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Biomedicine & Pharmacotherapy =... Apr 2023Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development... (Review)
Review
Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.
Topics: Humans; L-Lactate Dehydrogenase; Glycolysis; Lactic Acid; Colorectal Neoplasms; Probiotics; Tumor Microenvironment
PubMed: 36758316
DOI: 10.1016/j.biopha.2023.114371 -
Current Genetics Apr 2019Lactate dehydrogenase (LDH) widely exists in organisms, which catalyzes the interconversion of pyruvate into lactate with concomitant interconversion of NADH and NAD. In...
Lactate dehydrogenase (LDH) widely exists in organisms, which catalyzes the interconversion of pyruvate into lactate with concomitant interconversion of NADH and NAD. In this study, two L-type lactate dehydrogenase genes FgLDHL1 and FgLDHL2 were characterized in an ascomycete fungus Fusarium graminearum, a causal agent of wheat head blight. Both the single-gene deletion mutants of FgLDHL1 or FgLDHL2 exhibited phenotypic defects in vegetative growth, sporulation, spore germination, L-lactate biosynthesis and activity. Additionally, the two L-lactate dehydrogenases were involved in the utilization of carbon sources and maintenance of redox homeostasis during spore germination. Pathogenicity assays showed that ΔFgLDHL1 exhibits reduced virulence on wheat spikelets and on corn stigmas, suggesting that it was indirectly correlated with a reduced level of deoxynivalenol accumulation. These results indicate that FgLDHL1 and FgLDHL2 play multiple roles in the developmental processes and pathogenesis in F. graminearum, and help understand the functional diversity of D-/L-lactate dehydrogenase in phytopathogenic fungi.
Topics: Amino Acid Sequence; Environment; Fusarium; Genes, Fungal; Genetic Complementation Test; Hyphae; L-Lactate Dehydrogenase; Phenotype; Phylogeny; Plant Diseases; Sensitivity and Specificity; Sequence Analysis, DNA; Sequence Deletion; Spores, Fungal; Stress, Physiological
PubMed: 30474697
DOI: 10.1007/s00294-018-0909-6 -
Infectious Diseases (London, England) Jun 2023Measurements of pleural fluid biomarkers for rapid identification of complicated parapneumonic effusion (CPPE) are crucial for optimal management. Previous studies for...
BACKGROUND
Measurements of pleural fluid biomarkers for rapid identification of complicated parapneumonic effusion (CPPE) are crucial for optimal management. Previous studies for biomarker evaluation were however based on pleura culture, not modern DNA technique. Lactate has not been thoroughly studied earlier as a potential biomarker in this regard.
OBJECTIVES
To evaluate whether the routine biomarkers pH, glucose, lactate dehydrogenase (LDH) measured in pleural fluid in a microbiological well characterised cohort could differentiate simple parapneumonic effusion (SPPE) from CPPE and if pleural fluid lactate could be of additional use in this discrimination.
METHODS
Pleural fluid prospectively collected from adult patients ( = 112) with PPE admitted to the Departments of Infectious Diseases (DIDs) at four Stockholm County hospitals were characterised microbiologically with bacterial culture and 16S rDNA sequencing, and biochemically with pH, glucose, LDH and lactate.
RESULTS
Forty and seventy two patients were categorised as SPPE/CPPE. The median values between SPPE/CPPE differed significantly for all biomarkers with varying overlap. Receiver operating characteristics (ROC) curves showed the area under the curve (AUC) for pH 0.905 (CI 0.847-0.963), glucose 0.861 (CI 0.79-0.932), LDH 0.917 (CI 0.860-0.974) and lactate 0.927 (CI 0.877-0.977), corresponding to best cut-off levels and sensitivity/specificity for pH of 7.255, 0.819/0.9, glucose 5.35 mmol/L, 0.847/0.775, LDH 9.8 µcat/L, 0.905/0.825 and lactate 4.9 mmol/L, 0.875/0.85.
CONCLUSIONS
To distinguish between SPPE/CPPE, pH and LDH performed well, but optimal cut-off values differed from earlier established recommendations. Pleura lactate had the largest AUC of the investigated biomarkers and may be used in the analyses of PPE-staging.
Topics: Adult; Humans; Lactic Acid; Diagnosis, Differential; Pleural Effusion; Biomarkers; L-Lactate Dehydrogenase; Glucose
PubMed: 37021765
DOI: 10.1080/23744235.2023.2192278 -
The Journal of Eukaryotic Microbiology May 2021An NAD-linked lactate dehydrogenase (LDH) in a crude mitochondrial fraction obtained from Tetrahymena homogenates was previously reported by this laboratory. This...
