bims-glucam 2024-04-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–04–14
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.
Exploiting pancreatic cancer metabolism: challenges and opportunities.
Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.
The mechanism of extracellular CypB promotes glioblastoma adaptation to glutamine deprivation microenvironment.
SLC38A2 promotes cell proliferation and invasion by promoting glutamine metabolism in adenomyosis.
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.
A guide to ferroptosis in cancer.
Metabolic adaptations in cancer stem cells: A key to therapy resistance.
Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates.
Activating transcription factor 4: a regulator of stress response in human cancers.
Metabolic Signaling in Cancer Metastasis.
Effect of the dietary supplement PERMEAPROTECT+ TOLERANCE© on gut permeability in a human co-culture epithelial and immune cells model.
Prognostic and immunological implications of glutathione metabolism genes in lung adenocarcinoma: A focus on the core gene SMS and its impact on M2 macrophage polarization.
Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.
Amplification of Oxygen-Independent Free Radicals Based on a Glutathione Depletion and Biosynthesis Inhibition Strategy for Photothermal and Thermodynamic Therapy of Hypoxic Tumors.

bioRxiv. 2024 Mar 27. pii: 2024.03.26.582525. [Epub ahead of print]

Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.

Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Cagri G Besirli, Costas A Lyssiotis, Thomas J Wubben.

The bioenergetic demand of photoreceptors rivals that of cancer cells, and numerous metabolic similarities exist between these cells. Glutamine (Gln) anaplerosis via the tricarboxylic acid (TCA) cycle provides biosynthetic intermediates and is a hallmark of cancer metabolism. In this process, Gln is first converted to glutamate via glutaminase (GLS), which is a crucial pathway in many cancer cells. To date, no study has been undertaken to examine the role of Gln metabolism in vivo in photoreceptors. Here, mice lacking GLS in rod photoreceptors were generated. Animals lacking GLS experienced rapid photoreceptor degeneration with concomitant functional loss. Gln has multiple roles in metabolism including redox balance, biosynthesis of nucleotides and amino acids, and supplementing the TCA cycle. Few alterations were noted in redox balance. Unlabeled targeted metabolomics demonstrated few changes in glycolytic and TCA cycle intermediates, which corresponded with a lack of significant changes in mitochondrial function. GLS deficiency in rod photoreceptors did decrease the fractional labelling of TCA cycle intermediates when provided uniformly labeled 13 C-Gln in vivo . However, supplementation with alpha-ketoglutarate provided only marginal rescue of photoreceptor degeneration. Nonessential amino acids, glutamate and aspartate, were decreased in the retina of mice lacking GLS in rod photoreceptors. In accordance with this amino acid deprivation, the integrated stress response (ISR) was found to be activated with decreased global protein synthesis. Importantly, supplementation with asparagine delayed photoreceptor degeneration to a greater degree than alpha-ketoglutarate. These data show that GLS-mediated Gln catabolism is essential for rod photoreceptor amino acid biosynthesis, function, and survival.
Significance Statement: Glucose has been central in the study of photoreceptor cell metabolism. Recently, it was shown that fuel sources besides glucose can meet the metabolic needs of photoreceptors. Glutamine (Gln) is the most abundant circulating amino acid and has many biosynthetic and bioenergetic roles in cells. Glutaminolysis is the process by which Gln is metabolized into tricarboxylic acid cycle intermediates to provide biosynthetic precursors. Here, Gln is first converted to glutamate via the enzyme glutaminase (GLS). This research demonstrates that deletion of GLS in rod photoreceptors alters retinal metabolism, activates the integrated stress response (ISR), and results in rapid photoreceptor degeneration. As such, Gln is a critical fuel source that supports photoreceptor cell biomass, redox balance, and survival.

DOI: https://doi.org/10.1101/2024.03.26.582525
Trends Mol Med. 2024 Apr 10. pii: S1471-4914(24)00063-7. [Epub ahead of print]

Exploiting pancreatic cancer metabolism: challenges and opportunities.

