bims-glucam 2024-12-08 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–12–08
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolism and spatial transcription resolved heterogeneity of glutamine metabolism in cervical carcinoma.
Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.
NMR-based metabolomics combined with metabolic pathway analysis reveals metabolic heterogeneity of colorectal cancer tissue at different anatomical locations and stages.
Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.
Cell polarity proteins promote macropinocytosis in response to metabolic stress.
FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.
Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer.
TRIM2: a double-edged sword preventing apoptosis.
Targeting Caveolin-1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell-Mediated Immunotherapy.
Cellular responses to low nutrient conditions via activation of lysophosphatidic acid (LPA) receptor signaling in gastric cancer cells.
Glutamine Supplementation: A Possible Strategy to Help Mitigate Health Risks of Heat-Related Illness.
Lactate Dehydrogenase Inhibition Protects against Hepatic Fibrosis by Regulating Metabolic Reprogramming of Hepatic Stellate Cells.
Integrative analysis of toxicometabolomics and toxicoproteomics data: new molecular insights into thiazolidinedione-induced cardiotoxicity.
Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC).

BMC Cancer. 2024 Dec 06. 24(1): 1504

Metabolism and spatial transcription resolved heterogeneity of glutamine metabolism in cervical carcinoma.

Qian Liu, Jiayu Zhu, Guzalinuer Abulizi, Ayshamgul Hasim.

   BACKGROUND: Reprogramming of cellular metabolism is a pivotal mechanism employed by tumor cells to facilitate cell growth, proliferation, and differentiation, thereby propelling the progression of cancer. A comprehensive analysis of the transcriptional and metabolic landscape of cervical squamous cell carcinoma (CSCC) at high resolution could greatly enhance the precision of management and therapeutic strategies for this malignancy.
METHODS: The Air-flow-assisted Desorption Electrospray Ionization Mass Spectro-metric Imaging (AFADESI-MSI) and Spatial Transcriptomics techniques (ST) were employed to investigate the metabolic and transcription profiles of CSCC and normal tissues. For clinical validation, the expression of ASCT2(Ala, Ser, Cys transporter 2) was assessed using immune histochemistry in 122 cases of cervical cancer and 30 cases of cervicitis.
RESULTS: The AFADESI-MSI findings have revealed metabolic differences among different CSCC patients. Among them, the metabolic pathways of glutamine show more significant differences. After in situ detection of metabolites, the intensity of glutamate is observed to be significantly higher in cancerous tissue compared to normal tissue, but the intensity is not uniform. To elucidate the potential factors underlying alterations in glutamine metabolism across tissues, we employ ST to quantify mRNA levels. This analysis unveils significant perturbations in glutamine metabolism accompanied by extensive heterogeneity within cervical cancer tissues. After conducting a comprehensive analysis, it has been revealed that the differential expression of ASCT2(encoded by SLC1A5) in distinct regions of cervical cancer tissues plays a pivotal role in inducing heterogeneity in glutamine metabolism. Furthermore, the higher the expression level of ASCT2, the higher the intensity of glutamate is in the region. Further verification, it is found that the expression of ASCT2 protein in CSCC tissues is significantly higher than that in normal tissues (105/122, 86.07%).
CONCLUSIONS: This finding suggests that the variation in glutamine metabolism is not uniform throughout the tumor. The differential expression of ASCT2 in different regions of cervical cancer tissues seems to play a key role in causing this heterogeneity. This research has opened up new avenues for exploring the glutamine metabolic characteristics of CSCC which is essential for developing more effective targeted therapies.

Keywords:  AFADESI-MSI; Cervical carcinoma; Glutamine metabolism; Heterogeneity; ST

DOI:  https://doi.org/10.1186/s12885-024-13275-6
ASN Neuro. 2024 ;16(1): 2422268

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.

Derek C Lee, Linh Ta, Purna Mukherjee, Tomas Duraj, Marek Domin, Bennett Greenwood, Srada Karmacharya, Niven R Narain, Michael Kiebish, Christos Chinopoulos, Thomas N Seyfried.

  Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.

Keywords:  Fermentation; glioblastoma; glutaminolysis; mitochondrial substrate level phosphorylation; succinate

DOI:  https://doi.org/10.1080/17590914.2024.2422268
Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2412157121

Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.

Graham P Lobel, Nanumi Han, William A Molina Arocho, Michal Silber, Jason Shoush, Michael C Noji, Tsun Ki Jerrick To, Li Zhai, Nicholas P Lesner, M Celeste Simon, Malay Haldar.

  Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.

Keywords:  dendritic cells; glutamine; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2412157121
Int J Cancer. 2024 Dec 04.

NMR-based metabolomics combined with metabolic pathway analysis reveals metabolic heterogeneity of colorectal cancer tissue at different anatomical locations and stages.

Rongzhi Cai, LiXin Ke, Yan Zhao, Jiayun Zhao, Huanian Zhang, Peie Zheng, Lijing Xin, Changchun Ma, Yan Lin.

  Colorectal cancer (CRC) still remains the leading cause of cancer death worldwide. This study aimed to profile the metabolic differences of colorectal cancer tissues (CCT) at different stages and sites, as compared with their distant noncancerous tissues (DNT), to investigate the temporal and spatial heterogeneities of metabolic characterization. Our NMR-based metabolomics fingerprinting revealed that many of the metabolite levels were significantly altered in CCT compared to DNT and esophageal cancer tissues, indicating deregulations of glucose metabolism, one-carbon metabolism, glutamine metabolism, amino acid metabolism, fatty acid metabolism, TCA cycle, choline metabolism, and so forth. A total of five biomarker metabolites, including glucose, glutamate, alanine, valine and histidine, were identified to distinguish between early and advanced stages of CCT. Metabolites that distinguish the different anatomical sites of CCT include glucose, glycerol, glutamine, inositol, succinate, and citrate. Those significant metabolic differences in CRC tissues at different pathological stages and sites suggested temporal and spatial heterogeneities of metabolic characterization in CCT, providing a metabolic foundation for further study on biofluid metabolism in CRC early detection.

Keywords:  NMR‐based metabolomics; anatomical locations; colorectal cancer tissue; metabolic pathways; tumor stages

DOI:  https://doi.org/10.1002/ijc.35273
BMC Med. 2024 12 05. 22(1): 578

Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.

Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried.

  Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.

Keywords:  Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect

DOI:  https://doi.org/10.1186/s12916-024-03775-4
PLoS One. 2024 ;19(12): e0313962

Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.

Maxime Mahout, Laurent Schwartz, Romain Attal, Ashraf Bakkar, Sabine Peres.

Cancer cells are known to express the Warburg effect-increased glycolysis and formation of lactic acid even in the presence of oxygen-as well as high glutamine uptake. In tumors, cancer cells are surrounded by collagen, immune cells, and neoangiogenesis. Whether collagen formation, neoangiogenesis, and inflammation in cancer are associated with the Warburg effect needs to be established. Metabolic modelling has proven to be a tool of choice to understand biological reality better and make in silico predictions. Elementary Flux Modes (EFMs) are essential for conducting an unbiased decomposition of a metabolic model into its minimal functional units. EFMs can be investigated using our tool, aspefm, an innovative approach based on logic programming where biological constraints can be incorporated. These constraints allow networks to be characterized regardless of their size. Using a metabolic model of the human cell containing collagen, neoangiogenesis, and inflammation markers, we derived a subset of EFMs of biological relevance to the Warburg effect. Within this model, EFMs analysis provided more adequate results than parsimonious flux balance analysis and flux sampling. Upon further inspection, the EFM with the best linear regression fit to cancer cell lines exometabolomics data was selected. The minimal pathway, presenting the Warburg effect, collagen synthesis, angiogenesis, and release of inflammation markers, showed that collagen production was possible directly de novo from glutamine uptake and without extracellular import of glycine and proline, collagen's main constituents.

