Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.展开更多
Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein ...Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.展开更多
BACKGROUND:Sepsis is a highly heterogeneous organ dysfunction syndrome.There is limited evidence regarding phenotypes and clinical outcomes in sepsis patients with initial normal lactate levels.We sought to identify t...BACKGROUND:Sepsis is a highly heterogeneous organ dysfunction syndrome.There is limited evidence regarding phenotypes and clinical outcomes in sepsis patients with initial normal lactate levels.We sought to identify the lactate-based clinical phenotypes and outcomes of sepsis patients.METHODS:The Medical Information Mart for Intensive Care IV(MIMIC-IV)and eICU databases were used to conduct a retrospective cohort study.Adult sepsis patients were included.Lactate was measured via blood gas,and the same assay type was used across both databases.Serial lactate measurements were analyzed via a two-point classification system based on the highest values recorded during two consecutive 24-hour periods following ICU admission.The fi rst measurement window(T1)comprised the initial 24 h post-admission,whereas the second window(T2)covered 24-48 h post-admission.The lactate diff erence was defi ned as the numerical change between the highest lactate level at T2 and the highest level at T1.The time interval between these two measurements was fi xed,with T2 commencing immediately after T1,together encompassing the fi rst 48 h post-ICU admission.A normal lactate level was defi ned as≤2 mmol/L,and an elevated level was defi ned as>2 mmol/L.Sepsis patients were stratifi ed into four trajectory phenotypes:(1)normal-normal(N-N);(2)normal-elevated(N-E);(3)elevated-normal(E-N);and(4)elevated-elevated(E-E).The primary outcome was in-hospital mortality.RESULTS:This study enrolled 6,926 sepsis patients.The clinical phenotypes of the sepsis patients were as follows:N-N(24.4%),N-E(3.8%),E-N(36.4%),and E-E(35.3%).The in-hospital mortality rates of sepsis patients with the four phenotypes from the MIMIC-IV and eICU databases were as follows(N-N:18.9%vs.17.6%,P=0.66;N-E:35.3%vs.29.2%,P=0.45;E-N:16.6%vs.14.2%,P=0.14;E-E:43.6%vs.37.8%,P=0.01).After adjusting for age,sex,Sequential Organ Failure Assessment(SOFA)score,vasopressor therapy,and infection sites,the N-E phenotype was associated with a higher risk of in-hospital mortality(odds ratio[OR]1.44;95%confidence intervals[95%CI]1.11-1.86;P=0.006;adjusted OR 1.61;95%CI 1.23-2.11;P<0.001).The E-N phenotype was associated with the most favorable outcomes for in-hospital mortality in the multivariable analysis(adjusted OR 0.41;95%CI 0.36-0.46;P<0.001).The E-E phenotype was associated with the highest risk of in-hospital mortality in the overall cohort(adjusted OR 3.00;95%CI 2.67-3.37;P<0.001).CONCLUSION:In sepsis patients with normal initial lactate levels,serial lactate measurements could be valuable for prognostic assessment.展开更多
Background Inflammatory bowel disease causes intestinal structural damage,impairs gut function,hinders animal growth and development,and reduces farming efficiency.Previous studies demonstrated that lactate alleviates...Background Inflammatory bowel disease causes intestinal structural damage,impairs gut function,hinders animal growth and development,and reduces farming efficiency.Previous studies demonstrated that lactate alleviates dextran sulfate sodium(DSS)-induced inflammation and mitigates weight loss by enhancing intestinal barrier functions.However,the mechanisms underlying lactate-mediated protection of the intestinal epithelial barrier remain unclear.This study aimed to explore the protective effect of lactate on intestinal barrier damage in colitis piglets and the possible underlying mechanisms through in vivo and in vitro experiments.Methods A total of 6021-day-old weaned female piglets were randomly assigned into three groups based on weight:the control group(basal diet with physiological saline gavage),the DSS group(basal diet with 5%DSS gavage),and the DSS+LA group(2%lactate diet with 5%DSS gavage).There were 10 replicates per treatment,with 2 piglets per replicate.Jejunal morphology was assessed via hematoxylin and eosin staining,while Western blotting quantified the protein levels of proliferation markers,including cluster of differentiation 24(CD24),cyclin D1,and wingless/integrated(Wnt)/β-catenin signaling components.In vitro,0.08%DSS and 2–32 mmol/L sodium lactate-treated intestinal porcine epithelial cell line-J2(IPEC-J2)cells(n=4)were assessed for viability(Cell Counting Kit-8 assay),apoptosis(flow cytometry),and proliferation parameters,including cell cycle analysis and Leucine-rich repeat-containing G-protein coupled receptor 5(Lgr5+)stem cell quantification.Results In vivo,DSS administration induced jejunal villus shortening(P<0.05),downregulated protein levels of CD24,cyclin D1,casein kinase 1(CK1),and dishevelled-2(DVL2)(P<0.05).In vitro,DSS promoted apoptosis,inhibited proliferation,diminished the Lgr5+cell populations(P<0.05),and reduced S-phase cell proportions(P<0.05).Conversely,lactate supplementation ameliorated DSS-induced villus atrophy(P<0.05),restored CD24,cyclin D1,CK1,and DVL2 protein levels(P<0.05).Furthermore,in vitro,sodium lactate attenuated DSS-induced apoptosis(P<0.05),enhanced IPEC-J2 proliferation(P<0.05),expanded Lgr5+cells(P<0.05),and increased S-phase progression(P<0.05).Conclusions In summary,lactate ameliorated intestinal barrier damage in DSS-induced colitis by activating the Wnt/β-catenin pathway and restoring the balance between epithelial cell proliferation and apoptosis.This study provides novel mechanistic evidence supporting lactate's therapeutic potential for IBD management.展开更多
Background Selenium(Se)is an essential soil mineral that can be incorporated into animal feedstuffs.Because of a lack of soil Se in some regions,organic or inorganic supplementation strategies must be implemented to p...Background Selenium(Se)is an essential soil mineral that can be incorporated into animal feedstuffs.Because of a lack of soil Se in some regions,organic or inorganic supplementation strategies must be implemented to prevent deficiencies and promote optimal ovine health.Therefore,the objectives of this study were to assess how inorganic versus organic Se supplementation influenced ewe Se status and immune function during late gestation and postpartum.Dorset Rideau ewes(n=110)were fed a Se deficient diet from gestation d 110 through postpartum d 49 and received one of four daily oral Se treatments diluted in 5 mL of sugar water:0 mg Se,0.3 mg inorganic Se,0.3 mg organic Se,and 0.6 mg organic Se.Throughout the trial,the ewes received various immune challenges,including intramuscular immunizations with a novel antigen(ovalbumin;OVA)on trial d 0 and 10,an intradermal OVA challenge on d 20,and a lipopolysaccharide(LPS)endotoxin challenge on trial d 49.Results The organic Se treatment groups had higher serum Se concentrations on most trial days compared to the 0.3 mg inorganic and control groups(P<0.05).No significant treatment differences were found for the dermal hypersensitivity response to OVA,anti-OVA antibody response,glutathione peroxidase activity,cytokine response,cortisol response,or rectal temperature(P>0.05).However,4 h post-LPS injection,the serum albumin concentration was significantly lower in the 0.3 mg inorganic group compared to both organic Se groups,potentially indicating a higher degree of inflammation in the ewes supplemented with the inorganic Se.Conclusions The results of this study indicate that organic Se supplementation can promote a higher Se status in ewes over time,but Se supplementation during this study period did not affect tested immunological parameters.This lack of difference in immune responsiveness between groups may be due to an absence of true serum Se deficiencies in the Se-deficient group or the levels of Se supplementation being insufficient to significantly improve immunocompetence.展开更多
