المؤلفون: Maryna Bondarenko, Marion Le Grand, Yuval Shaked, Ziv Raviv, Guillemette Chapuisat, Cécile Carrère, Marie-Pierre Montero, Mailys Rossi, Eddy Pasquier, Manon Carré, Nicolas André

المصدر: Cancers; Volume 13; Issue 9; Pages: 2239

مصطلحات موضوعية: metronomic chemotherapy, intratumor heterogeneity, mathematical modeling, non-small cell lung cancer, glycolytic activity, lactate dehydrogenase

الوصف: Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is a widely observed phenomenon in advanced cancers, mainly due to intratumor clonal heterogeneity. How tumor clones progress and impact each other remains elusive. In this study, we developed 2D and 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematical model to better understand clone dynamics. Our results demonstrated that the drug-sensitive clones inhibit the proliferation of the drug-resistant ones under untreated conditions. Model predictions and their experimental in vitro and in vivo validations indicated that a metronomic schedule leads to a better regulation of tumor cell heterogeneity over time than a maximum-tolerated dose schedule, while achieving control of tumor progression. We finally showed that drug-sensitive and -resistant clones exhibited different metabolic statuses that could be involved in controlling the intratumor heterogeneity dynamics. Our data suggested that the glycolytic activity of drug-sensitive clones could play a major role in inhibiting the drug-resistant clone proliferation. Altogether, these computational and experimental approaches provide foundations for using metronomic therapy to control drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism to manage intratumor heterogeneity.

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العلاقة: https://dx.doi.org/10.3390/cancers13092239Test

الإتاحة: https://doi.org/10.3390/cancers13092239Test

المؤلفون: Yueqi Wang, Liping Guo, Chunming Liu, Yuchi Zhang, Sainan Li

المصدر: Molecules; Volume 26; Issue 9; Pages: 2467

مصطلحات موضوعية: Inonotus obliquus, ultrafiltration, liquid chromatography, ultrasonic-assisted extraction, lactate dehydrogenase inhibitor, myocardial infarction

جغرافية الموضوع: agris

الوصف: Extracts of the fungus Inonotus obliquus exhibit cytotoxic properties against different cancers; hence, this fungal species has been extensively studied. This study aimed to extract total triterpenoids from Inonotus obliquus using ionic liquids (ILs) and separate potential lactate dehydrogenase (LDH) inhibitors via ultrafiltration (UF)-high-speed countercurrent chromatography (HSCCC). Total triterpenoids from Inonotus obliquus were extracted by performing a single-factor experiment and employing a central composite design via ultrasonic-assisted extraction (UAE) and heat-assisted extraction (HAE). The extract was composed of 1-butyl-3-methylimidazolium bromide as the IL and methanol as the dispersant. Ultrafiltration-liquid chromatography (UF-LC) was used to rapidly scan the LDH inhibitors and betulin and lanosterol were identified as potential inhibitors. To obtain these target compounds, betulin and lanosterol with the purities of 95.9% and 97.8% were isolated from HSCCC within 120 min. Their structures were identified using several techniques, among which IL-HAE was fast and effective. This study reports the extraction of triterpenoids from Inonotus obliquus by IL for the first time. Collectively, the findings demonstrate that UF-LC is an effective tool for screening potential LDH inhibitors from crude extracts of I. obliquus and may help to identify bioactive substances against myocardial infarction, whereas high-purity compounds can be separated via UF-HSCCC.

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العلاقة: https://dx.doi.org/10.3390/molecules26092467Test

الإتاحة: https://doi.org/10.3390/molecules26092467Test

المؤلفون: Ariadna Schuck, Hyo Eun Kim, Júlia Konzen Moreira, Priscila Schmidt Lora, Yong-Sang Kim

المصدر: Sensors; Volume 21; Issue 5; Pages: 1852

مصطلحات موضوعية: lactate, lactate dehydrogenase, graphene, field-effect transistor, biosensor

