bims-glucam 2024-03-10 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒03‒10
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
Development of a prognostic model for muscle-invasive bladder cancer using glutamine metabolism.
Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism.
Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer.
Filament formation drives catalysis by glutaminase enzymes important in cancer progression.
Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma.
Precision unveiled: Synergistic genomic landscapes in breast cancer-Integrating single-cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics.
Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.
Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress.
Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.
Metabolic remodeling in cancer and senescence and its therapeutic implications.
Immunometabolic Maladaptations to the Tumor Microenvironment.
Unlocking apoptosis in triple negative breast cancer: Harnessing "glutamine trap" to amplify the efficacy of lapatinib-loaded mixed micelles.
The enigma of glutamine synthetase and b-catenin expression in hepatocellular adenoma in familial adenomatous polyposis coli.
Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy.
Pyroglutamate Acidosis 2023. A Review of 100 Cases.
Effectiveness of glutamine and arginine in wound healing of pressure ulcers: A systematic review protocol.
Discretised Flux Balance Analysis for Reaction-Diffusion Simulation of Single-Cell Metabolism.

J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74

A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.

Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.

  Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.

Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-024-02994-0
Comput Biol Med. 2024 Feb 27. pii: S0010-4825(24)00307-X. [Epub ahead of print]171 108223

Development of a prognostic model for muscle-invasive bladder cancer using glutamine metabolism.

Sida Hao, Lin Shen, Pengju Liu, Qin Yong, Yeqiang Wang, Xiangyi Zheng.

  BACKGROUND: Muscle-invasive bladder cancer (MIBC) is distinguished by its pronounced invasiveness and unfavorable prognosis. Immunotherapy and targeted therapy have emerged as key treatment options for various types of cancer. Altered metabolism is a defining characteristic of cancer cells, and there is mounting evidence suggesting the important role of glutamine metabolism (GM) in tumor metabolism. Nevertheless, the relationship between GM and clinical outcomes, immune microenvironment, and immunotherapy in MIBC remains unknown.METHODS: This study employed Mendelian randomization to explore the causal relationship between blood metabolites and bladder tumors. We systematically evaluated 373 glutamine metabolism-related genes and identified prognostic-related genes, leading to the construction of a glutamine-associated prognostic model. Further analysis confirmed the correlation between high and low-risk groups with the tumor microenvironment, immune cell infiltration, and tumor mutation burden. Subsequently, we assessed the relationship between the risk score and the sensitivity to various immunotherapies and anticancer drugs.
RESULTS: We identified 14 blood metabolites at the molecular level that have a causal relationship with bladder tumors. At the gene level, the study discussed differentially expressed GM genes in MIBC. First, we established a risk model predicting overall survival (OS) based on GM genes, confirming its reliable predictive ability in MIBC patients and validated it in a GEO cohort. Additionally, a reliable column line chart was created. Secondly, two distinct molecular subtypes were identified, and the associations between different risk groups and tumor microenvironment and immune infiltration were observed. In addition, the predicted risk values correlated with responses to a broad range of pharmaceutical agents.
CONCLUSION: In summary, we confirmed the causal relationship between blood metabolites and bladder tumors. Furthermore, a risk scoring model related to glutamine metabolism consisting of 9 genes was developed. This model could potentially serve as a useful tool for predicting prognosis and guiding the treatment of MIBC patients.

Keywords:  Glutamine metabolism; Immune infiltration; Mendelian randomization; Metabolic reprogramming; Muscle-invasive bladder cancer

DOI:  https://doi.org/10.1016/j.compbiomed.2024.108223
J Hepatol. 2024 Feb;pii: S0168-8278(23)05224-8. [Epub ahead of print]80(2): 293-308

Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism.

Qiangnu Zhang, Teng Wei, Wen Jin, Lesen Yan, Lulin Shi, Siqi Zhu, Yu Bai, Yuandi Zeng, Zexin Yin, Jilin Yang, Wenjian Zhang, Meilong Wu, Yusen Zhang, Gongze Peng, Stephanie Roessler, Liping Liu.