Maria Chiara De Santis, B Bockorny, E Hirsch, P Cappello, M Martini.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer, known for its challenging diagnosis and limited treatment options. The focus on metabolic reprogramming as a key factor in tumor initiation, progression, and therapy resistance has gained prominence. In this review we focus on the impact of metabolic changes on the interplay among stromal, immune, and tumor cells, as glutamine and branched-chain amino acids (BCAAs) emerge as pivotal players in modulating immune cell functions and tumor growth. We also discuss ongoing clinical trials that explore metabolic modulation for PDAC, targeting mitochondrial metabolism, asparagine and glutamine addiction, and autophagy inhibition. Overcoming challenges in understanding nutrient effects on immune-stromal-tumor interactions holds promise for innovative therapeutic strategies.

Keywords:  heterogeneity; immunotherapy; metabolic reprogramming; mitochondrial metabolism; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2024.03.008
Biochim Biophys Acta Mol Basis Dis. 2024 Apr 05. pii: S0925-4439(24)00141-8. [Epub ahead of print]1870(5): 167152

Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells.

Qi Zhang, Jixiang Zhou, Denggao Zhai, Qin Jiang, Manyi Yang, Maojun Zhou.

  Intrahepatic cholangiocarcinoma (ICC) is a kind of hepatobiliary tumor that is increasing in incidence and mortality. The gut microbiota plays a role in the onset and progression of cancer, however, the specific mechanism by which the gut microbiota acts on ICC remains unclear. In this study, feces and plasma from healthy controls and ICC patients were collected for 16S rRNA sequencing or metabolomics analysis. Gut microbiota analysis showed that gut microbiota abundance and biodiversity were altered in ICC patients compared with controls. Plasma metabolism analysis showed that the metabolite glutamine content of the ICC patient was significantly higher than that of the controls. KEGG pathway analysis showed that glutamine plays a vital role in ICC. In addition, the use of antibiotics in ICC animals further confirmed that changes in gut microbiota affect changes in glutamine. Further experiments showed that supplementation with glutamine inhibited ferroptosis and downregulated ALK5 and NOX1 expression in HuCCT1 cells. ALK5 overexpression or NOX1 overexpression increased NOX1, p53, PTGS2, ACSL4, LPCAT3, ROS, MDA and Fe2+ and decreased FTH1, SLC7A11 and GSH. Knockdown of NOX1 suppressed FIN56-induced ferroptosis. In vivo, supplementation with glutamine promoted tumor growth. Overexpression of ALK5 repressed tumor growth and induced ferroptosis in nude mice, which could be reversed by the addition of glutamine. Our results suggested that the gut microbiota altered glutamine metabolism to inhibit ferroptosis in ICC by regulating the ALK5/NOX1 axis.

Keywords:  ALK5/NOX1; Ferroptosis; Glutamine; Gut microbiota; Intrahepatic cholangiocarcinoma

DOI:  https://doi.org/10.1016/j.bbadis.2024.167152
Cancer Res. 2024 Apr 08. OF1-OF13

Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.

Arin Nam, Shashi Jain, Chengsheng Wu, Alejandro Campos, Ryan M Shepard, Ziqi Yu, Joshua P Reddy, Tami Von Schalscha, Sara M Weis, Mark Onaitis, Hiromi I Wettersten, David A Cheresh.

Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvβ3 via upregulation of the β3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvβ3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation.
SIGNIFICANCE: Upregulation of integrin αvβ3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related article by xxxx, p. xx.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2700
Cancer Lett. 2024 Apr 04. pii: S0304-3835(24)00255-6. [Epub ahead of print] 216862

The mechanism of extracellular CypB promotes glioblastoma adaptation to glutamine deprivation microenvironment.

Hang Yin, Yang Liu, Qiang Dong, Hongyu Wang, Yunji Yan, Xiaoqing Wang, Xiaoyu Wan, Guoqiang Yuan, Yawen Pan.