DOI: https://doi.org/10.1371/journal.pone.0313962
Nat Commun. 2024 Dec 03. 15(1): 10541

Cell polarity proteins promote macropinocytosis in response to metabolic stress.

Guillem Lambies, Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska M Galapate, Anagha Deshpande, Aniruddha J Deshpande, David A Scott, David W Dawson, Cosimo Commisso.

Macropinocytosis has emerged as a scavenging pathway that cancer cells exploit to survive in a nutrient-deprived microenvironment. Tumor cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as regulators of macropinocytosis. In normal epithelial cells, aPKCs associate with the scaffold proteins Par3 and Par6 to regulate cell polarity, affecting several targets, including the Par1 kinases and we find that each of these proteins is required for macropinocytosis. Mechanistically, aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the Par3 relocation to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and aPKCs support PDAC growth in vivo. Our findings enhance our understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

DOI: https://doi.org/10.1038/s41467-024-54788-9
FEBS J. 2024 Dec 06.

FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.

Elia Cappuccio, Max Holzknecht, Michèle Petit, Anne Heberle, Yana Rytchenko, Athanasios Seretis, Ciro L Pierri, Hubert Gstach, Pidder Jansen-Dürr, Alexander K H Weiss.

  This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.

Keywords:  FAHD1; ODx; ROS; TCA cycle; aging and cellular senescence; cancer metabolism; glutamine metabolism; mitochondrial dysfunction; mitochondrial metabolism

DOI:  https://doi.org/10.1111/febs.17345
J Vis Exp. 2024 Nov 15.

Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer.

Kathryn M Crotty, Samantha M Yeligar.

Alveolar macrophages (AMs) are the first line of cellular defense in the lower airway against pathogens. However, chronic and excessive alcohol use impairs the ability of AMs to phagocytize and clear pathogens from the alveolar space, in part through dysregulated fuel metabolism and bioenergetics. Our prior work has shown that chronic ethanol (EtOH) consumption impairs mitochondrial bioenergetics and increases lactate levels in AMs. Further, we recently demonstrated that EtOH increases glutamine dependency and glutamine-dependent maximal respiration while decreasing flexibility, shifting away from pyruvate-dependent respiration and towards glutamine-dependent respiration. Glutaminolysis is an important compensatory pathway for mitochondrial respiration when pyruvate is used for lactic acid production or when other fuel sources are insufficient. Using a mouse AM cell line, MH-S cells, exposed to either no EtOH or EtOH (0.08%) for 72 h, we determined the dependency of mitochondrial respiration and bioenergetics on glutamine as a fuel source using an extracellular flux bioanalyzer. Real-time measures were done in response to bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), an inhibitor of glutaminase 1, which prevents the enzymatic conversion of glutamine to glutamate, in media vehicle or in response to vehicle alone, followed by testing mitochondrial stress. The step-by-step protocol provided herein describes our methods and calculations for analyzing average levels of glutamine-dependent basal mitochondrial respiration, mitochondrial ATP-linked respiration, maximal mitochondrial respiration, and mitochondrial spare respiratory capacity across multiple biological and experimental replicates.

DOI: https://doi.org/10.3791/67579
FEBS J. 2024 Dec 01.

TRIM2: a double-edged sword preventing apoptosis.

Thomas Hollemann.

  TRIM2 belongs to the TRIM-NHL class of ubiquitin E3-ligases and inhibits apoptosis by a dual function. Liao et al. reported in the recent issue that under glutamine deprivation, TRIM2 transcription is activated by ATF4 to increase the uptake of long fatty acids into mitochondria. Here, TRIM2 acts as a direct activator of CPT1 independent of its E3 ubiquitin ligase activity and prevents apoptosis otherwise triggered by starvation. On the contrary, TRIM E3-ubiquitin ligase has been described to ubiquitinate and thus target proapoptotic BIM for its degradation in the proteasome. Thus, TRIM2 inhibits apoptosis classically via its ligase activity but also independent of this stimulating energy metabolism.