  BACKGROUND & AIMS: The role of solute carrier family 25 member 15 (SLC25A15), a critical component of the urea cycle, in hepatocellular carcinoma (HCC) progression remains poorly understood. This study investigated the impact of SLC25A15 on HCC progression and its mechanisms.METHODS: We systematically investigated the function of SLC25A15 in HCC progression using large-scale data mining and cell, animal, and organoid models. Furthermore, we analyzed its involvement in reprogramming glutamine metabolism.
RESULTS: SLC25A15 expression was significantly decreased in HCC tissues, and patients with low SLC25A15 levels had a poorer prognosis. Hypoxia-exposed HCC cells or tissues had lower SLC25A15 expression. A positive correlation between HNF4A, a transcription factor suppressed by hypoxia, and SLC25A15 was observed in both HCC tissues and cells. Modulating HNF4A levels altered SLC25A15 mRNA levels. SLC25A15 upregulated SLC1A5, increasing glutamine uptake. The reactive metabolic pathway of glutamine was increased in SLC25A15-deficient HCC cells, providing energy for HCC progression through additional lipid synthesis. Ammonia accumulation due to low SLC25A15 levels suppressed the expression of OGDHL (oxoglutarate dehydrogenase L), a switch gene that mediates SLC25A15 deficiency-induced reprogramming of glutamine metabolism. SLC25A15-deficient HCC cells were more susceptible to glutamine deprivation and glutaminase inhibitors. Intervening in glutamine metabolism increased SLC25A15-deficient HCC cells' response to anti-PD-L1 treatment.
CONCLUSION: SLC25A15 is hypoxia-responsive in HCC, and low SLC25A15 levels result in glutamine reprogramming through SLC1A5 and OGDHL regulation, promoting HCC progression and regulating cell sensitivity to anti-PD-L1. Interrupting the glutamine-derived energy supply is a potential therapeutic strategy for treating SLC25A15-deficient HCC.
IMPACT AND IMPLICATIONS: We first demonstrated the tumor suppressor role of solute carrier family 25 member 15 (SLC25A15) in hepatocellular carcinoma (HCC) and showed that its deficiency leads to reprogramming of glutamine metabolism to promote HCC development. SLC25A15 can serve as a potential biomarker to guide the development of precision therapeutic strategies aimed at targeting glutamine deprivation. Furthermore, we highlight that the use of an inhibitor of glutamine utilization can enhance the sensitivity of low SLC25A15 HCC to anti-PD-L1 therapy.

Keywords:  Glutamine; Hypoxia; Liver cancer; SLC25A15; Urea cycle

DOI:  https://doi.org/10.1016/j.jhep.2023.10.024
J Adv Res. 2024 Mar 02. pii: S2090-1232(24)00085-7. [Epub ahead of print]

Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer.

Jingyang Li, Di Zhang, Shaohui Wang, Peng Yu, Jiayi Sun, Yi Zhang, Xianli Meng, Juan Li, Li Xiang.

  INTRODUCTION: Baicalein, a bioactive component of Scutellaria baicalensis Georgi, has been shown to promote apoptosis in non-small cell lung cancer cells. However, previous studies have not determined if baicalein exerts proapoptotic effects by modulating the metabolic pathways.OBJECTIVE: To investigate if baicalein induces apoptosis in lung cancer cells by modulating the glutamine-mTOR metabolic pathway.
METHODS: The in vivo anti-lung cancer activity of baicalein (50, 100, and 200 mg/kg) was evaluated using a xenograft model. In vitro experiments were used to assess the efficacy of baicalein (for H1299: 12.5, 25, and 50 μM; for A549: 10, 20, and 40 μM) on lung cancer cell proliferation, colony formation, and apoptosis. Metabolomics analysis was performed using liquid chromatography-mass spectrometry. The binding of baicalein to glutamine transporters and glutaminase was examined using molecular docking. The overexpression of glutamine transporters was validated using qRT-PCR and western blot analyses. The levels of ASCT2, LAT1, GLS1, p-mTOR, mTOR, and apoptosis-related proteins were evaluated using western blot analysis.
RESULTS: Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro. Additionally, baicalein altered amino acid metabolites, especially glutamine metabolites, in H1299 and A549 cells. Mechanistically, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation. The expression of mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment. Importantly, we next demonstrated the suppression of mTOR signaling and the induction of apoptosis by baicalein were achieved by regulating glutamine metabolism.
CONCLUSION: Baicalein inhibited the mTOR signaling pathway and induced apoptosis by downregulating glutamine metabolism. The potential of baicalein to induce apoptosis in lung cancer cells by selectively targeting the glutamine-mTOR pathway suggests an encouraging approach for treating lung cancer.