  Glioblastoma, previously known as glioblastoma multiform (GBM), is a type of glioma with a high degree of malignancy and rapid growth rate. It is highly dependent on glutamine (Gln) metabolism during proliferation and lags in neoangiogenesis, leading to extensive Gln depletion in the core region of GBM. Gln-derived glutamate is used to synthesize the antioxidant Glutathione (GSH). We demonstrated that GSH levels are also reduced in Gln deficiency, leading to increased reactive oxygen species (ROS) levels. The ROS production induces endoplasmic reticulum (ER) stress, and the proteins in the ER are secreted into the extracellular medium. We collected GBM cell supernatants cultured with or without Gln medium; the core and peripheral regions of human GBM tumor tissues. Proteomic analysis was used to screen out the target-secreted protein CypB. We demonstrated that the extracellular CypB expression is associated with Gln deprivation. Then, we verified that GBM can promote the glycolytic pathway by activating HIF-1α to upregulate the expression of GLUT1 and LDHA expressions. Meanwhile, the DRP1 was activated, increasing mitochondrial fission, thus inhibiting mitochondrial function. To explore the specific mechanism of its regulation, we constructed a si-CD147 knockout model and added human recombinant CypB protein to verify that extracellular CypB influenced the expression of downstream p-AKT through its cell membrane receptor CD147 binding. Moreover, we confirmed that p-AKT could upregulate HIF-1α and DRP1. Finally, we observed that extracellular CypB can bind to the CD147 receptor, activate p-AKT, and upregulate HIF-1α and DRP1 in order to promote glycolysis while inhibiting mitochondrial function to adapt to the Gln-deprived microenvironment.

Keywords:  CypB; Glioblastoma; Glutamine deprivation; Warburg effect

DOI:  https://doi.org/10.1016/j.canlet.2024.216862
Exp Ther Med. 2024 May;27(5): 218

SLC38A2 promotes cell proliferation and invasion by promoting glutamine metabolism in adenomyosis.

Kui Wu, Wei Gong, Jia-Chang Hu, Ying-Chun Duan, Hui-Hui Ke, Li Chen.

  Adenomyosis is a benign uterine disorder that is associated with female infertility, a reduced clinical pregnancy rate and a high risk of miscarriage. Solute carrier family 38 member a2 (SLC38A2) is a glutamine (Gln) transporter that serves roles in various medical conditions. The present study aimed to reveal the role of SLC38A2 in adenomyosis. The mRNA expression levels of SLC38A2 in eutopic endometrial (EU) and ectopic endometrial (EC) tissues from adenomyotic patients were examined by reverse transcription-quantitative PCR. EU and EC cell proliferation and invasion were analyzed by Cell Counting Kit-8 and Transwell assays. Changes in the oxygen consumption rate (OCR) were determined to indicate the mitochondrial respiratory function and observed using a Seahorse analyzer. SLC38A2 expression in EC tissues was upregulated compared with that in normal endometrial tissues. SLC38A2 knockdown repressed EC cell proliferation and invasion. In addition, the Gln content and OCR were decreased in EC cells transfected with SLC38A2-knockdown lentivirus, whereas SLC38A2 overexpression had the opposite effect in EU cells. Furthermore, the increased proliferation and invasion rates and Gln level induced by SLC38A2 overexpression in EU cells were alleviated by CB-839, a glutaminase inhibitor. SLC38A2 overexpression promoted Gln metabolism and oxygen consumption rate, resulting in an increase in cell proliferation and invasion in the adenomyosis context. The present study indicated that reduction of SLC38A2 expression could be a novel target for adenomyosis therapy, and SLC38A2 may be a valuable clinical diagnostic molecule for adenomyosis.

Keywords:  OCR; SLC38A2; adenomyosis; glutamine

DOI:  https://doi.org/10.3892/etm.2024.12506
Nat Cell Biol. 2024 Apr 11.

A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.

Christopher Chidley, Alicia M Darnell, Benjamin L Gaudio, Evan C Lien, Anna M Barbeau, Matthew G Vander Heiden, Peter K Sorger.

Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.

DOI: https://doi.org/10.1038/s41556-024-01402-1
Br J Cancer. 2024 Apr 06.

DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.

Zhen Wang, Shouyi Tang, Luyao Cai, Qing Wang, Dan Pan, Yunmei Dong, Hao Zhou, Jing Li, Ning Ji, Xin Zeng, Yu Zhou, Ying-Qiang Shen, Qianming Chen.

BACKGROUND: Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood.
METHODS: Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects.
RESULTS: Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis.
CONCLUSION: Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

DOI: https://doi.org/10.1038/s41416-024-02670-2
Mol Oncol. 2024 Apr 08.

A guide to ferroptosis in cancer.

