bims-glucam 2024-09-29 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–09–29
eightteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.
Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.
Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates.
Glutamine transporters as effective targets in digestive system malignant tumor treatment.
Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
Spliceosomal vulnerability of MYCN-amplified neuroblastoma is contingent on PRMT5-mediated regulation of epitranscriptomic and metabolomic pathways.
Identifying targetable metabolic dependencies across colorectal cancer progression.
New Metabolomic Insights Into Cancer.
IDH2 and GLUD1 depletion arrests embryonic development through an H4K20me3 epigenetic barrier in porcine parthenogenetic embryos.
Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.
Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis.
Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells.
Integrating HRMAS-NMR Data and Machine Learning-Assisted Profiling of Metabolite Fluxes to Classify Low- and High-Grade Gliomas.
Glutamine promotes the proliferation of intestinal stem cells via inhibition of TP53-induced glycolysis and apoptosis regulator promoter methylation in burned mice.
NRF2 Activation by AR-20007 Preserves Renal Tubular Epithelial Cells from Antimycin A-Induced Cell Death via Glutathione Metabolism Regulation.
Metabolic reprogramming of macrophages in cancer therapy.
Implementation of Machine Learning-Based System for Early Diagnosis of Feline Mammary Carcinomas through Blood Metabolite Profiling.
Metabolic regulation in normal and leukemic stem cells.

Cells. 2024 Sep 19. pii: 1574. [Epub ahead of print]13(18):

Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.

Ashley Irin Cortes Ballen, Maryam Amosu, Surya Ravinder, Joey Chan, Emre Derin, Hasan Slika, Betty Tyler.

  Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

Keywords:  Warburg effect; glioblastoma multiforme; glycolysis; metabolic reprogramming; therapeutic drugs; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13181574
Sci Adv. 2024 Sep 20. 10(38): eadn2806

Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.

Carlos Galvan, Aimee A Flores, Victoria Cerrilos, Itzetl Avila, Conor Murphy, Wilson Zheng, Heather R Christofk, William E Lowry.

We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC)-initiating cells had no effect on tumorigenesis, despite the perceived requirement of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here, we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin. Genetic deletion of GLS had little effect on tumorigenesis due to the up-regulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We went on to show that posttranscriptional regulation of nutrient transporters appears to mediate metabolic flexibility in this SCC model. To define the limits of this flexibility, we genetically blocked both glycolysis and glutaminolysis simultaneously and found the abrogation of both of these carbon utilization pathways was enough to prevent both papilloma and frank carcinoma.

DOI: https://doi.org/10.1126/sciadv.adn2806
Infect Immun. 2024 Sep 26. e0028424

Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates.

Savannah E Sanchez, Travis J Chiarelli, Margaret A Park, Jason A Carlyon.

  Orientia tsutsugamushi a causal agent of scrub typhus, is an obligate intracellular bacterium that, akin to other rickettsiae, is dependent on host cell-derived nutrients for survival and thus pathogenesis. Based on limited experimental evidence and genome-based in silico predictions, O. tsutsugamushi is hypothesized to parasitize host central carbon metabolism (CCM). Here, we (re-)evaluated O. tsutsugamushi dependency on host cell CCM as initiated by glucose and glutamine. Orientia infection had no effect on host glucose and glutamine consumption or lactate accumulation, indicating no change in overall flux through CCM. However, host cell mitochondrial activity and ATP levels were reduced during infection and correspond with lower intracellular glutamine and glutamate pools. To further probe the essentiality of host CCM in O. tsutsugamushi proliferation, we developed a minimal medium for host cell cultivation and paired it with chemical inhibitors to restrict the intermediates and processes related to glucose and glutamine metabolism. These conditions failed to negatively impact O. tsutsugamushi intracellular growth, suggesting the bacterium is adept at scavenging from host CCM. Accordingly, untargeted metabolomics was utilized to evaluate minor changes in host CCM metabolic intermediates across O. tsutsugamushi infection and revealed that pathogen proliferation corresponds with reductions in critical CCM building blocks, including amino acids and TCA cycle intermediates, as well as increases in lipid catabolism. This study directly correlates O. tsutsugamushi proliferation to alterations in host CCM and identifies metabolic intermediates that are likely critical for pathogen fitness.IMPORTANCEObligate intracellular bacterial pathogens have evolved strategies to reside and proliferate within the eukaryotic intracellular environment. At the crux of this parasitism is the balance between host and pathogen metabolic requirements. The physiological basis driving O. tsutsugamushi dependency on its mammalian host remains undefined. By evaluating alterations in host metabolism during O. tsutsugamushi proliferation, we discovered that bacterial growth is independent of the host's nutritional environment but appears dependent on host gluconeogenic substrates, including amino acids. Given that O. tsutsugamushi replication is essential for its virulence, this study provides experimental evidence for the first time in the post-genomic era of metabolic intermediates potentially parasitized by a scrub typhus agent.