Keywords:  Apoptosis; Baicalein; Glutamine-mTOR metabolic pathway; Metabonomics; Non-small-cell lung cancer

DOI:  https://doi.org/10.1016/j.jare.2024.02.023
Nat Commun. 2024 Mar 04. 15(1): 1971

Filament formation drives catalysis by glutaminase enzymes important in cancer progression.

Shi Feng, Cody Aplin, Thuy-Tien T Nguyen, Shawn K Milano, Richard A Cerione.

The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide a view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression.

DOI: https://doi.org/10.1038/s41467-024-46351-3
Cancer Lett. 2024 Feb 29. pii: S0304-3835(24)00120-4. [Epub ahead of print] 216727

Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma.

An Song, Lei Wu, Bo-Xin Zhang, Qi-Chao Yang, Yuan-Tong Liu, Hao Li, Liang Mao, Dian Xiong, Hai-Jun Yu, Zhi-Jun Sun.

  Head and neck squamous cell carcinoma (HNSCC) is a formidable cancer type that poses significant treatment challenges, including radiotherapy (RT) resistance. The metabolic characteristics of tumors present substantial obstacles to cancer therapy, and the relationship between RT and tumor metabolism in HNSCC remains elusive. Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Here, we report that after RT, glutamine levels rise in HNSCC, and the glutamine transporter protein SLC1A5 is upregulated. Notably, blocking glutamine significantly enhances the therapeutic efficacy of RT in HNSCC. Furthermore, inhibition of glutamine combined with RT triggers immunogenic tumor ferroptosis, a form of nonapoptotic regulated cell death. Mechanistically, RT increases interferon regulatory factor (IRF) 1 expression by activating the interferon signaling pathway, and glutamine blockade augments this efficacy. IRF1 drives transferrin receptor expression, elevating intracellular Fe2+ concentration, disrupting iron homeostasis, and inducing cancer cell ferroptosis. Importantly, the combination treatment-induced ferroptosis is dependent on IRF1 expression. Additionally, blocking glutamine combined with RT boosts CD47 expression and hinders macrophage phagocytosis, attenuating the treatment effect. Dual-blocking glutamine and CD47 promote tumor remission and enhance RT-induced ferroptosis, thereby ameliorating the tumor microenvironment. Our work provides valuable insights into the metabolic and immunological mechanisms underlying RT-induced ferroptosis, highlighting a promising strategy to augment RT efficacy in HNSCC.

Keywords:  Ferroptosis; Glutamine metabolism; Head and neck squamous cell carcinoma; Immunotherapy; Radiotherapy

DOI:  https://doi.org/10.1016/j.canlet.2024.216727
Environ Toxicol. 2024 Mar 07.

Precision unveiled: Synergistic genomic landscapes in breast cancer-Integrating single-cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics.

Chenglu Jiang, Shengke Zhang, Lai Jiang, Zipei Chen, Haiqing Chen, Jinbang Huang, Jingyi Tang, Xiufang Luo, Guanhu Yang, Jie Liu, Hao Chi.