Fatma Isil Yapici, Christina M Bebber, Silvia von Karstedt.

  Ferroptosis is a newly identified iron-dependent type of regulated cell death that can also be regarded as death caused by the specific collapse of the lipid antioxidant defence machinery. Ferroptosis has gained increasing attention as a potential therapeutic strategy for therapy-resistant cancer types. However, many ferroptosis-inducing small molecules do not reach the pharmacokinetic requirements for their effective clinical use yet. Nevertheless, their clinical optimization is under development. In this review, we summarize the current understanding of molecular pathways regulating ferroptosis, how cells protect themselves from the induction of ferroptotic cell death, and how a better understanding of cancer cell metabolism can represent vulnerabilities for ferroptosis-based therapies. Lastly, we discuss the context-dependent effect of ferroptosis on various cell types within the tumor microenvironment and address controversies on how tissue ferroptosis might impact systemic cancer immunity in a paracrine manner.

Keywords:  cancer biology; cancer metabolism; cell death; ferroptosis; inflammation; iron

DOI:  https://doi.org/10.1002/1878-0261.13649
Biochim Biophys Acta Mol Basis Dis. 2024 Apr 08. pii: S0925-4439(24)00153-4. [Epub ahead of print] 167164

Metabolic adaptations in cancer stem cells: A key to therapy resistance.

Matthew Masoudi, Dilpreet Moti, Raha Masoudi, Abdul Auwal, M Matakabbir Hossain, Tasfik Ul Haque Pronoy, Khan Mohammad Rashel, Vinod Gopalan, Farhadul Islam.

  Cancer stem cells (CSCs) are a subset of tumor cells that can initiate and sustain tumor growth and cause recurrence and metastasis. CSCs are particularly resistant to conventional therapies compared to their counterparts, owing greatly to their intrinsic metabolic plasticity. Metabolic plasticity allows CSCs to switch between different energy production and usage pathways based on environmental and extrinsic factors, including conditions imposed by conventional cancer therapies. To cope with nutrient deprivation and therapeutic stress, CSCs can transpose between glycolysis and oxidative phosphorylation (OXPHOS) metabolism. The mechanism behind the metabolic pathway switch in CSCs is not fully understood, however, some evidence suggests that the tumor microenvironment (TME) may play an influential role mediated by its release of signals, such as Wnt/β-catenin and Notch pathways, as well as a background of hypoxia. Exploring the factors that promote metabolic plasticity in CSCs offers the possibility of eventually developing therapies that may more effectively eliminate the crucial tumor cell subtype and alter the disease course substantially.

Keywords:  Cancer stem cells; Glycolysis; Metabolic plasticity; Metastasis; Oxidative phosphorylation; Recurrence; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2024.167164
Bioorg Med Chem. 2024 Apr 03. pii: S0968-0896(24)00126-3. [Epub ahead of print]104 117712

Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates.

Patrick A Cardwell, Carlo Del Moro, Michael P Murphy, Adrian J Lapthorn, Richard C Hartley.

  Glutathione-S-transferases are key to the cellular detoxification of xenobiotics and products of oxidative damage. GSTs catalyse the reaction of glutathione (GSH) with electrophiles to form stable thioether adducts. GSTK1-1 is the main GST isoform in the mitochondrial matrix, but the GSTA1-1 and GSTA4-4 isoforms are also thought to be in the mitochondria with their distribution altering in transformed cells, thus potentially providing a cancer specific target. A mitochondria-targeted version of the GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), MitoCDNB, has been used to manipulate the mitochondrial GSH pool. To finesse this approach to target particular GST isoforms in the context of cancer, here we have determined the kcat/Km for the human isoforms of GSTK1-1, GSTA1-1 and GSTA4-4 with respect to GSH and CDNB. We show how the rate of the GST-catalysed reaction between GSH and CDNB analogues can be modified by both the electron withdrawing substituents, and by the position of the mitochondria-targeting triphenylphosphonium on the chlorobenzene ring to tune the activity of mitochondria-targeted substrates. These findings can now be exploited to selectively disrupt the mitochondrial GSH pools of cancer cells expressing particular GST isoforms.

