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Aging Feb 2023The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory....
The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.
Topics: Animals; L-Lactate Dehydrogenase; Drosophila melanogaster; Neuroglia; Neurons; Astrocytes; Memory Disorders; Lactic Acid; Lipids
PubMed: 36849157
DOI: 10.18632/aging.204565 -
Journal of Dairy Science Mar 2022In response to intramammary infection (IMI), blood-derived leukocytes are transferred into milk, which can be measured as an increase of somatic cell count (SCC)....
In response to intramammary infection (IMI), blood-derived leukocytes are transferred into milk, which can be measured as an increase of somatic cell count (SCC). Additionally, pathogen-dependent IgG increases in milk following infection. The IgG transfer into milk is associated with the opening of the blood-milk barrier, which is much more pronounced during gram-negative than gram-positive IMI. Thus, milk IgG concentration may help to predict the pathogen type causing IMI. Likewise, lactate dehydrogenase (LDH) and serum albumin (SA) cross the blood-milk barrier with IgG if its integrity is reduced. Because exact IgG analysis is complicated and difficult to automate, LDH activity and SA concentration aid as markers to predict the IgG transfer into milk in automatic milking systems (AMS). This study was conducted to test the hypothesis that LDH and SA in milk correlate with the IgG transfer, and in combination with SCC these factors allow the differentiation between gram-positive and gram-negative IMI or even more precisely the infection-causing pathogen. Further, the expression of these parameters in foremilk before (BME) and after (AME) milk ejection was tested. In the AMS, quarter milk samples (n = 686) from 48 Holstein-Friesian cows were collected manually BME and AME, followed by an aseptic sample for bacteriological culture. Mixed models were used to (1) predict the concentration of IgG transmitted from blood into milk based on LDH and SA; (2) use principal component analysis to evaluate joint patterns of SCC (cells/mL), IgG (mg/mL), LDH (U/L), and SA (mg/mL) and use the principal component scores to compare gram-positive, gram-negative, and control IMI types and BME versus AME samples; and (3) predict gram-positive and gram-negative IMI by inclusion of combined SCC-LDH and SCC-SA as predictors in the model. Overall, the SA and LDH had similar ability to predict IgG transmission from blood into milk. Comparing the areas under the curve (AUC) of the receiver operator characteristic curves, the SCC-LDH versus SCC-SA had lower gram-positive (AUC = 0.984 vs. 0.986) but similar gram-negative (AUC = 0.995 vs. 0.998) IMI prediction ability. The SCC, IgG, LDH, and SA were greater in gram-negative than in gram-positive IMI (BME and AME) in early lactation. All measured factors had higher values in milk samples taken BME than AME. In conclusion, LDH and SA could be used as replacement markers to indicate the presence of IgG transfer from blood into milk; in combination with SCC, both SA and LDH are suitable for differentiating IMI type, and BME is better for mastitis detection in AMS.
Topics: Animals; Cattle; Cattle Diseases; Cell Count; Female; L-Lactate Dehydrogenase; Mastitis, Bovine; Milk; Serum Albumin
PubMed: 34998550
DOI: 10.3168/jds.2021-20475 -
Disease Markers 2022: Periodontitis is one of the most common chronic bacterial infections in humans involving the tooth-supporting tissue. The present study aimed to evaluate and compare...
: Periodontitis is one of the most common chronic bacterial infections in humans involving the tooth-supporting tissue. The present study aimed to evaluate and compare salivary biomarkers, including lactate dehydrogenase (LDH) and hemoglobin A1c (HbA1c), between patients with severe chronic periodontitis and healthy individuals. : This study was performed on 29 patients with severe chronic periodontitis and 30 healthy individuals at Zahedan University of Medical Sciences, Zahedan, Iran, in 2021. Salivary samples were taken, and clinical parameters, including the clinical attachment loss (CAL) and probing pocket depth (PPD), were measured. Besides, the levels of LDH and HbA1c were measured using ELISA kits. The sensitivity, specificity, and positive and negative predictive values of HbA1c and LDH were examined for chronic periodontitis diagnosis. : Based on the present results, the levels of LDH and HbA1C did not show adequate sensitivity or specificity for screening chronic periodontitis. : According to the present findings, salivary biomarkers, including LDH and HbA1c, cannot be used with certainty for screening chronic periodontitis.
Topics: Biomarkers; Chronic Periodontitis; Glycated Hemoglobin; Humans; L-Lactate Dehydrogenase; Periodontal Index; Saliva
PubMed: 35521636
DOI: 10.1155/2022/1119038 -
Poultry Science Jan 2020Wooden breast (WB) results in significant losses to the broiler industry due to reductions in meat quality. While the etiology of WB is unknown, it is believed to be...
