Prehospital Lactate Levels Obtained in the Ambulance and Prediction of 2-Day In-Hospital Mortality in Patients With Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: To analyze the ability of prehospital lactate levels to predict 2-day in-hospital mortality in patients with traumatic brain injury (TBI), severe TBI (Glasgow Coma Scale (GCS) ≤ 8 points), and mild or moderate TBI (GCS ≥ 9 points). Second, 90-day mortality was also explored. METHODS: This was a prospective, multicenter, emergency medical services (EMSs) delivery, ambulance-based, derivation-validation cohort study developed in 5 tertiary hospitals (Spain), from November 1, 2019, to July 31, 2022. Patients were recruited from among all phone requests for emergency assistance among adults who were later evacuated to referral hospitals with acute TBI. The exclusion criteria were minors, pregnancy, trauma patients without TBI, delayed presentations, patients were discharged in situ, participants with cardiac arrest, and unavailability to obtain a blood sample. The primary outcome was all-cause 2-day in-hospital mortality and 90-day mortality in patients with moderate or mild TBI compared with patients with severe TBI. Clinical and analytical parameters (lactate and glucose) were collected. The discriminative power (area under the receiver operating characteristic curve [AUC]) and calibration curve were calculated for 2 geographically separated cohorts. RESULTS: A total of 509 patients were ultimately included. The median age was 58 years (interquartile range: 43-75), and 167 patients were female (32.8%). The primary outcome occurred in 9 (2.2%) of 415 patients with moderate or mild TBI and in 42 (44.7%) of 94 patients with severe TBI. The predictive capacity of the lactate concentration was globally validated in our cohort, for which the AUC was 0.874 (95% CI 0.805-0.942) for the validation cohort. The ability of the GCS score to predict lactate concentration was greater in patients with a GCS score ≥9 points, with an AUC of 0.925 (95% CI 0.808-1.000) and a negative predictive value of 99.09 (95% CI 98.55-99.64) in the validation cohort. CONCLUSION: Our results show the benefit of using lactate in all patients with TBI, particularly in those with a GCS ≥9 points. Routine incorporation of lactate in the screening of patients with TBI could presumably reduce mortality and deterioration rates because of quicker and better identification of patients at risk.

Evaluation of a nomogram model for predicting in-hospital mortality risk in patients with acute ST-elevation myocardial infarction and acute heart failure post-PCI.

OBJECTIVES: This study aims to identify the risk factors contributing to in-hospital mortality in patients with acute ST-elevation myocardial infarction (STEMI) who develop acute heart failure (AHF) post-percutaneous coronary intervention (PCI). Based on these factors, we constructed a nomogram to effectively identify high-risk patients. METHODS: In the study, a collective of 280 individuals experiencing an acute STEMI who then developed AHF following PCI were evaluated. These subjects were split into groups for training and validation purposes. Utilizing lasso regression in conjunction with logistic regression analysis, researchers sought to pinpoint factors predictive of mortality and to create a corresponding nomogram for forecasting purposes. To evaluate the model's accuracy and usefulness in clinical settings, metrics such as the concordance index (C-index), calibration curves, and decision curve analysis (DCA) were employed. RESULTS: Key risk factors identified included blood lactate, D-dimer levels, gender, left ventricular ejection fraction (LVEF), and Killip class IV. The nomogram demonstrated high accuracy (C-index: training set 0.838, validation set 0.853) and good fit (Hosmer-Lemeshow test: χ2 = 0.545, p = 0.762), confirming its clinical utility. CONCLUSION: The developed clinical prediction model is effective in accurately forecasting mortality among patients with acute STEMI who develop AHF after PCI.

Engineering new-to-nature biochemical conversions by combining fermentative metabolism with respiratory modules.

