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Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2023Reducing lactate accumulation has always been a goal of the mammalian cell biotechnology industry. When animal cells are cultured , the accumulation of lactate is mainly...
Reducing lactate accumulation has always been a goal of the mammalian cell biotechnology industry. When animal cells are cultured , the accumulation of lactate is mainly the combined result of two metabolic pathways. On one hand, glucose generates lactate under the function of lactate dehydrogenase A (LDHA); on the other hand, lactate can be oxidized to pyruvate by LDHB or LDHC and re-enter the TCA cycle. This study comprehensively evaluated the effects of LDH manipulation on the growth, metabolism and human adenovirus (HAdV) production of human embryonic kidney 293 (HEK-293) cells, providing a theoretical basis for engineering the lactate metabolism in mammalian cells. By knocking out gene and overexpression of and genes, the metabolic efficiency of HEK-293 cells was effectively improved, and HAdV production was significantly increased. Compared with the control cell, LDH manipulation promoted cell growth, reduced the accumulation of lactate and ammonia, significantly enhanced the efficiency of substrate and energy metabolism of cells, and significantly increased the HAdV production capacity of HEK-293 cells. Among these LDH manipulation measures, gene overexpression performed the best, with the maximum cell density increased by about 38.7%. The yield of lactate to glucose and ammonia to glutamine decreased by 33.8% and 63.3%, respectively; and HAdV titer increased by at least 16 times. In addition, the ATP production rate, ATP/O ratio, ATP/ADP ratio and NADH content of the modified cell lines were increased to varying degrees, and the energy metabolic efficiency was significantly improved.
Topics: Animals; Humans; L-Lactate Dehydrogenase; Lactic Acid; Adenoviruses, Human; Ammonia; HEK293 Cells; Glucose; Adenosine Triphosphate; Kidney; Mammals
PubMed: 37805860
DOI: 10.13345/j.cjb.220893 -
JTO Clinical and Research Reports Aug 2023There are no clinically validated prognostic biomarkers in the management of extensive-stage SCLC (ES-SCLC). We explored the association between clinical characteristics...
INTRODUCTION
There are no clinically validated prognostic biomarkers in the management of extensive-stage SCLC (ES-SCLC). We explored the association between clinical characteristics and survival outcomes in patients with ES-SCLC treated with chemoimmunotherapy.
METHODS
In this retrospective cohort study, patients with ES-SCLC treated with first-line platinum-etoposide chemotherapy and atezolizumab were identified from medical records. Pretreatment clinical characteristics, biochemical parameters, and tumor and treatment characteristics were collected. Univariate and multivariate Cox regression were used to evaluate treatment effect on progression-free survival (PFS) and overall survival (OS).
RESULTS
We evaluated 75 patients in total. The median PFS and OS were 6.1 months and 9.2 months, respectively. Statistically significant associations were found with lower lactate dehydrogenase and improved OS (hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 1.0-1.01, = 0.006), whereas higher age (HR = 0.94, 95% CI: 0.90-0.98, = 0.006) and lower neutrophil-to-lymphocyte ratio (HR = 1.08, 95% CI: 1.02-1.14, = 0.005) were associated with improved PFS. The number of chemotherapy cycles received were associated with both an improved PFS (HR = 0.57, 95% CI: 0.37-0.89, = 0.011) and OS (HR = 0.5, 95% CI: 0.30-0.84, = 0.008).
CONCLUSIONS
This study highlights the important effect of chemotherapy on survival. Furthermore, the association between lactate dehydrogenase and neutrophil-to-lymphocyte ratio on survival further suggests that baseline tumor burden and optimizing sarcopenia are important factors for clinicians to consider as we seek to develop personalized treatment for this disease.
PubMed: 37529402
DOI: 10.1016/j.jtocrr.2023.100544 -
Cellular Signalling Aug 2024Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies. Lactate dehydrogenase family genes (LDHs) play a critical role in tumor metabolism,...
BACKGROUND
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies. Lactate dehydrogenase family genes (LDHs) play a critical role in tumor metabolism, but their functions in HNSCC have not been investigated thoroughly. Thus, we aimed to explore the value of LDHs in HNSCC.