  BACKGROUND: Globally, breast cancer, with diverse subtypes and prognoses, necessitates tailored therapies for enhanced survival rates. A key focus is glutamine metabolism, governed by select genes. This study explored genes associated with T cells and linked them to glutamine metabolism to construct a prognostic staging index for breast cancer patients for more precise medical treatment.METHODS: Two frameworks, T-cell related genes (TRG) and glutamine metabolism (GM), stratified breast cancer patients. TRG analysis identified key genes via hdWGCNA and machine learning. T-cell communication and spatial transcriptomics emphasized TRG's clinical value. GM was defined using Cox analyses and the Lasso algorithm. Scores categorized patients as TRG_high+GM_high (HH), TRG_high+GM_low (HL), TRG_low+GM_high (LH), or TRG_low+GM_low (LL). Similarities between HL and LH birthed a "Mixed" class and the TRG_GM classifier. This classifier illuminated gene variations, immune profiles, mutations, and drug responses.
RESULTS: Utilizing a composite of two distinct criteria, we devised a typification index termed TRG_GM classifier, which exhibited robust prognostic potential for breast cancer patients. Our analysis elucidated distinct immunological attributes across the classifiers. Moreover, by scrutinizing the genetic variations across groups, we illuminated their unique genetic profiles. Insights into drug sensitivity further underscored avenues for tailored therapeutic interventions.
CONCLUSION: Utilizing TRG and GM, a robust TRG_GM classifier was developed, integrating clinical indicators to create an accurate predictive diagnostic map. Analysis of enrichment disparities, immune responses, and mutation patterns across different subtypes yields crucial subtype-specific characteristics essential for prognostic assessment, clinical decision-making, and personalized therapies. Further exploration is warranted into multiple fusions between metrics to uncover prognostic presentations across various dimensions.

Keywords:  biomarker discovery; breast cancer; drug toxicity; personalized medicine; single-cell analysis

DOI:  https://doi.org/10.1002/tox.24205
Innovation (Camb). 2024 Mar 04. 5(2): 100583

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.

Johan Gustafsson, Fariba Roshanzamir, Anders Hagnestål, Sagar M Patel, Oseeyi I Daudu, Donald F Becker, Jonathan L Robinson, Jens Nielsen.

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

DOI: https://doi.org/10.1016/j.xinn.2024.100583
Nutr Metab (Lond). 2024 Mar 08. 21(1): 12

Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress.

Yongjie Zhang, Yangli Wang, Xin Liao, Tong Liu, Fengyuan Yang, Kaiqiang Yang, Zhuohua Zhou, Yinxu Fu, Ting Fu, Aliaksei Sysa, Xiandan Chen, Yao Shen, Jianxin Lyu, Qiongya Zhao.

  Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely associated with lipid metabolism disturbances because of its important role in intermediary metabolism. However, the effect of glutamine supplementation on MAFLD progression remains unclear. Here, we used a high-fat diet (HFD)-induced MAFLD C57BL/6 mouse model, and glutamine was supplied in the drinking water at different time points for MAFLD prevention and reversal studies. A MAFLD prevention study was performed by feeding mice an HFD concomitant with 4% glutamine treatment for 24 weeks, whereas the MAFLD reversal study was performed based on 4% glutamine treatment for 13 weeks after feeding mice an HFD for 10 weeks. In the prevention study, glutamine treatment ameliorated serum lipid storage, hepatic lipid injury, and oxidative stress in HFD-induced obese mice, although glutamine supplementation did not affect body weight, glucose homeostasis, energy expenditure, and mitochondrial function. In the MAFLD reversal study, there were no noticeable changes in the basic physiological phenotype and hepatic lipid metabolism. In summary, glutamine might prevent, but not reverse, HFD-induced MAFLD in mice, suggesting that a cautious attitude is required regarding its use for MAFLD treatment.

Keywords:  Glutamine; Metabolic associated fatty liver disease; Oxidative stress; Prevention study; Reversal study

DOI:  https://doi.org/10.1186/s12986-024-00784-1
Genes Dev. 2024 Mar 07.

Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.

Veronica Ciuffoli, Xuesong Feng, Kan Jiang, Natalia Acevedo-Luna, Kyung Dae Ko, A Hong Jun Wang, Giulia Riparini, Mamduh Khateb, Brian Glancy, Stefania Dell'Orso, Vittorio Sartorelli.

