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Inflammation Dec 2022Lactate dehydrogenase (LDH) is a terminating enzyme in the metabolic pathway of anaerobic glycolysis with end product of lactate from glucose. The lactate formation is... (Review)
Review
Lactate dehydrogenase (LDH) is a terminating enzyme in the metabolic pathway of anaerobic glycolysis with end product of lactate from glucose. The lactate formation is crucial in the metabolism of glucose when oxygen is in inadequate supply. Lactate can also be formed and utilised by different cell types under fully aerobic conditions. Blood LDH is the marker enzyme, which predicts mortality in many conditions such as ARDS, serious COVID-19 and cancer patients. Lactate plays a critical role in normal physiology of humans including an energy source, a signaling molecule and a pH regulator. Depending on the pH, lactate exists as the protonated acidic form (lactic acid) at low pH or as sodium salt (sodium lactate) at basic pH. Lactate can affect the immune system and act as a signaling molecule, which can provide a "danger" signal for life. Several reports provide evidence that the serum lactate represents a chemical marker of severity of disease similar to LDH under inflammatory conditions. Since the mortality rate is much higher among COVID-19 patients, associated with high serum LDH, this article is aimed to review the LDH as a therapeutic target and lactate as potential marker for monitoring treatment response of inflammatory diseases. Finally, the review summarises various LDH inhibitors, which offer potential applications as therapeutic agents for inflammatory diseases, associated with high blood LDH. Both blood LDH and blood lactate are suggested as risk factors for the mortality of patients in serious inflammatory diseases.
Topics: Humans; L-Lactate Dehydrogenase; Lactic Acid; COVID-19; Glucose; Risk Factors
PubMed: 35588340
DOI: 10.1007/s10753-022-01680-7 -
Blood Advances Jul 2023The effect of aerobic glycolysis remains elusive in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Increasing evidence has revealed that dysregulation of...
The effect of aerobic glycolysis remains elusive in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Increasing evidence has revealed that dysregulation of deubiquitination is involved in glycolysis, by targeting glycolytic rate-limiting enzymes. Here, we demonstrated that upregulated deubiquitinase ubiquitin-specific peptidase 1 (USP1) expression correlated with poor prognosis in pediatric primary T-ALL samples. USP1 depletion abolished cellular proliferation and attenuated glycolytic metabolism. In vivo experiments showed that USP1 suppression decreased leukemia progression in nude mice. Inhibition of USP1 caused a decrease in both mRNA and protein levels in lactate dehydrogenase A (LDHA), a critical glycolytic enzyme. Moreover, USP1 interacted with and deubiquitinated polo-like kinase 1 (PLK1), a critical regulator of glycolysis. Overexpression of USP1 with upregulated PLK1 was observed in most samples of patients with T-ALL. In addition, PLK1 inhibition reduced LDHA expression and abrogated the USP1-mediated increase of cell proliferation and lactate level. Ectopic expression of LDHA can rescue the suppressive effect of USP1 silencing on cell growth and lactate production. Pharmacological inhibition of USP1 by ML323 exhibited cell cytotoxicity in human T-ALL cells. Taken together, our results demonstrated that USP1 may be a promising therapeutic target in pediatric T-ALL.
Topics: Animals; Child; Humans; Mice; Cell Line, Tumor; Disease Progression; Glycolysis; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactates; Mice, Nude; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Ubiquitin-Specific Proteases; Polo-Like Kinase 1
PubMed: 36912760
DOI: 10.1182/bloodadvances.2022008284 -
The American Journal of Emergency... Sep 2020Coronavirus disease 2019 (COVID-19) infection has now reached a pandemic state, affecting more than a million patients worldwide. Predictors of disease outcomes in these... (Review)
Review
Coronavirus disease 2019 (COVID-19) infection has now reached a pandemic state, affecting more than a million patients worldwide. Predictors of disease outcomes in these patients need to be urgently assessed to decrease morbidity and societal burden. Lactate dehydrogenase (LDH) has been associated with worse outcomes in patients with viral infections. In this pooled analysis of 9 published studies (n = 1532 COVID-19 patients), we evaluated the association between elevated LDH levels measured at earliest time point in hospitalization and disease outcomes in patients with COVID-19. Elevated LDH levels were associated with a ~6-fold increase in odds of developing severe disease and a ~16-fold increase in odds of mortality in patients with COVID-19. Larger studies are needed to confirm these findings.