This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage,a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options.L...This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage,a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options.Lactate,a metabolic byproduct,has been shown to have neuroprotective properties,including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients.However,the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown.In this study,we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes.In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores,reduced brain inflammation,and promoted lipid droplet formation in astrocytes within 24 hours.Lactate treatment increased free fatty acids levels in the brain.The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets,thus reducing cellular lipotoxicity.Moreover,lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5,a protein crucial for lipid droplet formation.The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate,indicating that lactate’s protective role is closely linked to lipid metabolism and lipid droplet formation.In vitro experiments on HT22 neuronal cells exposed to hemin-an agent used to simulate subarachnoid hemorrhage injury-demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential.Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects,further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate.This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage.It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes,thus mitigating brain damage and improving cell survival.These findings suggest that lactate,through its regulation of lipid metabolism,could be a potential therapeutic agent for subarachnoid hemorrhage.展开更多
Both linoleic acid(18:2 n-6,LA)andα-linolenic acid(18:3 n-3,ALA)are essential fatty acids for infants.The contents of LA and ALA,and their ratio exhibited significant changes in human milk over the past 4 decades,whi...Both linoleic acid(18:2 n-6,LA)andα-linolenic acid(18:3 n-3,ALA)are essential fatty acids for infants.The contents of LA and ALA,and their ratio exhibited significant changes in human milk over the past 4 decades,which were not well summarized.Here,we summarized these values in 9898 human breast milk samples of 6664 mothers from 50 countries in 81 studies.A literature search was conducted using PubMed,Embase,and Web of Science between January 1980 and October 2023.The 95%confidence interval of LA/ALA ratio across lactation and gestation ranged from 14.24 to 31.26.The LA content was higher in China and Turkey(>20%)whereas the ALA content was below 1%in Africa.The LA/ALA ratio in countries along the Mediterranean coast exceeded 20 or even 30.LA and ALA contents increased significantly(P<0.01)while the ratio remained stable over the last 40 years.Multivariate meta-regression results showed that regions significantly(P<0.01)determined the LA,ALA,and LA/ALA ratio.Especially,maternal diet could definitely explain the variation while the effects of gestational age,lactation period was not significant.Clinical trials demonstrated that decreasing the LA/ALA ratio increased docosahexaenoic acid(22:6 n-3,DHA)status,reduced arachidonic acid(20:4 n-6,AA)contents,exerted no effect on the visual function of infants,and reached no consensus on growth.The current review aims to provide an overview on the LA and ALA contents and their ratio in human breast milk to raise concern in infant formula.展开更多
The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous syst...The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.展开更多
BACKGROUND Acute pancreatitis(AP)is a severe condition,and abdominal effusion is a significant predictor of its severity and prognosis.However,the relationship between ascites characteristics and AP outcomes remains u...BACKGROUND Acute pancreatitis(AP)is a severe condition,and abdominal effusion is a significant predictor of its severity and prognosis.However,the relationship between ascites characteristics and AP outcomes remains undefined.AIM To assess the correlation between ascites characteristics and clinical prognosis in AP patients by comparing color depth and turbidity of early ascites.METHODS This study included 667 AP patients with ascites,categorized by color and turbidity into yellow clear(n=54),yellow turbid(n=293),red brown(n=320).The trendχ2 test was employed to analyze the incidence of organ failure(OF),infected pancreatic necrosis(IPN),and mortality across groups.Receiver operating charac teristic(ROC)curves were used to evaluate the predictive value of ascites cell count,amylase,protein,and lactate dehydrogenase(LDH)for abdominal compartment syndrome(ACS)and intra-abdominal hemorrhage.RESULTS AP patients with ascites exhibited higher scores of scoring systems(such as Bedside index for severity in AP,Acute Physiology and Chronic Health Examination II,etc.)and increased complications and mortality rates(all P<0.05)compared to those without ascites.A linear association was observed between ascites color depth and turbidity and the incidence of OF,pancreatic necrosis,IPN,and mortality(P<0.05).LDH in ascites demonstrated high accuracy in predicting ACS and intra-abdominal hemorrhage,with areas under the ROC curve of 0.77 and 0.79,respectively.CONCLUSION Early in AP,ascites correlates with OF,IPN,and mortality,showing linear associations with color depth and turbidity.Ascitic LDH reliably predicts ACS and intra-abdominal hemorrhage in AP patients.展开更多
Background This study investigated the potential impacts of increasing linoleic andα-linolenic acid intake during lactation and wean-to-breeding on subsequent reproduction of sows.A total of 309 sows(PIC Camborough L...Background This study investigated the potential impacts of increasing linoleic andα-linolenic acid intake during lactation and wean-to-breeding on subsequent reproduction of sows.A total of 309 sows(PIC Camborough L42)were balanced by parity(140 and 169 sows representing parity 1 to 2[P1-2]and 3 to 9[P3+],respectively)and assigned within parity to a 2×2 factorial arrangement.Factors included essential fatty acid(EFA)supplementation(control diets containing 1.2%linoleic and 0.15%α-linolenic acid or diets with 3.0%linoleic and 0.38%α-linolenic acid)and supplementation period(lactation or wean-to-breeding).Tallow(low EFA diets)or soybean oil(high EFA diets)were included at 4%in sorghum-soybean meal-wheat middlings-based diets to attain targeted EFA levels.Results High levels of EFA fed during lactation had no effect on feed intake or litter performance,but increased subsequent farrowing rate(P=0.027;82.1%vs.70.4%),tended to reduce the proportion of sows removed(P=0.070;12.4%vs.20.8%),decreased the number of total pigs born in the following litter(P=0.072;15.3 vs.16.2),and increased total pigs born alive per 100 sows weaned(P=0.062;1,122 vs.974),regardless of sow parity.Young sows(P1-2)consuming the high EFA diet during lactation displayed a shorter wean-to-estrus interval(P=0.035;4.2 vs.4.6),but P3+sows were unaffected.Increasing EFA intake for P3+sows,but not P1-2 sows,resulted in more sows bred by d 5(P=0.028;91.1%vs.81.7%)and more mummies in the subsequent litter(P=0.040;0.32 vs.0.16).Feeding increased EFA to P1-2 sows during the wean-to-breeding period decreased subsequent farrowing rate(P=0.042;72.0%vs.87.7%),and increased removal rate(P=0.003;28.8%vs.9.4%).Total pigs born alive per 100 sows weaned was reduced(P=0.007)in P1-2 sows when supplemented with EFA during wean-breeding(939 vs.1,149)but was not impacted in P3+sows(1,131 vs.982).Conclusions Supplemental EFA in lactation diets benefited subsequent reproduction of sows,regardless of parity.Increasing dietary levels of EFA during the wean-to-breeding period to younger sows negatively impacted subsequent reproduction.展开更多