Wooden breast (WB) results in significant losses to the broiler industry due to reductions in meat quality. While the etiology of WB is unknown, it is believed to be associated with localized hypoxia and decreased lactate levels in skeletal muscles, indicating the presence of altered lactate metabolism in WB. We hypothesized that the expression levels of the major signaling molecules that control lactate metabolism, including lactate dehydrogenases (LDHA and LDHB) and monocarboxylate transporters (MCT1 and MCT4), were altered in WB. Therefore, the objectives of this study were to evaluate whether there were changes in mRNA and protein levels of LDHA, LDHB, MCT1, and MCT4 in WB compared to normal breast (NB) muscles. Biochemical analysis for LDH enzyme activity in NB and WB muscles was studied. MicroRNA375 (miR-375) expression, known to be inversely associated with LDHB protein expression in human cells, was also investigated. The level of LDHA mRNA was 1.7-fold lower in WB tissues than in NB tissues (P < 0.0001). However, the LDHA protein levels were similar in WB and NB tissues. In contrast, the levels of LDHB mRNA and protein were 8.4-fold higher (P < 0.002) and 13.6-fold higher (P < 0.02) in WB than in NB tissues, respectively. The level of miR-375 was not different between WB and NB muscles. The specific LDH isoenzyme activity that converted lactate to pyruvate was 1.8-fold lower in WB compared to NB tissues (P < 0.01). The level of MCT1 mRNA was 2.3-fold higher in WB than those in NB muscles (P < 0.02). However, this upregulation was not observed with MCT1 protein expression levels. The expression levels of MCT4 mRNA and protein were elevated 2.8-fold (P < 0.02) and 3.5-fold (P < 0.004) in WB compared to NB tissues, respectively. Our current findings suggest the potential roles of LDHB and MCT4 on lactate metabolism and provide a unique molecular elucidation for altered lactate homeostasis in WB muscles of broilers.
Topics: Animals; Avian Proteins; Chickens; L-Lactate Dehydrogenase; Lactic Acid; Monocarboxylic Acid Transporters; Muscle Proteins; Pectoralis Muscles; Poultry Diseases
PubMed: 32416791
DOI: 10.3382/ps/pez572 -
Biomedicine & Pharmacotherapy =... Feb 2023T cells are the main force of anti-infection and antitumor and are also involved in autoimmune diseases. During the development of these diseases, T cells need to... (Review)
Review
T cells are the main force of anti-infection and antitumor and are also involved in autoimmune diseases. During the development of these diseases, T cells need to rapidly produce large amounts of energy to satisfy their activation, proliferation, and differentiation. In this review, we introduced lactate dehydrogenase A(LDHA), predominantly involved in glycolysis, which provides energy for T cells and plays a dual role in disease by mediating lactate production, non-classical enzyme activity, and oxidative stress. Mechanistically, the signaling molecule can interact with the LDHA promoter or regulate LDHA activity through post-translational modifications. These latest findings suggest that modulation of LDHA may have considerable therapeutic effects in diseases where T-cell activation is an important pathogenesis.
Topics: Lactate Dehydrogenase 5; L-Lactate Dehydrogenase; Cell Line, Tumor; T-Lymphocytes; Glycolysis; Cell Proliferation
PubMed: 36916398
DOI: 10.1016/j.biopha.2022.114164 -
Molecular Medicine Reports Sep 2021The pathological expression and function of lactate dehydrogenase A (LDHA), a key enzyme that converts pyruvate into lactic acid during glycolysis, remains unknown in...
The pathological expression and function of lactate dehydrogenase A (LDHA), a key enzyme that converts pyruvate into lactic acid during glycolysis, remains unknown in endometriosis. In the present study, LDHA expression in tissue samples was determined by immunohistochemistry. To examine whether LDHA was induced by hypoxia, primary cultured endometrial stromal cells (ESCs) and glandular epithelial Ishikawa cells were exposed to 1% O (hypoxia) or 21% O (normoxia). Cellular functions were assessed by flow cytometry, Transwell and Cell Counting Kit‑8 assays in LDHA‑silenced ESCs and Ishikawa cells. Mitochondrial functions were evaluated using mitochondrial membrane potential JC‑1 staining, reactive oxygen species flow cytometric analysis and ATP detection. Additionally, lactic acid production was examined and western blotting was used to evaluate the expression levels of proteins associated with apoptosis, cell cycle and glycolysis, as well as regulatory proteins involved in epithelial‑mesenchymal transformation and glycolytic pathways. LDHA was localized to endometrial glandular cells and stromal cells. However, LDHA protein expression was higher in endometriotic lesions compared with that in normal and eutopic endometria. LDHA expression levels in ectopic glandular cells were higher during the proliferative stage compared with during the secretory stage. Hypoxia treatment of Ishikawa cells and ESCs markedly induced the mRNA and protein expression of LDHA. Silencing of LDHA expression in Ishikawa cells and THESC cells significantly promoted impaired mitochondrial function and apoptosis while inhibiting migration and glycolysis. However, it had no obvious effect on proliferation. In conclusion, the present study revealed that LDHA was highly expressed in endometriotic tissues, where it may serve a notable role in the occurrence and development of endometriosis.