Keywords:  Orientia tsutsugamushi; Rickettsiales; amino acid parasitism; central carbon metabolism; intracellular pathogen; nutrient parasitism; obligate intracellular bacterium; rickettsial disease; scrub typhus; untargeted metabolomics

DOI:  https://doi.org/10.1128/iai.00284-24
Oncol Res. 2024 ;32(10): 1661-1671

Glutamine transporters as effective targets in digestive system malignant tumor treatment.

Fei Chu, Kai Tong, Xiang Gu, Mei Bao, Yanfen Chen, Bin Wang, Yanhua Shao, Ling Wei.

  Glutamine is one of the most abundant non-essential amino acids in human plasma and plays a crucial role in many biological processes of the human body. Tumor cells take up a large amount of glutamine to meet their rapid proliferation requirements, which is supported by the upregulation of glutamine transporters. Targeted inhibition of glutamine transporters effectively inhibits cell growth and proliferation in tumors. Among all cancers, digestive system malignant tumors (DSMTs) have the highest incidence and mortality rates, and the current therapeutic strategies for DSMTs are mainly surgical resection and chemotherapy. Due to the relatively low survival rate and severe side effects associated with DSMTs treatment, new treatment strategies are urgently required. This article summarizes the glutamine transporters involved in DSMTs and describes their role in DSMTs. Additionally, glutamine transporter-target drugs are discussed, providing theoretical guidance for the further development of drugs DSMTs treatment.

Keywords:  Cancer; Glutamine transporter; Inhibitors; Targeted therapy

DOI:  https://doi.org/10.32604/or.2024.048287
Cell Rep. 2024 Sep 20. pii: S2211-1247(24)01126-4. [Epub ahead of print]43(10): 114775

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.

Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani.

  Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges to identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens and by performing genetic and pharmacological experiments. Our analysis uncovers synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

Keywords:  CP: Cancer; CP: Metabolism; PTEN; cancer metabolism; cancer therapies; glioma; metabolic state vulnerabilities; mitochondrial electron transport chain; multivariate modeling; oxidative phosphorylation; synthetic lethality

DOI:  https://doi.org/10.1016/j.celrep.2024.114775
Cancer Lett. 2024 Sep 21. pii: S0304-3835(24)00658-X. [Epub ahead of print] 217263

Spliceosomal vulnerability of MYCN-amplified neuroblastoma is contingent on PRMT5-mediated regulation of epitranscriptomic and metabolomic pathways.

Jodie Bojko, Madhu Kollareddy, Marianna Szemes, Jacob Bellamy, Evon Poon, Ahmad Moukachar, Danny Legge, Emma E Vincent, Nicholas Jones, Sally Malik, Alex Greenhough, Alex Paterson, Ji Hyun Park, Kelli Gallacher, Louis Chesler, Karim Malik.

