a pyramidal (PYR), pyramidal + plyometric training (PYR + PLY), polarized (POL), and polarized + plyometric training (POL + PLY) periodization. The periodization patterns were isolated manipulations of TID, while training load was kept constant. Participants were tested pre‐ and post‐intervention for body mass, velocity at 2 and 4 mmol·L−1 of blood lactate concentration (vBLa2, vBLa4), absolute and relative ⩒O2peak and 5‐km running time trial performance, counter movement jump and squat jump. There were significant group × time interactions for vBla4 (p = 0.0235), CMJ (p = 0.0234), SJ (p = 0.0168), and 5‐km running time trial performance (p = 0.0035). Specifically, vBla4 and 5‐km running time trial performance showed the largest post‐intervention improvements in PYR + PLY (2.4% and 1.6%) and POL + PLY (2.1% and 1.8%), respectively. No significant interactions were observed for body mass, absolute and relative ⩒O2peak, peak heart rate, lactate peak and rating of perceived exertion. In conclusion, an 8‐week training periodization seems to be effective in improving performance of well‐trained endurance runners. Including plyometric training once a week appeared to be more efficacious in maximizing running performance improvements, independently from the TID adopted. [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]

We report the first example of a chiral polymer—cellulose—being dissolved in both enantiomers of a chiral solvent. We synthesized six room temperature ionic liquids (ILs) based on imidazolium and 1,2,3‐triazolium cations and lactate as chiral anion. Some of them have not been described before. We characterize the dissolution of cellulose in the ILs, which are found to be relatively good cellulose solvents with a solubility of up to 18.5 wt.‐%. At the same time, we find solubility differences of up to a factor of 3 between the enantiomers of the solvent, which is a very pronounced chiral recognition effect. Interestingly, the racemate of the solvent dissolves significantly less cellulose than either enantiopure form, which is a significant deviation from ideal mixing behavior. We also report the physicochemical properties of the six ILs (density, viscosity, decomposition temperature, NMR and circular dichroism spectra). Based on molecular dynamics simulations of the solutions and a model which we have published before, we attempt a semi‐quantitative prediction of the cellulose solubility, which yields solid results for the enantiopure solvents. From the simulation results, we obtain microscopic insight into the hydrogen bond network of the complex mixtures in which many different hydrogen bond donors and acceptors compete. [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]

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]

Feeding microbial communities with both organic and inorganic substrates can improve sustainability and feasibility of chain elongation processes. Sustainably produced H2, CO2, and CO can be co‐fed to microorganisms as a source for acetyl‐CoA, while a small amount of an ATP‐generating organic substrate helps overcome the kinetic hindrances associated with autotrophic carboxylate production. Here, we operated two semi‐continuous bioreactor systems with continuous recirculation of H2, CO2, and CO while co‐feeding an organic model feedstock (lactate and acetate) to understand how a mixotrophic community is shaped during carboxylate production. Contrary to the assumption that H2, CO2, and CO support chain elongation via ethanol production in open cultures, significant correlations (p < 0.01) indicated that relatives of Clostridium luticellarii and Eubacterium aggregans produced carboxylates (acetate to n‐caproate) while consuming H2, CO2, CO, and lactate themselves. After 100 days, the enriched community was dominated by these two bacteria coexisting in cyclic dynamics shaped by the CO partial pressure. Homoacetogenesis was strongest when the acetate concentration was low (3.2 g L−1), while heterotrophs had the following roles: Pseudoramibacter, Oscillibacter, and Colidextribacter contributed to n‐caproate production and Clostridium tyrobutyricum and Acidipropionibacterium spp. grew opportunistically producing n‐butyrate and propionate, respectively. The mixotrophic chain elongation community was more efficient in carboxylate production compared with the heterotrophic one and maintained average carbon fixation rates between 0.088 and 1.4 g CO2 equivalents L−1 days−1. The extra H2 and CO consumed routed 82% more electrons to carboxylates and 50% more electrons to carboxylates longer than acetate. This study shows for the first time long‐term, stable production of short‐ and medium‐chain carboxylates with a mixotrophic community. [ABSTRACT FROM AUTHOR]

Summary: The present study provided a new alternative for efficiently producing lipopeptides by calcium lactate and expanded potential applications of lipopeptides for ensuring food safety. The results indicated that the addition of calcium lactate significantly improved bacillomycin D production. When fed 150 mL of fermentation medium with 6.5 g/L calcium lactate at the batch fermentation time of 102 h, the maximum production of C14 bacillomycin D (C14BD), C15 bacillomycin D (C15BD), C16 bacillomycin D (C16BD), C17 bacillomycin D (C17BD) and total C14‐17 bacillomycin D (TBD) were 298.96, 345.43, 149.56, 216.6 and 1010.55 mg/L at 162 h, respectively. In addition, calcium lactate effectively induced biosynthesis of bacillomycin D through upregulating 2‐ketobutyric acid in the valine, leucine and isoleucine biosynthesis (VLIB) pathway that was closely related to threonine dehydratase and threonine and increasing expression of bacillomycin D synthase genes. Moreover, bacillomycin D could remarkably inhibit spore germination of Aspergillus flavus in rice. [ABSTRACT FROM AUTHOR]

