bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2024‒08‒18
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Deacetylation of GLUD1 maintains the survival of lung adenocarcinoma cells under glucose starvation by inhibiting autophagic cell death.
  2. Glycolysis, The Sweet Appetite of the Tumour Microenvironment.
  3. Arsenic-induced disruption of circadian rhythms and glutamine anaplerosis in human urothelial carcinoma.
  4. GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
  5. Metabolomics and cellular altered pathways in cancer biology: A review.
  6. Mitochondrial complex I promotes kidney cancer metastasis.
  7. Glutathione-Dependent Pathways in Cancer Cells.
  8. Metabolomic characterization of monoclonal antibody-producing Chinese hamster lung (CHL)-YN cells in glucose-controlled serum-free fed-batch operation.
  9. Gamma-glutamyl transferase secreted by Helicobacter pylori promotes the development of gastric cancer by affecting the energy metabolism and histone methylation status of gastric epithelial cells.
  10. Adapt and shape: metabolic features within the metastatic niche.
  11. Impact of SARS-CoV-2 infection on immune cell cuproptosis in patients with lung adenocarcinoma via glutamine regulation.
  12. Metabolic profiling of atypical meningioma and recurrent meningioma: a comparative analysis with proton magnetic resonance spectroscopy.
  13. Effects of H9N2 avian influenza virus infection on metabolite content and gene expression in chick DF1 cells.
  14. LC-MS analysis of chiral amino acids in human urine reveals D-amino acids as potential biomarkers for colorectal cancer.
  15. Decreased glutathione synthesis in granulosa cells, but not oocytes, of growing follicles decreases fertility in mice.
  16. Hyaluronic acid-coated porphyrin nanoplatform with oxygen sustained supplying and glutathione depletion for enhancing photodynamic/ion/chemo synergistic cancer treatment.
  17. SIRT1 promotes doxorubicin-induced breast cancer drug resistance and tumor angiogenesis via regulating GSH-mediated redox homeostasis.
  18. Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments.
  19. Glutathione-dependent degradation of SMARCA2/4 for targeted lung cancer therapy with improved selectivity.
  20. Nebulized Glutathione as a Key Antioxidant for the Treatment of Oxidative Stress in Neurodegenerative Conditions.
  1. Cell Insight. 2024 Oct;3(5): 100186
    Deacetylation of GLUD1 maintains the survival of lung adenocarcinoma cells under glucose starvation by inhibiting autophagic cell death.
    Qifan Hu, Longhua Sun, Zhujun Cheng, Lei Wang, Xiaorui Wan, Jing Xu, Junyao Cheng, Zuorui Wang, Yi Yuan, Keru Wang, Tianyu Han.
      Enhanced glutamine catabolism is one of the main metabolic features of cancer, providing energy and intermediate metabolites for cancer progression. However, the functions of glutamine catabolism in cancer under nutrient deprivation need to be further clarified. Here, we discovered that deacetylation of glutamate dehydrogenase 1 (GLUD1), one of the key enzymes in glutamine catabolism, maintains the survival of lung adenocarcinoma (LUAD) cells under glucose starvation by inhibiting autophagic cell death. We found that glucose starvation increased GLUD1 activity by reducing its acetylation on Lys84 and promoted its active hexamer formation. Besides, deacetylation of GLUD1 induced its cytoplasmic localization, where GLUD1 was ubiquitinated in K63-linkage by TRIM21, leading to the binding of GLUD1 with cytoplasmic glutaminase KGA. These two effects enhanced glutamine metabolism both in mitochondria and cytoplasm, increased the production of alpha-ketoglutarate (α-KG). Meanwhile, cytoplasmic GLUD1 also interacted with p62 and prevented its acetylation, leading to the inhibition of p62 body formation. All these effects blocked autophagic cell death of LUAD cells under glucose starvation. Taken together, our results reveal a novel function of GLUD1 under glucose deprivation in LUAD cells and provide new insights into the functions of glutamine catabolism during cancer progression.
    DOI:  https://doi.org/10.1016/j.cellin.2024.100186
  2. Cancer Lett. 2024 Aug 08. pii: S0304-3835(24)00551-2. [Epub ahead of print] 217156
    Glycolysis, The Sweet Appetite of the Tumour Microenvironment.
    Zeinab Kooshan, Lilibeth Cárdenas-Piedra, Judith Clements, Jyotsna Batra.
      Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.
    Keywords:  Glucose metabolism; Warburg effect; cancer therapy; clinical implications; hypoxia; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.217156
  3. J Trace Elem Med Biol. 2024 Aug 02. pii: S0946-672X(24)00127-5. [Epub ahead of print]86 127507
    Arsenic-induced disruption of circadian rhythms and glutamine anaplerosis in human urothelial carcinoma.