Approximately 50% of poor prognosis neuroblastomas arise due to MYCN over-expression. We previously demonstrated that MYCN and PRMT5 proteins interact and PRMT5 knockdown led to apoptosis of MYCN amplified (MNA) neuroblastoma. Here we evaluate the highly selective first-in-class PRMT5 inhibitor GSK3203591 and its in vivo analogue GSK3326593 as targeted therapeutics for MNA neuroblastoma. Cell-line analyses show MYCN-dependent growth inhibition and apoptosis, with approximately 200-fold greater sensitivity of MNA neuroblastoma lines. RNA sequencing of three MNA neuroblastoma lines treated with GSK3203591 reveal deregulated MYCN transcriptional programmes and altered mRNA splicing, converging on key regulatory pathways such as DNA damage response, epitranscriptomics and cellular metabolism. Stable isotope labelling experiments in the same cell lines demonstrate that glutamine metabolism is impeded following GSK3203591 treatment, linking with disruption of the MLX/Mondo nutrient sensors via intron retention of MLX mRNA. Interestingly, glutaminase (GLS) protein decreases after GSK3203591 treatment despite unchanged transcript levels. We demonstrate that the RNA methyltransferase METTL3 and cognate reader YTHDF3 proteins are lowered following their mRNAs undergoing GSK3203591-induced splicing alterations, indicating epitranscriptomic regulation of GLS; accordingly, we observe decreases of GLS mRNA m6A methylation following GSK3203591 treatment, and decreased GLS protein following YTHDF3 knockdown. In vivo efficacy of GSK3326593 is confirmed by increased survival of Th-MYCN mice, with drug treatment triggering splicing events and protein decreases consistent with in vitro data. Together our study demonstrates the PRMT5-dependent spliceosomal vulnerability of MNA neuroblastoma and identifies the epitranscriptome and glutamine metabolism as critical determinants of this sensitivity.

DOI: https://doi.org/10.1016/j.canlet.2024.217263
Mol Metab. 2024 Sep 25. pii: S2212-8778(24)00168-6. [Epub ahead of print] 102037

Identifying targetable metabolic dependencies across colorectal cancer progression.

Danny N Legge, Tracey J Collard, Ewelina Stanko, Ashley J Hoskin, Amy K Holt, Caroline J Bull, Madhu Kollareddy, Jake Bellamy, Sarah Groves, Eric H Ma, Emma Hazelwood, David Qualtrough, Borko Amulic, Karim Malik, Ann C Williams, Nicholas Jones, Emma E Vincent.

  Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system - comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

Keywords:  Colorectal cancer; adenocarcinoma; adenoma; asparagine; asparagine synthetase; oncometabolism

DOI:  https://doi.org/10.1016/j.molmet.2024.102037
Cancer J. 2024 Sep-Oct 01;30(5):30(5): 301-306

New Metabolomic Insights Into Cancer.

Jiangjiang Zhu.

ABSTRACT: Cancer has been marked by metabolic irregularities that fuel various aggressive activities such as rapid cell proliferation, evasion of the immune system, and spread to distant organs. Therefore, exploiting cancer metabolism for diagnosis, monitoring, or treatment has been extensively studied in the past couple of decades with various molecular and cellular techniques. More recently, investigating cancer diagnostics and treatments through advanced metabolomics has emerged, and these comprehensive approaches provide a holistic understanding of cancer metabolism, which supported the discovery of metabolic targets relevant across multiple cancer types and the development of more effective treatments. This study offers highlights of new knowledge on cancer metabolism enabled by recent metabolomics studies and their potential applications in aiding cancer research and predicting cancer treatment outcomes. Specifically, we discussed the use of advanced metabolomics in cancer metabolism, tumor microenvironment, and cancer immunotherapy studies to provide valuable insights that can shape future research efforts in the dynamic field of cancer metabolism research.

DOI: https://doi.org/10.1097/PPO.0000000000000740
Zool Res. 2024 Nov 18. pii: 2095-8137(2024)06-1175-13. [Epub ahead of print]45(6): 1175-1187

IDH2 and GLUD1 depletion arrests embryonic development through an H4K20me3 epigenetic barrier in porcine parthenogenetic embryos.