Topics: Adult; Apoptosis; Cell Proliferation; Endometriosis; Endometrium; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Glycolysis; Humans; Hypoxia; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Protective Agents; RNA, Messenger; Reactive Oxygen Species; Stromal Cells
PubMed: 34278456
DOI: 10.3892/mmr.2021.12276 -
PloS One 2017In the asexual stages, Toxoplasma gondii stage converts between acute phase rapidly replicating tachyzoites and chronic phase slowly dividing bradyzoites....
In the asexual stages, Toxoplasma gondii stage converts between acute phase rapidly replicating tachyzoites and chronic phase slowly dividing bradyzoites. Correspondingly, T. gondii differentially expresses two distinct genes and isoforms of the lactate dehydrogenase enzyme, expressing LDH1 exclusively in the tachyzoite stage and LDH2 preferentially in the bradyzoite stage. LDH catalyzes the interconversion of pyruvate and lactate in anaerobic growth conditions and is utilized for energy supply, however, the precise role of LDH1 and LDH2 in parasite biology in the asexual stages is still unclear. Here, we investigated the biological role of LDH1 and LDH2 in the asexual stages, and the vaccine strain potential of deletion mutants lacking LDH1, LDH2, or both genes (Δldh1, Δldh2 and Δldh1/2). Deletion of LDH1 reduced acute parasite virulence, impaired bradyzoite differentiation in vitro, and markedly reduced chronic stage cyst burdens in vivo. In contrast, deletion of LDH2 impaired chronic stage cyst burdens without affecting virulence or bradyzoite differentiation. Deletion of both LDH1 and LDH2 induced a more severe defect in chronic stage cyst burdens. These LDH mutant phenotypes were not associated with any growth defect. Vaccination of mice with a low dose of mutants deleted for LDH elicited effective protective immunity to lethal challenge infection, demonstrating the vaccine potential of LDH deletion mutants. These results suggest that lactate dehydrogenase in T. gondii controls virulence, bradyzoite differentiation, and chronic infection and reveals the potential of LDH mutants as vaccine strains.
Topics: Amino Acid Sequence; Animals; Cells, Cultured; Escherichia coli; Female; Gene Knockout Techniques; Humans; Isoenzymes; L-Lactate Dehydrogenase; Mice, Inbred BALB C; Mutation; Random Allocation; Recombinant Proteins; Toxoplasma; Toxoplasmosis; Vaccination; Virulence
PubMed: 28323833
DOI: 10.1371/journal.pone.0173745 -
Scientific Reports Jul 2017Lactate dehydrogenase A (LDHA) has been reported to be involved in the initiation and progression of tumors. However, the potential role of LDHA in pituitary adenoma...
Lactate dehydrogenase A (LDHA) has been reported to be involved in the initiation and progression of tumors. However, the potential role of LDHA in pituitary adenoma (PA) remains unknown. In this study, we showed that the expression levels of LDHA mRNA and protein were significantly elevated in invasive PA samples, and positively correlated with higher Ki-67 index. Overexpression of LDHA in a PA cell line (GH3) promoted glucose uptake through the upregulation of glucose transporter-1 (Glut1), lactate secretion and induced cellular invasion by upregulation of matrix metalloproteinase2 (MMP2). LDHA also promoted GH3 cell proliferation through induction of cell cycle progression via activation of the Akt-GSK-3β-cyclinD1 pathway. Accordingly, oxamate-induced inhibition of LDHA suppressed glucose uptake, lactate secretion, invasion and proliferation in GH3 cells via down regulation of Glut1 and MMP2 expression and inhibition of the Akt-GSK-3β-cyclinD1 pathway. Moreover, oxamate induced GH3 cell apoptosis by increasing mitochondrial reactive oxygen species (ROS) generation. In vivo, LDHA overexpression promoted tumor growth, and oxamate delayed tumor growth. In primary PA cell cultures, oxamate also effectively suppressed invasion and proliferation. Our data indicate that LDHA is involved in promoting the progression of PA, and oxamate might be a promising therapeutic agent for the treatment of PA.