BACKGROUND Liver transplantation(LT)is the preferred treatment for end-stage liver diseases.Early allograft failure(EAF)can result in death or retransplantation.One of the key factors predicting EAF is the degree of g...BACKGROUND Liver transplantation(LT)is the preferred treatment for end-stage liver diseases.Early allograft failure(EAF)can result in death or retransplantation.One of the key factors predicting EAF is the degree of graft injury,which is typically assessed by elevated alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.Aminotransferase levels exceeding 5000 U/L within 48 hours of LT are indicative of poor short-term graft survival.AIM To investigate outcomes in liver transplant recipients with peak aminotransferase levels exceeding 5000 U/L and to identify predictors of EAF.METHODS Adult patients who underwent LT from a deceased(brain-dead)donor between 2011 and 2024 at Hospital de Clínicas de Porto Alegre were screened.Patients with peak AST or ALT levels>5000 U/L post-LT were included,excluding those with vascular thrombosis.EAF was defined as death or retransplantation within 90 days.A receiver operating characteristic curve were generated for each EAF predictor to determine the area under the curve(AUC).Sensitivity,specificity,negative predictive value,and positive predictive value were calculated for each predictor’s best cutoff,as defined by the Youden Index.Survival curves were plotted using the Kaplan-Meier method.RESULTS Between 2011 and 2024,341 patients underwent LT.Of these,29(8.5%)patients had AST and/or ALT levels exceeding 5000 U/L within the first 48 hours post-LT.Four patients were excluded due to vascular thrombosis,resulting in a study cohort of 25 patients.EAF were also observed in 11 patients.One-year and five-year graft survival rates were 51.7%and 42.6%,respectively.For patients without EAF,one-year and five-year graft survivals were 92.3%and 76.2%,respectively.The key predictors of EAF included serum factor V and arterial lactate levels on postoperative day(POD)1,with AUCs of 0.936 and 0.919,respectively.The optimal cutoff for EAF prediction were 26.2%for serum factor V and 9 mmol/L for arterial lactate.CONCLUSION Aminotransferase levels>5000 U/L were associated with high EAF risk.However,favorable graft function indicators on POD 1 were associated with long-term survival comparable to that of general LT recipients.Serum factor V and arterial lactate levels emerged as valuable prognostic markers.展开更多
Breast cancer(BC)has the highest prevalence among cancers specific to women,and its incidence rates are increasing in many countries.Subtypes of BC,including HER2-positive or triple-negative BC,exhibit differing treat...Breast cancer(BC)has the highest prevalence among cancers specific to women,and its incidence rates are increasing in many countries.Subtypes of BC,including HER2-positive or triple-negative BC,exhibit differing treatment responses;consequently,demand for personalized therapy is increasing,and relevant precision medicine strategies are under development.Aerobic glycolysis in cancer cells can lead to excessive lactate production,which in turn promotes lactylation and influences tumor cell behavior.Epigenetic alterations and metabolic reprogramming are prominent characteristics of tumors.Because lactate and lactylation are important in cancer,further investigation of the mechanisms underlying lactate metabolism and lactylation,and the development of therapeutic strategies targeting these processes,are topics of increasing interest.This review describes current research on lactate metabolism and lactylation in BC,thus offering new perspectives for advancing treatment and management toward more precise and personalized approaches that will ultimately increase BC survival rates and patient quality of life.展开更多
BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental...BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental factors.Despite recent therapeutic advances,survival rates remain dismal,underscoring an urgent need for novel therapeutic targets.AIM To investigate the role of hypoxia-inducible factor 1-alpha(HIF1A)in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A(LDHA),which is crucial for the glycolytic pathway in hypoxic tumor environments.METHODS Utilizing transcriptomic data from multiple public databases,we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses.The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues,associated with poor prognosis.HIF1A directly regulates LDHA,enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness.Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target,underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.展开更多
BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and ...BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.展开更多
Lactate,as a metabolite,plays a significant role in a number of fields,including medical diagnostics,exercise physiology and food science.Traditional methods for lactate measurement often involve expensive and cumbers...Lactate,as a metabolite,plays a significant role in a number of fields,including medical diagnostics,exercise physiology and food science.Traditional methods for lactate measurement often involve expensive and cumbersome instrumentation.This study developed a portable and low-cost lactate measurement system,including independently detectable hardware circuits and user-friendly embedded software,computer,and smartphone applications.The experiment verified that the relative error of the detection current in the device circuit was less than 1%.The electrochemical performance was measured by comparing the[Fe(CN)_(6)]^(3−)/[Fe(CN)_(6)]^(4−)solution with the desktop electrochemical workstation CHI660E,and a nearly consistent chronoamperometry(CA)curve was obtained.Two modified lactate sensors were used for CA testing of lactate.Within the concentration range of 0.1 mmol·L^(−1)to 20 mmol·L^(−1),there was a good linear relationship between lactate concentration and steady-state current,with a correlation coefficient(R2)greater than 0.99 and good repeatability,demonstrating the reliability of the developed device.The lactate measurement system developed in this study not only provides excellent detection performance and reliability,but also achieves portability and low cost,providing a new solution for lactate measurement.展开更多
An increasing number of studies have focused on depleting lactate and modulating the tumor’s lactic microenvironment to interfere with tumor progression,particularly in breast cancer.Lactate accumulation in tumors co...An increasing number of studies have focused on depleting lactate and modulating the tumor’s lactic microenvironment to interfere with tumor progression,particularly in breast cancer.Lactate accumulation in tumors contributes to a highly acidic microenvironment that promotes cancer cell survival and resistance to therapies.However,existing lactate depletion agents,primarily enzymes and macromolecules,fall short of clinical applications due to poor stability and their ability to only perform solitary lactate depletion without interfering with the transport process.Consequently,the development of stable molecules that deplete lactate and interfere with lactate transport is critically needed.Therefore,in this study,chlorin e6(Ce6)-gadolinium chloride(GdCl_(3))-flavin adenine dinucleotide(FAD)/tamoxifen(TAM)molecular chelates were prepared.The chelates fully interfered with lactate transport,depleted lactate in the tumor microenvironment,mitigated photodynamic therapy resistance,and realized synergistic photodynamic-hormonal therapy.FAD has promising capabilities in regulating lactate levels and mitigating acidic microenvironments.However,a strategy for depleting lactate by chelating the coenzyme FAD to form nanoparticles has not yet been reported.Tamoxifen disrupts tumor development and interferes with lactate transport by binding to estrogen receptor and inhibiting the expression of monocarboxylate transporter.In addition,coupling with Gd^(3+)increased the solubility of Ce6,thereby improving the photodynamic therapy effectiveness.This innovative strategy improves therapeutic efficacy and offers a promising approach for breast cancer treatment.展开更多
