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
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 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
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
The interaction between the lactate receptor GPR81(also known as hydroxycarboxylic acid receptor 1,or HCAR1)and Splicing Factor Proline-and Glutamine-Rich protein promotes the tumor cell malignancy.GPR81 nuclear trans...The interaction between the lactate receptor GPR81(also known as hydroxycarboxylic acid receptor 1,or HCAR1)and Splicing Factor Proline-and Glutamine-Rich protein promotes the tumor cell malignancy.GPR81 nuclear translocation plays an important role in driving cancer progression and could serve as a potential therapeutic target.Yang et al concluded in their study that lactate and its receptor,GPR81,play crucial roles in cancer progression,and are key players in linking the lactate-rich tumor microenvironment to cancer cell behavior.The ability of nuclear GPR81 to directly regulate gene expression,combined with extracellular matrix-mediated mechanical signaling,creates a potentially robust system for the coordinated adaptation and survival of cancer cells.Understanding these interactions could lead to the discovery of new therapeutic targets and improved treatment strategies for cancer.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 Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy,with its pathogenesis involving dysregulation of multiple genes,including adenomatous polyposis coli and p53.Emerging evidence suggests that ...BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy,with its pathogenesis involving dysregulation of multiple genes,including adenomatous polyposis coli and p53.Emerging evidence suggests that microRNA 195(miR195)plays a critical role in carcinogenesis by modulating the phosphatidylinositol 3 kinase(PI3K)/protein kinase B(AKT)signaling pathway through phosphatase and tensin homologue(PTEN),thereby influencing cellular metabolism.Loss of PTEN function leads to hyperactivation of PI3K/AKT signaling pathway,resulting in upregulated expression of lactate dehydrogenase-5(LDH-5)and promoting the tumor progression.AIM To explore the clinical relevance of miR195,LDH-5,and PTEN expression patterns in CRC patient tissues and their association with clinicopathological features and prognosis.METHODS We enrolled 53 CRC patients who received surgical resection at our hospital from January 2020 to February 2022.Fresh tumor tissues and paired adjacent normal tissues(>5 cm from the tumor margin)were collected.The mRNA expression of miR195 was quantified by real-time quantitative polymerase chain reaction,while the protein expression of LDH-5 and PTEN were assessed via immunohistochemistry.Differences in molecular expression between tumor and adjacent normal tissues were compared,along with their correlations with clinicopathological parameters and prognosis.RESULTS The positive rate of miR195 in CRC tissues(35.85%)was significantly lower than that in adjacent normal tissues(90.57%).LDH-5 displayed a higher positive rate(79.25%)in the tissues compared to normal tissues(11.32%),while PTEN expression was markedly reduced in tumors(28.30%vs 94.34%,P<0.05).Elevated expression of miR195 was observed in CRC tissues from patients with earlier tumor,node,metastasis(TNM)stages and without lymph node metastasis.Conversely,higher expression of LDH-5 was associated with advanced TNM stages,lower differentiation grades,and the presence of lymph node metastasis.Additionally,PTEN expression was higher in patients with smaller tumor diameters and no lymph node metastasis(P<0.05).In CRC tissues,miR195 showed a negative correlation with LDH-5(r=-0.883,P=0.015)but a positive correlation with PTEN(r=0.429,P=0.006).LDH-5 was negatively associated with PTEN(r=-0.396,P<0.001).Patients with miR195 positivity,LDH-5 negativity,and PTEN positivity demonstrated significantly better prognosis(P<0.05).CONCLUSION Low miR195 and PTEN expression,coupled high LDH-5 expression could constitutes a hallmark molecular signature of CRC progression.These signature may act as potential markers for diagnosis and disease assessment,and prognostic evaluation in CRC patients,eventually improving CRC management.展开更多