Keywords:  ATF4; TRIM2; apoptosis; glutamine; proteasome; starvation

DOI:  https://doi.org/10.1111/febs.17342
Adv Sci (Weinh). 2024 Dec 04. e2408373

Targeting Caveolin-1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell-Mediated Immunotherapy.

Dewen Zhan, Zhimin Du, Shang Zhang, Juanru Huang, Jian Zhang, Hui Zhang, Zhongrui Liu, Eline Menu, Jinheng Wang.

  The cell membrane transport capacity and surface targets of multiple myeloma (MM) cells heavily influence chemotherapy and immunotherapy. Here, it is found that caveolin-1 (CAV1), a primary component of membrane lipid rafts and caveolae, is highly expressed in MM cells and is associated with MM progression and drug resistance. CAV1 knockdown decreases MM cell adhesion to stromal cells and attenuates cell adhesion-mediated drug resistance to bortezomib. CAV1 inhibition in MM cells enhances natural killer cell-mediated cytotoxicity through increasing CXCL10, SLAMF7, and CD112. CAV1 suppression reduces mitochondrial membrane potential, increases reactive oxygen species, and inhibits autophagosome-lysosome fusion, resulting in the disruption of redox homeostasis. Additionally, CAV1 knockdown enhances glutamine addiction by increasing ASCT2 and LAT1 and dysregulates glutathione metabolism. As a result of CAV1 inhibition, MM cells are more sensitive to starvation, glutamine depletion, and glutamine transporter inhibition, and grow more slowly in vivo in a mouse model treated with bortezomib. The observation that CAV1 inhibition modulated by 6-mercaptopurine, daidzin, and statins enhances the efficacy of bortezomib in vitro and in vivo highlights the translational significance of these FDA-approved drugs in improving MM outcomes. These data demonstrate that CAV1 serves as a potent therapeutic target for enhancing chemotherapy and immunotherapy for MM.

Keywords:  caveolin‐1; glutathione metabolism; immunotherapy; multiple myeloma; natural killer cell; redox homeostasis

DOI:  https://doi.org/10.1002/advs.202408373
Adv Biol Regul. 2024 Nov 30. pii: S2212-4926(24)00056-3. [Epub ahead of print]96 101068

Cellular responses to low nutrient conditions via activation of lysophosphatidic acid (LPA) receptor signaling in gastric cancer cells.

Narumi Yashiro, Miwa Takai, Mao Yamamoto, Yuka Kusumoto, Shion Nagano, Anri Taniguchi, Moemi Tamura, Toshifumi Tsujiuchi.

  In the center of the solid tumor, abnormal vascular architecture impedes sufficient blood supply, leading to continuous hypoxia and nutrient deprivation for the tumor cells. Lysophosphatidic acid (LPA) receptor signaling is known to drive a range of malignant behaviors in cancer cells. This study aimed to explore the impact of LPA receptors on cellular functions in gastric cancer AGS cells cultured under low nutrient conditions. When AGS cells were cultured in media containing low glucose (2000 mg/L), low glutamine (1 mM), or low amino acids (50 % content), LPA receptor expression levels were significantly altered. The growth activity of AGS cells cultured in low glucose- and low amino acid-containing media was suppressed by LPA. Conversely, LPA increased the growth activity of AGS cells cultured in low glutamine-containing media. AGS cell motility increased under low glucose and low glutamine conditions, while low amino acid conditions decreased cell motility. Additionally, the viability of AGS cells in response to cisplatin (CDDP) was enhanced under low glucose, low glutamine, and low amino acid conditions. The motility and viability of AGS cells in response to CDDP were significantly increased by AM966 (LPA1 antagonist), GRI-977143 (LPA2 agonist) and (2S)-OMPT (LPA3 agonist). These results suggest that LPA receptor signaling is significantly implicated in regulating malignant properties in AGS cells under low nutrient conditions.