  By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and impaired regeneration. Psat1, α-KG, and glutamine were reduced in MuSCs of old mice. α-KG or glutamine re-established appropriate muscle regeneration of adult conditional Psat1 -/- mice and of old mice. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest α-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.

Keywords:  aging; glutamine; ketoglutarate; muscle regeneration; muscle stem cells

DOI:  https://doi.org/10.1101/gad.351428.123
Trends Endocrinol Metab. 2024 Mar 06. pii: S1043-2760(24)00037-7. [Epub ahead of print]

Metabolic remodeling in cancer and senescence and its therapeutic implications.

Yeonju Kim, Yeji Jang, Mi-Sung Kim, Chanhee Kang.

  Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.

Keywords:  aging; cancer; metabolism; senescence; senotherapy

DOI:  https://doi.org/10.1016/j.tem.2024.02.008
Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]

Immunometabolic Maladaptations to the Tumor Microenvironment.

Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.

Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.

DOI: https://doi.org/10.1101/cshperspect.a041547
Biomater Adv. 2024 Mar 02. pii: S2772-9508(24)00065-7. [Epub ahead of print]159 213822

Unlocking apoptosis in triple negative breast cancer: Harnessing "glutamine trap" to amplify the efficacy of lapatinib-loaded mixed micelles.

Rohan Ghadi, Kaushik Kuche, Tushar Date, Bhargavi Nallamothu, Dasharath Chaudhari, Sanyog Jain.

  Certain aggressive cancers, such as triple-negative breast cancer (TNBC), heavily bank on glutamine for their proliferation and survival. In this context, TNBC functions as a "glutamine trap," extracting circulating glutamine at a rate surpassing that of any other organ. Moreover, the overexpression of Alanine, Serine, Cysteine Transporter 2 (ASCT2), a key player in glutamine uptake, further underscores the significance of targeted therapy to enhance TNBC treatment. This led to the exploration of a novel approach involving hydrophobized Pluronic-based mixed micelles achieved through the use of docosahexaenoic acid and stapled with glutamine for displaying inherent ASCT2 targeting ability-a formulation termed LPT G-MM. LPT G-MM exhibited optimal characteristics, including a size of 163.66 ± 10.34 nm, a polydispersity index of 0.237 ± 0.083, and an enhanced drug loading capacity of approximately 15 %. Transmission electron microscopy validated the spherical shape of these micelles. In vitro release studies demonstrated drug release in a sustained manner without the risk of hemolysis. Importantly, LPT G-MM displayed heightened cellular uptake, increased cytotoxicity, a lower IC50 value, elevated reactive oxygen species, induced mitochondrial membrane depolarization, and a greater apoptosis index in TNBC cell lines compared to free LPT. The pharmacokinetic profile of LPT G-MM revealed a substantial rise in half-life (t1/2) by approximately 1.48-fold and an elevation in the area under the curve [AUC(0→∞)] by approximately 1.19-fold. Moreover, there was a significant reduction in the percentage of tumor volume by approximately 7.26-fold, along with decreased serum toxicity markers compared to free LPT. In summary, LPT G-MM demonstrated promising potential in boosting payload capacities and targeting specificity in the context of TNBC treatment.

Keywords:  Docosahexaenoic acid; Glutamine; Mixed micelles; Pluronic; Triple negative breast cancer

DOI:  https://doi.org/10.1016/j.bioadv.2024.213822
Virchows Arch. 2024 Mar 08.

The enigma of glutamine synthetase and b-catenin expression in hepatocellular adenoma in familial adenomatous polyposis coli.

Annette S H Gouw, Christine Sempoux, Paulette Bioulac-Sage.



Keywords:  Beta-catenin; Familial adenomatous polyposis; Glutamine synthetase; Hepatocellular adenoma; Immunohistochemistry

DOI:  https://doi.org/10.1007/s00428-024-03772-1
J Transl Med. 2024 Mar 03. 22(1): 229

Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy.

