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Seminars in Cancer Biology Nov 2022The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis,... (Review)
Review
The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis, fatty acid oxidation, and glutaminolysis. It is about one hundred years ago since Warburg observed that cancer cells prefer aerobic glycolysis even in normoxic conditions, favoring their high proliferation rate. A pivotal enzyme driving this phenomenon is lactate dehydrogenase (LDH), and this review describes prognostic and therapeutic opportunities associated with this enzyme, focussing on tumors with limited therapeutic strategies and life expectancy (i.e., pancreatic and thoracic cancers). Expression levels of LDH-A in pancreatic cancer tissues correlate with clinicopathological features: LDH-A is overexpressed during pancreatic carcinogenesis and showed significantly higher expression in more aggressive tumors. Similarly, LDH levels are a marker of negative prognosis in patients with both adenocarcinoma or squamous cell lung carcinoma, as well as in malignant pleural mesothelioma. Additionally, serum LDH levels may play a key role in the clinical management of these diseases because they are associated with tissue damage induced by tumor burden. Lastly, we discuss the promising results of strategies targeting LDH as a treatment strategy, reporting recent preclinical and translational studies supporting the use of LDH-inhibitors in combinations with current/novel chemotherapeutics that can synergistically target the oxygenated cells present in the tumor.
Topics: Humans; Glycolysis; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lung Neoplasms; Pancreatic Neoplasms; Energy Metabolism; Mesothelioma; Pleural Neoplasms; Thoracic Neoplasms
PubMed: 36096316
DOI: 10.1016/j.semcancer.2022.09.001 -
Bioorganic & Medicinal Chemistry Nov 2021Parasitic diseases remain a major public health concern for humans, claiming millions of lives annually. Although different treatments are required for these diseases,... (Review)
Review
Parasitic diseases remain a major public health concern for humans, claiming millions of lives annually. Although different treatments are required for these diseases, drug usage is limited due to the development of resistance and toxicity, which necessitate alternative therapies. It has been shown in the literature that parasitic lactate dehydrogenases (LDH) and malate dehydrogenases (MDH) have unique pharmacological selective and specificity properties compared to other isoforms, thus highlighting them as viable therapeutic targets involved in aerobic and anaerobic glycolytic pathways. LDH and MDH are important therapeutic targets for invasive parasites because they play a critical role in the progression and development of parasitic diseases. Any strategy to impede these enzymes would be fatal to the parasites, paving the way to develop and discover novel antiparasitic agents. This review aims to highlight the importance of parasitic LDH and MDH as therapeutic drug targets in selected obligate apicoplast parasites. To the best of our knowledge, this review presents the first comprehensive review of LDH and MDH as potential antiparasitic targets for drug development studies.
Topics: Animals; Antiparasitic Agents; Cryptosporidium parvum; Drug Development; Humans; L-Lactate Dehydrogenase; Malate Dehydrogenase; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium; Schistosoma; Toxoplasma; Trichomonas vaginalis
PubMed: 34687983
DOI: 10.1016/j.bmc.2021.116458 -
Clinical and Experimental Dermatology Jul 2020Lactate dehydrogenase (LDH) is used in dermatology practice, particularly as a prognostic marker for cutaneous lymphoma. LDH is an intracellular enzyme involved in... (Review)
Review
Lactate dehydrogenase (LDH) is used in dermatology practice, particularly as a prognostic marker for cutaneous lymphoma. LDH is an intracellular enzyme involved in anaerobic glycolysis, and is found at low concentrations in the blood. LDH is produced in every tissue, thus cell damage releases LDH into the circulation, so the causes of elevated LDH levels are multiple. The utility of LDH in dermatology practice is reviewed, alongside current diagnostic and staging guidelines.
Topics: Adolescent; Child; Child, Preschool; Dermatology; Disease Progression; Female; Humans; Infant; Infant, Newborn; L-Lactate Dehydrogenase; Lymphoma; Male; Melanoma; Neoplasm Staging; Reference Values; Skin Neoplasms
PubMed: 31755143
DOI: 10.1111/ced.14134 -
Experimental & Molecular Medicine Oct 2023Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a...
Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, C-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by the cell's own status or the environmental status.
Topics: Histones; Lactic Acid; Acetylation; L-Lactate Dehydrogenase; Epigenesis, Genetic
PubMed: 37779146
DOI: 10.1038/s12276-023-01095-w -
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 -
Journal of Pharmacological Sciences Dec 2023Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/macrophage lineage. Excessive resorbing activities of osteoclasts are...
Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/macrophage lineage. Excessive resorbing activities of osteoclasts are involved in destructive bone diseases. The detailed mechanism of acidification at the bone adhesion surface during the bone resorption process of osteoclasts remains to be defined. During glycolysis, pyruvate proceeds to the tricarboxylic cycle under aerobic conditions and pyruvate is converted to lactate via lactate dehydrogenase A (LDHA) under anaerobic conditions. However, tumor cells produce ATP during aerobic glycolysis and large amounts of pyruvate are converted to lactate and H by LDHA. Lactate and H are excreted outside the cell, whereby they are involved in invasion of tumor cells due to the pH drop around the cell. In this study, we focused on aerobic glycolysis and investigated the production of lactate by LDHA in osteoclasts. Expression of LDHA and monocarboxylate transporter 4 (MCT4) was upregulated during osteoclast differentiation. Intracellular and extracellular lactate levels increased with upregulation of LDHA and MCT4, respectively. FX11 (an LDHA inhibitor) inhibited osteoclast differentiation and suppressed the bone-resorbing activity of osteoclasts. We propose that inhibition of LDHA may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.
Topics: Humans; Osteogenesis; Lactate Dehydrogenase 5; Osteoclasts; Bone Resorption; Lactates; Glycolysis; Pyruvates; L-Lactate Dehydrogenase
PubMed: 37973217
DOI: 10.1016/j.jphs.2023.09.005 -
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 -
Archives of Microbiology Dec 2021Staphylococcus xylosus is a gram-positive bacterium that has attracted much attention due to its increasing clinical appearance, frequently associated with serious...
Staphylococcus xylosus is a gram-positive bacterium that has attracted much attention due to its increasing clinical appearance, frequently associated with serious multidrug resistance cases. L-lactate dehydrogenase (LDH) has been related to drug resistance in several bacterial species. However, the mechanism of multidrug resistance in S. xylosus remains unclear as well as the involvement of LDH in such resistance. To explore the relationship between multidrug resistance and LDH in S. xylosus, we used tylosin-resistant S. xylosus as the parent strain to construct ldh knockout and complemented strains. Then, we tested their resistance to macrolides, lincosamides, tetracyclines, and aminoglycosides. In addition, the enzyme activity, metabolite content, and transcriptional level of key genes involved in the TCA cycle and thioredoxin system were determined to clarify the mechanism of resistance. We observed that the resistance to multiple antibiotics increased significantly after ldh knockout, especially that to lincomycin, whereas antibiotic sensitivity was partially restored in the complemented strain. The levels of pyruvate, nicotinamide adenine dinucleotide, and reactive oxygen species decreased significantly upon ldh knockout, and the activity of isocitrate dehydrogenase and malate dehydrogenase decreased. These results indicate that the lack of LDH promotes multidrug resistance in S. xylosus by inhibiting the TCA cycle and regulating the thioredoxin system.
Topics: Anti-Bacterial Agents; Drug Resistance, Multiple; L-Lactate Dehydrogenase; Staphylococcus
PubMed: 34962581
DOI: 10.1007/s00203-021-02625-8 -
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 -
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