الوصف: Lactate is an important organic molecule that is produced in excess during anaerobic metabolism when oxygen is absent in the human organism. The concentration of this substance in the body can be related to several medical conditions, such as hemorrhage, respiratory failure, and ischemia. Herein, we describe a graphene-based lactate biosensor to detect the concentrations of L-lactic acid in different fluids (buffer solution and plasma). The active surface (graphene) of the device was functionalized with lactate dehydrogenase enzyme using different substances (Nafion, chitosan, and glutaraldehyde) to guarantee stability and increase selectivity. The devices presented linear responses for the concentration ranges tested in the different fluids. An interference study was performed using ascorbic acid, uric acid, and glucose, and there was a minimum variation in the Dirac point voltage during detection of lactate in any of the samples. The stability of the devices was verified at up to 50 days while kept in a dry box at room temperature, and device operation was stable until 12 days. This study demonstrated graphene performance to monitor L-lactic acid production in human samples, indicating that this material can be implemented in more simple and low-cost devices, such as flexible sensors, for point-of-care applications.

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العلاقة: Biosensors; https://dx.doi.org/10.3390/s21051852Test

الإتاحة: https://doi.org/10.3390/s21051852Test

المؤلفون: Edward V. Prochownik, Huabo Wang

المصدر: Cells; Volume 10; Issue 4; Pages: 762

مصطلحات موضوعية: anaplerosis, glutaminolysis, lactate dehydrogenase, malic enzyme, pyruvate carboxylase, TCA cycle, Warburg effect

الوصف: Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

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العلاقة: Cellular Pathology; https://dx.doi.org/10.3390/cells10040762Test

الإتاحة: https://doi.org/10.3390/cells10040762Test

المؤلفون: Gal Sapir, David Shaul, Naama Lev-Cohain, Jacob Sosna, Moshe J. Gomori, Rachel Katz-Brull

المصدر: Metabolites; Volume 11; Issue 4; Pages: 210

مصطلحات موضوعية: ischemic stroke, reperfusion, lactate dehydrogenase, pyruvate dehydrogenase, dissolution dynamic nuclear polarization, brain slices

الوصف: Ischemic stroke is a leading cause for neurologic disability worldwide, for which reperfusion is the only available treatment. Neuroimaging in stroke guides treatment, and therefore determines the clinical outcome. However, there are currently no imaging biomarkers for the status of the ischemic brain tissue. Such biomarkers could potentially be useful for guiding treatment in patients presenting with ischemic stroke. Hyperpolarized 13C MR of [1-13C]pyruvate is a clinically translatable method used to characterize tissue metabolism non-invasively in a relevant timescale. The aim of this study was to utilize hyperpolarized [1-13C]pyruvate to investigate the metabolic consequences of an ischemic insult immediately during reperfusion and upon recovery of the brain tissue. The rates of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) were quantified by monitoring the rates of [1-13C]lactate and [13C]bicarbonate production from hyperpolarized [1-13C]pyruvate. 31P NMR of the perfused brain slices showed that this system is suitable for studying ischemia and recovery following reperfusion. This was indicated by the levels of the high-energy phosphates (tissue viability) and the chemical shift of the inorganic phosphate signal (tissue pH). Acidification, which was observed during the ischemic insult, has returned to baseline level following reperfusion. The LDH/PDH activity ratio increased following ischemia, from 47.0 ± 12.7 in the control group (n = 6) to 217.4 ± 121.3 in the ischemia-reperfusion group (n = 6). Following the recovery period (ca. 1.5 h), this value had returned to its pre-ischemia (baseline) level, suggesting the LDH/PDH enzyme activity ratio may be used as a potential indicator for the status of the ischemic and recovering brain.

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العلاقة: Endocrinology and Clinical Metabolic Research; https://dx.doi.org/10.3390/metabo11040210Test

الإتاحة: https://doi.org/10.3390/metabo11040210Test

المؤلفون: Keun-Yeong Jeong, Jae-Jun Sim, Min Hee Park, Hwan Mook Kim

المصدر: Cancers; Volume 13; Issue 7; Pages: 1518

مصطلحات موضوعية: colorectal cancer, lactate calcium salt, anaerobic glycolysis, hypoxia, lactate dehydrogenase B, hypoxia-inducible factor