The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metast...The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate’s role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate’s importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.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
Oxaliplatin(OXA)can be used as a palliative treatment for advanced hepatocellular carcinoma(HCC).While most patients still have rapid disease progression after OXA due to the drug resistance.The lactate dehydrogenase ...Oxaliplatin(OXA)can be used as a palliative treatment for advanced hepatocellular carcinoma(HCC).While most patients still have rapid disease progression after OXA due to the drug resistance.The lactate dehydrogenase A(LDHA)inhibitors can reduce the inflammation-induced effects,metastasis,and proliferation potential of cancer cells.Here,we adopt the water-in-oil attractive Pickering emulsion gel(APEG)to deliver OXA and LDHA inhibitor,GSK2837808A(GSK).OXA is dissolved in water and GSK is dissolved in iodized oil.This drugs-loaded APEG has good biocompatibility and can release OXA and GSK slowly.OXA+GSK@gel has significant anti-tumor effect on HCC model,which can effectively inhibit tumor cell proliferation and promote tumor cell apoptosis.Meanwhile,flow analysis confirm that it could activate the tumor immune microenvironment in HCC.The infiltration of CD8^(+)T cells is increased,thereby providing better anti-tumor effect.The results suggest that the APEGs loaded with OXA and GSK can effectively improve the delivery efficiency and enhance the anti-tumor therapy.展开更多
BACKGROUND Colorectal cancer(CRC)remains a major global health burden due to its high incidence and mortality,with treatment efficacy often hindered by tumor hetero-geneity,drug resistance,and a complex tumor microenv...BACKGROUND Colorectal cancer(CRC)remains a major global health burden due to its high incidence and mortality,with treatment efficacy often hindered by tumor hetero-geneity,drug resistance,and a complex tumor microenvironment(TME).Lactate metabolism plays a pivotal role in reshaping the TME,promoting immune eva-sion and epithelial-mesenchymal transition,making it a promising target for novel therapeutic strategies and prognostic modeling in CRC.AIM To offer an in-depth analysis of the role of lactate metabolism in CRC,high-lighting its significance in the TME and therapeutic response.METHODS Utilizing single-cell and transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas,we identified key lactate metabolic activities,particularly in the monocyte/macrophage subpopulation.RESULTS Seven lactate metabolism-associated genes were significantly linked to CRC prognosis and used to construct a predictive model.This model accurately forecasts patient outcomes and reveals notable distinct patterns of immune infiltration and transcriptomic profiles mutation profiles between high-and low-risk groups.High-risk patients demonstrated elevated immune cell infiltration,increased mutation frequencies,and heightened sensitivity to specific drugs(AZD6482,tozasertib,and SB216763),providing a foundation for personalized treatment approaches.Additionally,a nomogram integrating clinical and metabolic data effectively predicted 1-,3-,and 5-year survival rates.CONCLUSION This report underscored the pivotal mechanism of lactate metabolism in CRC prognosis and suggest novel avenues for therapeutic intervention.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
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
The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid ...The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors.In response to low oxygen availability,the Hypoxia Inducible Factors(HIF-1/2/3α)act as metabolic mediators,producing extracellular metabolites in the tumor microenvironment that influence the immune cells.The modulation of lactate and adenosine on immune evasion has been widely described;however,under hypoxic conditions,it has been barely addressed.Evidence has demonstrated an interplay between cancer and the immune cells,and the present review explores thefindings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context.Moreover,new insights based on systemic oxygen administration are discussed,which might counterbalance the effect mediated by lactate and adenosine,to recover anti-tumor immunity.Thus,the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.展开更多