Cheng-Lin Zhan, Qin-Yue Lu, Song-Hee Lee, Xiao-Han Li, Ji-Dam Kim, Gyu-Hyun Lee, Jae-Min Sim, Hyeon-Ji Song, Ying-Yan Jin, Xiang-Shun Cui.

  Isocitrate dehydrogenase 2 (IDH2) and glutamate dehydrogenase 1 (GLUD1) are key enzymes involved in the production of α-ketoglutarate (α-KG), a metabolite central to the tricarboxylic acid cycle and glutamine metabolism. In this study, we investigated the impact of IDH2 and GLUD1 on early porcine embryonic development following IDH2 and GLUD1 knockdown (KD) via double-stranded RNA (dsRNA) microinjection. Results showed that KD reduced α-KG levels, leading to delayed embryonic development, decreased blastocyst formation, increased apoptosis, reduced blastomere proliferation, and pluripotency. Additionally, IDH2 and GLUD1 KD induced abnormally high levels of trimethylation of lysine 20 of histone H4 (H4K20me3) at the 4-cell stage, likely resulting in transcriptional repression of embryonic genome activation (EGA)-related genes. Notably, KD of lysine methyltransferase 5C ( KMT5C) and supplementation with exogenous α-KG reduced H4K20me3 expression and partially rescued these defects, suggesting a critical role of IDH2 and GLUD1 in the epigenetic regulation and proper development of porcine embryos. Overall, this study highlights the significance of IDH2 and GLUD1 in maintaining normal embryonic development through their influence on α-KG production and subsequent epigenetic modifications.

Keywords:  A-ketoglutarate; Embryonic development; GLUD1; H4K20me3; IDH2

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2024.219
Free Radic Res. 2024 Sep 24. 1-24

Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.

Junichi Fujii.

  The production of reactive oxygen species (ROS) is elevated via metabolic hyperactivation in response to a variety of stimuli such as growth factors and inflammation. Tolerable amounts of ROS moderately inactivate enzymes via oxidative modification, which can be reversed back to the native form in a redox-dependent manner. The excessive production of ROS, however, causes cell dysfunction and death. Redox-reactive enzymes are present in primary metabolic pathways such as glycolysis and the tricarboxylic acid cycle, and these act as floodgates for carbon flux. Oxidation of a specific form of cysteine inhibits glyceraldehyde-3-phosphate dehydrogenase, which is reversible, and causes an accumulation of upstream intermediary compounds that increases the flux of glucose-6-phosphate to the pentose phosphate pathway. These reactions increase the NADPH and ribose-5-phosphate that are available for reductive reactions and nucleotide synthesis, respectively. On the other hand, oxidative inactivation of mitochondrial aconitase increases citrate, which is then recruited to synthesize fatty acids in the cytoplasm. Decreases in the use of carbohydrate for ATP production can be compensated via amino acid catabolism, and this metabolic change makes nitrogen available for nucleic acid synthesis. Coupling of the urea cycle also converts nitrogen to urea and polyamine, the latter of which supports cell growth. This metabolic remodeling stimulates the proliferation of tumor cells and fibrosis in oxidatively damaged tissues. Oxidative modification of these enzymes is generally reversible in the early stages of oxidizing reactions, which suggests that early treatment with appropriate antioxidants promotes the maintenance of natural metabolism.

Keywords:  Glycolysis; TCA cycle; metabolic remodeling; reactive sulfhydryl; urea cycle

DOI:  https://doi.org/10.1080/10715762.2024.2407147
JCI Insight. 2024 Aug 13. pii: e178453. [Epub ahead of print]9(18):

Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis.

Greg Contento, Jo-Anne Am Wilson, Brintha Selvarajah, Manuela Platé, Delphine Guillotin, Valle Morales, Marcello Trevisani, Vanessa Pitozzi, Katiuscia Bianchi, Rachel C Chambers.

