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International Journal of Molecular... Mar 2023Lactate/malate dehydrogenases (Ldh/Maldh) are ubiquitous enzymes involved in the central metabolic pathway of plants and animals. The role of malate dehydrogenases in...
Lactate/malate dehydrogenases (Ldh/Maldh) are ubiquitous enzymes involved in the central metabolic pathway of plants and animals. The role of malate dehydrogenases in the plant system is very well documented. However, the role of its homolog L-lactate dehydrogenases still remains elusive. Though its occurrence is experimentally proven in a few plant species, not much is known about its role in rice. Therefore, a comprehensive genome-wide in silico investigation was carried out to identify all Ldh genes in model plants, rice and , which revealed Ldh to be a multigene family encoding multiple proteins. Publicly available data suggest its role in a wide range of abiotic stresses such as anoxia, salinity, heat, submergence, cold and heavy metal stress, as also confirmed by our qRT-PCR analysis, especially in salinity and heavy metal mediated stresses. A detailed protein modelling and docking analysis using Schrodinger Suite reveals the presence of three putatively functional L-lactate dehydrogenases in rice, namely OsLdh3, OsLdh7 and OsLdh9. The analysis also highlights the important role of Ser-219, Gly-220 and His-251 in the active site geometry of OsLdh3, OsLdh7 and OsLdh9, respectively. In fact, these three genes have also been found to be highly upregulated under salinity, hypoxia and heavy metal mediated stresses in rice.
Topics: Animals; L-Lactate Dehydrogenase; Oryza; Arabidopsis; Malates; Lactate Dehydrogenases; Evolution, Molecular; Metals, Heavy; Stress, Physiological; Gene Expression Regulation, Plant; Plant Proteins; Phylogeny
PubMed: 36982973
DOI: 10.3390/ijms24065900 -
Genetic Testing and Molecular Biomarkers Mar 2022Lactate dehydrogenase (LDH) is a marker of injury and disease as it is expressed extensively in numerous cell types and tissues. Moreover it is released during tissue...
Lactate dehydrogenase (LDH) is a marker of injury and disease as it is expressed extensively in numerous cell types and tissues. Moreover it is released during tissue breakdown, and is elevated in cancerous tissues. However, the clinical significance and prognostic value of LDH as a tumor marker have been subject to considerable discussion. In this study, clinical serum LDH data from patients with cervical cancer (CC), CC microarray data, and RNA-seq data were integrated to assess the expression of LDH in CC. A total of 204 patients with newly diagnosed CC and 204 age-matched healthy controls were included to evaluate serum LDH levels in CC and non-cancer samples. External microarrays and RNA-seq datasets were collected for the differential expression analysis of LDH in CC and non-cancer tissue samples. Kaplan-Meier survival curves of the prognostic value of LDH for CC were plotted for RNA-seq data. Functional enrichment analysis was performed for the genes co-expressed with LDH. The data from our in-house clinical cases as well as the data extracted from microarrays and RNA-seq databases demonstrated significant overexpression of LDH in CC samples. Elevated LDH expression levels were associated with poor overall survival in CC patients. The genes co-expressed with LDH were significantly correlated with the biological processes and pathways, associated with nuclear division, the condensed chromosome, protein serine/threonine kinase activity, and the cell cycle. In conclusion, LDH upregulation might serve as a therapeutic and prognostic biomarker for CC.
Topics: Biomarkers, Tumor; Female; Humans; Kaplan-Meier Estimate; L-Lactate Dehydrogenase; Prognosis; Uterine Cervical Neoplasms
PubMed: 35349377
DOI: 10.1089/gtmb.2021.0006 -
Oncoimmunology 2020Lactate dehydrogenase (LDH) levels are inversely related with response to checkpoint inhibitors. Elevated LDH levels are the product of enhanced glycolytic activity of... (Review)
Review
Lactate dehydrogenase (LDH) levels are inversely related with response to checkpoint inhibitors. Elevated LDH levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis due to hypoxia, the latter being associated with high tumor burden. In this review, we elucidate the effects of glycolysis and hypoxia on antitumor immunity and set forth ways to improve response to immunotherapy in cancer patients with elevated LDH levels. We discuss the current knowledge on combining immunotherapy with glycolysis inhibitors, anti-acidifying drugs, anti-angiogenic or cytoreductive therapy.
Topics: Biomarkers; Glycolysis; Humans; Immunotherapy; L-Lactate Dehydrogenase; Neoplasms
PubMed: 32158624
DOI: 10.1080/2162402X.2020.1731942 -
Nature Communications Oct 2023Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient...
Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient LDHD activity. Here, we perform a systematic biochemical study of mouse LDHD (mLDHD) and determine the crystal structures of mLDHD in FAD-bound form and in complexes with FAD, Mn and a series of substrates or products. We demonstrate that mLDHD is an Mn-dependent general dehydrogenase which exhibits catalytic activity for D-lactate and other D-2-hydroxyacids containing hydrophobic moieties, but no activity for their L-isomers or D-2-hydroxyacids containing hydrophilic moieties. The substrate-binding site contains a positively charged pocket to bind the common glycolate moiety and a hydrophobic pocket with some elasticity to bind the varied hydrophobic moieties of substrates. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of LDHD, and the functional roles of mutations in the pathogenesis of D-lactic acidosis.
Topics: Animals; Mice; Humans; Acidosis, Lactic; Lactate Dehydrogenases; Lactic Acid; Hydroxy Acids; Binding Sites; L-Lactate Dehydrogenase; Mammals
PubMed: 37863926
DOI: 10.1038/s41467-023-42456-3 -
Cancer Research Oct 2023Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of...
UNLABELLED
Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to compare metabolic fluxes used by parental breast cancer cells and their brain- and lung-homing derivatives. Divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This strong Warburg effect was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, which correlated with lung metastasis in patients with breast cancer. Although feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of metastasis to the lung but not to other organs, independent of other transcriptomic signatures. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in patients with breast cancer.
SIGNIFICANCE
Lung-homing metastatic breast cancer cells express an elevated ratio of lactate dehydrogenase to pyruvate dehydrogenase, indicating that ratios of specific metabolic gene transcripts have potential as metabolic biomarkers for predicting organ-specific metastasis.
Topics: Humans; Female; Breast Neoplasms; L-Lactate Dehydrogenase; Lung Neoplasms; Biomarkers; Neoplasms, Second Primary; Lung; Lactates; Pyruvates; Melanoma, Cutaneous Malignant
PubMed: 37526524
DOI: 10.1158/0008-5472.CAN-23-0153 -
Proteomics Aug 2021Serum lactate dehydrogenase (LDH) has been established as a prognostic indicator given its differential expression in COVID-19 patients. However, the molecular...
Serum lactate dehydrogenase (LDH) has been established as a prognostic indicator given its differential expression in COVID-19 patients. However, the molecular mechanisms underneath remain poorly understood. In this study, 144 COVID-19 patients were enrolled to monitor the clinical and laboratory parameters over 3 weeks. Serum LDH was shown elevated in the COVID-19 patients on admission and declined throughout disease course, and its ability to classify patient severity outperformed other biochemical indicators. A threshold of 247 U/L serum LDH on admission was determined for severity prognosis. Next, we classified a subset of 14 patients into high- and low-risk groups based on serum LDH expression and compared their quantitative serum proteomic and metabolomic differences. The results showed that COVID-19 patients with high serum LDH exhibited differentially expressed blood coagulation and immune responses including acute inflammatory responses, platelet degranulation, complement cascade, as well as multiple different metabolic responses including lipid metabolism, protein ubiquitination and pyruvate fermentation. Specifically, activation of hypoxia responses was highlighted in patients with high LDH expressions. Taken together, our data showed that serum LDH levels are associated with COVID-19 severity, and that elevated serum LDH might be consequences of hypoxia and tissue injuries induced by inflammation.
Topics: Adult; Aged; COVID-19; Female; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Prognosis; Proteomics; Severity of Illness Index
PubMed: 33987944
DOI: 10.1002/pmic.202100002 -
Cancer Medicine Oct 2020Previous studies have provided evidence of the high expression of lactate dehydrogenase (LDH) in multiple solid tumors; however, its prognostic relationship with... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Previous studies have provided evidence of the high expression of lactate dehydrogenase (LDH) in multiple solid tumors; however, its prognostic relationship with metastatic prostate cancer (mPCa) remains controversial. We performed a meta-analysis to better understand the prognostic potential of LDH in mPCa.
METHODS
In our investigation, we included PubMed, Embase, Web of Science, and Cochrane Library as web-based resources, as well as studies published before January 2020 on the predictive value of LDH in mPCa. We independently screened the studies according to the inclusion and exclusion criteria, evaluated the quality of the literature, extracted the data, and used RevMan 5.3 and STATA12.0 software for analysis.
RESULT
From the 38 published studies, the records of 9813 patients with mPCa were included in this meta-analysis. We observed that higher levels of LDH in patients with mPCa were significantly associated with poorer overall survival (OS) (HR = 2.17, 95% CI: 1.91-2.47, P < .00001) and progression-free survival (PFS) (HR = 1.60, 95% CI: 1.20-2.13, P = .001). The subgroup analyses indicated that the negative prognostic impact of higher levels of LDH on the oncologic outcomes of mPCa was significant regardless of ethnicity, publication year, sample size, analysis type, treatment type, age, and disease state.
CONCLUSION
Our analysis suggested the association between a higher level of LDH and poorer OS and PFS in patients with mPCa. As a parameter that can be conveniently evaluated, the LDH levels should be included as a valuable biomarker in the management of mPCa.
Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Prostatic Neoplasms; Risk Assessment; Risk Factors; Time Factors; Up-Regulation
PubMed: 32452656
DOI: 10.1002/cam4.3108 -
Redox Biology Jan 2020Research over the past seventy years has established that mitochondrial-l-lactate dehydrogenase (m-L-LDH) is vital for mitochondrial bioenergetics. However, in recent...
Research over the past seventy years has established that mitochondrial-l-lactate dehydrogenase (m-L-LDH) is vital for mitochondrial bioenergetics. However, in recent report, Fulghum et al. concluded that lactate is a poor fuel for mitochondrial respiration [1]. In the present study, we have followed up on these findings and conducted an independent investigation to determine if lactate can support mitochondrial bioenergetics. We demonstrate herein that lactate can fuel the bioenergetics of heart, muscle, and liver mitochondria. Lactate was just as effective as pyruvate at stimulating mitochondrial coupling efficiency. Inclusion of LDH (sodium oxamate or GSK 2837808A) and pyruvate dehydrogenase (PDH; CPI-613) inhibitors abolished respiration in mitochondria energized with lactate. Lactate also fueled mitochondrial ROS generation and was just as effective as pyruvate at stimulating HO production. Additionally, lactate-induced ROS production was inhibited by both LDH and PDH inhibitors. Enzyme activity measurements conducted on permeabilized mitochondria revealed that LDH is localized in mitochondria. In aggregate, we can conclude that mitochondrial LDH fuels bioenergetics in several tissues by oxidizing lactate.
Topics: Animals; Cell Respiration; L-Lactate Dehydrogenase; Lactic Acid; Mice; Mitochondria; Mitochondria, Liver; Mitochondria, Muscle; Models, Biological; Organ Specificity; Oxidation-Reduction
PubMed: 31610469
DOI: 10.1016/j.redox.2019.101339 -
Biomacromolecules Jul 2019Stimuli-responsive polymers are an efficient means of targeted therapy. Compared to conventional agents, they increase bioavailability and efficacy. In particular,...
Stimuli-responsive polymers are an efficient means of targeted therapy. Compared to conventional agents, they increase bioavailability and efficacy. In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials. In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite, characteristic of a hypoxic environment found in cancerous tumors. NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH). The oxamate-functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex. When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%). The OxNP-LDH complexes were not responsive to structurally related small molecules. This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.
Topics: Acrylamides; Biological Availability; Cell Line, Tumor; Humans; Hydrogels; L-Lactate Dehydrogenase; Lactic Acid; Macromolecular Substances; Nanoparticles; Neoplasms; Polymers; Proteins; Tumor Hypoxia; Tumor Microenvironment
PubMed: 31117354
DOI: 10.1021/acs.biomac.9b00470 -
Brain and Behavior Jan 2024Ischemic stroke (IS) is one of the major global health problems. It is not clear whether there is a causal relationship between lactate dehydrogenase (LDH) and the risk... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
Ischemic stroke (IS) is one of the major global health problems. It is not clear whether there is a causal relationship between lactate dehydrogenase (LDH) and the risk of IS attacks. The purpose of this study was to investigate whether LDH has a causal relationship with the development of IS.
METHODS
The genome-wide association data of LDH and IS were obtained through a Mendelian randomization-based platform. Single nucleotide polymorphisms (SNP) that were significantly associated with LDH were identified and used as instrumental variables, and a two-sample Mendelian randomization study was used to examine the causal relationship between LDH and IS. The statistical methods included Inverse-variance weighted approach, MR-Egger regression, and weighted median estimator.
RESULTS
We selected 15 SNPs of genome-wide significance from Genome-wide association study database with LDH as instrumental variables. A consistent causal association between LDH and IS was observed by different assessment methods. The results of the inverse-variance weighted method suggested an inverse association between LDH and higher genetic predictability of IS risk (OR, 0.997; 95%CI 0.995-0.999). The weighted median estimate showed consistent results with the MR-Egger method (weighted median estimate: OR, 0.995; 95%CI 0.992-0.999; MR-Egger method: OR, 0.996; 95%CI 0.992-0.999). The inverse-variance weighted method indicates a causal association between LDH and IS (β = -0.002563, SE = 0.00128, p = .0453). MR-Egger analysis (β = -0.004498, SE = 0.001877, p = .03) and the weighted median method suggested that LDH and IS also existed causal relationship (β = -0.004861, SE = 0.001801, p = .00695).
CONCLUSIONS
Our Mendelian randomization results suggest that LDH is inversely associated with the risk of developing IS, and are contrary to the results of previous observational studies.
Topics: Humans; Ischemic Stroke; Genome-Wide Association Study; L-Lactate Dehydrogenase; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide
PubMed: 38376049
DOI: 10.1002/brb3.3352