Background Lactational performance depends heavily on age,health,and nutrition.L-Citrulline(Cit)is an effective precursor of L-arginine(Arg),an amino acid that has important roles in synthesis of nitric oxide(NO)and p...Background Lactational performance depends heavily on age,health,and nutrition.L-Citrulline(Cit)is an effective precursor of L-arginine(Arg),an amino acid that has important roles in synthesis of nitric oxide(NO)and polyamines.Ruminal microbes degrade extracellular Arg;however,extracellular L-citrulline(Cit)is not degraded by ruminal microbes due to lack of uptake and can be fed unencapsulated as a precursor for Arg.As NO is a vasodilator,an increase in blood flow and transport of molecules to mammary tissue may enhance lactational performance and milk composition.Increases in polyamine production may increase milk protein synthesis within mammary tissue,thus increasing milk protein content.This study determined,for the first time,effects of dietary Cit supplementation on milk production and milk composition of Alpine dairy goats.Methods Does were synchronized to estrus and bred to Alpine bucks.Parturition was induced on d 149 of gestation and does were suckled overnight allowing kid(s)to obtain colostrum before being milked 24 h later(d 1 of lactation).Does were assigned to either control(CON,n=24)or Cit(CIT,n=23)diets.The isonitrogenous control diet consisted of 97.63%basal diet and 2.37%supplement(1.37%L-alanine and 1.00%soybean hydrogenated oil).The CIT supplemented diet consisted of 97.63%basal diet and 2.37%supplement(0.5%Cit,0.5%L-glutamine,1%soybean hydrogenated oil,0.37%cornstarch).Diets were group fed ad-libitum by treatment group.Blood samples were collected on d 0 and 30 of lactation,milk volumes measured twice daily,and on d 10,20,and 40 of lactation,milk samples were collected.Results CIT-treated does had greater daily milk production(P<0.05)and there was an effect of day of lactation on daily milk production(P<0.0001).Sire had significant effect on daily milk production as well(P<0.05).Milk compositional analyses revealed Cit supplementation increased solid-non-fat(SNF;P<0.05)and protein(P<0.05)content in milk.Conclusions Our novel results indicate that dietary supplementation of Cit fed ad-libitum in Alpine does increased daily milk yield,milk SNF content,and protein content.Supplemental Cit may be a proxy for Arg in goats to enhance lactational performance.展开更多
Background Lactate is a classical byproduct of glucose metabolism,and the main lactate production pathway depends on glycolysis.Lactate stabilized HIF1αby inhibiting PHD activity,leading to hypoxic stress response an...Background Lactate is a classical byproduct of glucose metabolism,and the main lactate production pathway depends on glycolysis.Lactate stabilized HIF1αby inhibiting PHD activity,leading to hypoxic stress response and exacerbating glycolysis in multiple tissues.However,the redox induction mechanism of lactate in mammary gland has not been understood yet.Herein,we describe a lactate-responsive HIF1α/circadian control mechanism in oxidative stress in the mammary glands of dairy cows.Results The in vivo study showed that dairy cows with high lactate concentrations are associated with reduced milk yield and more ROS accumulation in mammary gland.Western blot results in MAC-T cells showed positive correlation between lactate concentrations,expression of HIF1αand oxidative stress indicators,but not circadian core components.To test how lactate-mediated HIF1αdysfunction leads to cell protection process,we investigated altered expression of circadian core related genes following HIF1αstabilization.We found that stabilized HIF1αby lactate inhibited stimulated expression of circadian core components due to the similarity of HRE and E-box transcription elements.Furthermore,we found that lactate treatment strengthened the binding of HIF1αwith BMAL1,HMOX1 and FOXO3 in MAC-T cells.Moreover,HIF1αknockdown altered expression of circadian rhythm related genes and reduced oxidative stress state.Conclusion In summary,our study highlights the central role of competitive transcriptional element occupancy in lactate-mediated oxidative stress of mammary gland,which is caused by HIF1αstabilization and circadian rhythm dysfunction.Our findings introduce a novel nutritional strategy with potential applications in dairy farming for optimizing milk production and maintaining mammary gland health.展开更多
BACKGROUND Childhood intestinal lymphoma is characterized by its insidious onset and the absence of specific clinical symptoms.The thinner abdominal wall in children significantly aids in the ultrasound visualization ...BACKGROUND Childhood intestinal lymphoma is characterized by its insidious onset and the absence of specific clinical symptoms.The thinner abdominal wall in children significantly aids in the ultrasound visualization of the abdominal cavity and intestines.Although many typical cases of intestinal lymphoma can be diagnosed through ultrasound,physicians often either overlook these values or assume that ultrasound has limited diagnostic value for intestinal lymphoma.AIM To clarify the diagnosis of intestinal lymphoma and classify its severity using ultrasound,as well as to correlate this with prognosis.METHODS The correlation between ultrasound diagnostic outcomes,laboratory indicators,and clinical prognosis was analyzed to demonstrate the effectiveness of ultrasound in assessing the severity of intestinal lymphoma and to provide new evidence for the diagnosis and treatment of the disease in children.A retro-spective analysis was conducted on the sonographic images and case data of 28 children diagnosed with intestinal lymphoma and confirmed by surgical pathology.Additionally,we sought to determine the correlation between ultrasonic classification of lymphoma,lactate dehydrogenase(LDH)values,pathological classification,and prognosis.RESULTS Ultrasound was utilized to categorize 28 cases of intestinal lymphoma into focal segmental(15 cases)and extensive(13 cases)types.Ultrasound classification and LDH levels were significantly correlated with prognosis(P<0.05),while pathological type,age,gender,and treatment modality showed no significant correlation(P>0.05).Among ultrasound manifestations,there was a significant difference in LDH levels between the segmental and extensive groups(P<0.05).The prognosis for children with extensive intestinal lymphoma was poorer than that for children with localized segmental intestinal lymphoma(P<0.05).CONCLUSION Ultrasound can be used in the diagnosis and classification of intestinal lymphoma in children.Extensive intestinal lymphoma is associated with significantly elevated LDH and poor prognosis.展开更多
Metabolic dysfunction-associated steatohepatitis(MASH)and alcoholic steatohepatitis(ASH)are severe forms of chronic liver disease,characterized by inflammation,oxidative stress,lipid dysregulation,and fibrosis.Epigene...Metabolic dysfunction-associated steatohepatitis(MASH)and alcoholic steatohepatitis(ASH)are severe forms of chronic liver disease,characterized by inflammation,oxidative stress,lipid dysregulation,and fibrosis.Epigenetic changes,including acetylation,methylation,phosphorylation,ubiquitination,sumoylation,and lactylation of histones,dynamically regulate gene expression by altering the chromatin structure.Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases.Lactylation which is a novel post-translational modification(PTM)of histone,has been observed as a crucial contributor to liver physiology as well as pathobiology.This modification,characterized by the addition of lactate to lysine residues on histones,influences gene expression and cellular metabolism in the liver.Intriguingly,elevated lactate levels in the liver,resulting from either chronic alcohol consumption or a highfat/fructose-rich diet,may promote histone lactylation,particularly at histone 3 at lysine 18(H3K18),which facilitates the transcription of pro-inflammatory and fibrogenic genes.This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways,resulting in further liver damage.This review aims to elucidate the role of histone lactylation in MASH.Although a direct demonstration of histone lactylation in ASH has not yet been reported,the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis.Finally,we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
基金supported by Applied Basic Research Joint Fund Project of Yunnan Province,No.202301AY070001-200Middle-aged Academic and Technical Training Project for High-Level Talents,No.202105AC160065+1 种基金Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases,No.YWLCYXZX2023300077Key Clinical Specialty of Neurology in Yunnan Province,No.300064(all to CL)。
文摘Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.