Keywords:  Cellular functions; Gastric cancer cells; LPA receptors; Low nutrition; Lysophosphatidic acid

DOI:  https://doi.org/10.1016/j.jbior.2024.101068
J Nutr Metab. 2024 ;2024 1638244

Glutamine Supplementation: A Possible Strategy to Help Mitigate Health Risks of Heat-Related Illness.

Micah Zuhl, Jonathan Specht, Sage Beatty, Christine Mermier.

  A rise in body temperature caused by physical work, including exercise, in a hot climate can lead to heat-related illnesses such as exertional heat exhaustion and stroke. Individuals who work physically demanding occupations in hot environments are at heightened risk of heat injury. The mechanisms that contribute to heat illness resulting from physical work in the heat are complex and include dehydration, tissue ischemia and damage, oxidative stress, and inflammatory events. Therefore, it is important to develop strategies that address these mechanistic underpinnings to prevent exacerbation to heat illness. Glutamine is an amino acid that has been considered conditionally essential during situations of biological stress (e.g., tissue burn, exercise, sepsis) due to high rates of tissue consumption. Evidence suggests that glutamine may serve as an important nutrient during heat stress and when combined with other preventative measures (e.g., cooling techniques, work/rest ratios, clothing) may help to mitigate heat illness among individuals working in extreme climates. The aim of this review is to examine the current literature on the role of glutamine during heat stress.

Keywords:  exercise; glutamine; heat; illness; occupation

DOI:  https://doi.org/10.1155/jnme/1638244
J Agric Food Chem. 2024 Dec 04.

Lactate Dehydrogenase Inhibition Protects against Hepatic Fibrosis by Regulating Metabolic Reprogramming of Hepatic Stellate Cells.

Lisi Li, Qi Lei, Yifan Zhen, Lixue Cao, Yujia Dong, Xifu Liu, Meng Wang.

  Hepatic stellate cells (HSCs) activation results in liver fibrosis. When HSCs are activated, metabolism is reprogrammed. However, metabolic alteration in HSCs activation has not been sufficiently addressed. This study aims to investigate the role of lactate dehydrogenase (LDH) inhibition in HSCs activation with an emphasis on the metabolic reprogramming. Mice were subjected to carbon tetrachloride (CCl4) to induce liver injury. In addition, the primary HSCs were isolated for mechanism investigation. Our study demonstrated that LDH inhibition impaired HSCs activation through suppressing the enhanced glycolysis by blocking nicotinamide adenine dinucleotide (NAD+) regeneration. Meanwhile, LDH inhibition also impeded the glutamine metabolism through the lactic acid/histone deacetylase (HDAC)/histone acetylation/cellular-myelocytomatosis viral oncogene (c-Myc) signaling pathway. Our findings demonstrated that LDH inhibition is a potential target for liver fibrosis treatment, which provides new insight into the pathogenesis of liver fibrosis from the aspect of metabolic reprogramming, contributing to the design of a novel therapeutic strategy in the management of liver fibrosis.

Keywords:  glutaminolysis; glycolysis; hepatic fibrosis; hepatic stellate cells; lactate dehydrogenase

DOI:  https://doi.org/10.1021/acs.jafc.4c08211
Metabolomics. 2024 Dec 04. 21(1): 1

Integrative analysis of toxicometabolomics and toxicoproteomics data: new molecular insights into thiazolidinedione-induced cardiotoxicity.

Abdullah Al Sultan, Zahra Rattray, Nicholas J W Rattray.

