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Biomedicine & Pharmacotherapy =... Mar 2022Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain... (Review)
Review
Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glycolysis; Humans; L-Lactate Dehydrogenase; Mitochondria; Neoplasms; Oxamic Acid; Phenformin; Radiation Tolerance; Reactive Oxygen Species; Temozolomide
PubMed: 35124385
DOI: 10.1016/j.biopha.2022.112686 -
Glia Aug 2024Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate...
Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type-specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also "funnel" lactate through their "myelinic" channels between gap junction-coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.
Topics: Animals; Oligodendroglia; Axons; L-Lactate Dehydrogenase; Glycolysis; Mice; Down-Regulation; Mice, Inbred C57BL; Lactate Dehydrogenase 5; Astrocytes; Mice, Transgenic; Isoenzymes; Gap Junctions; Mice, Knockout
PubMed: 38587131
DOI: 10.1002/glia.24533 -
Biomarkers in Medicine Oct 2022The enzyme lactate dehydrogenase (LDH) is a good marker of general hyperinflammation correlated with mortality for COVID-19, and is therefore used in prognosis tools.... (Randomized Controlled Trial)
Randomized Controlled Trial
The enzyme lactate dehydrogenase (LDH) is a good marker of general hyperinflammation correlated with mortality for COVID-19, and is therefore used in prognosis tools. In a current COVID-19 clinical randomized trial (CRT), the blood level of LDH was selected as an inclusion criterion. However, LDH decreased during the pandemic; hence, the impact of this decrease on the prognostic value of LDH for mortality was evaluated. Data on LDH levels in 843 patients were obtained and analyzed. Relative risk, standard error and receiver operating characteristic curves were calculated for two cutoff values. Relative risk lost validity and the area under the curve narrowed by trimester during the pandemic. The progressive decrease in LDH impacted the capacity to predict mortality in COVID-19. More studies are needed to validate this finding and its implications.
Topics: Humans; COVID-19; L-Lactate Dehydrogenase; Pandemics; Prognosis; Retrospective Studies; ROC Curve
PubMed: 36052694
DOI: 10.2217/bmm-2022-0364 -
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 -
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 -
International Journal of Molecular... Nov 2023Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome...
Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome from murine colon carcinoma CT26 induces cachectic features in both murine and human adipocytes that are associated with metabolic alterations such as enhanced lactate production and decreased oxygen consumption. The use of oxamate, which inhibits lactate dehydrogenase activity, hinders the effects induced by CT26 secretome. Interestingly, the CT26 secretome elicits an increased level of lactate dehydrogenase and decreased expression of adiponectin. These modifications are driven by the STAT3 signalling cascade since the inhibition of STAT3 with WP1066 impedes the formation of the cachectic condition and the alteration of lactate dehydrogenase and adiponectin levels. Collectively, these findings show that STAT3 is responsible for the altered lactate dehydrogenase and adiponectin levels that, in turn, could participate in the worsening of this pathology and highlight a step forward in the comprehension of the mechanisms underlying the onset of the cachectic condition in adipocytes.
Topics: Humans; Mice; Animals; Adiponectin; Cachexia; Down-Regulation; Quality of Life; Up-Regulation; Adipocytes; L-Lactate Dehydrogenase; STAT3 Transcription Factor
PubMed: 38003534
DOI: 10.3390/ijms242216343 -
Open Veterinary Journal 2022Lactate dehydrogenase (LDH) isoenzymes may be useful in the differential diagnosis of pleural effusion (PE) and ascitic fluid (AF) etiologies in cats since tissue damage...
BACKGROUND
Lactate dehydrogenase (LDH) isoenzymes may be useful in the differential diagnosis of pleural effusion (PE) and ascitic fluid (AF) etiologies in cats since tissue damage induces their release, changing the pattern of their activity.
AIM
This study aimed to determine the diagnostic utility of measuring LDH levels and isoenzyme activities in PE or AF in cats with malignancy.
METHODS
LDH levels and isoenzyme activities in the serum, PE, and AF were compared among cats in the malignant, infectious, and non-malignant, non-infectious groups. A receiver operating characteristic (ROC) analysis was performed to assess the accuracy in diagnosing feline malignancy.
RESULTS
Significant differences in LDH level and LDH isoenzyme activities in the PE and AF were observed among the three groups. The combination of LDH level and LDH-1 activity in PE or AF had the highest area under the ROC (AUC) values for discriminating malignant effusion from non-malignant effusion. The AUC of the combination of LDH level and LDH-1 activity in PE or AF was 0.874. The sensitivity and specificity of using the combination of LDH level (cut-off: <2,269 U/l) and LDH-1 activity (cut-off: <4.8%) in PE or AF for predicting malignancy with the highest AUC value were 94.4% and 72.7%, respectively.
CONCLUSION
Our results suggest that the combination of LDH level and LDH-1 activity in PE or AF is a potential factor for diagnosing malignancy. Considering that LDH isoenzymes can be measured inexpensively and easily, LDH tests can be readily accommodated in veterinary clinical practice.
Topics: Cats; Animals; Isoenzymes; Ascitic Fluid; Pleural Effusion; Pleural Effusion, Malignant; L-Lactate Dehydrogenase; Cat Diseases
PubMed: 36589389
DOI: 10.5455/OVJ.2022.v12.i5.19 -
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 -
Methods in Molecular Biology (Clifton,... 2021Pyroptosis is a new type of programmed cell death identified in recent years, which destroys the integrity of cell membranes by punching pores on them, resulting in cell...
Pyroptosis is a new type of programmed cell death identified in recent years, which destroys the integrity of cell membranes by punching pores on them, resulting in cell lysis. Light- and dark-colored vesicles/pore-like structures on the membranes of pyroptotic cells are generally observed using light microscope, accompanied by cell swelling and cytoplasmic release. However, due to the release of the cell contents in both pyroptosis and necrosis, it is difficult to distinguish them solely by morphological characteristics. The mechanism of pyroptosis involves three major signaling pathways, all activating downstream gasdermin (GSDM) D and E, which results in the formation of pores (10-15 nm) on the cell membrane, while small cytoplasmic molecules such as interleukin (IL)-1 and IL-18 flow out from the pores and cause inflammation. The occurrence of pyroptosis can be determined by a combination of markers. These include cleavage of GSDM D and E, activation and release of IL-1β and IL-18, and activation of cysteinyl aspartate specific proteinase (caspase-1, -3, -4, -5, and -11). This chapter discusses several common methods to assist researchers in detecting pyroptosis.
Topics: Caspases; Flow Cytometry; Humans; L-Lactate Dehydrogenase; Neoplasms; Pyroptosis; Tumor Cells, Cultured
PubMed: 34033101
DOI: 10.1007/978-1-0716-1162-3_13 -
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