基金supported by grants from National Natural Science Foundation of China (82402543)National High Level Hospital Clinical Research Funding (2022-PUMCH-B-109)+2 种基金CAMS Innovation Fund for Medical Sciences (CIFMS)(2021-I2M-1-020)Opening Foundation of Agile and Intelligent Computing Key Laboratory of Sichuan ProvinceSpecial Research Fund for Central Universities,Peking Union Medical College (3332024120)
文摘BACKGROUND:Sepsis is a highly heterogeneous organ dysfunction syndrome.There is limited evidence regarding phenotypes and clinical outcomes in sepsis patients with initial normal lactate levels.We sought to identify the lactate-based clinical phenotypes and outcomes of sepsis patients.METHODS:The Medical Information Mart for Intensive Care IV(MIMIC-IV)and eICU databases were used to conduct a retrospective cohort study.Adult sepsis patients were included.Lactate was measured via blood gas,and the same assay type was used across both databases.Serial lactate measurements were analyzed via a two-point classification system based on the highest values recorded during two consecutive 24-hour periods following ICU admission.The fi rst measurement window(T1)comprised the initial 24 h post-admission,whereas the second window(T2)covered 24-48 h post-admission.The lactate diff erence was defi ned as the numerical change between the highest lactate level at T2 and the highest level at T1.The time interval between these two measurements was fi xed,with T2 commencing immediately after T1,together encompassing the fi rst 48 h post-ICU admission.A normal lactate level was defi ned as≤2 mmol/L,and an elevated level was defi ned as>2 mmol/L.Sepsis patients were stratifi ed into four trajectory phenotypes:(1)normal-normal(N-N);(2)normal-elevated(N-E);(3)elevated-normal(E-N);and(4)elevated-elevated(E-E).The primary outcome was in-hospital mortality.RESULTS:This study enrolled 6,926 sepsis patients.The clinical phenotypes of the sepsis patients were as follows:N-N(24.4%),N-E(3.8%),E-N(36.4%),and E-E(35.3%).The in-hospital mortality rates of sepsis patients with the four phenotypes from the MIMIC-IV and eICU databases were as follows(N-N:18.9%vs.17.6%,P=0.66;N-E:35.3%vs.29.2%,P=0.45;E-N:16.6%vs.14.2%,P=0.14;E-E:43.6%vs.37.8%,P=0.01).After adjusting for age,sex,Sequential Organ Failure Assessment(SOFA)score,vasopressor therapy,and infection sites,the N-E phenotype was associated with a higher risk of in-hospital mortality(odds ratio[OR]1.44;95%confidence intervals[95%CI]1.11-1.86;P=0.006;adjusted OR 1.61;95%CI 1.23-2.11;P<0.001).The E-N phenotype was associated with the most favorable outcomes for in-hospital mortality in the multivariable analysis(adjusted OR 0.41;95%CI 0.36-0.46;P<0.001).The E-E phenotype was associated with the highest risk of in-hospital mortality in the overall cohort(adjusted OR 3.00;95%CI 2.67-3.37;P<0.001).CONCLUSION:In sepsis patients with normal initial lactate levels,serial lactate measurements could be valuable for prognostic assessment.
基金funded by the Sichuan Science and Technology Program(2021ZDZX0009)the earmarked fund from the National Natural Science Foundation of China(31972577)。
文摘Background Inflammatory bowel disease causes intestinal structural damage,impairs gut function,hinders animal growth and development,and reduces farming efficiency.Previous studies demonstrated that lactate alleviates dextran sulfate sodium(DSS)-induced inflammation and mitigates weight loss by enhancing intestinal barrier functions.However,the mechanisms underlying lactate-mediated protection of the intestinal epithelial barrier remain unclear.This study aimed to explore the protective effect of lactate on intestinal barrier damage in colitis piglets and the possible underlying mechanisms through in vivo and in vitro experiments.Methods A total of 6021-day-old weaned female piglets were randomly assigned into three groups based on weight:the control group(basal diet with physiological saline gavage),the DSS group(basal diet with 5%DSS gavage),and the DSS+LA group(2%lactate diet with 5%DSS gavage).There were 10 replicates per treatment,with 2 piglets per replicate.Jejunal morphology was assessed via hematoxylin and eosin staining,while Western blotting quantified the protein levels of proliferation markers,including cluster of differentiation 24(CD24),cyclin D1,and wingless/integrated(Wnt)/β-catenin signaling components.In vitro,0.08%DSS and 2–32 mmol/L sodium lactate-treated intestinal porcine epithelial cell line-J2(IPEC-J2)cells(n=4)were assessed for viability(Cell Counting Kit-8 assay),apoptosis(flow cytometry),and proliferation parameters,including cell cycle analysis and Leucine-rich repeat-containing G-protein coupled receptor 5(Lgr5+)stem cell quantification.Results In vivo,DSS administration induced jejunal villus shortening(P<0.05),downregulated protein levels of CD24,cyclin D1,casein kinase 1(CK1),and dishevelled-2(DVL2)(P<0.05).In vitro,DSS promoted apoptosis,inhibited proliferation,diminished the Lgr5+cell populations(P<0.05),and reduced S-phase cell proportions(P<0.05).Conversely,lactate supplementation ameliorated DSS-induced villus atrophy(P<0.05),restored CD24,cyclin D1,CK1,and DVL2 protein levels(P<0.05).Furthermore,in vitro,sodium lactate attenuated DSS-induced apoptosis(P<0.05),enhanced IPEC-J2 proliferation(P<0.05),expanded Lgr5+cells(P<0.05),and increased S-phase progression(P<0.05).Conclusions In summary,lactate ameliorated intestinal barrier damage in DSS-induced colitis by activating the Wnt/β-catenin pathway and restoring the balance between epithelial cell proliferation and apoptosis.This study provides novel mechanistic evidence supporting lactate's therapeutic potential for IBD management.