METHODS
The association between LDHs expression and mutations, methylation, copy number variations (CNVs), alternative splicing (AS) and competing endogenous RNA (ceRNA) was investigated in The Cancer Genome Atlas (TCGA). The expression level of LDHs in OSCC tissues and adjacent normal tissues was verified by qPCR. Algorithms, such as ssGSEA, ESTIMATE, xCell and TIDE were utilized to analyze the characteristics of immune infiltration. Pathway alternations were enriched by GO, GSEA and KEGG analysis. The Mantel test was employed to elucidate the correlation between metabolism and the tumor microenvironment (TME). Subsequently, MTT and colony formation assays were utilized to assess the impact of LDHB knockdown on cellular proliferation. Additionally, ATP and lactate assays were performed to examine metabolic alterations. Co-culture experiments further investigated the effect of LDHB knockdown on T cell differentiation.
RESULTS
LDHs were completely analyzed in multiple databases, among which LDHB was differentially expressed in HNSCC and significantly associated with prognosis. Low LDHB expression had better clinicopathological characteristics. Downregulated LDHB expression was associated with enhanced immune cell infiltration and could influence tumor metabolism. Despite having worse cytotoxic T lymphocyte dysfunction, the LDHB group was predicted to respond more favorably to immune checkpoint inhibitors (ICIs) therapy. Moreover, the correlation between metabolism and TME was depicted. In vitro, LDHB knockdown resulted in inhibited cell proliferation, increased lactate levels and decreased ATP levels, while promoted the Th1 differentiation of T cells.
CONCLUSIONS
Our study provided a comprehensive analysis of the LDHs and illustrated low LDHB expression could inhibit tumor cell proliferation and ATP production by influencing metabolism, with improved immune cell infiltration and better response to immunotherapy.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; L-Lactate Dehydrogenase; Immunotherapy; Head and Neck Neoplasms; Tumor Microenvironment; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Differentiation; Isoenzymes
PubMed: 38719019
DOI: 10.1016/j.cellsig.2024.111200 -
Journal of Personalized Medicine Apr 2024(1) Background: This study evaluates the predictive effectiveness of biomarkers in diagnosing newborn sepsis. (2) Methods: This was a case-control study conducted on...
(1) Background: This study evaluates the predictive effectiveness of biomarkers in diagnosing newborn sepsis. (2) Methods: This was a case-control study conducted on neonates hospitalized at the Clinical Hospital "Louis Turcanu", Timisoara, Romania, from October 2018 to July 2023. Using a vacutainer collection device, venous blood was collected at admission for complete blood tests, including ferritin, hemoglobin, LDH, and blood culture analysis. Neonates were divided into two groups: sepsis-positive and sepsis-negative. The outcome of interest was a diagnosis of sepsis. (3) Results: Data from 86 neonates, 51 of whom had been confirmed to have sepsis, were analyzed. This study found no significant difference in gestational age, infant weight, fetal growth restriction, or APGAR score between neonates with and without sepsis. However, there was a higher incidence of sepsis among neonates delivered via cesarean section. Neonatal patients with sepsis showed significantly higher levels of neonatal serum ferritin and LDH compared to those without sepsis. Ferritin and LDH biomarkers demonstrated excellent discriminatory capabilities in diagnosing neonatal sepsis. Logistic regression analysis revealed a significant association between elevated ferritin and LDH levels and the likelihood of neonatal sepsis, while anemia did not show a significant association. (4) Conclusions: LDH and ferritin concentrations are found to be predictive biomarkers for neonatal sepsis, indicating a potential role in detecting susceptible neonates and implementing prompt interventions to improve patient outcomes.
PubMed: 38793057
DOI: 10.3390/jpm14050476 -
Cancer Research Apr 2024Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML)....
UNLABELLED
Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.
SIGNIFICANCE
Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML. See related commentary by Boët and Sarry, p. 950.