An NAD-linked lactate dehydrogenase (LDH) in a crude mitochondrial fraction obtained from Tetrahymena homogenates was previously reported by this laboratory. This fraction contains the NADH and succinate oxidase system as well as the mitochondrial cytochromes and carries out oxidative phosphorylation. The preparation catalyzes the oxidation of D- and L-lactate linked only to certain analogs of NAD; it has not been possible to demonstrate NAD-dependent D- or L-lactate oxidation nor is there any evidence that either of these enzymes is a flavoprotein as indicated by their inability to reduce directly certain artificial electron acceptors. A lactate racemase is not present.
Topics: L-Lactate Dehydrogenase; Lactate Dehydrogenases; Mitochondria; Nucleotides; Oxidation-Reduction; Pyridines; Tetrahymena
PubMed: 33749960
DOI: 10.1111/jeu.12851 -
Clinica Chimica Acta; International... Apr 2020Lactate dehydrogenase C4 (LDH-C4) as a cancer/testis antigen (CTA) is abnormally expressed in some malignant tumors. However, the expression and clinical significance of...
BACKGROUND
Lactate dehydrogenase C4 (LDH-C4) as a cancer/testis antigen (CTA) is abnormally expressed in some malignant tumors. However, the expression and clinical significance of LDH-C4 in breast cancer (BC) has not been characterized.
METHODS
We determined LDHC mRNA expression in serum and serum-derived exosomes of BC patients by quantitative RT-PCR. We also evaluated the protein expression of LDH-C4 in BC tissues using high-throughput tissue microarray analysis and immunohistochemistry.
RESULTS
Our results showed high mRNA expression level of LDHC in serum and serum-derived exosomes of BC patients. The LDHC level in serum and exosomes could distinguish BC cases from healthy individuals based on their AUCs of 0.9587 and 0.9464, respectively. Besides, the LDHC level in exosomes of BC patients associated with tumor size, and positively correlated with HER2 and Ki-67 expressions (all with P < 0.05). Serum and exosomal level of LDHC negatively correlated with medical treatment and positively with the recurrence of BC. Survival analysis showed that LDH-C4 expression negatively correlated with BC prognosis.
CONCLUSION
Serum and exosomal LDHC may be an effective indicator for the diagnosis, efficacy evaluation, and monitoring the recurrence of BC. LDH-C4 may act as a biomarker that predicts BC prognosis.
Topics: Adult; Area Under Curve; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Exosomes; Female; Humans; Isoenzymes; L-Lactate Dehydrogenase; Male; Middle Aged; Prognosis; RNA, Messenger; Recurrence; Survival Analysis; Treatment Outcome
PubMed: 31794764
DOI: 10.1016/j.cca.2019.11.032 -
Cancer Cell Sep 2016Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to...
Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD(+) to pyruvate, NADH and H(+), controls lysosomal acidification, vesicle maturation, and intracellular proteolysis. LDHB activity is necessary for basal autophagy and cancer cell proliferation not only in oxidative cancer cells but also in glycolytic cancer cells.
Topics: Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lysosomes; Mice; Neoplasms
PubMed: 27622334
DOI: 10.1016/j.ccell.2016.08.005 -
PloS One 2022In recent times, the study of metabolic pathways has become inevitable and predominant for a variety of research fields as cancer biology and immunology. L-lactate as a...
BACKGROUND
In recent times, the study of metabolic pathways has become inevitable and predominant for a variety of research fields as cancer biology and immunology. L-lactate as a product of anaerobic glycolysis has shown to be an important indicator of the cellular metabolic status and can be associated with diverse cellular effects. For this reason, L-lactate assay kits are of high demand when metabolic effects need to be considered. Nevertheless, commercially available kits are not affordable if multiple samples must be evaluated.
PRINCIPAL FINDING
In this work, we develop an easy and cost-effective colorimetric assay for quantification of L-lactate suitable for cells with low or high L-lactate production based on LDH activity and suitable for 96 well-plate format. Using different metabolic regulators, we demonstrate the capacity of the assay to detect and quantify L-lactate from the supernatant of HeLa cancer cell line. Furthermore, we validate the assay against a commercially available kit by demonstrating no significant difference between both assays. Finally, we show that the assay is capable of quantifying L-lactate in primary cells such as hPBMCs that were stimulated with toll-like receptor ligands and treated with different metabolic regulators.
CONCLUSION
We herein present an easy custom assay that is suitable for cells with low and high L-lactate production at very low cost compared to commercially available kits. These advantages of the custom assay can simplify the research in the field of metabolism and related fields.
Topics: Cell Line; Colorimetry; Cost-Benefit Analysis; Glycolysis; L-Lactate Dehydrogenase; Lactic Acid
PubMed: 35867690
DOI: 10.1371/journal.pone.0271818 -
Journal of Bone and Mineral Research :... Dec 2020Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes because these pathologies are characterized by a shift from oxidative to...
Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes because these pathologies are characterized by a shift from oxidative to glycolytic metabolism. We have previously reported such glycolytic shift in aged bone as a major contributor to bone loss in mice. We and others also showed the importance of oxidative phosphorylation (OxPhos) for osteoblast differentiation. It is therefore reasonable to propose that stimulation of OxPhos will have bone anabolic effect. One strategy widely used in cancer research to stimulate OxPhos is inhibition of glycolysis. In this work, we aimed to evaluate the safety and efficacy of pharmacological inhibition of glycolysis to stimulate OxPhos and promote osteoblast bone-forming function and bone anabolism. We tested a range of glycolytic inhibitors including 2-deoxyglucose, dichloroacetate, 3-bromopyruvate, and oxamate. Of all the studied inhibitors, only a lactate dehydrogenase (LDH) inhibitor, oxamate, did not show any toxicity in either undifferentiated osteoprogenitors or osteoinduced cells in vitro. Oxamate stimulated both OxPhos and osteoblast differentiation in osteoprogenitors. In vivo, oxamate improved bone mineral density, cortical bone architecture, and bone biomechanical strength in both young and aged C57BL/6J male mice. Oxamate also increased bone formation by osteoblasts without affecting bone resorption. In sum, our work provided a proof of concept for the use of anti-glycolytic strategies in bone and identified a small molecule LDH inhibitor, oxamate, as a safe and efficient bone anabolic agent. © 2020 American Society for Bone and Mineral Research (ASBMR).
Topics: Anabolic Agents; Animals; Glycolysis; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Oxidative Phosphorylation
PubMed: 32729639
DOI: 10.1002/jbmr.4142 -
Bioelectrochemistry (Amsterdam,... Aug 2023Flavin-dependent L-lactate dehydrogenase (LDH) from baker's yeast (Saccharomyces cerevisiae) reversibly catalyzes the oxidation of L-lactate to L-pyruvate. In this...
Flavin-dependent L-lactate dehydrogenase (LDH) from baker's yeast (Saccharomyces cerevisiae) reversibly catalyzes the oxidation of L-lactate to L-pyruvate. In this study, four different enzymatic constructs were generated, and their catalytic and electrochemical properties were compared. Specifically, a truncated form of the native enzyme that includes only the catalytic domain, the native enzyme that includes an intrinsic electron-transferring cytochrome b2, a novel artificial enzyme containing a minimal cytochrome c and a version of the enzyme containing a fusion between two cytochromes were designed. All four variants were successfully expressed in Escherichia coli and presented properly matured heme domains. Assessing in vitro biocatalytic performance as reflected by lactate oxidation revealed the fusion-containing enzyme to be ∼ 12 times more active than the native enzyme. Electrochemical studies of electrode drop-casted enzyme variants also showed the superior performance of the dual-cytochrome construct, which displayed a lower average redox-potential for lactate oxidation, oxygen insensitivity in the lactate oxidation potential range and a wider dynamic range for lactate sensing, relative to the native enzyme. Moreover, product inhibition of this variant occurred at much higher lactate concentrations than with the native enzyme. In addition, when lower potentials were scanned using cyclic voltammetry, lactate-dependent oxygen reduction was measured for the dual-cytochrome fusion enzyme.
Topics: L-Lactate Dehydrogenase; Kinetics; Oxidation-Reduction; Saccharomyces cerevisiae; Pyruvic Acid; Lactic Acid; Cytochromes c; Oxygen
PubMed: 36931144
DOI: 10.1016/j.bioelechem.2023.108406 -
Molecules (Basel, Switzerland) Nov 2021Plasmodium lactate dehydrogenase (pLH) is one of the enzymes in glycolysis with potential target for chemotherapy. This study aimed to clone, overexpress and...
Plasmodium lactate dehydrogenase (pLH) is one of the enzymes in glycolysis with potential target for chemotherapy. This study aimed to clone, overexpress and characterize soluble recombinant lactate dehydrogenase from in a bacterial system. Synthetic lactate dehydrogenase (-LDH) gene was cloned into pET21a expression vector, transformed into strain BL21 (DE3) expression system and then incubated for 18 h, 20 °C with the presence of 0.5 mM isopropyl β-d-thiogalactoside in Terrific broth supplemented with Magnesium sulfate, followed by protein purifications using Immobilized Metal Ion Affinity Chromatography and size exclusion chromatography (SEC). Enzymatic assay was conducted to determine the activity of the enzyme. SDS-PAGE analysis revealed that protein of 34 kDa size was present in the soluble fraction. In SEC, a single peak corresponding to the size of -LDH protein was observed, indicating that the protein has been successfully purified. From MALDI-TOF analysis findings, a peptide score of 282 was established, which is significant for lactate dehydrogenase from revealed via MASCOT analysis. Secondary structure analysis of CD spectra indicated 79.4% α helix and 1.37% β strand structure. Specific activity of recombinant -LDH was found to be 475.6 U/mg, confirming the presence of active protein. Soluble -LDH that is biologically active was produced, which can be used further in other malaria studies.
Topics: Antimalarials; L-Lactate Dehydrogenase; Malaria; Plasmodium knowlesi
PubMed: 34771034
DOI: 10.3390/molecules26216625