الوصف: Hypoxic cancer cells meet their growing energy requirements by upregulating glycolysis, resulting in increased glucose consumption and lactate production. Herein, we used a unique approach to change in anaerobic glycolysis of cancer cells by lactate calcium salt (CaLac). Human colorectal cancer (CRC) cells were used for the study. Intracellular calcium and lactate influx was confirmed following 2.5 mM CaLac treatment. The enzymatic activation of lactate dehydrogenase B (LDHB) and pyruvate dehydrogenase (PDH) through substrate reaction of CaLac was investigated. Changes in the intermediates of the tricarboxylic acid (TCA) cycle were confirmed. The cell viability assay, tube formation, and wound-healing assay were performed as well as the confirmation of the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). In vivo antitumor effects were evaluated using heterotopic and metastatic xenograft animal models with 20 mg/kg CaLac administration. Intracellular calcium and lactate levels were increased following CaLac treatment in CRC cells under hypoxia. Then, enzymatic activation of LDHB and PDH were increased. Upon PDH knockdown, α-ketoglutarate levels were similar between CaLac-treated and untreated cells, indicating that TCA cycle restoration was dependent on CaLac-mediated LDHB and PDH reactivation. CaLac-mediated remodeling of cancer-specific anaerobic glycolysis induced destabilization of HIF-1α and a decrease in VEGF expression, leading to the inhibition of the migration of CRC cells. The significant inhibition of CRC growth and liver metastasis by CaLac administration was confirmed. Our study highlights the potential utility of CaLac supplementation in CRC patients who display reduced therapeutic responses to conventional modes owing to the hypoxic tumor microenvironment.

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العلاقة: Cancer Therapy; https://dx.doi.org/10.3390/cancers13071518Test

الإتاحة: https://doi.org/10.3390/cancers13071518Test

المؤلفون: Piotr Kaczka, Katarzyna Kubicka, Amit Batra, Marcin Maciejczyk, Edyta Kopera, Justyna Bira, Tomasz Zając

المصدر: Nutrients; Volume 13; Issue 4; Pages: 1064

مصطلحات موضوعية: medium distance runners, β-hydroxy-β-methylbutyrate, HMB, Ca-HMB (calcium salt of HMB), L-Arginine α-ketoglutarate, AAKG, Arg, countermovement jump, creatine kinase, lactate dehydrogenase

جغرافية الموضوع: agris

الوصف: The aim of the study was to determine the effect of simultaneous supplementation of β-hydroxy-β-methylbutyrate and L-Arginine α-ketoglutarate on lower limb power and muscle damage in medium distance runners aged 15.3 (±0.9) years old. Methods: The study group consisted of 40 volunteers aged 14–17 years practicing medium distance running for at least two years. The study lasted 12 days and followed a randomized, double-blind, placebo-controlled, parallel design. All subjects attended a familiarization session on day 0 before the test. The subjects were randomly divided into two groups: supplements and placebo group. The same training cycle protocol was used in both groups during the 12-day training period. Morning warm-up involved 10 min jogging at 60–75% of maximal heart rate and countermovement jump height measurement. Main training units were carried out for both groups with the same volume. Training load assessment (the daily session Rating of Perceived Exertion (s-RPE) method) method takes into consideration the intensity and the duration of the training session to calculate the “training load” (TL). Results: At the end of the training cycle, a significant (p = 0.002) decrease in the countermovement jump (CMJ) height was found in the placebo group when compared to the baseline. In the supplement group, there was no decrease in the countermovement jump height. Creatine kinase and lactate dehydrogenase concentration increased during the training days similarly in both groups and decreased on rest days. There were no differences between groups in enzymes concentration. The research results indicate that the supplement combination used in the supplements group prevented a reduction in the CMJ values. In contrast to the supplements group, in the placebo group, the CMJ changes were statistically significant: a noticeable (p = 0.002) decrease in CMJ was noted between the baseline measurement and the 6th measurement. The well-being of the subjects from both groups changed significantly during the training period, ...