  Fibrosis is a chronic disease characterized by excessive extracellular matrix production, which leads to disruption of organ function. Fibroblasts are key effector cells of this process, responding chiefly to the pleiotropic cytokine transforming growth factor-β1 (TGF-β1), which promotes fibroblast to myofibroblast differentiation. We found that extracellular nutrient availability profoundly influenced the TGF-β1 transcriptome of primary human lung fibroblasts and that biosynthesis of amino acids emerged as a top enriched TGF-β1 transcriptional module. We subsequently uncovered a key role for pyruvate in influencing glutaminase (GLS1) inhibition during TGF-β1-induced fibrogenesis. In pyruvate-replete conditions, GLS1 inhibition was ineffective in blocking TGF-β1-induced fibrogenesis, as pyruvate can be used as the substrate for glutamate and alanine production via glutamate dehydrogenase (GDH) and glutamic-pyruvic transaminase 2 (GPT2), respectively. We further show that dual targeting of either GPT2 or GDH in combination with GLS1 inhibition was required to fully block TGF-β1-induced collagen synthesis. These findings embolden a therapeutic strategy aimed at additional targeting of mitochondrial pyruvate metabolism in the presence of a glutaminolysis inhibitor to interfere with the pathological deposition of collagen in the setting of pulmonary fibrosis and potentially other fibrotic conditions.

Keywords:  Cell biology; Collagens; Fibrosis; Glucose metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.178453
Traffic. 2024 Sep;25(9): e12956

Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells.

Aliye Ezgi Güleç Taşkıran, Hepşen H Hüsnügil, Zahra E Soltani, Göksu Oral, Nazlı S Menemenli, Chuanpit Hampel, Kerstin Huebner, Katharina Erlenbach-Wuensch, Ilir Sheraj, Regine Schneider-Stock, Aytekin Akyol, Nalan Liv, Sreeparna Banerjee.

  Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.

Keywords:  Rab7a; chemoresponse; drug trapping; lysosome; nutrient limitation

DOI:  https://doi.org/10.1111/tra.12956
Interdiscip Sci. 2024 Sep 27.

Integrating HRMAS-NMR Data and Machine Learning-Assisted Profiling of Metabolite Fluxes to Classify Low- and High-Grade Gliomas.

Safia Firdous, Zubair Nawaz, Rizwan Abid, Leo L Cheng, Syed Ghulam Musharraf, Saima Sadaf.

  Diagnosing and classifying central nervous system tumors such as gliomas or glioblastomas pose a significant challenge due to their aggressive and infiltrative nature. However, recent advancements in metabolomics and magnetic resonance spectroscopy (MRS) offer promising avenues for differentiating tumor grades both in vivo and ex vivo. This study aimed to explore tissue-based metabolic signatures to classify/distinguish between low- and high-grade gliomas. Forty-six histologically confirmed, intact solid tumor samples from glioma patients were analyzed using high-resolution magic angle spinning nuclear magnetic resonance (HRMAS-NMR) spectroscopy. By integrating machine learning (ML) algorithms, spectral regions with the most discriminative potential were identified. Validation was performed through univariate and multivariate statistical analyses, along with HRMAS-NMR analyses of 46 paired plasma samples. Amongst the various ML models applied, the logistics regression identified 46 spectral regions capable of sub-classifying gliomas with accuracy 87% (F1-measure 0.87, Precision 0.82, Recall 0.93), whereas the extra-tree classifier identified three spectral regions with predictive accuracy of 91% (F1-measure 0.91, Precision 0.85, Recall 0.97). Wilcoxon test presented 51 spectral regions significantly differentiating low- and high-grade glioma groups (p < 0.05). Based on sensitivity and area under the curve values, 40 spectral regions corresponding to 18 metabolites were considered as potential biomarkers for tissue-based glioma classification and amongst these N-acetyl aspartate, glutamate, and glutamine emerged as the most important markers. These markers were validated in paired plasma samples, and their absolute concentrations were computed. Our results demonstrate that the metabolic markers identified through the HRMAS-NMR-ML analysis framework, and their associated metabolic networks, hold promise for targeted treatment planning and clinical interventions in the future.

