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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 -
Italian Journal of Pediatrics Sep 2023Early identification of intravenous immunoglobulin (IVIG) resistance contributes to better management of Kawasaki disease (KD). This study aims to establish an effective...
BACKGROUND
Early identification of intravenous immunoglobulin (IVIG) resistance contributes to better management of Kawasaki disease (KD). This study aims to establish an effective prediction model for IVIG resistance in the Chinese population.
METHODS
A total of 658 eligible patients diagnosed with KD were enrolled in this study, with 461 in the training cohort and 197 in the validation cohort. The demographic characteristics and potential risk factors were compared between IVIG-responsive and resistant groups. Predictors were selected by the Akaike information criterion. The nomogram's performance was evaluated by calibration curve, decision curve analysis, and operating characteristic curve.
RESULTS
White blood cell counts (WBC), neutrophil-lymphocyte ratio (N/L ratio), hematocrit (HCT), albumin (ALB), total bilirubin (TBIL), lactate dehydrogenase (LDH), and creatinine (Cr) were detected as predictors of IVIG resistance. A predictive nomogram incorporating these predictors was constructed using the training cohort. The calibration curve and decision curve analysis showed good discrimination and calibration of the proposed nomogram in both training and validation sets, and the area under the receiver operating characteristic curve (AUROC) in both sets was 75.8% and 74.2%, respectively.
CONCLUSION
This study identified WBC, N/L ratio, HCT, ALB, TBIL, LDH, and Cr as predictors for IVIG resistance in patients with KD. The proposed novel nomogram with a high level of accuracy and reliability may benefit clinical decision-making upon treatment initiation.
Topics: Humans; Asian People; Bilirubin; Creatinine; Immunoglobulins, Intravenous; L-Lactate Dehydrogenase; Leukocyte Count; Mucocutaneous Lymph Node Syndrome; Reproducibility of Results; Drug Resistance
PubMed: 37749617
DOI: 10.1186/s13052-023-01531-7 -
Journal of Inflammation Research 2023To establish and verify a comprehensive prognostic nomogram for predicting survival outcomes and improving the prognosis for non-metastatic nasopharyngeal carcinoma...
PURPOSE
To establish and verify a comprehensive prognostic nomogram for predicting survival outcomes and improving the prognosis for non-metastatic nasopharyngeal carcinoma (NPC).
PATIENTS AND METHODS
Our retrospective study screened 613 cases of non-metastatic NPC who received radiotherapy from July 2012 to December 2016. A reliable nomogram was formulated for predicting overall survival (OS) and progression-free survival (PFS) using all independent predictors selected by Cox regression analysis. A comparison is conducted between the current staging and the predictive performance of the nomogram. Internal validation was performed in a single center using the validation cohort to assess predictive accuracy and discrimination.
RESULTS
High-density lipoprotein cholesterol, Epstein-Barr virus DNA and lactate dehydrogenase were determined to be valuable predictive indicators for predicting OS and PFS. Triglycerides were a valuable predictive indicator for predicting OS. Calibration curves demonstrated that the nomogram had remarkable correspondence between the prediction outcomes and the actual observations. Receiver operating characteristic curves showed that the nomogram had greater area under the curve and more satisfactory discrimination capability than the current TNM staging. Decision curve analysis revealed that the nomogram had high net clinical benefits. Significant differences were observed when low- and high-risk groups were stratified via Kaplan-Meier curves.
CONCLUSION
Our proposed nomogram combining lipid metabolic markers and lactate dehydrogenase could assist clinicians in the accurate prognostic prediction of non-metastatic NPC patients and provide personalized treatment recommendations.
PubMed: 37520664
DOI: 10.2147/JIR.S416801 -
American Journal of Physiology. Cell... Oct 2023Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a...
Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metformin increases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to produce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potential contribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treatment (16-776 μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78 µM, metformin induced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, < 0.01) along with decreasing the [NAD]:[NADH] ratio (776 µM, < 0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39 µM, < 0.01). On the other hand, in human skeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased under metformin treatment ( < 0.05). In conclusion, the findings suggest that metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-dependent lactate production in primary human myotubes. Metformin shifts the equilibrium of lactate dehydrogenase (LDH) reaction by low dose-induced phosphorylation of pyruvate dehydrogenase (PDH) resulting in inhibition of pyruvate oxidation and high dose-induced increase in NADH, which explains the dose-dependent lactate production of differentiated human skeletal muscle cells.