Keywords:  Cancer; Glutathione; Glutathione-S-transferase; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1016/j.bmc.2024.117712
Front Cell Dev Biol. 2024 ;12 1370012

Activating transcription factor 4: a regulator of stress response in human cancers.

Di Wu, Jie Liang.

  Activating transcription factor 4 (ATF4) is an adaptive response regulator of metabolic and oxidative homeostasis. In response to cellular stress, ATF4 is activated and functions as a regulator to promote cell adaptation for survival. As a transcriptional regulator, ATF4 also widely participates in the regulation of amino acid metabolism, autophagy, redox homeostasis and endoplasmic reticulum stress. Moreover, ATF4 is associated with the initiation and progression of glioblastoma, hepatocellular carcinoma, colorectal cancer, gastric cancer, breast cancer, prostate cancer and lung cancer. This review primarily aims to elucidate the functions of ATF4 and its role in multiple cancer contexts. This review proposes potential therapeutic targets for clinical intervention.

Keywords:  autophagy; cancer; metabolism; stress; transcription

DOI:  https://doi.org/10.3389/fcell.2024.1370012
Cancer Discov. 2024 Mar 29. OF1-OF19

Metabolic Signaling in Cancer Metastasis.

Sarah Krieg, Sara Isabel Fernandes, Constantinos Kolliopoulos, Ming Liu, Sarah-Maria Fendt.

Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors and they are crucial substrates for posttranslational modifications on histone and nonhistone proteins. Moreover, metabolic enzymes can have moonlighting functions by acting catalytically, mainly as protein kinases, or noncatalytically through protein-protein interactions. Here, we summarize the current knowledge on metabolic signaling in cancer metastasis.
SIGNIFICANCE: Effective drugs for the prevention and treatment of metastases will have an immediate impact on patient survival. To overcome the current lack of such drugs, a better understanding of the molecular processes that are an Achilles heel in metastasizing cancer cells is needed. One emerging opportunity is the metabolic changes cancer cells need to undergo to successfully metastasize and grow in distant organs. Mechanistically, these metabolic changes not only fulfill energy and biomass demands, which are often in common between cancer and normal but fast proliferating cells, but also metabolic signaling which enables the cell state changes that are particularly important for the metastasizing cancer cells.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0174
Heliyon. 2024 Apr 15. 10(7): e28320

Effect of the dietary supplement PERMEAPROTECT+ TOLERANCE© on gut permeability in a human co-culture epithelial and immune cells model.

Anne Abot, Nicolas Pomié, Gwendoline Astre, Patrice D Cani, Justine Aussant, Emmanuel Barrat, Claude Knauf.

   Background and objective: The leaky gut syndrome is characterized by an intestinal hyperpermeability observed in multiple chronic disorders. Alterations of the gut barrier are associated with translocation of bacterial components increasing inflammation, oxidative stress and eventually dysfunctions of cellular interactions at the origin pathologies. Therapeutic and/or preventive approaches have to focus on the identification of novel targets to improve gut homeostasis. In this context, this study aims to identify the role of PERMEAPROTECT + TOLERANE©, known as PERMEA, a food complement composed of a combination of factors (including l-Glutamine) known to improve gut physiology.
Methods: We tested the effects of PERMEA or l-Glutamine alone (as reference) on gut permeability (FITC dextran method, expression of tight junctions) and its inflammatory/oxidative consequences (cytokines and redox assays, RT-qPCR) in a co-culture of human cells (peripheral blood mononuclear cells and intestinal epithelial cells) challenged with TNFα.
Results: PERMEA prevented intestinal hyperpermeability induced by inflammation. This was linked with its antioxidant and immunomodulatory properties showing a better efficacity than l-Glutamine alone on several parameters including permeability, global antioxidant charge and production of cytokines.
Conclusion: PERMEA is more efficient to restore intestinal physiology, reinforcing the concept that combination of food constituents could be used to prevent the development of numerous diseases.

Keywords:  Antioxidant; Epithelial cells; Immune cells; Intestinal permeability

DOI:  https://doi.org/10.1016/j.heliyon.2024.e28320
Int Immunopharmacol. 2024 Apr 08. pii: S1567-5769(24)00458-2. [Epub ahead of print]132 111940

Prognostic and immunological implications of glutathione metabolism genes in lung adenocarcinoma: A focus on the core gene SMS and its impact on M2 macrophage polarization.