Keywords:  Gliomas; HRMAS-NMR; High-grade glioma; Machine learning; Metabolic fingerprinting; Metabolites

DOI:  https://doi.org/10.1007/s12539-024-00642-x
Burns Trauma. 2024 ;12 tkae045

Glutamine promotes the proliferation of intestinal stem cells via inhibition of TP53-induced glycolysis and apoptosis regulator promoter methylation in burned mice.

Panyang Zhang, Dan Wu, Xule Zha, Sen Su, Yajuan Zhang, Yan Wei, Lin Xia, Shijun Fan, Xi Peng.

   Background: Intestinal stem cells (ISCs) play a pivotal role in maintaining intestinal homeostasis and facilitating the restoration of intestinal mucosal barrier integrity. Glutamine (Gln) is a crucial energy substrate in the intestine, promoting the proliferation of ISCs and mitigating damage to the intestinal mucosal barrier after burn injury. However, the underlying mechanism has not yet been fully elucidated. The objective of this study was to explore the mechanism by which Gln facilitates the proliferation of ISCs.
Methods: A mouse burn model was established to investigate the impact of Gln on intestinal function. Subsequently, crypts were isolated, and changes in TP53-induced glycolysis and apoptosis regulator (TIGAR) expression were assessed using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, immunohistochemistry, and immunofluorescence. The effects of TIGAR on cell proliferation were validated through CCK-8, EdU, and clonogenicity assays. Furthermore, the effect of TIGAR on Yes-associated protein (YAP) nuclear translocation and ferroptosis was examined by western blotting and immunofluorescence staining. Finally, dot blot analysis and methylation-specific PCR were performed to evaluate the effect of Gln on TIGAR promoter methylation.
Results: The mRNA and protein levels of TIGAR decreased after burn injury, and supplementation with Gln increased the expression of TIGAR. TIGAR accelerates the nuclear translocation of YAP, thereby increasing the proliferation of ISCs. Concurrently, TIGAR promotes the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione to suppress ferroptosis in ISCs. Subsequent investigations demonstrated that Gln inhibits TIGAR promoter methylation by increasing the expression of the demethylase ten-eleven translocation. This change increased TIGAR transcription, increased NADPH synthesis, and reduced oxidative stress, thereby facilitating the restoration of intestinal mucosal barrier integrity post-burn injury.
Conclusions: Our data confirmed the inhibitory effect of Gln on TIGAR promoter methylation, which facilitates YAP translocation into the nucleus and suppresses ferroptosis, ultimately promoting the proliferation of ISCs.

Keywords:  Burn injury; Ferroptosis; Glutamine; Intestinal stem cells; Methylation; Proliferation; TP53-induced glycolysis and apoptosis regulator

DOI:  https://doi.org/10.1093/burnst/tkae045
Biol Pharm Bull. 2024 ;47(9): 1557-1564

NRF2 Activation by AR-20007 Preserves Renal Tubular Epithelial Cells from Antimycin A-Induced Cell Death via Glutathione Metabolism Regulation.

Jian Yoo, Jeyun Jo, Sugyeong Ha, Jinsook Kwak, Mi-Jeong Kim, Jeongwon Kim, Hwiyeong Lee, Doyeon Kim, Byeong Moo Kim, Jisu Kim, Hwayoung Yun, Minseob Koh, Ki Wung Chung.

  Oxidative stress plays a crucial role in the development and progression of various kidney diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is the primary transcription factor that protects cells from oxidative stress by regulating cytoprotective genes including those involved in the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and cell death. Antimycin A, an inhibitor of complex III of the electron transport chain, causes oxidative stress and reduces GSH levels. In this study, we induced mitochondrial damage in rat renal proximal tubular cells using antimycin A and investigated cellular viability and levels of NRF2 and GSH. Treatment with antimycin A altered the expression of antioxidant genes, including reduction in the transcription of glutathione-cysteine ligase subunits (Gclc and Gclm) and glutathione reductase (Gsr1), followed by a reduction in total GSH content with a concomitant decrease in NRF2 protein expression. AR-20007, previously described as an NRF2 activator, stabilizes and increases NRF2 protein expression in cells. By stimulating NRF2, AR-20007 increased the expression of antioxidant and detoxifying enzymes, thereby enhancing protection against oxidative stress induced by antimycin A. These data suggest that NRF2 activation effectively inhibits antimycin A-induced oxidative stress and that NRF2 may be a promising therapeutic target for preventing cell death during acute kidney injury.