Topics: Humans; Lactic Acid; Metformin; NAD; Oxidation-Reduction; Muscle Fibers, Skeletal; Pyruvates; Oxidoreductases; Lactate Dehydrogenases
PubMed: 37694284
DOI: 10.1152/ajpcell.00186.2023 -
BMC Cancer Sep 2023Whether serum lactate dehydrogenase-to-albumin ratio (LAR) influenced the outcomes of colorectal cancer (CRC) patients after radical surgery remained unclear. Therefore,...
BACKGROUND
Whether serum lactate dehydrogenase-to-albumin ratio (LAR) influenced the outcomes of colorectal cancer (CRC) patients after radical surgery remained unclear. Therefore, this study sought to examine how LAR influences the short-term and long-term outcomes of CRC patients who have undergone radical surgery.
METHODS
This study retrospectively included CRC patients who underwent radical resection between January 2011 and January 2020. We compared short-term outcomes, as well as overall survival (OS) and disease-free survival (DFS), among various groups. Both univariate and multivariate logistic regression analyses were utilized to pinpoint independent risk factors associated with overall complications and major complications. Moreover, Cox regression analysis were conducted for OS and DFS. Odds ratio (OR) and Hazard ratio (HR) were adjusted.
RESULTS
This study encompassed a cohort of 3868 patients. 3440 patients were in the low LAR group and 428 patients constituted the high LAR group. In the high LAR group, patients experienced significantly longer operative times (p < 0.01), larger intraoperative blood loss (p < 0.01), and extended postoperative hospital stays (p < 0.01). Additionally, the incidence of both overall complications (p < 0.01) and major complications (p < 0.01) was higher in the high LAR group compared to the low LAR group. Furthermore, LAR was emerged as an independent prognostic factor for overall complications [OR/95% CI: (1.555/1.237 to 1.954), p < 0.01] and major complications [OR/95% CI: (2.178/1.279 to 3.707), p < 0.01]. As for long-term survival, the high LAR group had worse OS in stage II (p < 0.01) and stage III (p < 0.01). In both stage II (p < 0.01) and stage III (p < 0.01), the high LAR group exhibited poorer DFS. Additionally, according to Cox regression analysis, LAR was identified as an independent predictor for both OS [HR/95% CI: (1.930/1.554 to 2.398), p < 0.01] and DFS [HR/95% CI: (1.750/1.427 to 2.146), p < 0.01].
CONCLUSION
LAR emerged as an independent predictor not only for overall complications and major complications but also for both OS and DFS, highlighting its significance and deserving the attention of surgeons.
Topics: Humans; Colorectal Neoplasms; Lactate Dehydrogenases; Prognosis; Retrospective Studies; Serum Albumin, Human
PubMed: 37770882
DOI: 10.1186/s12885-023-11446-5 -
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 -
Hematology, Transfusion and Cell Therapy 2023Pre-apheresis peripheral blood CD34+ cell count (PBCD34+) is the most important predictor of good cell mobilization before hematopoietic stem cell transplantation,...
INTRODUCTION
Pre-apheresis peripheral blood CD34+ cell count (PBCD34+) is the most important predictor of good cell mobilization before hematopoietic stem cell transplantation, albeit flow cytometry is not always immediately available. Identification of surrogate markers can be useful. The CD34+ cells proliferate after mobilization, resulting in elevated lactate dehydrogenase (LDH) activity and correlating with the PBCD34+ count.
OBJECTIVE
To determine the LDH cut-off value at which adequate CD34+ cell mobilization is achieved and its diagnostic yield.
MATERIALS AND METHODS
A total of 103 patients who received an autologous stem cell transplantation (ASCT) between January 2015 and January 2020 were included. Demographic and laboratory characteristics were obtained, including complete blood count, pre-apheresis PBCD34+ and LDH levels. Receiver operating characteristic (ROC) curves were performed to identify the optimal serum LDH activity cut-off points for ≥ 2 and ≥ 4 × 10 cells/kg post-mobilization CD34+ count and their diagnostic yield.
RESULTS
A post-mobilization serum LDH cut-off value of 462 U/L yielded a sensitivity (Se) = 86.8% (positive predictive value [PPV] = 72.7%), a pre- and post-mobilization serum LDH difference cut-off value of 387 U/L, an Se = 45.7% (PPV = 97%) and an LDH ratio of 2.46, with an Se = 47.1% (PPV = 97%) for an optimal mobilization count (CD34+ ≥ 4 × 10).