基金Ontario Ministry of Agriculture,Food and Agribusiness(OMAFA)Natural Sciences and Engineering Research Council of Canada(NSERC)+1 种基金AdisseoOntario Sheep Farmers。
文摘Background Selenium(Se)is an essential soil mineral that can be incorporated into animal feedstuffs.Because of a lack of soil Se in some regions,organic or inorganic supplementation strategies must be implemented to prevent deficiencies and promote optimal ovine health.Therefore,the objectives of this study were to assess how inorganic versus organic Se supplementation influenced ewe Se status and immune function during late gestation and postpartum.Dorset Rideau ewes(n=110)were fed a Se deficient diet from gestation d 110 through postpartum d 49 and received one of four daily oral Se treatments diluted in 5 mL of sugar water:0 mg Se,0.3 mg inorganic Se,0.3 mg organic Se,and 0.6 mg organic Se.Throughout the trial,the ewes received various immune challenges,including intramuscular immunizations with a novel antigen(ovalbumin;OVA)on trial d 0 and 10,an intradermal OVA challenge on d 20,and a lipopolysaccharide(LPS)endotoxin challenge on trial d 49.Results The organic Se treatment groups had higher serum Se concentrations on most trial days compared to the 0.3 mg inorganic and control groups(P<0.05).No significant treatment differences were found for the dermal hypersensitivity response to OVA,anti-OVA antibody response,glutathione peroxidase activity,cytokine response,cortisol response,or rectal temperature(P>0.05).However,4 h post-LPS injection,the serum albumin concentration was significantly lower in the 0.3 mg inorganic group compared to both organic Se groups,potentially indicating a higher degree of inflammation in the ewes supplemented with the inorganic Se.Conclusions The results of this study indicate that organic Se supplementation can promote a higher Se status in ewes over time,but Se supplementation during this study period did not affect tested immunological parameters.This lack of difference in immune responsiveness between groups may be due to an absence of true serum Se deficiencies in the Se-deficient group or the levels of Se supplementation being insufficient to significantly improve immunocompetence.
基金National Nature Science Foundation of China,No.81870944(to FL).
文摘This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage,a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options.Lactate,a metabolic byproduct,has been shown to have neuroprotective properties,including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients.However,the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown.In this study,we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes.In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores,reduced brain inflammation,and promoted lipid droplet formation in astrocytes within 24 hours.Lactate treatment increased free fatty acids levels in the brain.The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets,thus reducing cellular lipotoxicity.Moreover,lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5,a protein crucial for lipid droplet formation.The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate,indicating that lactate’s protective role is closely linked to lipid metabolism and lipid droplet formation.In vitro experiments on HT22 neuronal cells exposed to hemin-an agent used to simulate subarachnoid hemorrhage injury-demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential.Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects,further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate.This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage.It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes,thus mitigating brain damage and improving cell survival.These findings suggest that lactate,through its regulation of lipid metabolism,could be a potential therapeutic agent for subarachnoid hemorrhage.
基金supported by National Key R&D Program of China(2021YFD2100700).
文摘Both linoleic acid(18:2 n-6,LA)andα-linolenic acid(18:3 n-3,ALA)are essential fatty acids for infants.The contents of LA and ALA,and their ratio exhibited significant changes in human milk over the past 4 decades,which were not well summarized.Here,we summarized these values in 9898 human breast milk samples of 6664 mothers from 50 countries in 81 studies.A literature search was conducted using PubMed,Embase,and Web of Science between January 1980 and October 2023.The 95%confidence interval of LA/ALA ratio across lactation and gestation ranged from 14.24 to 31.26.The LA content was higher in China and Turkey(>20%)whereas the ALA content was below 1%in Africa.The LA/ALA ratio in countries along the Mediterranean coast exceeded 20 or even 30.LA and ALA contents increased significantly(P<0.01)while the ratio remained stable over the last 40 years.Multivariate meta-regression results showed that regions significantly(P<0.01)determined the LA,ALA,and LA/ALA ratio.Especially,maternal diet could definitely explain the variation while the effects of gestational age,lactation period was not significant.Clinical trials demonstrated that decreasing the LA/ALA ratio increased docosahexaenoic acid(22:6 n-3,DHA)status,reduced arachidonic acid(20:4 n-6,AA)contents,exerted no effect on the visual function of infants,and reached no consensus on growth.The current review aims to provide an overview on the LA and ALA contents and their ratio in human breast milk to raise concern in infant formula.
文摘The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.
基金Supported by National Natural Science Foundation of China,No.82360136Jiangxi Clinical Research Center for Gastroenterology,No.20223BCG74011.
文摘BACKGROUND Acute pancreatitis(AP)is a severe condition,and abdominal effusion is a significant predictor of its severity and prognosis.However,the relationship between ascites characteristics and AP outcomes remains undefined.AIM To assess the correlation between ascites characteristics and clinical prognosis in AP patients by comparing color depth and turbidity of early ascites.METHODS This study included 667 AP patients with ascites,categorized by color and turbidity into yellow clear(n=54),yellow turbid(n=293),red brown(n=320).The trendχ2 test was employed to analyze the incidence of organ failure(OF),infected pancreatic necrosis(IPN),and mortality across groups.Receiver operating charac teristic(ROC)curves were used to evaluate the predictive value of ascites cell count,amylase,protein,and lactate dehydrogenase(LDH)for abdominal compartment syndrome(ACS)and intra-abdominal hemorrhage.RESULTS AP patients with ascites exhibited higher scores of scoring systems(such as Bedside index for severity in AP,Acute Physiology and Chronic Health Examination II,etc.)and increased complications and mortality rates(all P<0.05)compared to those without ascites.A linear association was observed between ascites color depth and turbidity and the incidence of OF,pancreatic necrosis,IPN,and mortality(P<0.05).LDH in ascites demonstrated high accuracy in predicting ACS and intra-abdominal hemorrhage,with areas under the ROC curve of 0.77 and 0.79,respectively.CONCLUSION Early in AP,ascites correlates with OF,IPN,and mortality,showing linear associations with color depth and turbidity.Ascitic LDH reliably predicts ACS and intra-abdominal hemorrhage in AP patients.
文摘Background This study investigated the potential impacts of increasing linoleic andα-linolenic acid intake during lactation and wean-to-breeding on subsequent reproduction of sows.A total of 309 sows(PIC Camborough L42)were balanced by parity(140 and 169 sows representing parity 1 to 2[P1-2]and 3 to 9[P3+],respectively)and assigned within parity to a 2×2 factorial arrangement.Factors included essential fatty acid(EFA)supplementation(control diets containing 1.2%linoleic and 0.15%α-linolenic acid or diets with 3.0%linoleic and 0.38%α-linolenic acid)and supplementation period(lactation or wean-to-breeding).Tallow(low EFA diets)or soybean oil(high EFA diets)were included at 4%in sorghum-soybean meal-wheat middlings-based diets to attain targeted EFA levels.Results High levels of EFA fed during lactation had no effect on feed intake or litter performance,but increased subsequent farrowing rate(P=0.027;82.1%vs.70.4%),tended to reduce the proportion of sows removed(P=0.070;12.4%vs.20.8%),decreased the number of total pigs born in the following litter(P=0.072;15.3 vs.16.2),and increased total pigs born alive per 100 sows weaned(P=0.062;1,122 vs.974),regardless of sow parity.Young sows(P1-2)consuming the high EFA diet during lactation displayed a shorter wean-to-estrus interval(P=0.035;4.2 vs.4.6),but P3+sows were unaffected.Increasing EFA intake for P3+sows,but not P1-2 sows,resulted in more sows bred by d 5(P=0.028;91.1%vs.81.7%)and more mummies in the subsequent litter(P=0.040;0.32 vs.0.16).Feeding increased EFA to P1-2 sows during the wean-to-breeding period decreased subsequent farrowing rate(P=0.042;72.0%vs.87.7%),and increased removal rate(P=0.003;28.8%vs.9.4%).Total pigs born alive per 100 sows weaned was reduced(P=0.007)in P1-2 sows when supplemented with EFA during wean-breeding(939 vs.1,149)but was not impacted in P3+sows(1,131 vs.982).Conclusions Supplemental EFA in lactation diets benefited subsequent reproduction of sows,regardless of parity.Increasing dietary levels of EFA during the wean-to-breeding period to younger sows negatively impacted subsequent reproduction.