   INTRODUCTION: Despite the well-established efficacy of thiazolidinediones (TZDs), including pioglitazone and rosiglitazone, in type II diabetes management, their potential contribution to heart failure risk remains a significant area of uncertainty. This incomplete understanding, which persists despite decades of clinical use of TZDs, has generated ongoing controversy and unanswered questions regarding their safety profiles, ultimately limiting their broader clinical application.
OBJECTIVE AND METHODS: This study presented a multi-omics approach, integrating toxicoproteomics and toxicometabolomics data with the goal of uncovering novel mechanistic insights into TZD cardiotoxicity and identifying molecular signatures predictive of side effect progression.
RESULTS: Network analysis of proteo-metabolomic data revealed a distinct fingerprint of disrupted biochemical pathways, which were primarily related to energy metabolism. Downregulation of oxidative phosphorylation and fatty acid synthesis was coupled with increased activity in anaerobic glycolysis, the pentose phosphate pathway, and amino acid and purine metabolism. This suggests a potential metabolic shift in AC16 cells from fatty acid oxidation towards anaerobic glycolysis, potentially contributing to observed cardiotoxicity. Additionally, the study identified a marked disruption in the glutathione system, indicating an imbalanced redox state triggered by TZD exposure. Importantly, our analysis identified key molecular signatures across omics datasets, including prominent signatures of amino acids like L-ornithine, L-tyrosine and glutamine, which are evidently associated with heart failure, supporting their potential use for the early prediction of cardiotoxicity progression.
CONCLUSION: By uncovering a novel mechanistic explanation for TZD cardiotoxicity, this study simultaneously illuminates potential therapeutic interventions, opening avenues for future research to improve the safety profile of TZD agents. (250 words).

Keywords:  Cardiotoxicity; Mitochondrial energetics; Oxidative stress; Thiazolidinediones; Toxicometabolomics; Toxicoproteomics

DOI:  https://doi.org/10.1007/s11306-024-02201-3
Phytomedicine. 2024 Nov 30. pii: S0944-7113(24)00935-8. [Epub ahead of print]136 156279

Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC).

Jarinya Chaopreecha, Nut Phueakphud, Ampa Suksatu, Sucheewin Krobthong, Suwimon Manopwisedjaroen, Nattawadee Panyain, Suradej Hongeng, Arunee Thitithanyanont, Patompon Wongtrakoongate.

   BACKGROUND: Andrographolide is a medicinal compound which possesses anti-SARS-CoV-2 activity. A number of cellular targets of andrographolide have been identified by target predictions and computational studies.
PURPOSE: However, a potential cellular target of andrographolide has never been explored in SARS-CoV-2 infected lung epithelial cells. We aimed to identify cellular pathways involved in andrographolide-mediated anti-SARS-CoV-2 activity.
METHODS: The viral infection was determined by immunofluorescence staining, enzyme-linked immunosorbent assay and focus-forming assay. Proteomic analysis was employed to identify cellular pathways and key proteins controlled by andrographolide in the human lung epithelial cells Calu-3 infected by SARS-CoV-2. Immunofluorescence staining was used to test protein expression and localization. Western blot and realtime PCR were utilized to elucidate gene expression. Cellular glutathione level was examined by a reduced/oxidized glutathione assay. An ectopic gene expression was delivered by plasmid transfection.
RESULTS: Gene ontology analysis indicates that proteins involved in nuclear factor erythroid 2-related factor 2 (NRF2)-regulated pathways were differentially expressed by andrographolide. Notably, andrographolide increased expression and nuclear localization of the transcription factor NRF2. In addition, transcriptional expression of GCLC and glutamate-cysteine ligase modifier subunit (GCLM), which are NRF2 target genes, were induced by andrographolide. We further find that infection of SARS-CoV-2 resulted in a reduction of glutathione level in Calu-3; the effect that was rescued by andrographolide. Moreover, andrographolide also induced expression of the glutathione producing enzyme GCLC in SARS-CoV-2 infected lung epithelial cells. Importantly, an ectopic over-expression of GCLC or treatment of N-acetyl-L-cysteine in Calu-3 cells led to a decrease in SARS-CoV-2 infection.
CONCLUSION: Collectively, our findings suggest the interplay between GCLC-mediated glutathione biogenesis induced by andrographolide and the anti-SARS-CoV-2 activity. The glutathione biogenesis and recycling pathways should be further exploited as a targeted therapy against SARS-CoV-2 infection.

Keywords:  Andrographolide; GCLC; Glutathione; Proteomic; SAR-CoV-2

DOI:  https://doi.org/10.1016/j.phymed.2024.156279