CONCLUSION
The LDH measurement represents a fast and affordable way to predict PBCD34+ mobilization in cases where flow cytometry is not immediately available. According to the LDH diagnostic yield, it could be used as a surrogate marker in transplant centers, supporting the CD34+ count, which remains the gold standard.
PubMed: 36163321
DOI: 10.1016/j.htct.2022.07.007 -
International Immunopharmacology Sep 2023Accurate and rapid laboratory diagnosis of COVID-19 infection and its deterioration is one of the milestones of pandemic control. Therefore, this study aimed to compare...
BACKGROUND
Accurate and rapid laboratory diagnosis of COVID-19 infection and its deterioration is one of the milestones of pandemic control. Therefore, this study aimed to compare the diagnostic and prognostic accuracy of the mainly used laboratory biomarkers (WBCS, neutrophil and lymphocyte percentages, CRP, ferritin, IL-6, D-dimer, procalcitonin, and LDH) in the sera of severe COVID-19 Egyptian patients to assess the most appropriate biomarker used in severe COVID-19 patients.
METHODS
A total of 180 unvaccinated severe COVID-19 patients were enrolled in our study. Demographic data, hospitalization time, medical history, oxygen saturation, respiratory rate, oxygen supply, laboratory findings, and thorax tomography of the patients were obtained retrospectively from the hospital's electronic information system.
RESULTS
Our results revealed that the levels of neutrophil percentage, CRP, IL-6, PCT, and LDH were significantly increased while lymphocyte percentage was significantly decreased among nonsurvival severe COVID-19 patients when compared with survival ones. By using ROC curve analysis, IL-6, and LDH are the most sensitive and specific markers for the prediction of bad prognosis and mortality among severe COVID-19 patients with 100% and 93% sensitivity and 93.7% specificity; respectively. IL-6 and LDH showed significant correlations with the other parameters, which suggested their association with the severity of COVID-19.
CONCLUSION
By using survival severe COVID-19 patients as a control group, our results showed that blood neutrophil percentage, serum CRP, IL-6, PCT, and LDH were significantly increased in non-survivors as compared to survivors. As biomarkers, our results revealed that IL-6 and LDH are good predictors of mortality among severe COVID-19 patients.
Topics: Humans; COVID-19; Interleukin-6; Retrospective Studies; Biomarkers; Lactate Dehydrogenases; C-Reactive Protein; L-Lactate Dehydrogenase
PubMed: 37459785
DOI: 10.1016/j.intimp.2023.110626 -
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 -
Diagnosis (Berlin, Germany) Aug 2023Given the difficulty in the differential diagnosis of acute bacterial meningitis (BM) and viral meningitis (VM), we aimed to compare the ability of cerebrospinal fluid...
OBJECTIVES
Given the difficulty in the differential diagnosis of acute bacterial meningitis (BM) and viral meningitis (VM), we aimed to compare the ability of cerebrospinal fluid (CSF) biomarkers, such as lactate, glucose, lactate dehydrogenase (LDH), C-reactive protein (CRP), total white blood cell count, and predominance of neutrophils, as single tests to differentiate microbiologically defined acute BM and VM.
METHODS
CSF samples were divided into three groups: BM (n=17), VM (n=14) (both with the etiological agent identified), and normal control groups (n=26).
RESULTS
All the biomarkers studied were significantly higher in the BM group than in the VM or control groups (p>0.05). CSF lactate showed the best diagnostic clinical performance characteristics: sensitivity (94.12%), specificity (100%), positive and negative predictive value (100 and 97.56%, respectively), positive and negative likelihood ratio (38.59 and 0.06, respectively), accuracy (98.25%), and AUC (0.97). CSF CRP is excellent for screening BM and VM, as its best feature is its specificity (100%). CSF LDH is not recommended for screening or case-finding. LDH levels were higher in Gram-negative diplococcus than in Gram-positive diplococcus. Other biomarkers were not different between Gram-positive and negative bacteria. The highest level of agreement between the CSF biomarkers was between CSF lactate and CRP [kappa coefficient, 0.91 (0.79; 1.00)].
CONCLUSIONS
All markers showed significant differences between the studied groups and were increased in acute BM. CSF lactate is better than the other biomarkers studied for screening acute BM due to its high specificity.
Topics: Humans; Diagnosis, Differential; Meningitis; Biomarkers; C-Reactive Protein; Lactic Acid; L-Lactate Dehydrogenase
PubMed: 37023413
DOI: 10.1515/dx-2023-0013