基金Supported by Financiamento e IncentivoàPesquisa of Hospital de Clínicas de Porto Alegre,No.170271.
文摘BACKGROUND Liver transplantation(LT)is the preferred treatment for end-stage liver diseases.Early allograft failure(EAF)can result in death or retransplantation.One of the key factors predicting EAF is the degree of graft injury,which is typically assessed by elevated alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.Aminotransferase levels exceeding 5000 U/L within 48 hours of LT are indicative of poor short-term graft survival.AIM To investigate outcomes in liver transplant recipients with peak aminotransferase levels exceeding 5000 U/L and to identify predictors of EAF.METHODS Adult patients who underwent LT from a deceased(brain-dead)donor between 2011 and 2024 at Hospital de Clínicas de Porto Alegre were screened.Patients with peak AST or ALT levels>5000 U/L post-LT were included,excluding those with vascular thrombosis.EAF was defined as death or retransplantation within 90 days.A receiver operating characteristic curve were generated for each EAF predictor to determine the area under the curve(AUC).Sensitivity,specificity,negative predictive value,and positive predictive value were calculated for each predictor’s best cutoff,as defined by the Youden Index.Survival curves were plotted using the Kaplan-Meier method.RESULTS Between 2011 and 2024,341 patients underwent LT.Of these,29(8.5%)patients had AST and/or ALT levels exceeding 5000 U/L within the first 48 hours post-LT.Four patients were excluded due to vascular thrombosis,resulting in a study cohort of 25 patients.EAF were also observed in 11 patients.One-year and five-year graft survival rates were 51.7%and 42.6%,respectively.For patients without EAF,one-year and five-year graft survivals were 92.3%and 76.2%,respectively.The key predictors of EAF included serum factor V and arterial lactate levels on postoperative day(POD)1,with AUCs of 0.936 and 0.919,respectively.The optimal cutoff for EAF prediction were 26.2%for serum factor V and 9 mmol/L for arterial lactate.CONCLUSION Aminotransferase levels>5000 U/L were associated with high EAF risk.However,favorable graft function indicators on POD 1 were associated with long-term survival comparable to that of general LT recipients.Serum factor V and arterial lactate levels emerged as valuable prognostic markers.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82302626)Gusu Health Talent Project of Suzhou,China(Grant No.GSWS2022076)Suzhou Key Laboratory of Intelligent Critical Illness Biomarkers Translational Research Project(Grant No.SZS2024029)。
文摘Breast cancer(BC)has the highest prevalence among cancers specific to women,and its incidence rates are increasing in many countries.Subtypes of BC,including HER2-positive or triple-negative BC,exhibit differing treatment responses;consequently,demand for personalized therapy is increasing,and relevant precision medicine strategies are under development.Aerobic glycolysis in cancer cells can lead to excessive lactate production,which in turn promotes lactylation and influences tumor cell behavior.Epigenetic alterations and metabolic reprogramming are prominent characteristics of tumors.Because lactate and lactylation are important in cancer,further investigation of the mechanisms underlying lactate metabolism and lactylation,and the development of therapeutic strategies targeting these processes,are topics of increasing interest.This review describes current research on lactate metabolism and lactylation in BC,thus offering new perspectives for advancing treatment and management toward more precise and personalized approaches that will ultimately increase BC survival rates and patient quality of life.
文摘BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental factors.Despite recent therapeutic advances,survival rates remain dismal,underscoring an urgent need for novel therapeutic targets.AIM To investigate the role of hypoxia-inducible factor 1-alpha(HIF1A)in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A(LDHA),which is crucial for the glycolytic pathway in hypoxic tumor environments.METHODS Utilizing transcriptomic data from multiple public databases,we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses.The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues,associated with poor prognosis.HIF1A directly regulates LDHA,enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness.Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target,underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.
文摘BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.
基金supported by National Natural Science Foundation of China(No.62006092)Natural Science Research Project of Anhui Educational Committee(No.2023AH030081)+1 种基金2023 New Era Education Provincial Quality Engineering Project(Graduate Education)(No.2023cxcysj103)2024 New Era Education Provincial Quality Engineering Project(Graduate Education)。
文摘Lactate,as a metabolite,plays a significant role in a number of fields,including medical diagnostics,exercise physiology and food science.Traditional methods for lactate measurement often involve expensive and cumbersome instrumentation.This study developed a portable and low-cost lactate measurement system,including independently detectable hardware circuits and user-friendly embedded software,computer,and smartphone applications.The experiment verified that the relative error of the detection current in the device circuit was less than 1%.The electrochemical performance was measured by comparing the[Fe(CN)_(6)]^(3−)/[Fe(CN)_(6)]^(4−)solution with the desktop electrochemical workstation CHI660E,and a nearly consistent chronoamperometry(CA)curve was obtained.Two modified lactate sensors were used for CA testing of lactate.Within the concentration range of 0.1 mmol·L^(−1)to 20 mmol·L^(−1),there was a good linear relationship between lactate concentration and steady-state current,with a correlation coefficient(R2)greater than 0.99 and good repeatability,demonstrating the reliability of the developed device.The lactate measurement system developed in this study not only provides excellent detection performance and reliability,but also achieves portability and low cost,providing a new solution for lactate measurement.
基金supported by the National Natural Science Foundation of China(No.82373206)Zhejiang Provincial Natural Science Foundation of China under Grant No LHDMZ24H300002National Key Research and Development Program of China(No.2022YFE0107800,2023YFA1008603).
文摘An increasing number of studies have focused on depleting lactate and modulating the tumor’s lactic microenvironment to interfere with tumor progression,particularly in breast cancer.Lactate accumulation in tumors contributes to a highly acidic microenvironment that promotes cancer cell survival and resistance to therapies.However,existing lactate depletion agents,primarily enzymes and macromolecules,fall short of clinical applications due to poor stability and their ability to only perform solitary lactate depletion without interfering with the transport process.Consequently,the development of stable molecules that deplete lactate and interfere with lactate transport is critically needed.Therefore,in this study,chlorin e6(Ce6)-gadolinium chloride(GdCl_(3))-flavin adenine dinucleotide(FAD)/tamoxifen(TAM)molecular chelates were prepared.The chelates fully interfered with lactate transport,depleted lactate in the tumor microenvironment,mitigated photodynamic therapy resistance,and realized synergistic photodynamic-hormonal therapy.FAD has promising capabilities in regulating lactate levels and mitigating acidic microenvironments.However,a strategy for depleting lactate by chelating the coenzyme FAD to form nanoparticles has not yet been reported.Tamoxifen disrupts tumor development and interferes with lactate transport by binding to estrogen receptor and inhibiting the expression of monocarboxylate transporter.In addition,coupling with Gd^(3+)increased the solubility of Ce6,thereby improving the photodynamic therapy effectiveness.This innovative strategy improves therapeutic efficacy and offers a promising approach for breast cancer treatment.