    Shu-Jyuan Chang, Wan-Tzu Chen, Chee-Yin Chai.
      Inorganic arsenic (iAs)-induced urothelial carcinoma (UC) develops into a poor-prognosis malignancy. Arsenic-induced oxidative stress contributes to circadian rhythm disruption altered metabolism. Glutamine anaplerosis is a common metabolic feature of rapidly proliferating malignant cells, in which glutaminase (GLS) is a key enzyme in this process. Therefore, this study intends to determine if arsenic-induced oxidative stress can alter circadian rhythms and promote glutamine anaplerosis. Exonic expression of core circadian molecules (CLOCK, ARNTL, and NR1D1) and GLS in varying grades of UC were assessed using 423 bladder cancer samples from the TCGA Urothelial Bladder Cancer (BLCA) dataset. The levels of circadian proteins and metabolic markers in 44 UC patients from non-black foot disease (BFD) and BFD areas were detected by immunohistochemistry. In vitro and in vivo experiments elucidated the regulatory mechanisms of arsenic-mediated circadian disturbance and metabolic alteration. Public database analysis showed that ARNTL, NR1D1, and GLS exhibited greater expression in more high-grade UC. Strong immunoreactivity for BMAL1, GLS, and low levels of NR1D1 were found in malignant urothelial lesions, especially in arsenic-exposed UC. Arsenic-induced overexpression of BMAL1 and GLS involves activation of NADH: quinone oxidoreductase 1 (NQO1), continuously altering the NADH oscillations to promote glutamate metabolism in SV-HUC-1, T24 and BFTC-905 cells. These phenomenon were also demonstrated in the urothelium of arsenic-exposed animals. The present findings highlight the potential clinical significance of BMAL1 and GLS in UC in the BFD region. Furthermore, these results suggest that arsenic interferes with circadian rhythm and glutamine anaplerosis by NADH oscillatory imbalance in urothelial cells and urothelial cancer cells, predisposing them to malignant development.
    Keywords:  Arsenite; Circadian rhythms; Glutamine anaplerosis; Urothelial carcinoma
    DOI:  https://doi.org/10.1016/j.jtemb.2024.127507
  4. Dev Cell. 2024 Aug 02. pii: S1534-5807(24)00455-6. [Epub ahead of print]
    GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
    Inés Soro-Arnáiz, Gillian Fitzgerald, Sarah Cherkaoui, Jing Zhang, Paola Gilardoni, Adhideb Ghosh, Ori Bar-Nur, Evi Masschelein, Pierre Maechler, Nicola Zamboni, Martin Poms, Alessio Cremonesi, Juan Carlos Garcia-Cañaveras, Katrien De Bock, Raphael Johannes Morscher.
      Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation.
    Keywords:  GLUD1; glutamine metabolism; malate aspartate shuttle; metabolite compartmentalization; muscle stem cells; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.015
  5. J Biochem Mol Toxicol. 2024 Sep;38(9): e23807
    Metabolomics and cellular altered pathways in cancer biology: A review.
    Jitender Kumar Bhardwaj, Anshu Siwach, Som Nath Sachdeva.
      Cancer is a deadly disease that affects a cell's metabolism and surrounding tissues. Understanding the fundamental mechanisms of metabolic alterations in cancer cells would assist in developing cancer treatment targets and approaches. From this perspective, metabolomics is a great analytical tool to clarify the mechanisms of cancer therapy as well as a useful tool to investigate cancer from a distinct viewpoint. It is a powerful emerging technology that detects up to thousands of molecules in tissues and biofluids. Like other "-omics" technologies, metabolomics involves the comprehensive investigation of micromolecule metabolites and can reveal important details about the cancer state that is otherwise not apparent. Recent developments in metabolomics technologies have made it possible to investigate cancer metabolism in greater depth and comprehend how cancer cells utilize metabolic pathways to make the amino acids, nucleotides, and lipids required for tumorigenesis. These new technologies have made it possible to learn more about cancer metabolism. Here, we review the cellular and systemic effects of cancer and cancer treatments on metabolism. The current study provides an overview of metabolomics, emphasizing the current technologies and their use in clinical and translational research settings.
    Keywords:  bioinformatics; biomarker; cancer; metabolic reprogramming; metabolomics
    DOI:  https://doi.org/10.1002/jbt.23807
  6. Nature. 2024 Aug 14.
    Mitochondrial complex I promotes kidney cancer metastasis.
    Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
    DOI:  https://doi.org/10.1038/s41586-024-07812-3
  7. Int J Mol Sci. 2024 Aug 01. pii: 8423. [Epub ahead of print]25(15):
    Glutathione-Dependent Pathways in Cancer Cells.
    Elena Kalinina.
      The most abundant tripeptide-glutathione (GSH)-and the major GSH-related enzymes-glutathione peroxidases (GPxs) and glutathione S-transferases (GSTs)-are highly significant in the regulation of tumor cell viability, initiation of tumor development, its progression, and drug resistance. The high level of GSH synthesis in different cancer types depends not only on the increasing expression of the key enzymes of the γ-glutamyl cycle but also on the changes in transport velocity of its precursor amino acids. The ability of GPxs to reduce hydroperoxides is used for cellular viability, and each member of the GPx family has a different mechanism of action and site for maintaining redox balance. GSTs not only catalyze the conjugation of GSH to electrophilic substances and the reduction of organic hydroperoxides but also take part in the regulation of cellular signaling pathways. By catalyzing the S-glutathionylation of key target proteins, GSTs are involved in the regulation of major cellular processes, including metabolism (e.g., glycolysis and the PPP), signal transduction, transcription regulation, and the development of resistance to anticancer drugs. In this review, recent findings in GSH synthesis, the roles and functions of GPxs, and GST isoforms in cancer development are discussed, along with the search for GST and GPx inhibitors for cancer treatment.
    Keywords:  GSH; S-glutathionylation; cancer cells; glutathione peroxidase; glutathione transferase
    DOI:  https://doi.org/10.3390/ijms25158423
  8. Biotechnol Bioeng. 2024 Sep;121(9): 2848-2867
    Metabolomic characterization of monoclonal antibody-producing Chinese hamster lung (CHL)-YN cells in glucose-controlled serum-free fed-batch operation.
    Puriwat Sukwattananipaat, Hirotaka Kuroda, Noriko Yamano-Adachi, Takeshi Omasa.
      The fast-growing Chinese hamster lung (CHL)-YN cell line was recently developed for monoclonal antibody production. In this study, we applied a serum-free fed-batch cultivation process to immunoglobulin (Ig)G1-producing CHL-YN cells, which were then used to design a dynamic glucose supply system to stabilize the extracellular glucose concentration based on glucose consumption. Glucose consumption of the cultures rapidly oscillated following three phases of glutamine metabolism: consumption, production, and re-consumption. Use of the dynamic glucose supply prolonged the viability of the CHL-YN-IgG1 cell cultures and increased IgG1 production. Liquid chromatography with tandem mass spectrometry-based target metabolomics analysis of the extracellular metabolites during the first glutamine shift was conducted to search for depleted compounds. The results suggest that the levels of four amino acids, namely arginine, aspartate, methionine, and serine, were sharply decreased in CHL-YN cells during glutamine production. Supporting evidence from metabolic and gene expression analyses also suggest that CHL-YN cells acquired ornithine- and cystathionine-production abilities that differed from those in Chinese hamster ovary-K1 cells, potentially leading to proline and cysteine biosynthesis.
    Keywords:  CHL‐YN cells; CHO cells; Chinese hamster lung; fed‐batch; glucose feeding development; metabolomics
    DOI:  https://doi.org/10.1002/bit.28777
  9. Cell Commun Signal. 2024 Aug 15. 22(1): 402
    Gamma-glutamyl transferase secreted by Helicobacter pylori promotes the development of gastric cancer by affecting the energy metabolism and histone methylation status of gastric epithelial cells.
    Xin Jiang, Weijun Wang, Zeyu Wang, Zhe Wang, Huiying Shi, Lingjun Meng, Suya Pang, Mengke Fan, Rong Lin.
      BACKGROUND: Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer.METHODS: A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays.
    RESULTS: H. pylori can colonize the host's stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression.
    CONCLUSIONS: H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.
    Keywords:   Helicobacter pylori ; Alpha-ketoglutarate; Energy metabolism; Gamma-glutamyl transferase; Methylation; Wnt/β-catenin
    DOI:  https://doi.org/10.1186/s12964-024-01780-x
  10. Trends Endocrinol Metab. 2024 Aug 08. pii: S1043-2760(24)00197-8. [Epub ahead of print]
    Adapt and shape: metabolic features within the metastatic niche.
    Erica Pranzini, Luigi Ippolito, Elisa Pardella, Elisa Giannoni, Paola Chiarugi.