Linxuan Miao, Chenglin Lu, Bin Zhang, Huili Li, Xu Zhao, Haoran Chen, Ying Liu, Xiaonan Cui.

  Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.

Keywords:  Immunotherapy; Natural killer cells; Solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-024-05033-w
Clin Med (Lond). 2024 Feb 29. pii: S1470-2118(24)00018-6. [Epub ahead of print] 100030

Pyroglutamate Acidosis 2023. A Review of 100 Cases.

Gordon W Stewart.

  This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.

Keywords:  5-oxoproline; acetaminophen; anion gap; cysteine; flucloxacillin; glutathione; hyperammonaemia; metabolic acidosis; paracetamol; pyroglutamate; pyroglutamic acidosis; vigabatrin

DOI:  https://doi.org/10.1016/j.clinme.2024.100030
J Tissue Viability. 2024 Mar 02. pii: S0965-206X(24)00026-3. [Epub ahead of print]

Effectiveness of glutamine and arginine in wound healing of pressure ulcers: A systematic review protocol.

Tim Torsy, Inge Tency, Dimitri Beeckman, Flore De Vylder.

  INTRODUCTION: Various nutrients play a physiological role in the healing process of pressure ulcers (PUs). Nutritional interventions include the administration of enteral nutritional supplements and formulas containing arginine, glutamine, and micronutrients. The aim of this systematic review is to evaluate the effectiveness of enteral nutritional supplements and formulas containing arginine and glutamine on wound-related outcomes. These include (1) time to healing, (2) changes in wound size, (3) local wound infection, (4) PU recurrence, and (5) PU-related pain.MATERIALS AND METHODS: This protocol was developed according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). A search will be conducted in the Cochrane Library, EMBASE, PubMed (MEDLINE), CINAHL (EBSCOhost interface) and Web of Science. In addition, a manual search will be conducted to identify relevant records. Except for systematic reviews, no restrictions will be placed on the study design, the population studied or the setting. Studies that do not address PUs, in vitro studies and studies that do not report wound-related outcomes will be excluded. Study selection, risk of bias assessment and data extraction will be performed independently by three researchers. Depending on the extent of heterogeneity of interventions, follow-up time and populations, results will be summarised either by meta-analysis or narrative synthesis.
CONCLUSIONS: This is the first systematic review to identify, evaluate and summarise the current evidence for enteral arginine and glutamine supplementation on wound-related outcomes in PUs. The review will provide a solid basis for deriving valid and clinically relevant conclusions in this area.

Keywords:  Arginine; Glutamine; Nutrition; Pressure ulcer; Systematic review; Wound healing

DOI:  https://doi.org/10.1016/j.jtv.2024.03.001
Bull Math Biol. 2024 03 06. 86(4): 39

Discretised Flux Balance Analysis for Reaction-Diffusion Simulation of Single-Cell Metabolism.

Yin Hoon Chew, Fabian Spill.

  Metabolites have to diffuse within the sub-cellular compartments they occupy to specific locations where enzymes are, so reactions could occur. Conventional flux balance analysis (FBA), a method based on linear programming that is commonly used to model metabolism, implicitly assumes that all enzymatic reactions are not diffusion-limited though that may not always be the case. In this work, we have developed a spatial method that implements FBA on a grid-based system, to enable the exploration of diffusion effects on metabolism. Specifically, the method discretises a living cell into a two-dimensional grid, represents the metabolic reactions in each grid element as well as the diffusion of metabolites to and from neighbouring elements, and simulates the system as a single linear programming problem. We varied the number of rows and columns in the grid to simulate different cell shapes, and the method was able to capture diffusion effects at different shapes. We then used the method to simulate heterogeneous enzyme distribution, which suggested a theoretical effect on variability at the population level. We propose the use of this method, and its future extensions, to explore how spatiotemporal organisation of sub-cellular compartments and the molecules within could affect cell behaviour.

Keywords:  Cell shape; Flux balance analysis; Grid-based; Metabolism; Reaction–diffusion; Spatial method

DOI:  https://doi.org/10.1007/s11538-024-01264-6