Anaerobic microbial fermentations provide high product yields and are a cornerstone of industrial bio-based processes. However, the need for redox balancing limits the array of fermentable substrate-product combinations. To overcome this limitation, here we design an aerobic fermentative metabolism that allows the introduction of selected respiratory modules. These can use oxygen to re-balance otherwise unbalanced fermentations, hence achieving controlled respiro-fermentative growth. Following this design, we engineer and characterize an obligate fermentative Escherichia coli strain that aerobically ferments glucose to stoichiometric amounts of lactate. We then re-integrate the quinone-dependent glycerol 3-phosphate dehydrogenase and demonstrate glycerol fermentation to lactate while selectively transferring the surplus of electrons to the respiratory chain. To showcase the potential of this fermentation mode, we direct fermentative flux from glycerol towards isobutanol production. In summary, our design permits using oxygen to selectively re-balance fermentations. This concept is an advance freeing highly efficient microbial fermentation from the limitations imposed by traditional redox balancing.

Evaluating tissue hypoxia and the response to fluid administration in septic shock patients: a metabolic cluster analysis.

BACKGROUND: The selection of adequate indicators of tissue hypoxia for guiding the resuscitation process of septic patients is a highly relevant issue. Current guidelines advocate for the use of lactate as sole metabolic marker, which may be markedly limited, and the integration of different variables seems more adequate. In this study, we explored the metabolic profile and its implications in the response to the administration of a fluid challenge in early septic shock patients. METHODS: Observational study including septic shock patients within 24 h of ICU admission, monitored with a cardiac output estimation system, with ongoing resuscitation. Hemodynamic and metabolic variables were measured before and after a fluid challenge (FC). A two-step cluster analysis was used to define the baseline metabolic profile, including lactate, central venous oxygen saturation (ScvO2), central venous-to-arterial carbon dioxide difference (PcvaCO2), and PcvaCO2 corrected by the difference in arterial-to-venous oxygen content (PcvaCO2/CavO2). RESULTS: Seventy-seven fluid challenges were analyzed. Cluster analysis revealed two distinct metabolic profiles at baseline. Cluster A exhibited lower ScvO2, higher PcvaCO2, and lower PcvaCO2/CavO2. Increases in cardiac output (CO) were associated with increases in VO2 exclusively in cluster A. Baseline isolated metabolic variables did not correlate with VO2 response, and changes in ScvO2 and PcvaCO2 were associated to VO2 increase only in cluster A. CONCLUSIONS: In a population of early septic shock patients, two distinct metabolic profiles were identified, suggesting tissue hypoxia or dysoxia. Integrating metabolic variables enhances the ability to detect those patients whose VO2 might increase as results of fluid administration.

Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension.

BACKGROUND: High levels of lactate are positively associated with prognosis and mortality in pulmonary hypertension (PH). Lactate dehydrogenase A (LDHA) is a key enzyme for the production of lactate. This study is undertaken to investigate the role and molecular mechanisms of lactate and LDHA in PH. METHODS: Lactate levels were measured by a lactate assay kit. LDHA expression and localization were detected by western blot and Immunofluorescence. Proliferation and migration were determined by CCK8, western blot, EdU assay and scratch-wound assay. The right heart catheterization and right heart ultrasound were measured to evaluate cardiopulmonary function. RESULTS: In vitro, we found that lactate promoted proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in an LDHA-dependent manner. In vivo, we found that LDHA knockdown reduced lactate overaccumulation in the lungs of mice exposed to hypoxia. Furthermore, LDHA knockdown ameliorated hypoxia-induced vascular remodeling and right ventricular dysfunction. In addition, the activation of Akt signaling by hypoxia was suppressed by LDHA knockdown both in vivo and in vitro. The overexpression of Akt reversed the inhibitory effect of LDHA knockdown on proliferation in PASMCs under hypoxia. Finally, LDHA inhibitor attenuated vascular remodeling and right ventricular dysfunction in Sugen/hypoxia mouse PH model, Monocrotaline (MCT)-induced rat PH model and chronic hypoxia-induced mouse PH model. CONCLUSIONS: Thus, LDHA-mediated lactate production promotes pulmonary vascular remodeling in PH by activating Akt signaling pathway, suggesting the potential role of LDHA in regulating the metabolic reprogramming and vascular remodeling in PH.