Graft failure is the worst complication of organ transplantation.Considering liver transplantation,aminotransferase levels have been demonstrated to be a precursor of severe graft failure,in particular when they excee...Graft failure is the worst complication of organ transplantation.Considering liver transplantation,aminotransferase levels have been demonstrated to be a precursor of severe graft failure,in particular when they exceed 5000 U/L in the immediate post-operation.However,some studies show that the outcome of the transplanted liver is not determinable by biochemistry alone.One of the most relevant studies is the one published by Lazzarotto-da-Silva et al.In this retrospective study,341 transplanted livers are considered.In 25 cases,this severe biochemical insult has been reported.But despite this event,more than half had significant long-term survival.One of the most valuable elements that emerge from this work is the identification of two easily measurable markers-serum factor V and arterial lactate,which independently can indicate the graft's 90-day outcome.This finding provides a key clinical picture to distinguish patients who are most likely to recover from those destined for irreversible graft loss.In a time where organs are increasingly scarce,these discoveries could facilitate more prudent use of retransplantation,improving both individual outcomes and the overall distribution of resources.This study contributes significantly to a deeper understanding of early graft injury,although larger prospective studies are needed.It highlights the need to move beyond singular value thresholds and toward integrated,evidence-based decision making during the crucial early posttransplant period.This study not only captures risk but also provides a tool for intervention.展开更多
Aim:To explore the clinical characteristics of reversible respiratory chain deficiency in infants and young children.Methods:A retrospective analysis was conducted on the clinical data of a newborn with recurrent resp...Aim:To explore the clinical characteristics of reversible respiratory chain deficiency in infants and young children.Methods:A retrospective analysis was conducted on the clinical data of a newborn with recurrent respiratory distress and elevated lactate levels,and relevant literature was reviewed.The patient,male,22 days old,had difficulty breathing,no weight gain,and symptoms such as shortness of breath and cyanosis after birth,which lasted for 68 days.There was no history of birth asphyxia rescue;Treatment with antibiotics,respiratory support,diuresis,acid correction,multiple vitamins,and levocarnitine did not improve symptoms;Gradual worsening of breathing difficulties accompanied by feeding difficulties and slow weight gain;Multiple rechecks of blood gas analysis indicate an increase in lactate levels.The laboratory results showed that the child in this case had obvious clinical manifestations of MD.Genetic examination showed MT-TE gene mutation,and the mother was a carrier of MT-TE gene mutation.Conclusion:In the face of recurrent respiratory distress accompanied by elevated lactate levels in newborns,when clinical manifestations of unexplained lactate levels,feeding difficulties,poor aspiration,reduced spontaneous activity,and low muscle tone occur,the possibility of mitochondrial disease should be considered,and genetic testing should be actively improved to clarify the diagnosis.This type of disease is different from other types of mitochondrial diseases.After active and effective treatment,the prognosis is good.The key is early diagnosis,reasonable treatment,timely development of reasonable treatment plans,reduction of complications,and improvement of the final prognosis of the child.展开更多
Background:Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation,which has been linked to tumor progression and therapeutic resistance.However,the contribution of lactate met...Background:Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation,which has been linked to tumor progression and therapeutic resistance.However,the contribution of lactate metabolism and its receptor,hydroxycarboxylic acid receptor 1(HCAR1),in ferroptosis regulation in gastric cancer(GC)remains poorly understood.Focusing specifically on its effects on cell proliferation,ferroptosis regulation,and the disruption of lactate-mediatedmetabolic pathways,the study aimed to clarify the role ofHCAR1 in GC progression.Methods:Bioinformatics analysis identified prognostic genes associated with