Keywords:  AR-20007; antimycin A; glutathione (GSH); nuclear factor erythroid 2-related factor 2 (NRF2); oxidative stress

DOI:  https://doi.org/10.1248/bpb.b24-00295
Trends Endocrinol Metab. 2024 Sep 19. pii: S1043-2760(24)00244-3. [Epub ahead of print]

Metabolic reprogramming of macrophages in cancer therapy.

Xudong Wang, Shaolong Zhang, Dixuan Xue, Dante Neculai, Jin Zhang.

  Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.

Keywords:  cancer therapy; macrophage; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tem.2024.08.009
Metabolites. 2024 Sep 17. pii: 501. [Epub ahead of print]14(9):

Implementation of Machine Learning-Based System for Early Diagnosis of Feline Mammary Carcinomas through Blood Metabolite Profiling.

Vidhi Kulkarni, Igor F Tsigelny, Valentina L Kouznetsova.

  Background: Feline mammary carcinoma (FMC) is a prevalent and fatal carcinoma that predominantly affects unspayed female cats. FMC is the third most common carcinoma in cats but is still underrepresented in research. Current diagnosis methods include physical examinations, imaging tests, and fine-needle aspiration. The diagnosis through these methods is sometimes delayed and unreliable, leading to increased chances of mortality. Objectives: The objective of this study was to identify the biomarkers, including blood metabolites and genes, related to feline mammary carcinoma, study their relationships, and develop a machine learning (ML) model for the early diagnosis of the disease. Methods: We analyzed the blood metabolites of felines with mammary carcinoma using the pathway analysis feature in MetaboAnalyst software, v. 5.0. We utilized machine-learning (ML) methods to recognize FMC using the blood metabolites of sick patients. Results: The metabolic pathways that were elucidated to be associated with this disease include alanine, aspartate and glutamate metabolism, Glutamine and glutamate metabolism, Arginine biosynthesis, and Glycerophospholipid metabolism. Furthermore, we also elucidated several genes that play a significant role in the development of FMC, such as ERBB2, PDGFA, EGFR, FLT4, ERBB3, FIGF, PDGFC, PDGFB through STRINGdb, a database of known and predicted protein-protein interactions, and MetaboAnalyst 5.0. The best-performing ML model was able to predict metabolite class with an accuracy of 85.11%. Conclusion: Our findings demonstrate that the identification of the biomarkers associated with FMC and the affected metabolic pathways can aid in the early diagnosis of feline mammary carcinoma.

Keywords:  early diagnosis; feline mammary cancer; machine learning; metabolomics

DOI:  https://doi.org/10.3390/metabo14090501
Trends Pharmacol Sci. 2024 Sep 20. pii: S0165-6147(24)00166-4. [Epub ahead of print]

Metabolic regulation in normal and leukemic stem cells.

Cheuk-Him Man, Changzheng Li, Xi Xu, Meng Zhao.

  Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are crucial for ensuring hematopoietic homeostasis and driving leukemia progression, respectively. Recent research has revealed that metabolic adaptations significantly regulate the function and survival of these stem cells. In this review, we provide an overview of how metabolic pathways regulate oxidative and proteostatic stresses in HSCs during homeostasis and aging. Furthermore, we highlight targetable metabolic pathways and explore their interactions with epigenetics and the microenvironment in addressing the chemoresistance and immune evasion capacities of LSCs. The metabolic differences between HSCs and LSCs have profound implications for therapeutic strategies.

Keywords:  bone marrow microenvironment; drug resistance; epigenetic; hematopoietic stem cell; leukemic stem cell; metabolism; oxidative stress; proteostatic stress

DOI:  https://doi.org/10.1016/j.tips.2024.08.004