New spin coated multilayer lactate biosensor for acidosis monitoring in continuous flow assisted with an electrochemical pH probe.

A LOx-based electrochemical biosensor for high-level lactate determination was developed. For the construction of the biosensor, chitosan and Nafion layers were integrated by using a spin coating procedure, leading to less porous surfaces in comparison with those recorded after a drop casting procedure. The analytical performance of the resulting biosensor for lactate determination was evaluated in batch and flow regime, displaying satisfactory results in both modes ranging from 0.5 to 20 mM concentration range for assessing the lactic acidosis. Finally, the lactate levels in raw serum samples were estimated using the biosensor developed and verified with a blood gas analyzer. Based on these results, the biosensor developed is promising for its use in healthcare environment, after its proper miniaturization. A pH probe based on common polyaniline-based electrochemical sensor was also developed to assist the biosensor for the lactic acidosis monitoring, leading to excellent results in stock solutions ranging from 6.0 to 8.0 mM and raw plasma samples. The results were confirmed by using two different approaches, blood gas analyzer and pH-meter. Consequently, the lactic acidosis monitoring could be achieved in continuous flow regime using both (bio)sensors.

A New Genetic Signature of Lactate Metabolism-Associated Genes Predicting Clinically Distinctive Features and Tumor Microenvironment in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is characterized by its high malignancy and challenging prognosis. A significant aspect of cancer is metabolic reprogramming, where lactate serves as a crucial metabolite that contributes to the development of cancer and the tumor microenvironment (TME). Current studies have indicated that lactate plays a significant role in the progression of CRC. However, the relationship between lactate and the tumor microenvironment remains understudied, underscoring the potential of lactate as a novel biomarker. METHODS: We sourced transcriptomic data for colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and the Gene Expression Omnibus (GEO) portals, along with the corresponding clinical information. Utilizing univariate Cox regression in conjunction with LASSO regression analysis, we identified genes involved in lactate metabolism that are associated with CRC prognosis. Subsequently, we developed models based on multi-factor Cox regression. To evaluate the correlation between tumor mutational burden (TMB), tumor microenvironment (TME), and lactate scores with patient survival, we conducted gene set enrichment analysis (GSEA) and immunogenic signature analyses. RESULTS: 3 lactate metabolism-related genes (LMRGs) (SLC16A8, GATA1, and PYGL) were used to construct models that categorized patients into 2 subgroups based on their lactate scores. The function of the differential genes between the 2 subgroups was mainly enriched in cell cycle and mRNA division, and the prognosis of patients in the high score subgroup was poor. Furthermore, a significant positive correlation was observed between TMB and LMRGs scores in the high-scoring group (P = 0.003, r2 = 0.12). Lastly, LMRGs also reflected the characteristics of TME, with differences in immune cells and immune checkpoints between the 2 subgroups. CONCLUSIONS: LMRGs may serve as a promising biomarker for predicting prognostic survival in CRC patients and to assess the TME.

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A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice.

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of D-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter D-serine, by its precursor L-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards L-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.

Effects of pacing strategy on metabolic responses to 2-min intense exercise in Thoroughbred horses.