Enriched in glycolytic enzymes, paucicellular and hypovascular intrasynovial flexor tendons fail to mount an effective healing response after injury and repair. In contrast, well‐vascularized extrasynovial flexor tendons possess high levels of oxidative phosphorylation (OXPHOS) enzymes and have a markedly improved healing capacity. This study was designed to compare the metabolic profiles of the two types of tendons and to evaluate the impact of metabolic reprogramming on early intrasynovial tendon healing in a clinically relevant canine model. Results showed that healthy intrasynovial tendons expressed higher levels of PDK1 and GAPDH and lower levels of SCX and IGF1 than did extrasynovial tendons. PDK1 encodes a subtype of pyruvate dehydrogenase kinase (PDK) that inhibits OXPHOS. Consistently, ATP production via glycolysis was favored in intrasynovial tendon cells whereas OXPHOS was the preferred pathway in extrasynovial tendon cells. Inhibition of glycolysis in vitro increased SCX expression in intrasynovial tendon cells. Therefore, dichloroacetate (DCA), a PDK1 inhibitor, was used in vivo to shift intrasynovial tendon ATP production from glycolysis to OXPHOS. Oral DCA administration reduced serum lactate concentration and increased acetyl‐CoA content in repaired intrasynovial tendons and led to reduced TLR4 and IL1B and increased IGF1, SCX, and TGFB3 expressions in treated intrasynovial tendons compared to controls. Immunohistochemistry staining with anti‐Ki67 and anti‐CD31 antibodies revealed marked increases in cellularity and neovascularization in treated intrasynovial tendons. Clinical significance: The findings of this experiment indicate that improved gene expression and histological outcomes can be achieved by regulating glucose metabolism in the early stages following intrasynovial tendon repair. [ABSTRACT FROM AUTHOR]

Lactate, once recognized as a wasty product from anaerobic glycolysis, is proved to be a pivotal signal molecule. Lactate accumulation occurs in diverse physiological and pathological settings due to the imbalance between lactate production and clearance. Under the condition with drastic changes in local microenvironment, such as tumorigenesis, inflammation, and microbial infection, the glycolysis turns to be active in surrounding cells leading to increased lactate release. Meanwhile, lactate can be utilized by these cells as an energy substrate and acts as a signal molecule to regulate cell functions through receptor‐dependent or independent pathways. In this review, we tended to tease out the contribution of lactate in tumor progression and immunomodulation. And we also discussed the accessory role of lactate, beyond as the energy source only, in the growth of invading pathogens. [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]

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]

Background: Point-of-care tools are invaluable in the emergency department. Arterial lactate has been used for prognostication in subsets of population in the emergency department but not often for a heterogeneous population. Objectives: We aimed to study the use of arterial lactate as a prognostication and disposition tool in an undifferentiated population presenting to the emergency department. Methods: We conducted a prospective study among all consenting emergency department patients with age >18 years, who had an arterial blood gas performed as a part of routine care and had a lactate value ⩾2 mmol/L. We collected data on demographics, comorbidities and patient disposition from the emergency department and 28-day mortality as a follow-up telephonically. Results: We included 469 patients with a median age of 37 years. Sixteen provisional diagnoses were made in the emergency department, and pneumonia/lower respiratory tract infection was relatively higher (13.6%). The median lactate was 4.6 (interquartile range = 3.2–7) with 155 patients (33%) being transferred to intensive care unit and 62 deaths (13.2%) recorded at 28 days. Furthermore, we observed optimum values for lactates at 5 mmol/L predicted intensive care unit admissions and 6 mmol/L predicted mortality. A unit increase in arterial lactate in the emergency department significantly increased mortality by 66% (95% confidence interval = 1.45–1.88; p < 0.001) and had a 2.15 times (95% confidence interval = 1.63–2.83; p < 0.001) significantly higher chance of being transferred to the intensive care unit. Conclusion: Arterial lactate can be used as a prognostication tool for a heterogeneous population presenting to the emergency department. Clinical significance: Point-of-care investigations such as arterial lactate can help the emergency physician make quick decisions on the floor and guide prognostication and disposition. [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]

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]

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]

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]