Topics: Humans; Animals; Mice; Nuclear Proteins; Transcription Factors; Lactic Acid; Cell Line, Tumor; Leukemia, Myeloid, Acute; Lactate Dehydrogenases; Bromodomain Containing Proteins; Cell Cycle Proteins
PubMed: 38285895
DOI: 10.1158/0008-5472.CAN-23-0291 -
Frontiers in Immunology 2023Rapidly progressive interstitial lung disease (RP-ILD) is the most serious complication of anti-melanoma differentiation-associated gene 5-positive dermatomyositis...
Predictors of rapidly progressive interstitial lung disease and prognosis in Chinese patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis.
BACKGROUND
Rapidly progressive interstitial lung disease (RP-ILD) is the most serious complication of anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5 DM). This study was performed to assess the prognostic factors of patients with anti-MDA5 DM and the clinical characteristics and predictors of anti-MDA5 DM in combination with RP-ILD.
METHODS
In total, 73 MDA5 DM patients were enrolled in this study from March 2017 to December 2021. They were divided into survival and non-survival subgroups and non-RP-ILD and RP-ILD subgroups.
RESULTS
The lactate dehydrogenase (LDH) concentration and prognostic nutritional index (PNI) were independent prognostic factors in patients with anti-MDA5 DM: the elevated LDH was associated with increased mortality ( = 0.01), whereas the elevated PNI was associated with reduced mortality ( < 0.001). The elevated LDH was independent risk prognostic factor for patients with anti-MDA5 DM (HR 2.42, 95% CI: 1.02-4.83, p = 0.039), and the elevated PNI was independent protective prognostic factor (HR, 0.27; 95% CI, 0.08 - 0.94; = 0.039). Patients who had anti-MDA5 DM with RP-ILD had a significantly higher white blood cell count and LDH concentration than those without RP-ILD ( = 0.007 and = 0.019, respectively). In contrast, PNI was significantly lower in patients with RP-ILD than those without RP-ILD ( < 0.001). The white blood cell count and elevated LDH were independent and significant risk factors for RP-ILD (OR 1.54, 95% CI: 1.12 - 2.13, p = 0.009 and OR 8.68, 95% CI: 1.28 - 58.83, p = 0.027, respectively), whereas the lymphocyte was an independent protective factor (OR, 0.11; 95% CI, 0.01 - 0.81; = 0.03).
CONCLUSION
The elevated LDH and elevated PNI were independent prognostic factors for patients with anti-MDA5 DM. The elevated LDH was independent risk factor for RP-ILD. Patients with anti-MDA5 DM could benefit from the measurement of LDH and PNI, which are inexpensive and simple parameters that could be used for diagnosis as well as prediction of the extent of lung involvement and prognosis.
Topics: Humans; Dermatomyositis; East Asian People; Prognosis; L-Lactate Dehydrogenase; Lung Diseases, Interstitial; Cell Differentiation
PubMed: 37691917
DOI: 10.3389/fimmu.2023.1209282 -
Cureus Mar 2024Background Breast carcinoma has been the most prevalent cancer in women, with research-based evidence showing a significant rise in the incidence of cancer and related...
Background Breast carcinoma has been the most prevalent cancer in women, with research-based evidence showing a significant rise in the incidence of cancer and related morbidity and mortality in the Indian subcontinent. The predictive value of plasmatic lactate dehydrogenase (LDH) levels has been studied in breast cancer. Numerous studies have connected high LDH values to a poor prognosis, increased risk of incidence, recurrence, and associated mortality in patients with breast carcinoma. This study aimed to assess the clinical profile of breast carcinoma and determine the correlation of serum lactate dehydrogenase levels with the stage of the disease and assessment of high-risk features using histopathology and immunohistochemistry. Methods A total of 75 patients with carcinoma breast were enrolled for this study and classified into two groups: upfront surgery and post-adjuvant therapy. Serum LDH levels were estimated a day before the surgery (baseline) and on postoperative days 1, 7, 14, and 30. The clinical tumor, node, metastasis (cTNM) staging was correlated with pathological tumor, node, metastasis TNM (pTNM) staging and immunohistochemistry findings. Results The clinical characteristics of breast cancer, serum LDH levels, and stage of the disease were collected and analyzed. A significant decreasing trend was noted in LDH values post-op days, and statistically significant higher LDH values were noted in the triple-negative group, positive lymph nodes, and positive lymphovascular invasion patients. Conclusion Regularly elevated levels or an unanticipated rise in serum LDH might indicate poor outcomes. Hence, this non-specific enzyme marker can be suggested to be used routinely to assess disease outcomes.