Evidence suggests that positive pacing strategy improves exercise performance and fatigue tolerance in athletic events lasting 1-5 min. This study investigated muscle metabolic responses to positive and negative pacing strategies in Thoroughbred horses. Eight Thoroughbred horses performed 2 min treadmill running using positive (1 min at 110% maximal O2 uptake [V̇O2max], followed by 1 min at 90% V̇O2max) and negative (1 min at 90% V̇O2max, followed by 1 min at 110% V̇O2max) pacing strategies. The arterial-mixed venous O2 difference did not significantly differ between the two strategies. Plasma lactate levels increased toward 2 min, with significantly higher concentrations during positive pacing than during negative pacing. Muscle glycogen level was significantly lower at 1 and 2 min of positive pacing than those of negative pacing. Metabolomic analysis showed that the sum of glycolytic intermediates increased during the first half of positive pacing and the second half of negative pacing. Regardless of pacing strategy, the sum of tricarboxylic acid cycle metabolites increased during the first half but remained unchanged thereafter. Our data suggest that positive pacing strategy is likely to activate glycolytic metabolism to a greater extent compared to negative pacing, even though the total workload is identical.

The Association of Genetic Markers Involved in Muscle Performance Responding to Lactate Levels during Physical Exercise Therapy by Nordic Walking in Patients with Long COVID Syndrome: A Nonrandomized Controlled Pilot Study.

Several genetic markers have shown associations with muscle performance and physical abilities, but the response to exercise therapy is still unknown. The aim of this study was to test the response of patients with long COVID through an aerobic physical therapy strategy by the Nordic walking program and how several genetic polymorphisms involved in muscle performance influence physical capabilities. Using a nonrandomized controlled pilot study, 29 patients who previously suffered from COVID-19 (long COVID = 13, COVID-19 = 16) performed a Nordic walking exercise therapy program for 12 sessions. The influence of the ACE (rs4646994), ACTN3 (rs1815739), AMPD1 (rs17602729), CKM (rs8111989), and MLCK (rs2849757 and rs2700352) polymorphisms, genotyped by using single nucleotide primer extension (SNPE) in lactic acid concentration was established with a three-way ANOVA (group × genotype × sessions). For ACE polymorphism, the main effect was lactic acid (p = 0.019). In ACTN3 polymorphism, there were no main effects of lactic acid, group, or genotype. However, the posthoc analysis revealed that, in comparison with nonlong COVID, long COVID increased lactic acid concentrations in Nordic walking sessions in CT and TT genotypes (all p < 0.05). For AMPD1 polymorphism, there were main effects of lactic acid, group, or genotype and lactic acid × genotype or lactic acid × group × genotype interactions (all p < 0.05). The posthoc analysis revealed that, in comparison with nonlong COVID, long COVID increased lactic acid concentrations in Nordic walking sessions in CC and CT genotypes (all p < 0.05). Physical therapy strategy through Nordic walking enhanced physical capabilities during aerobic exercise in post-COVID19 patients with different genotypes in ACTN3 c.1729C>T and AMPD1 c.34C>T polymorphisms. These findings suggest that individuals who reported long COVID who presumably exercised less beforehand appeared to be less able to exercise, based on lactate levels, and the effect of aerobic physical exercise enhanced physical capabilities conditioned by several genetic markers in long COVID patients.

The impact of lutein-loaded poly(lactic-co-glycolic acid) nanoparticles following topical application: An in vitro and in vivo study.

Antioxidant therapies are of interest in the prevention and management of ocular disorders such as cataracts. Although an active area of interest, topical therapy with antioxidants for the treatment of cataracts is complicated by multiple ocular anatomical barriers, product stability, and solubility. Entrapment and delivery of antioxidants with poly(lactic-co-glycolic acid) nanoparticles is a possible solution to these challenges, however, little is known regarding their effects in vitro or in vivo. Our first aim was to investigate the impact of blank and lutein loaded PLGA nanoparticles on viability and development of reactive oxygen species in lens epithelial cells in vitro. Photo-oxidative stress was induced by ultraviolet light exposure with cell viability and reactive oxygen species monitored. Next, an in vivo, selenite model was utilized to induce cataract formation in rodents. Eyes were treated topically with both free lutein and lutein loaded nanoparticles (LNP) at varying concentrations. Eyes were monitored for the development of anterior segment changes and cataract formation. The ability of nanodelivered lutein to reach the anterior segment of the eye was evaluated by liquid chromatography coupled to mass spectrometry of aqueous humor samples and liquid chromatography coupled to tandem mass spectrometry (targeted LC-MS/MS) of lenses. LNP had a minimal impact on the viability of lens epithelial cells during the short exposure timeframe (24 h) and at concentrations < 0.2 µg LNP/µl. A significant reduction in the development of reactive oxygen species was also noted. Animals treated with LNPs at an equivalent lutein concentration of 1,278 µg /mL showed the greatest reduction in cataract scores. Lutein delivery to the anterior segment was confirmed through evaluation of aqueous humor and lens sample evaluation. Topical treatment was not associated with the development of secondary keratitis or anterior uveitis when applied once daily for one week. LNPs may be an effective in the treatment of cataracts.