ferroptosis in GC.Receiver operating characteristic(ROC)curves were generated to assess the diagnostic potential of the predictive genes.The biological role of HCAR1 was investigated through gain and loss-of-function experiments in GC cell lines,followed by assessments of cell viability,oxidative stress indicators,gene/protein expression,and ferroptosis sensitivity under lactate stimulation or HCAR1modulation.Results:HCAR1 was significantly upregulated in GC tissues and linked to poor patient outcomes.Silencing HCAR1 inhibited GC cell growth and induced ferroptosis,as shown by increased levels of reactive oxygen species(ROS)and malondialdehyde(MDA),along with decreased expression of solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4).Conversely,HCAR1 overexpression or exposure to extracellular lactate inhibited ferroptosis and activated antioxidant defenses.Mechanistically,lactate activation of HCAR1 increases ATP levels,which in turn inactivates AMP-activated protein kinase(AMPK).It also upregulates stearoyl-CoA desaturase 1(SCD1)through the sterol regulatory element binding protein 1(SREBP1)signaling pathway.Blocking HCAR1 reversed these effects and restored ferroptosis sensitivity.Conclusion:HCAR1 mediates lactate-driven ferroptosis resistance in GC through the AMPK-SCD1 signaling pathway.Targeting the HCAR1-lactate axis may offer a promising strategy for overcoming metabolic adaptation and improving GC treatment outcomes.展开更多
Background:Whether lactated Ringer's solution is clinically superior to normal saline for routine intravenous administration of fluids is uncertain.Methods:In an open-label,two-period,two-sequence,cross-sectional,...Background:Whether lactated Ringer's solution is clinically superior to normal saline for routine intravenous administration of fluids is uncertain.Methods:In an open-label,two-period,two-sequence,cross-sectional,cluster-randomized,crossover trial,we assigned hospitals in Ontario,Canada,to use either lactated Ringer's solution or normal saline hospital-wide for a period of 12 weeks.展开更多
Poly(3-hydroxybutyrate-co-lactate)[P(3HB-co-LA)]is a highly promising valuable biodegradable material with good biocompatibility and degradability.Vibrio natriegens,owing to its fast-growth,wide substrate spectrum cha...Poly(3-hydroxybutyrate-co-lactate)[P(3HB-co-LA)]is a highly promising valuable biodegradable material with good biocompatibility and degradability.Vibrio natriegens,owing to its fast-growth,wide substrate spectrum characteristics,was selected to produce P(3HB-co-LA).Herein,the crucial role of acetyltransferase PN96-18060 for PHB synthesis in V.natriegens was identified.Heterologous pathway of P(3HB-co-LA)was introduced into V.natriegens successfully,in addition,overexpression of the dldh gene led to 1.84 fold enhancement of the lactate content in P(3HB-co-LA).Finally,the production of P(3HB-co-LA)was characterized under different carbon sources.The lactate fraction in P(3HB-co-LA)was increased to 28.3 mol%by the modification,about 1.84 times of that of the control.This is the first successful case of producing the P(3HB-co-LA)in V.natriegens.Collectively,this study showed that V.natriegens is an attractive host organism for producing P(3HB-co-LA)and has great potential to produce other co-polymers.展开更多
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 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 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 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.
文摘The interaction between the lactate receptor GPR81(also known as hydroxycarboxylic acid receptor 1,or HCAR1)and Splicing Factor Proline-and Glutamine-Rich protein promotes the tumor cell malignancy.GPR81 nuclear translocation plays an important role in driving cancer progression and could serve as a potential therapeutic target.Yang et al concluded in their study that lactate and its receptor,GPR81,play crucial roles in cancer progression,and are key players in linking the lactate-rich tumor microenvironment to cancer cell behavior.The ability of nuclear GPR81 to directly regulate gene expression,combined with extracellular matrix-mediated mechanical signaling,creates a potentially robust system for the coordinated adaptation and survival of cancer cells.Understanding these interactions could lead to the discovery of new therapeutic targets and improved treatment strategies for cancer.