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العلاقة: Sports Nutrition; https://dx.doi.org/10.3390/nu13041064Test

الإتاحة: https://doi.org/10.3390/nu13041064Test

المؤلفون: Naama Lev-Cohain, Gal Sapir, Sivaranjan Uppala, Atara Nardi-Schreiber, Shraga Goldberg, Yael Adler-Levy, Jacob Sosna, J. Gomori, Rachel Katz-Brull

المصدر: Sci; Volume 3; Issue 1; Pages: 8

مصطلحات موضوعية: lactate dehydrogenase, alanine transaminase, MDR2 knockout, dissolution dynamic nuclear polarization, perfused precision cut liver slices

الوصف: The clinical characterization of small hepatocellular carcinoma (HCC) lesions in the liver and differentiation from heterogeneous inflammatory or fibrotic background is important for early detection and treatment. Metabolic monitoring of hyperpolarized 13C-labeled substrates has been suggested as a new avenue for diagnostic magnetic resonance. The metabolism of hyperpolarized [1-13C]pyruvate was monitored in mouse precision-cut liver slices (PCLS) of aged MDR2-KO mice, which served as a model for heterogeneous liver and HCC that develops similarly to the human disease. The relative in-cell activities of lactate dehydrogenase (LDH) to alanine transaminase (ALT) were found to be 0.40 ± 0.06 (n = 3) in healthy livers (from healthy mice), 0.90 ± 0.27 (n = 3) in heterogeneously inflamed liver, and 1.84 ± 0.46 (n = 3) in HCC. Thus, the in-cell LDH/ALT activities ratio was found to correlate with the progression of the disease. The results suggest that the LDH/ALT activities ratio may be useful in the assessment of liver disease. Because the technology used here is translational to both small liver samples that may be obtained from image-guided biopsy (i.e., ex vivo investigation) and to the intact liver (i.e., in a noninvasive MRI scan), these results may provide a path for differentiating heterogeneous liver from HCC in human subjects.

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العلاقة: https://dx.doi.org/10.3390/sci3010008Test

الإتاحة: https://doi.org/10.3390/sci3010008Test

المؤلفون: Maria Dolores Moya-Garzon, Jose Antonio Gomez-Vidal, Alfonso Alejo-Armijo, Joaquin Altarejos, Juan Roberto Rodriguez-Madoz, Miguel Xavier Fernandes, Eduardo Salido, Sofia Salido, Monica Diaz-Gavilan

المصدر: Journal of Personalized Medicine; Volume 11; Issue 2; Pages: 74

مصطلحات موضوعية: hyperoxaluria, oxalate, inhibitor, small molecule drug, glycolate oxidase, lactate dehydrogenase, liver selective distribution

الوصف: Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

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العلاقة: Mechanisms of Diseases; https://dx.doi.org/10.3390/jpm11020074Test

الإتاحة: https://doi.org/10.3390/jpm11020074Test

المؤلفون: Subir Roy Chowdhury, Cheryl Peltier, Sen Hou, Amandeep Singh, James B. Johnston, Spencer B. Gibson, Aaron J. Marshall, Versha Banerji

المصدر: Cancers; Volume 13; Issue 2; Pages: 354

مصطلحات موضوعية: mitochondrial respiration, chronic lymphocytic leukemia (CLL), B-cell receptor (BCR), ibrutinib (IB), Bruton tyrosine kinase (BTK) inhibitor, plasma chemokine (C-C motif) ligands 3 and 4 (CCL3 and CCL4), β-2 microglobulin (β-2 M), lactate dehydrogenase (LDH)

الوصف: Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or the effect of progression on ibrutinib treatment on respiration of CLL cells. We evaluated the impact of low and standard dose ibrutinib on CLL cells from patients treated in vivo on mitochondrial respiration using Oroboros oxygraph. Cytokines CCL3 and CCL4 were evaluated using the Mesoscale. Western blot analysis was used to evaluate the BCR and apoptotic pathways. We observed no difference in the mitochondrial respiration rates or levels of plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4), β-2 microglobulin (β-2 M) and lactate dehydrogenase (LDH) between low and standard doses of ibrutinib. This may confirm why clinical observations of the safety and efficacy of low dose ibrutinib are observed in practice. Of interest, we also observed that the mitochondrial respiration of CLL cells paralleled the increase in β-2 M and LDH at progression. Our study further supports mitochondrial respiration as a biomarker for response and progression on ibrutinib in CLL cells and a valuable pre-clinical tool.

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العلاقة: Cancer Therapy; https://dx.doi.org/10.3390/cancers13020354Test

الإتاحة: https://doi.org/10.3390/cancers13020354Test