Outcomes and prognosis of postpartum hemorrhage according to management protocol: an 11-year retrospective study from two referral centers.

BACKGROUND: No standard treatment guidelines have been established for postpartum hemorrhage (PPH). We aimed to assess the differences in outcomes and prognoses between patients with PPH who underwent surgical and non-surgical treatment. METHODS: This retrospective study included 230 patients diagnosed with PPH at two referral hospitals between August 2013 and October 2023. The patients were divided into non-surgical (group 1, n = 159) and surgical intervention groups (group 2, n = 71). A subgroup analysis was performed by dividing the surgical intervention group into immediate (n = 45) and delayed surgical intervention groups (n = 26). RESULTS: Initial lactic acid levels and shock index were significantly higher in group 2 (2.85 ± 1.37 vs. 4.54 ± 3.63 mmol/L, p = 0.001, and 0.83 ± 0.26 vs. 1.10 ± 0.51, p < 0.001, respectively). Conversely, initial heart rate and body temperature were significantly lower in group 2 (92.5 ± 21.0 vs. 109.0 ± 28.1 beat/min, p < 0.001, and 37.3 ± 0.8 °C vs. 37.0 ± 0.9 °C, p = 0.011, respectively). Logistic regression analysis identified low initial body temperature, high lactic acid level, and shock index as independent predictors of surgical intervention (p = 0.029, p = 0.027, and p = 0.049, respectively). Regarding the causes of PPH, tone was significantly more prevalent in group 1 (57.2% vs. 35.2%, p = 0.002), whereas trauma was significantly more prevalent in group 2 (24.5% vs. 39.4%, p = 0.030). Group 2 had worse overall outcomes and prognoses than group 1. The subgroup analysis showed significantly higher rates of uterine atony combined with other causes, hysterectomy, and disseminated intravascular coagulopathy in the delayed surgical intervention group than the immediate surgical intervention group (42.2% vs. 69.2%, p = 0.027; 51.1% vs. 73.1%, p = 0.049; and 17.8% vs. 46.2%, p = 0.018, respectively). CONCLUSIONS: Patients with PPH presenting with increased lactic acid levels and shock index and decreased body temperature may be surgical candidates. Additionally, immediate surgical intervention in patients with uterine atony combined with other causes of PPH could improve prognosis and reduce postoperative complications.

In vitro evaluation of PLGA loaded hesperidin on colorectal cancer cell lines: an insight into nano delivery system.