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.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy,with its pathogenesis involving dysregulation of multiple genes,including adenomatous polyposis coli and p53.Emerging evidence suggests that microRNA 195(miR195)plays a critical role in carcinogenesis by modulating the phosphatidylinositol 3 kinase(PI3K)/protein kinase B(AKT)signaling pathway through phosphatase and tensin homologue(PTEN),thereby influencing cellular metabolism.Loss of PTEN function leads to hyperactivation of PI3K/AKT signaling pathway,resulting in upregulated expression of lactate dehydrogenase-5(LDH-5)and promoting the tumor progression.AIM To explore the clinical relevance of miR195,LDH-5,and PTEN expression patterns in CRC patient tissues and their association with clinicopathological features and prognosis.METHODS We enrolled 53 CRC patients who received surgical resection at our hospital from January 2020 to February 2022.Fresh tumor tissues and paired adjacent normal tissues(>5 cm from the tumor margin)were collected.The mRNA expression of miR195 was quantified by real-time quantitative polymerase chain reaction,while the protein expression of LDH-5 and PTEN were assessed via immunohistochemistry.Differences in molecular expression between tumor and adjacent normal tissues were compared,along with their correlations with clinicopathological parameters and prognosis.RESULTS The positive rate of miR195 in CRC tissues(35.85%)was significantly lower than that in adjacent normal tissues(90.57%).LDH-5 displayed a higher positive rate(79.25%)in the tissues compared to normal tissues(11.32%),while PTEN expression was markedly reduced in tumors(28.30%vs 94.34%,P<0.05).Elevated expression of miR195 was observed in CRC tissues from patients with earlier tumor,node,metastasis(TNM)stages and without lymph node metastasis.Conversely,higher expression of LDH-5 was associated with advanced TNM stages,lower differentiation grades,and the presence of lymph node metastasis.Additionally,PTEN expression was higher in patients with smaller tumor diameters and no lymph node metastasis(P<0.05).In CRC tissues,miR195 showed a negative correlation with LDH-5(r=-0.883,P=0.015)but a positive correlation with PTEN(r=0.429,P=0.006).LDH-5 was negatively associated with PTEN(r=-0.396,P<0.001).Patients with miR195 positivity,LDH-5 negativity,and PTEN positivity demonstrated significantly better prognosis(P<0.05).CONCLUSION Low miR195 and PTEN expression,coupled high LDH-5 expression could constitutes a hallmark molecular signature of CRC progression.These signature may act as potential markers for diagnosis and disease assessment,and prognostic evaluation in CRC patients,eventually improving CRC management.
基金supported by the National Natural Science Foundation of China(Nos.8227061256 and 871386269 to Peixiang Lan,No.82171760 to Song Chen)Startup Funding from Tongji Hospital(to Peixiang Lan).
文摘The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate’s role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate’s importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.
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.
基金supported by Natural Science Foundation of Zhejiang Province(Nos.LY20H160033,LY22H160019)National Key Research and Development Program of China(No.YS2021YFC3000089)+1 种基金Zhejiang Province Science and Technology Plan Project(No.2024C03175)National Natural Science Foundation of China(Nos.82074208,22278352,82473004).
文摘Oxaliplatin(OXA)can be used as a palliative treatment for advanced hepatocellular carcinoma(HCC).While most patients still have rapid disease progression after OXA due to the drug resistance.The lactate dehydrogenase A(LDHA)inhibitors can reduce the inflammation-induced effects,metastasis,and proliferation potential of cancer cells.Here,we adopt the water-in-oil attractive Pickering emulsion gel(APEG)to deliver OXA and LDHA inhibitor,GSK2837808A(GSK).OXA is dissolved in water and GSK is dissolved in iodized oil.This drugs-loaded APEG has good biocompatibility and can release OXA and GSK slowly.OXA+GSK@gel has significant anti-tumor effect on HCC model,which can effectively inhibit tumor cell proliferation and promote tumor cell apoptosis.Meanwhile,flow analysis confirm that it could activate the tumor immune microenvironment in HCC.The infiltration of CD8^(+)T cells is increased,thereby providing better anti-tumor effect.The results suggest that the APEGs loaded with OXA and GSK can effectively improve the delivery efficiency and enhance the anti-tumor therapy.
基金Supported by Henan Province Science and Technology Research Project,No.232102310043Henan Provincial Science and Technology Research and Development Plan Joint Fund,No.222103810047Key Scientific Research Project Plan of Colleges and Universities in Henan Province,No.22A320033.