PubMed: 38601401
DOI: 10.7759/cureus.55932 -
Cell Death & Disease Mar 2024Metabolic reprogramming, a hallmark of cancer, is closely associated with tumor development and progression. Changes in glycolysis play a crucial role in conferring...
Metabolic reprogramming, a hallmark of cancer, is closely associated with tumor development and progression. Changes in glycolysis play a crucial role in conferring radiation resistance to tumor cells. How radiation changes the glycolysis status of cancer cells is still unclear. Here we revealed the role of TAB182 in regulating glycolysis and lactate production in cellular response to ionizing radiation. Irradiation can significantly stimulate the production of TAB182 protein, and inhibiting TAB182 increases cellular radiosensitivity. Proteomic analysis indicated that TAB182 influences several vital biological processes, including multiple metabolic pathways. Knockdown of TAB182 results in decreased lactate production and increased pyruvate and ATP levels in cancer cells. Moreover, knocking down TAB182 reverses radiation-induced metabolic changes, such as radioresistant-related lactate production. TAB182 is necessary for activating LDHA transcription by affecting transcription factors SP1 and c-MYC; its knockdown attenuates the upregulation of LDHA by radiation, subsequently suppressing lactate production. Targeted suppression of TAB182 significantly enhances the sensitivity of murine xenograft tumors to radiotherapy. These findings advance our understanding of glycolytic metabolism regulation in response to ionizing radiation, which may offer significant implications for developing new strategies to overcome tumor radioresistance.
Topics: Humans; Animals; Mice; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Proteomics; Cell Line, Tumor; Glycolysis; Lactates; Radiation Tolerance
PubMed: 38480704
DOI: 10.1038/s41419-024-06588-8 -
International Journal of Biological... 2023Glycine decarboxylase (GLDC) is one of the core enzymes for glycine metabolism and its biological roles in prostate cancer (PCa) are unclear. First, we found that GLDC...
Glycine decarboxylase (GLDC) is one of the core enzymes for glycine metabolism and its biological roles in prostate cancer (PCa) are unclear. First, we found that GLDC plays a central role in glycolysis in 540 TCGA PCa patients. Subsequently, a metabolomic microarray showed that GLDC enhanced aerobic glycolysis in PCa cells, and GLDC and its enzyme activity enhanced glucose uptake, lactate production and lactate dehydrogenase (LDH) activity in PCa cells. Next, we found that GLDC was highly expressed in PCa, was directly regulated by hypoxia-inducible factor (HIF1-α) and regulated downstream LDHA expression. In addition, GLDC and its enzyme activity showed a strong ability to promote the migration and invasion of PCa both and . Furthermore, we found that the GLDC-high group had a higher TP53 mutation frequency, lower CD8+ T-cell infiltration, higher immune checkpoint expression, and higher immune exclusion scores than the GLDC-low group. Finally, the GLDC-based prognostic risk model by applying LASSO Cox regression also showed good predictive power for the clinical characteristics and survival in PCa patients. This evidence indicates that GLDC plays crucial roles in glycolytic metabolism, invasion and metastasis, and immune escape in PCa, and it is a potential therapeutic target for prostate cancer.
Topics: Male; Humans; Glycine Dehydrogenase (Decarboxylating); Glycolysis; Prostatic Neoplasms
PubMed: 37781511
DOI: 10.7150/ijbs.85893 -
Cell Death & Disease Jan 2024Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell...
Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.
Topics: Humans; Carcinoma, Renal Cell; Lactate Dehydrogenase 5; Phosphorylation; Cell Line, Tumor; Carcinoma; Kidney Neoplasms; Cell Proliferation; Gene Expression Regulation, Neoplastic; Tacrolimus Binding Proteins
PubMed: 38233415
DOI: 10.1038/s41419-024-06450-x