Topics: Adenoma; Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glucose; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Mice; Neoplasm Invasiveness; Neoplasm Transplantation; Pituitary Neoplasms; Signal Transduction; Up-Regulation
PubMed: 28680051
DOI: 10.1038/s41598-017-04366-5 -
Applied and Environmental Microbiology Jan 2021Growth of PCA on lactate was enhanced by laboratory adaptive evolution. The enhanced growth was considered to be attributed to increased expression of the genes,...
Growth of PCA on lactate was enhanced by laboratory adaptive evolution. The enhanced growth was considered to be attributed to increased expression of the genes, encoding a succinyl-coenzyme A (CoA) synthetase. To further investigate the function of the succinyl-CoA synthetase, the genes were deleted from The mutant showed defective growth on lactate but not on acetate. Introduction of the genes into the mutant restored the full potential to grow on lactate. These results verify the importance of the succinyl-CoA synthetase in growth on lactate. Genome analysis of species identified candidate genes, GSU1623, GSU1624, and GSU1620, for lactate dehydrogenase. Deletion mutants of the identified genes for d-lactate dehydrogenase (ΔGSU1623 ΔGSU1624 mutant) or l-lactate dehydrogenase (ΔGSU1620 mutant) could not grow on d-lactate or l-lactate but could grow on acetate and l- or d-lactate, respectively. Introduction of the respective genes into the mutants allowed growth on the corresponding lactate stereoisomer. These results suggest that the identified genes were essential for d- or l-lactate utilization. The reporter assay demonstrated that the putative promoter regions were more active during growth on lactate than during growth on acetate, indicating that the genes for the lactate dehydrogenases were expressed more during growth on lactate than during growth on acetate. The gene deletion phenotypes and the expression profiles indicate that there are metabolic switches between lactate and acetate. This study advances the understanding of anaerobic lactate utilization in Lactate is a microbial fermentation product as well as a source of carbon and electrons for microorganisms in the environment. Furthermore, lactate is a common amendment for stimulation of microbial growth in environmental biotechnology applications. However, anaerobic metabolism of lactate has been poorly studied for environmentally relevant microorganisms. species are found in various environments and environmental biotechnology applications. By employing genomic and genetic approaches, succinyl-CoA synthetase and lactate dehydrogenase were identified as key enzymes in anaerobic metabolism of lactate in , a representative species. Differential gene expression during growth on lactate and acetate was observed, demonstrating that could metabolically switch to adapt to available substrates in the environment. The findings provide new insights into basic physiology in lactate metabolism as well as cellular responses to growth conditions in the environment and can be informative for the application of lactate in environmental biotechnology.
Topics: Anaerobiosis; Bacterial Proteins; Gene Expression Regulation, Bacterial; Geobacter; L-Lactate Dehydrogenase; Lactic Acid; Succinate-CoA Ligases
PubMed: 33158892
DOI: 10.1128/AEM.01968-20 -
Development (Cambridge, England) Sep 2019The dramatic growth that occurs during larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands...
The dramatic growth that occurs during larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands by increasing carbohydrate metabolism and lactate dehydrogenase (LDH) activity. The resulting metabolic program is ideally suited for synthesis of macromolecules and mimics the manner by which cancer cells rely on aerobic glycolysis. To explore the potential role of LDH in promoting biosynthesis, we examined how mutations influence larval development. Our studies unexpectedly found that mutants grow at a normal rate, indicating that LDH is dispensable for larval biomass production. However, subsequent metabolomic analyses suggested that mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P), the production of which also influences larval redox balance. Consistent with this possibility, larvae lacking both LDH and G3P dehydrogenase (GPDH1) exhibit growth defects, synthetic lethality and decreased glycolytic flux. Considering that human cells also generate G3P upon inhibition of lactate dehydrogenase A (LDHA), our findings hint at a conserved mechanism in which the coordinate regulation of lactate and G3P synthesis imparts metabolic robustness to growing animal tissues.
Topics: Adenosine Triphosphate; Animals; Animals, Genetically Modified; Drosophila melanogaster; Female; Glycerolphosphate Dehydrogenase; Glycolysis; Homeostasis; L-Lactate Dehydrogenase; Lactic Acid; Larva; Male; Mutation; NAD; Oxidation-Reduction; Sugars
PubMed: 31399469
DOI: 10.1242/dev.175315