Jianjian Qiu, Zhiping Wang, Yilin Yu, Yangling Zheng, Meifang Li, Cheng Lin.

  Glutathione metabolism (GM) is a crucial part of various metabolic and pathophysiological processes. However, its role in lung adenocarcinoma (LUAD) has not been comprehensively studied. This study aimed to explore the potential relationship between GM genes, the prognosis, and the immune microenvironment of patients with LUAD. We constructed a risk signature model containing seven GM genes using Lasso combined Cox regression and validated it using six GEO datasets. Our analysis showed that it is an independent prognostic factor. Functional enrichment analysis revealed that the GM genes were significantly enriched in cell proliferation, cell cycle regulation, and metabolic pathways. Clinical and gene expression data of patients with LUAD were obtained from the TCGA database and patients were divided into high- and low-risk groups. The high-risk patient group had a poor prognosis, reduced immune cell infiltration, poor response to immunotherapy, high sensitivity to chemotherapy, and low sensitivity to targeted therapy. Subsequently, single-cell transcriptome analysis using the GSE143423 and GSE127465 datasets revealed that the core SMS gene was highly enriched in M2 Macrophages. Finally, nine GEO datasets and multiple fluorescence staining revealed a correlation between the SMS expression and M2 macrophage polarization. Our prognostic model in which the core SMS gene is closely related to M2 macrophage polarization is expected to become a novel target and strategy for tumor therapy.

Keywords:  Glutathione metabolism genes; Lung adenocarcinoma; M2 macrophage; Risk signature model; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.111940
Bioorg Chem. 2024 Apr 02. pii: S0045-2068(24)00230-X. [Epub ahead of print]147 107325

Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Xi Sheng, Meng-Meng Wang, Guan-Dong Zhang, Yan Su, Hong-Bao Fang, Zheng-Hong Yu, Zhi Su.

  Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

Keywords:  Apoptosis; Autophagy; Cancer cell metabolism; Ir(III) complex; Mitochondria targeting

DOI:  https://doi.org/10.1016/j.bioorg.2024.107325
ACS Appl Mater Interfaces. 2024 Apr 09.

Amplification of Oxygen-Independent Free Radicals Based on a Glutathione Depletion and Biosynthesis Inhibition Strategy for Photothermal and Thermodynamic Therapy of Hypoxic Tumors.

Haowu Huang, Wenqiu Li, Yiwang Zhao, Shunyu Yao, Xiaoqing Liu, Mingxing Liu, Huiling Guo.

  Thermodynamic therapy (TDT) based on oxygen-independent free radicals exhibits promising potential for the treatment of hypoxic tumors. However, its therapeutic efficacy is seriously limited by the premature release of the drug and the free radical scavenging effect of glutathione (GSH) in tumors. Herein, we report a GSH depletion and biosynthesis inhibition strategy using EGCG/Fe-camouflaged gold nanorod core/ZIF-8 shell nanoparticles embedded with azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) and L-buthionine-sulfoximine (BSO) for tumor-targeting photothermal (PTT) and thermodynamic therapy (TDT). This nanoplatform (GNR@ZIF-8-AIPH/BSO@EGCG/Fe, GZABEF) endows a pH-responsive release performance. With the 67 kDa lamin receptor (67LR)-targeting ability of EGCG, GZABEF could selectively release oxygen-independent free radicals in tumor cells under 1064 nm laser irradiation. More importantly, Fe3+-mediated GSH depletion and BSO-mediated GSH biosynthesis inhibition significantly boosted the accumulation of alkyl radicals. In 4T1 cells, GZABEF induced cancer cell death via intracellular GSH depletion and GSH peroxidase 4 (GPX4) inactivation. In a subcutaneous xenograft model of 4T1, GZABEF demonstrated remarkable tumor growth inhibition (78.2%). In addition, excellent biosafety and biocompatibility of GZABEF were observed both in vitro and in vivo. This study provides inspiration for amplified TDT/PTT-mediated antitumor efficacy.

Keywords:  glutathione depletion; oxygen-independent free radicals; photothermal therapy; thermodynamic therapy; tumor-targeting

DOI:  https://doi.org/10.1021/acsami.3c17157