BACKGROUND: Colorectal cancer is a common disease worldwide with non-specific symptoms such as blood in the stool, bowel movements, weight loss and fatigue. Chemotherapy drugs can cause side effects such as nausea, vomiting and a weakened immune system. The use of antioxidants such as hesperidin could reduce the side effects, but its low bioavailability is a major problem. In this research, we aimed to explore the drug delivery and efficiency of this antioxidant on the HCT116 colorectal cancer cell line by loading hesperidin into PLGA nanoparticles. MATERIALS AND METHODS: Hesperidin loaded PLGA nanoparticles were produced by single emulsion evaporation method. The physicochemical properties of the synthesized hesperidin-loaded nanoparticles were determined using SEM, AFM, FT-IR, DLS and UV-Vis. Subsequently, the effect of the PLGA loaded hesperidin nanoparticles on the HCT116 cell line after 48 h was investigated by MTT assay at three different concentrations of the nanoparticles. RESULT: The study showed that 90% of hesperidin were loaded in PLGA nanoparticles by UV-Vis spectrophotometry and FT-IR spectrum. The nanoparticles were found to be spherical and uniform with a hydrodynamic diameter of 76.2 nm in water. The release rate of the drug was about 93% after 144 h. The lowest percentage of cell viability of cancer cells was observed at a concentration of 10 µg/ml of PLGA nanoparticles loaded with hesperidin. CONCLUSION: The results indicate that PLGA nanoparticles loaded with hesperidin effectively reduce the survival rate of HCT116 colorectal cancer cells. However, further studies are needed to determine the appropriate therapeutic dosage and to conduct animal and clinical studies.

ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells.

Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 is an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment of colorectal cancer is not reported. Functional analysis data show that colorectal cancer cells respond to specific concentration of lactate to accelerate invasion and metastasis, and ASIC3 is the main actor in this process. Mechanism reveal de novo lipid synthesis is a regulatory process of ASIC3, down-regulated ASIC3 increases and interacts with ACC1 and SCD1, which are key enzymes in de novo lipid synthesis pathway, this interaction results in increased unsaturated fatty acids, which in turn induce EMT to promote metastasis, and overexpression of ASIC3 reduces acidic TME-enhanced colorectal cancer metastasis. Clinical samples of colorectal cancer also exhibit decreased ASIC3 expression, and low ASIC3 expression is associated with metastasis and stage of colorectal cancer. This study is the first to identify the role of the ASIC3-ACC1/SCD1 axis in acid-enhanced colorectal cancer metastasis. The expression pattern of ASIC3 in colorectal cancer differs significantly from that in other types of cancers, ASIC3 may serve as a novel and reliable marker for acidic microenvironmental in colorectal cancer, and potentially a therapeutic target.

Lactate promotes microglial scar formation and facilitates locomotor function recovery by enhancing histone H4 lysine 12 lactylation after spinal cord injury.

Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived histone lactylation in the repair of spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and lactylation are upregulated in the spinal cord after SCI. Notably, H4K12la was significantly elevated in the microglia of the injured spinal cord, whereas exogenous lactate treatment further elevated H4K12la in microglia after SCI. Functionally, lactate treatment promoted microglial proliferation, scar formation, axon regeneration, and locomotor function recovery after SCI. Mechanically, lactate-mediated H4K12la elevation promoted PD-1 transcription in microglia, thereby facilitating SCI repair. Furthermore, a series of rescue experiments confirmed that a PD-1 inhibitor or microglia-specific AAV-sh-PD-1 significantly reversed the therapeutic effects of lactate following SCI. This study illustrates the function and mechanism of lactate/H4K12la/PD-1 signaling in microglia-mediated tissue repair and provides a novel target for SCI therapy.

Genome-wide association studies for citric and lactic acids in dairy sheep milk in a New Zealand flock.

The objectives of this study were to estimate genetic parameters for citric acid content (CA) and lactic acid content (LA) in sheep milk and to identify the associated candidate genes in a New Zealand dairy sheep flock. Records from 165 ewes were used. Heritability estimates based on pedigree records for CA and LA were 0.65 and 0.33, respectively. The genetic and phenotypic correlations between CA and LA were strong-moderate and negative. Estimates of genomic heritability for CA and LA were also high (0.85, 0.51) and the genomic correlation between CA and LA was strongly negative (-0.96 ± 0.11). No significant associations were found at the Bonferroni level. However, one intragenic SNP in C1QTNF1 (chromosome 11) was associated with CA, at the chromosomal significance threshold. Another SNP associated with CA was intergenic (chromosome 15). For LA, the most notable SNP was intragenic in CYTH1 (chromosome 11), the other two SNPs were intragenic in MGAT5B and TIMP2 (chromosome 11), and four SNPs were intergenic (chromosomes 1 and 24). The functions of candidate genes indicate that CA and LA could potentially be used as biomarkers for energy balance and clinical mastitis. Further research is recommended to validate the present results.

Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation.

Aim: Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown. Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke. Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke. In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes. The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection. Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining. Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains. Additionally, Ldha specific knockout in astrocytes (Aldh1l1 CreERT2; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups. Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke. Conclusion: Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke.

The Warburg Effect Revisited through Blood and Electron Flow.

The Warburg effect describes the propensity of many cancers to consume glucose avidly and convert it to lactate in the presence of oxygen. The benefit of the Warburg effect on cancer cells remains enigmatic, particularly because extracellular disposal of incompletely oxidized lactate is wasteful. However, lactate is not discarded from the body, but rather recycled as pyruvate for metabolism through the tricarboxylic acid cycle in oxidative tissues and cells. Hence, tissue and interorgan metabolism play important roles in tumor metabolism. The production of tumor lactate to be recycled elsewhere parallels the Cori cycle, in which lactate produced by muscle activity is shuttled to the liver, where it is converted to pyruvate and subsequently stored as glucose moieties in glycogen. This perspective will consider this organismal contextwhile discussing how glucose is used in tumors. We highlight several key articles published decades ago in Cancer Research that are foundational to our current understanding of cancer biology and metabolism.

Recovery effect of self-myofascial release treatment using different type of a foam rollers.

Among athletes, foam rolling is popular technique of myofascial release aimed to support recovery processes and counteract delayed onset muscle soreness. However, there is no consensus on the optimal parameters of the roller texture used in the procedure. The study aimed to determine whether using rollers with different textures and hardness (smooth/soft, grooved/mid, serrated/hard) in myofascial release affects post-exertional restitution rate and the level of perceived DOMS (Delayed Onset Muscle Soreness) after intense anaerobic exercise. The study involved 60 healthy and physically active men randomly divided into three experimental groups and one control group (passive rest)-each consisting of 15 individuals: STH-rolling with a smooth roller; G-rolling with a grooved roller; TP-rolling with a serrated roller; Pass-passive rest group. After performing a exercise test (one-minute high-intensity squat), blood lactate (LA), creatine kinase (CK) and pain perception (VAS Scale) were monitored. The analysis of the average LA concentration in the blood 30 min post-exercise showed a statistical difference for all rolling groups compared to the passive rest group: STH (p < 0.001), G (p < 0.001), TP (p = 0.035). No statistically significant differences were found between the CK measurement results in individual assessments. Statistically significant differences in VAS values were observed between G (p = 0.013) and TP (p = 0.006) groups and the Pass group at 48 h, as well as between STH (p = 0.003); G (p = 0.001); TP (p < 0.001) groups and the Pass group at 72 h. Based on statistical data, a strong influence (η2 = 0.578) of time on the quadriceps VAS variable was noted. The research results confirm the effectiveness of rolling in supporting immediate and prolonged recovery. The conducted studies indicate a significantly better pace of post-exertional recovery after a rolling procedure lasting at least 120 s. The texture and hardness of the tool used did not matter with such a duration of the treatment.

The Multiple Roles of Lactate in the Skeletal Muscle.

Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years. The signalling role of lactate occurs through binding with the GPR81 receptor, which triggers the typical signalling cascade of the G-protein-coupled receptors. Recently, it has been demonstrated that lactate regulates chromatin state and gene transcription by binding to histones. This review aims to describe the different roles of lactate in skeletal muscle, in both healthy and pathological conditions, and to highlight how lactate can influence muscle regeneration by acting directly on satellite cells.