Poly(vinyl chloride) (PVC) is one of the most widely applied plastics in the world, with inherent mechanical brittleness and inflexibility in room temperature. With the growing concern for health and safety, especially in some fields (children's toys, food packaging, medical supplies) that require high‐safety plastics, there is an urgent need to develop phthalate‐free high‐performance green PVC products. Herein, by blending novel green oligomeric lactate plasticizers 1, 4‐cyclohexane dimethanol oligomeric lactate‐levulinate (CDOL‐L) and 1,4‐cyclohexane dimethanol oligomeric lactate‐levulinic acid ketal ester (CDOL‐LKE), highly stretchable and highly stable PVC‐based plastics were prepared successfully. CDOL‐L and CDOL‐LKE were synthesized by a green route of esterification and ketalization using biomass as the main raw material, and their structures were jointly confirmed by Fourier transform infrared spectroscopy, 1H NMR and TOF‐MS. Through performance testing, CDOL‐L or CDOL‐LKE plasticized PVC material were determined to have triple high stability (thermal, mechanical and migration stability) superior to DOP, DOTP and ATBC plasticized PVC. The PVC plasticized by CDOL‐L exhibited break at elongation as high as 833.0% at 50 phr addition and 877.1% at 60 phr addition. Moreover, PVC plasticized by 50 phr CDOL‐LKE exhibited relatively better thermal stability (Ti,CDOL‐LKE = 271.4°C) for the special ketal structure on the plasticizer. In conclusion, CDOL‐L and CDOL‐LKE showed potential to substitute traditional plasticizers and pointed a new direction for the preparation of high‐performance PVC‐based plastics. [ABSTRACT FROM AUTHOR]

Estimations of accurate and reliable NMR chemical shift values, coupling patterns and constants within a reasonable timeframe remain significantly challenging, and the unavailability of reliable software strategies for the prediction of low‐field (e.g., 60 MHz) spectra from those acquired at higher operating frequencies hampers their direct comparison. Hence, this study explored the applications of accessible software options for predicting these parameters in the 1H NMR profiles of analytes as a function of magnetic field strength; this was performed for individual analytes and also for complex biofluid matrices featured in metabolomics investigations. For this purpose, results from the very first successful experimental acquisition and simulation of the 1H NMR profiles of intact human salivary supernatant samples on a 60 MHz benchtop spectrometer were evaluated. Using salivary metabolite concentrations determined at 400 MHz, it was demonstrated that simulation of the low‐field spectra of five biomolecules with the most prominent 1H resonances detectable allowed multiple component fits to be applied to experimental spectra. Hence, these salivary 1H NMR profiles could be successfully predicted throughout the 45–600 MHz operating frequency range. With the exception of propionate resonance multiplets, which revealed more complex coupling patterns at low field and required more astute computational and fitting options, valuable quantitative metabolomics data on salivary acetate, formate, methanol and glycine could be attained from low‐field spectrometres. These studies are both timely and pertinent in view of the recent advancement of low‐field benchtop NMR facilities for diagnostically significant biomarker tracking in biofluids. Experiments performed with added ammonium chloride to facilitate the release of salivary metabolites from biopolymer binding sites provided evidence that a small but nevertheless significant proportion of propionate, but not lactate, was bound to such sites, an observation of much relevance to biomolecule quantification in salivary metabolomics investigations. [ABSTRACT FROM AUTHOR]

Objective: To investigate maternal lactate concentrations in labour and the puerperium. Design: Reference study. Setting: Tertiary obstetric unit. Population: 1279 pregnant women with good perinatal outcomes at term. Methods: Electronic patient records were searched for women who had lactate measured on the day of delivery or in the following 24 hours, but who were subsequently found to have a very low likelihood of sepsis, based on their outcomes. Main outcome measures: The normative distribution of lactate and C‐reactive protein (CRP), differences according to the mode of birth, and the proportion of results above the commonly used cut‐offs (≥2 and ≥4 mmol/l). Results: Lactate varied between 0.4–5.4 mmol/l (median 1.8 mmol/l, interquartile range [IQR] 1.3–2.5). It was higher in women who had vaginal deliveries than caesarean sections (median 1.9 vs. 1.6 mmol/l, pdiff < 0.001), demonstrating the association with labour (particularly active pushing in the second stage). In contrast, CRP was more elevated in women who had caesarean sections (median 71.8 mg/l) than those who had vaginal deliveries (33.4 mg/l, pdiff < 0.001). In total, 40.8% had a lactate ≥2 mmol/l, but 95.3% were <4 mmol/l. Conclusions: Lactate in labour and the puerperium is commonly elevated above the levels expected in healthy pregnant or non‐pregnant women. There is a paucity of evidence to support using lactate or CRP to make decisions about antibiotics around the time of delivery but, as lactate is rarely higher than 4 mmol/l, this upper limit may still represent a useful severity marker for the investigation and management of sepsis in labour. [ABSTRACT FROM AUTHOR]