文摘BACKGROUND Colorectal cancer(CRC)remains a major global health burden due to its high incidence and mortality,with treatment efficacy often hindered by tumor hetero-geneity,drug resistance,and a complex tumor microenvironment(TME).Lactate metabolism plays a pivotal role in reshaping the TME,promoting immune eva-sion and epithelial-mesenchymal transition,making it a promising target for novel therapeutic strategies and prognostic modeling in CRC.AIM To offer an in-depth analysis of the role of lactate metabolism in CRC,high-lighting its significance in the TME and therapeutic response.METHODS Utilizing single-cell and transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas,we identified key lactate metabolic activities,particularly in the monocyte/macrophage subpopulation.RESULTS Seven lactate metabolism-associated genes were significantly linked to CRC prognosis and used to construct a predictive model.This model accurately forecasts patient outcomes and reveals notable distinct patterns of immune infiltration and transcriptomic profiles mutation profiles between high-and low-risk groups.High-risk patients demonstrated elevated immune cell infiltration,increased mutation frequencies,and heightened sensitivity to specific drugs(AZD6482,tozasertib,and SB216763),providing a foundation for personalized treatment approaches.Additionally,a nomogram integrating clinical and metabolic data effectively predicted 1-,3-,and 5-year survival rates.CONCLUSION This report underscored the pivotal mechanism of lactate metabolism in CRC prognosis and suggest novel avenues for therapeutic intervention.
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.
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The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors.In response to low oxygen availability,the Hypoxia Inducible Factors(HIF-1/2/3α)act as metabolic mediators,producing extracellular metabolites in the tumor microenvironment that influence the immune cells.The modulation of lactate and adenosine on immune evasion has been widely described;however,under hypoxic conditions,it has been barely addressed.Evidence has demonstrated an interplay between cancer and the immune cells,and the present review explores thefindings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context.Moreover,new insights based on systemic oxygen administration are discussed,which might counterbalance the effect mediated by lactate and adenosine,to recover anti-tumor immunity.Thus,the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.
文摘Graft failure is the worst complication of organ transplantation.Considering liver transplantation,aminotransferase levels have been demonstrated to be a precursor of severe graft failure,in particular when they exceed 5000 U/L in the immediate post-operation.However,some studies show that the outcome of the transplanted liver is not determinable by biochemistry alone.One of the most relevant studies is the one published by Lazzarotto-da-Silva et al.In this retrospective study,341 transplanted livers are considered.In 25 cases,this severe biochemical insult has been reported.But despite this event,more than half had significant long-term survival.One of the most valuable elements that emerge from this work is the identification of two easily measurable markers-serum factor V and arterial lactate,which independently can indicate the graft's 90-day outcome.This finding provides a key clinical picture to distinguish patients who are most likely to recover from those destined for irreversible graft loss.In a time where organs are increasingly scarce,these discoveries could facilitate more prudent use of retransplantation,improving both individual outcomes and the overall distribution of resources.This study contributes significantly to a deeper understanding of early graft injury,although larger prospective studies are needed.It highlights the need to move beyond singular value thresholds and toward integrated,evidence-based decision making during the crucial early posttransplant period.This study not only captures risk but also provides a tool for intervention.
文摘Aim:To explore the clinical characteristics of reversible respiratory chain deficiency in infants and young children.Methods:A retrospective analysis was conducted on the clinical data of a newborn with recurrent respiratory distress and elevated lactate levels,and relevant literature was reviewed.The patient,male,22 days old,had difficulty breathing,no weight gain,and symptoms such as shortness of breath and cyanosis after birth,which lasted for 68 days.There was no history of birth asphyxia rescue;Treatment with antibiotics,respiratory support,diuresis,acid correction,multiple vitamins,and levocarnitine did not improve symptoms;Gradual worsening of breathing difficulties accompanied by feeding difficulties and slow weight gain;Multiple rechecks of blood gas analysis indicate an increase in lactate levels.The laboratory results showed that the child in this case had obvious clinical manifestations of MD.Genetic examination showed MT-TE gene mutation,and the mother was a carrier of MT-TE gene mutation.Conclusion:In the face of recurrent respiratory distress accompanied by elevated lactate levels in newborns,when clinical manifestations of unexplained lactate levels,feeding difficulties,poor aspiration,reduced spontaneous activity,and low muscle tone occur,the possibility of mitochondrial disease should be considered,and genetic testing should be actively improved to clarify the diagnosis.This type of disease is different from other types of mitochondrial diseases.After active and effective treatment,the prognosis is good.The key is early diagnosis,reasonable treatment,timely development of reasonable treatment plans,reduction of complications,and improvement of the final prognosis of the child.