Topics: Betacoronavirus; Biomarkers; C-Reactive Protein; COVID-19; Coronavirus Infections; Global Health; Humans; L-Lactate Dehydrogenase; Pandemics; Pneumonia, Viral; SARS-CoV-2; Severity of Illness Index; Survival Rate
PubMed: 32738466
DOI: 10.1016/j.ajem.2020.05.073 -
American Journal of Physiology. Renal... May 2021Cellular metabolic rates in the kidney are critical for maintaining normal renal function. In a hypoxic milieu, cells rely on glycolysis to meet energy needs, resulting... (Comparative Study)
Comparative Study
Cellular metabolic rates in the kidney are critical for maintaining normal renal function. In a hypoxic milieu, cells rely on glycolysis to meet energy needs, resulting in the generation of pyruvate and NADH. In the absence of oxidative phosphorylation, the continuation of glycolysis is dependent on the regeneration of NAD from NADH accompanied by the fermentation of pyruvate to lactate. This reaction is catalyzed by lactate dehydrogenase (LDH) isoform A (LDHA), whereas LDH isoform B (LDHB) catalyzes the opposite reaction. LDH is widely used as a potential injury marker as it is released from damaged cells into the urine and serum; however, the precise isoform-specific cellular localization of the enzyme along the nephron has not been characterized. By combining immunohistochemistry results and single-cell RNA-sequencing data on healthy mouse kidneys, we identified that LDHA is primarily expressed in proximal segments, whereas LDHB is expressed in the distal parts of the nephron. In vitro experiments in mouse and human renal proximal tubule cells showed an increase in LDHA following hypoxia with no change in LDHB. Using immunofluorescence, we observed that the overall expression of both LDHA and LDHB proteins decreased following renal ischemia-reperfusion injury as well as in the adenine-diet-induced model of chronic kidney disease. Single-nucleus RNA-sequencing analyses of kidneys following ischemia-reperfusion injury revealed a significant decline in the number of cells expressing detectable levels of and ; however, cells that were positive showed increased average expression postinjury, which subsided during the recovery phase. These data provide information on the cell-specific expression of LDHA and LDHB in the normal kidney as well as following acute and chronic kidney disease. Cellular release of lactate dehydrogenase (LDH) is being used as an injury marker; however, the exact localization of LDH within the nephron remains unclear. We show that LDH isoform A is expressed proximally, whereas isoform B is expressed distally. Both subunit expressions were significantly altered in models of acute kidney injury and chronic kidney disease. Our study provides new insights into basal and postinjury renal lactate metabolism.
Topics: Acute Kidney Injury; Animals; Biomarkers; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Kidney; L-Lactate Dehydrogenase; Male; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Time Factors; Mice
PubMed: 33719570
DOI: 10.1152/ajprenal.00628.2020 -
Scientific Reports May 2023L-Lactate is a major waste compound in cultured animal cells. To develop a sustainable animal cell culture system, we aimed to study the consumption of L-lactate using a...
L-Lactate is a major waste compound in cultured animal cells. To develop a sustainable animal cell culture system, we aimed to study the consumption of L-lactate using a photosynthetic microorganism. As genes involved in L-lactate utilization were not found in most cyanobacteria and microalgae, we introduced the NAD-independent L-lactate dehydrogenase gene from Escherichia coli (lldD) into Synechococcus sp. PCC 7002. The lldD-expressing strain consumed L-lactate added to basal medium. This consumption was accelerated by expression of a lactate permease gene from E. coli (lldP) and an increase in culture temperature. Intracellular levels of acetyl-CoA, citrate, 2-oxoglutarate, succinate, and malate, and extracellular levels of 2-oxoglutarate, succinate, and malate, increased during L-lactate utilization, suggesting that the metabolic flux from L-lactate was distributed toward the tricarboxylic acid cycle. This study provides a perspective on L-lactate treatment by photosynthetic microorganisms, which would increase the feasibility of animal cell culture industries.