基金supported by funding from Texas A&M AgriLife ResearchPrairie View A&M University International Center for Goat Research。
文摘Background Lactational performance depends heavily on age,health,and nutrition.L-Citrulline(Cit)is an effective precursor of L-arginine(Arg),an amino acid that has important roles in synthesis of nitric oxide(NO)and polyamines.Ruminal microbes degrade extracellular Arg;however,extracellular L-citrulline(Cit)is not degraded by ruminal microbes due to lack of uptake and can be fed unencapsulated as a precursor for Arg.As NO is a vasodilator,an increase in blood flow and transport of molecules to mammary tissue may enhance lactational performance and milk composition.Increases in polyamine production may increase milk protein synthesis within mammary tissue,thus increasing milk protein content.This study determined,for the first time,effects of dietary Cit supplementation on milk production and milk composition of Alpine dairy goats.Methods Does were synchronized to estrus and bred to Alpine bucks.Parturition was induced on d 149 of gestation and does were suckled overnight allowing kid(s)to obtain colostrum before being milked 24 h later(d 1 of lactation).Does were assigned to either control(CON,n=24)or Cit(CIT,n=23)diets.The isonitrogenous control diet consisted of 97.63%basal diet and 2.37%supplement(1.37%L-alanine and 1.00%soybean hydrogenated oil).The CIT supplemented diet consisted of 97.63%basal diet and 2.37%supplement(0.5%Cit,0.5%L-glutamine,1%soybean hydrogenated oil,0.37%cornstarch).Diets were group fed ad-libitum by treatment group.Blood samples were collected on d 0 and 30 of lactation,milk volumes measured twice daily,and on d 10,20,and 40 of lactation,milk samples were collected.Results CIT-treated does had greater daily milk production(P<0.05)and there was an effect of day of lactation on daily milk production(P<0.0001).Sire had significant effect on daily milk production as well(P<0.05).Milk compositional analyses revealed Cit supplementation increased solid-non-fat(SNF;P<0.05)and protein(P<0.05)content in milk.Conclusions Our novel results indicate that dietary supplementation of Cit fed ad-libitum in Alpine does increased daily milk yield,milk SNF content,and protein content.Supplemental Cit may be a proxy for Arg in goats to enhance lactational performance.
基金supported by National Nature Science Foundation of China(32102552 and 32172741).
文摘Background Lactate is a classical byproduct of glucose metabolism,and the main lactate production pathway depends on glycolysis.Lactate stabilized HIF1αby inhibiting PHD activity,leading to hypoxic stress response and exacerbating glycolysis in multiple tissues.However,the redox induction mechanism of lactate in mammary gland has not been understood yet.Herein,we describe a lactate-responsive HIF1α/circadian control mechanism in oxidative stress in the mammary glands of dairy cows.Results The in vivo study showed that dairy cows with high lactate concentrations are associated with reduced milk yield and more ROS accumulation in mammary gland.Western blot results in MAC-T cells showed positive correlation between lactate concentrations,expression of HIF1αand oxidative stress indicators,but not circadian core components.To test how lactate-mediated HIF1αdysfunction leads to cell protection process,we investigated altered expression of circadian core related genes following HIF1αstabilization.We found that stabilized HIF1αby lactate inhibited stimulated expression of circadian core components due to the similarity of HRE and E-box transcription elements.Furthermore,we found that lactate treatment strengthened the binding of HIF1αwith BMAL1,HMOX1 and FOXO3 in MAC-T cells.Moreover,HIF1αknockdown altered expression of circadian rhythm related genes and reduced oxidative stress state.Conclusion In summary,our study highlights the central role of competitive transcriptional element occupancy in lactate-mediated oxidative stress of mammary gland,which is caused by HIF1αstabilization and circadian rhythm dysfunction.Our findings introduce a novel nutritional strategy with potential applications in dairy farming for optimizing milk production and maintaining mammary gland health.
基金Supported by the Fujian Province Science and Technology Innovation Joint Fund Project,No.2021Y9188。
文摘BACKGROUND Childhood intestinal lymphoma is characterized by its insidious onset and the absence of specific clinical symptoms.The thinner abdominal wall in children significantly aids in the ultrasound visualization of the abdominal cavity and intestines.Although many typical cases of intestinal lymphoma can be diagnosed through ultrasound,physicians often either overlook these values or assume that ultrasound has limited diagnostic value for intestinal lymphoma.AIM To clarify the diagnosis of intestinal lymphoma and classify its severity using ultrasound,as well as to correlate this with prognosis.METHODS The correlation between ultrasound diagnostic outcomes,laboratory indicators,and clinical prognosis was analyzed to demonstrate the effectiveness of ultrasound in assessing the severity of intestinal lymphoma and to provide new evidence for the diagnosis and treatment of the disease in children.A retro-spective analysis was conducted on the sonographic images and case data of 28 children diagnosed with intestinal lymphoma and confirmed by surgical pathology.Additionally,we sought to determine the correlation between ultrasonic classification of lymphoma,lactate dehydrogenase(LDH)values,pathological classification,and prognosis.RESULTS Ultrasound was utilized to categorize 28 cases of intestinal lymphoma into focal segmental(15 cases)and extensive(13 cases)types.Ultrasound classification and LDH levels were significantly correlated with prognosis(P<0.05),while pathological type,age,gender,and treatment modality showed no significant correlation(P>0.05).Among ultrasound manifestations,there was a significant difference in LDH levels between the segmental and extensive groups(P<0.05).The prognosis for children with extensive intestinal lymphoma was poorer than that for children with localized segmental intestinal lymphoma(P<0.05).CONCLUSION Ultrasound can be used in the diagnosis and classification of intestinal lymphoma in children.Extensive intestinal lymphoma is associated with significantly elevated LDH and poor prognosis.
基金Supported by the Science and Engineering Research Board,No.CRG/2022/002149the Indian Council of Medical Research,No.ICMR/02/833/IGP-2024 and No.R.12016/12/2023-HR.
文摘Metabolic dysfunction-associated steatohepatitis(MASH)and alcoholic steatohepatitis(ASH)are severe forms of chronic liver disease,characterized by inflammation,oxidative stress,lipid dysregulation,and fibrosis.Epigenetic changes,including acetylation,methylation,phosphorylation,ubiquitination,sumoylation,and lactylation of histones,dynamically regulate gene expression by altering the chromatin structure.Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases.Lactylation which is a novel post-translational modification(PTM)of histone,has been observed as a crucial contributor to liver physiology as well as pathobiology.This modification,characterized by the addition of lactate to lysine residues on histones,influences gene expression and cellular metabolism in the liver.Intriguingly,elevated lactate levels in the liver,resulting from either chronic alcohol consumption or a highfat/fructose-rich diet,may promote histone lactylation,particularly at histone 3 at lysine 18(H3K18),which facilitates the transcription of pro-inflammatory and fibrogenic genes.This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways,resulting in further liver damage.This review aims to elucidate the role of histone lactylation in MASH.Although a direct demonstration of histone lactylation in ASH has not yet been reported,the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis.Finally,we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.