Cancer cells shift their glucose catabolism from aerobic respiration to lactic fermentation even in the presence of oxygen, and this is known as the "Warburg effect". To accommodate the high glucose demands and to avoid lactate accumulation, the expression levels of human glucose transporters (GLUTs) and human monocarboxylate transporters (MCTs) are elevated to maintain metabolic homeostasis. Therefore, inhibition of GLUTs and/or MCTs provides potential therapeutic strategies for cancer treatment. Here, we summarize recent advances in the structural characterization of GLUTs and MCTs, providing a comprehensive understanding of their transport and inhibition mechanisms to facilitate further development of anticancer therapies. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) dysregulation has been characterized in canine OS, with previous data suggesting that constitutive STAT3 activation contributes to survival and proliferation in OS cell lines in vitro. Recently, the contribution of STAT3 to tumour metabolism has been described across several tumour histologies, and understanding the metabolic implications of STAT3 loss may elucidate novel therapeutic approaches with synergistic activity. The objective of this work was to characterize metabolic benchmarks associated with STAT3 loss in canine OS. STAT3 expression and activation was evaluated using western blotting in canine OS cell lines OSCA8 and Abrams. STAT3 was deleted from these OS cell lines using CRISPR‐Cas9, and the effects on proliferation, invasion and metabolism (respirometry, intracellular lactate) were determined. Loss of STAT3 was associated with decreased basal and compensatory glycolysis in canine OS cell lines, without modulation of cellular proliferation. Loss of STAT3 also resulted in diminished invasive capacity in vitro. Interestingly, the absence of STAT3 did not impact sensitivity to doxorubicin in vitro. Our data demonstrate that loss of STAT3 modulates features of aerobic glycolysis in canine OS impacting capacities for cellular invasions, suggesting a role for this transcription factor in metastasis. [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]

Asprosin is an orexigenic adipokine that regulates appetite and glucose homeostasis in mammals. To date, only fragmentary findings are reported regarding its role in testicular activities. In the current investigation, immunolocalization and direct action of asprosin in adult mice testis was evaluated. Immunohistochemical and immunoblot studies were performed to analyse the testicular expression of asprosin. Intratesticular treatment of asprosin (0.1 μg and 1.0 μg per testis) was given to evaluate its direct action on testicular functions. Sertoli and Leydig cells were found to be immuno‐positive for asprosin. Intratesticular administration of asprosin resulted into a significant increase in glucose and lactate levels along with enhanced expression of asprosin receptor OLFR734, insulin receptor (IR), glucose transporter 8 (GLUT 8), lactate dehydrogenase (LDH) activity and monocorboxylate transporters (MCT2 and 4). In addition, asprosin administration increased the testicular expression of cell proliferation (proliferating cell nuclear antigen: PCNA), cell survival (B cell lymphoma 2: Bcl2) and decreased germ cell apoptosis (Cysteine aspartic acid protease 3: Caspase 3) leading to increased sperm counts. Further, asprosin treatment resulted into increased level of total cholesterol, testosterone and steroidogenic markers (steroidogenic acute regulatory protein: StAR; 3beta‐hydroxysteroid dehydrogenases: 3β HSD and 17beta‐hydroxysteroid dehydrogenases: 17β HSD). Asprosin treatment promotes testicular glucose uptake and lactate synthesis to provide energy for steroidogenesis and spermatogenesis. The significant correlation between the asprosin‐induced increased IR expression and increased testosterone, glucose and lactate levels suggests its role in increased survival and proliferation but decrease in germ cell apoptosis. This study proposed asprosin's role as an autocrine/paracrine regulator of testicular functions in adult mice. [ABSTRACT FROM AUTHOR]

In this work, Eu3+‐doped SnO2 nanoparticles are prepared and embedded into MXene (Ti3C2) laminates, and Ti3C2@Eu‐SnO2 composites are obtained. Cyclic voltammetry (CV) and scanning electron microscopy (SEM) characterization show that the composites have excellent electrochemical properties and unique morphology. The electrochemical impedance spectroscopy (EIS) and Fourier transform infrared spectrometer (FTIR) results of lactate oxidase (Lox) immobilized on Ti3C2@Eu‐SnO2 indicate that Eu‐SnO2, Ti3C2, and Lox have a good hybrid coordination and biocompatibility. The enzymatic electrochemical biosensor constructed with Ti3C2@Eu‐SnO2/Lox on glassy carbon electrode (GCE) reveals an excellent linear relationship in the lactate concentration ranging from 1.0×10−9 to 1.0×10−4 mol L−1. It has a low detection limit of 3.38×10−10 mol L−1 and high sensitivity of 4.815 mA nmol−1 L cm−2. Furthermore, the fabricated biosensor has a reasonable recovery rate for determining lactate in human serum. [ABSTRACT FROM AUTHOR]