Topics: Animals; L-Lactate Dehydrogenase; Malates; Escherichia coli; Ketoglutaric Acids; Lactic Acid; Synechococcus; Succinates
PubMed: 37142758
DOI: 10.1038/s41598-023-34289-3 -
Biosensors Dec 2022The demand for glucose uptake and the accompanying enhanced glycolytic energy metabolism is one of the most important features of cancer cells. Unlike the aerobic... (Review)
Review
The demand for glucose uptake and the accompanying enhanced glycolytic energy metabolism is one of the most important features of cancer cells. Unlike the aerobic metabolic pathway in normal cells, the large amount of pyruvate produced by the dramatic increase of glycolysis in cancer cells needs to be converted to lactate in the cytoplasm, which cannot be done without a large amount of lactate dehydrogenase (LDH). This explains why elevated serum LDH concentrations are usually seen in cancer patient populations. LDH not only correlates with clinical prognostic survival indicators, but also guides subsequent drug therapy. Besides their role in cancers, LDH is also a biomarker for malaria and other diseases. Therefore, it is urgent to develop methods for sensitive and convenient LDH detection. Here, this review systematically summarizes the clinical impact of lactate dehydrogenase detection and principles for LDH detection. The advantages as well as limitations of different detection methods and the future trends for LDH detection were also discussed.
Topics: Humans; L-Lactate Dehydrogenase; Energy Metabolism; Glycolysis; Neoplasms
PubMed: 36551112
DOI: 10.3390/bios12121145 -
Asian Pacific Journal of Cancer... Oct 2021We examined the lactate dehydrogenase (LDH) enzyme levels in the saliva of vapers (e-cigarette users) and compared the data with cigarette smokers and a control group of... (Comparative Study)
Comparative Study Review
BACKGROUND
We examined the lactate dehydrogenase (LDH) enzyme levels in the saliva of vapers (e-cigarette users) and compared the data with cigarette smokers and a control group of non-smokers and non-vapers.
METHODS
Subjects were recruited among those responding to a social media announcement or patients attending the SEGi Oral Health Care Centre between May and December 2019, and among some staff at the centre. Five ml of unstimulated whole saliva was collected and salivary LDH enzyme activity levels were measured with a LDH colorimetric assay kit. Salivary LDH activity level was determined for each group and compared statistically.
RESULTS
Eighty-eight subjects were categorized into three groups (control n=30, smokers n=29, and vapers n=29). The mean ± standard deviation (SD) values for salivary LDH activity levels for vapers, smokers, and control groups were 35.15 ± 24.34 mU/ml, 30.82 ± 20.73 mU/ml, and 21.45 ± 15.30 mU/ml, respectively. The salivary LDH activity levels of smoker and vaper groups were significantly higher than in the control group (p = 0.031; 0.017). There was no significant difference of salivary LDH activity level in vapers when compared with smokers (p= 0.234).
CONCLUSION
Our findings showed higher LDH levels in the saliva of vapers when compared with controls, confirming cytotoxic and harmful effects of e-cigarettes on the oral mucosa.
Topics: Adult; Aged; Area Under Curve; Electronic Nicotine Delivery Systems; Female; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Non-Smokers; ROC Curve; Saliva; Sensitivity and Specificity; Smokers; Tobacco Products; Young Adult
PubMed: 34710999
DOI: 10.31557/APJCP.2021.22.10.3227 -
ELife Jun 2022Lactate oxidation with NAD as electron acceptor is a highly endergonic reaction. Some anaerobic bacteria overcome the energetic hurdle by flavin-based electron...
Lactate oxidation with NAD as electron acceptor is a highly endergonic reaction. Some anaerobic bacteria overcome the energetic hurdle by flavin-based electron bifurcation/confurcation (FBEB/FBEC) using a lactate dehydrogenase (Ldh) in concert with the electron-transferring proteins EtfA and EtfB. The electron cryo-microscopically characterized (Ldh-EtfAB) complex of at 2.43 Å resolution consists of a mobile EtfAB shuttle domain located between the rigid central Ldh and the peripheral EtfAB base units. The FADs of Ldh and the EtfAB shuttle domain contact each other thereby forming the D (dehydrogenation-connected) state. The intermediary Glu37 and Glu139 may harmonize the redox potentials between the FADs and the pyruvate/lactate pair crucial for FBEC. By integrating Alphafold2 calculations a plausible novel B (bifurcation-connected) state was obtained allowing electron transfer between the EtfAB base and shuttle FADs. Kinetic analysis of enzyme variants suggests a correlation between NAD binding site and D-to-B-state transition implicating a 75° rotation of the EtfAB shuttle domain. The FBEC inactivity when truncating the ferredoxin domain of EtfA substantiates its role as redox relay. Lactate oxidation in Ldh is assisted by the catalytic base His423 and a metal center. On this basis, a comprehensive catalytic mechanism of the FBEC process was proposed.