文摘Background:Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation,which has been linked to tumor progression and therapeutic resistance.However,the contribution of lactate metabolism and its receptor,hydroxycarboxylic acid receptor 1(HCAR1),in ferroptosis regulation in gastric cancer(GC)remains poorly understood.Focusing specifically on its effects on cell proliferation,ferroptosis regulation,and the disruption of lactate-mediatedmetabolic pathways,the study aimed to clarify the role ofHCAR1 in GC progression.Methods:Bioinformatics analysis identified prognostic genes associated with ferroptosis in GC.Receiver operating characteristic(ROC)curves were generated to assess the diagnostic potential of the predictive genes.The biological role of HCAR1 was investigated through gain and loss-of-function experiments in GC cell lines,followed by assessments of cell viability,oxidative stress indicators,gene/protein expression,and ferroptosis sensitivity under lactate stimulation or HCAR1modulation.Results:HCAR1 was significantly upregulated in GC tissues and linked to poor patient outcomes.Silencing HCAR1 inhibited GC cell growth and induced ferroptosis,as shown by increased levels of reactive oxygen species(ROS)and malondialdehyde(MDA),along with decreased expression of solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4).Conversely,HCAR1 overexpression or exposure to extracellular lactate inhibited ferroptosis and activated antioxidant defenses.Mechanistically,lactate activation of HCAR1 increases ATP levels,which in turn inactivates AMP-activated protein kinase(AMPK).It also upregulates stearoyl-CoA desaturase 1(SCD1)through the sterol regulatory element binding protein 1(SREBP1)signaling pathway.Blocking HCAR1 reversed these effects and restored ferroptosis sensitivity.Conclusion:HCAR1 mediates lactate-driven ferroptosis resistance in GC through the AMPK-SCD1 signaling pathway.Targeting the HCAR1-lactate axis may offer a promising strategy for overcoming metabolic adaptation and improving GC treatment outcomes.
文摘Background:Whether lactated Ringer's solution is clinically superior to normal saline for routine intravenous administration of fluids is uncertain.Methods:In an open-label,two-period,two-sequence,cross-sectional,cluster-randomized,crossover trial,we assigned hospitals in Ontario,Canada,to use either lactated Ringer's solution or normal saline hospital-wide for a period of 12 weeks.
基金supported by the National Natural Science Foundation of China(22278137)the National Key R&D Program of China(2021YFC2103500)Partially supported by Open Funding Project of the State Key Laboratory of Bioreactor Engineering.
文摘Poly(3-hydroxybutyrate-co-lactate)[P(3HB-co-LA)]is a highly promising valuable biodegradable material with good biocompatibility and degradability.Vibrio natriegens,owing to its fast-growth,wide substrate spectrum characteristics,was selected to produce P(3HB-co-LA).Herein,the crucial role of acetyltransferase PN96-18060 for PHB synthesis in V.natriegens was identified.Heterologous pathway of P(3HB-co-LA)was introduced into V.natriegens successfully,in addition,overexpression of the dldh gene led to 1.84 fold enhancement of the lactate content in P(3HB-co-LA).Finally,the production of P(3HB-co-LA)was characterized under different carbon sources.The lactate fraction in P(3HB-co-LA)was increased to 28.3 mol%by the modification,about 1.84 times of that of the control.This is the first successful case of producing the P(3HB-co-LA)in V.natriegens.Collectively,this study showed that V.natriegens is an attractive host organism for producing P(3HB-co-LA)and has great potential to produce other co-polymers.