Topics: Electron Transport; Electrons; Kinetics; L-Lactate Dehydrogenase; Lactates; NAD; Oxidation-Reduction
PubMed: 35748623
DOI: 10.7554/eLife.77095 -
Biomarkers : Biochemical Indicators of... Mar 2021The aim of our study was to analyse the short-term prognostic value of different biomarkers in patients with COVID-19. (Observational Study)
Observational Study
PURPOSE
The aim of our study was to analyse the short-term prognostic value of different biomarkers in patients with COVID-19.
METHODS
We included patients admitted to emergency department with COVID-19 and available concentrations of cardiac troponin I (cTnI), D-dimer, C-reactive protein (CRP) and lactate dehydrogenase (LDH). Patients were classified for each biomarker into two groups (low vs. high concentrations) according to their best cut-off point, and 30-day all-cause death was evaluated.
RESULTS
After multivariate adjustment, cTnI ≥21 ng/L, D-dimer ≥1112 ng/mL, CRP ≥10 mg/dL and LDH ≥334 U/L at admission were associated with an increased risk of 30-day all-cause death (hazard ratio (HR) 4.30; 95% CI 1.74-10.58; = 0.002; HR 3.35; 95% CI 1.58-7.13; = 0.002; HR 2.25; 95% CI 1.13-4.50; = 0.021; HR 2.00; 95% CI 1.04-3.84; = 0.039, respectively). The area under the curve for cTnI was 0.825 (95% CI 0.759-0.892) and, in comparison, was significantly better than CRP (0.685; 95% CI 0.600-0.770; = 0.009) and LDH (0.643; 95% CI 0.534-0.753; = 0.006) but non-significantly better than D-dimer (0.756; 95% CI 0.674-0.837; = 0.115).
CONCLUSIONS
In patients with COVID-19, increased concentrations of cTnI, D-dimer, CRP and LDH are associated with short-term mortality. Of these, cTnI provides better mortality risk prediction. However, differences with D-dimer were non-significant.
Topics: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; COVID-19; Cause of Death; Female; Fibrin Fibrinogen Degradation Products; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Patient Admission; Predictive Value of Tests; Prognosis; ROC Curve; Retrospective Studies; Treatment Outcome; Troponin I
PubMed: 33426934
DOI: 10.1080/1354750X.2021.1874052 -
Aging Jun 2020Lactate dehydrogenase (LDH) catalyzes the conversion of glycolysis-derived pyruvate to lactate. Lactate has been shown to play key roles in brain energetics and memory...
Lactate dehydrogenase (LDH) catalyzes the conversion of glycolysis-derived pyruvate to lactate. Lactate has been shown to play key roles in brain energetics and memory formation. However, lactate levels are elevated in aging and Alzheimer's disease patients, and it is not clear whether lactate plays protective or detrimental roles in these contexts. Here we show that transcript levels are elevated and cycle with diurnal rhythm in the heads of aged flies and this is associated with increased LDH protein, enzyme activity, and lactate concentrations. To understand the biological significance of increased gene expression, we genetically manipulated levels in adult neurons or glia. Overexpression of in both cell types caused a significant reduction in lifespan whereas down-regulation resulted in lifespan extension. Moreover, pan-neuronal overexpression of disrupted circadian locomotor activity rhythms and significantly increased brain neurodegeneration. In contrast, reduction of in neurons delayed age-dependent neurodegeneration. Thus, our unbiased genetic approach identified and lactate as potential modulators of aging and longevity in flies.
Topics: Animals; Animals, Genetically Modified; Brain; Circadian Rhythm; Drosophila Proteins; Drosophila melanogaster; Female; Humans; L-Lactate Dehydrogenase; Lactic Acid; Locomotion; Longevity; Male; Neurons
PubMed: 32484787
DOI: 10.18632/aging.103373