      The success of disseminating cancer cells (DTCs) at specific metastatic sites is influenced by several metabolic factors. Even before DTCs arrival, metabolic conditioning from the primary tumor participates in creating a favorable premetastatic niche at distant organs. In addition, DTCs adjust their metabolism to better survive along the metastatic journey and successfully colonize their ultimate destination. However, the idea that the environment of the target organs may metabolically impact the metastatic fate is often underestimated. Here, we review the coexistence of two distinct strategies by which cancer cells shape and/or adapt to the metabolic profile of colonized tissues, ultimately creating a proper soil for their seeding and proliferation.
    Keywords:  metabolic adaptation; metastatic niche; nutrient availability; organotropism; tissue metabolism
    DOI:  https://doi.org/10.1016/j.tem.2024.07.016
  11. Int Immunopharmacol. 2024 Aug 10. pii: S1567-5769(24)01433-4. [Epub ahead of print]140 112912
    Impact of SARS-CoV-2 infection on immune cell cuproptosis in patients with lung adenocarcinoma via glutamine regulation.
    Dan Wang, Xijin Deng, Shanshan Li, Si Ri Gu Leng Sana.
      OBJECTIVE: Lung adenocarcinoma (LA), the most prevalent type of lung cancer, is associated with a high mortality rate, especially among patients with cancer previously infected with coronavirus disease (COVID-19). Therefore, this study aimed to explore the mechanisms by which COVID-19 exacerbates LA progression in a clinical setting.METHODS: The experiment involved collecting serum samples from three groups: a healthy control group (Con, n = 20), a lung adenocarcinoma group (LA, n = 30), and a group of lung adenocarcinoma patients with first-time COVID-19 infection (C-LA, n = 58). Metabolites were analyzed using liquid chromatography-mass spectrometry, and differentially expressed metabolites were identified through bioinformatics analysis. The concentrations of glutathione (GSH), reactive oxygen species (ROS), and copper ions (Cu2+) in the serum of patients in the Con and C-LA groups were measured. Mitochondrial morphological changes in monocytes and lymphocytes were observed using electron microscopy.
    RESULTS: Metabolomic analysis revealed 142 distinct metabolites, among which glutamine (Gln) expression was significantly decreased in the C-LA group. Compared to the Con group, the C-LA group showed a significant decrease in GSH and a notable increase in ROS and Cu2+. Further research revealed that the mitochondria of monocytes and lymphocytes in the C-LA group exhibited corresponding alterations indicative of cuproptosis.
    CONCLUSIONS: SARS-CoV-2 infection may reduce Gln levels, leading to reduced GSH levels, copper overload, and increased death of immune cells, which may further exacerbate rapid tumor development. Thus, glutamine regulation plays an important role in LA progression in patients with COVID-19 and represents a potential therapeutic target.
    Keywords:  COVID-19; Cuproptosis; Glutamine; Lung adenocarcinoma; Mitochondria
    DOI:  https://doi.org/10.1016/j.intimp.2024.112912
  12. J Neurosurg. 2024 Aug 16. 1-10
    Metabolic profiling of atypical meningioma and recurrent meningioma: a comparative analysis with proton magnetic resonance spectroscopy.
    Tomomi Kuninaka, Kazutaka Kisyaba, Shigetaka Kobayashi, Hideki Nagamine, Yohei Hokama, Kenichi Sugawara, Masahiko Nishimura, Shogo Ishiuchi.
      OBJECTIVE: Meningiomas are predominantly benign, but some cases exhibit recurrent growth after surgery and undergo malignant transformation to WHO grade 2 or grade 3. Despite progress in genetic analyses, advancements in metabolomic analysis remain less established. Herein, the authors investigated metabolic activity differences between WHO grade 1 meningiomas and WHO grade 2 or 3 meningiomas by noninvasively using proton magnetic resonance spectroscopy (1H-MRS), aiming to preoperatively estimate malignancy. They also reviewed the literature to elucidate this aspect of meningioma research.METHODS: At Ryukyu University Hospital, the authors focused on 93 patients diagnosed with meningioma between 2011 and 2021. The inclusion criteria encompassed prior surgery, pathological diagnoses of meningioma, and preoperative 1H-MRS. Group I included 71 patients with WHO grade 1 meningioma and group II included 22 patients, comprising 19 and 3 with WHO grade 2 and 3 meningioma, respectively. The authors retrospectively conducted a comparative analysis of patient backgrounds and tumor metabolites.
    RESULTS: Group I and II did not differ significantly in terms of patient demographic characteristics (age and sex). Group II demonstrated a significantly lower extent of tumor resection (p < 0.01), higher MIB-1 labeling index (LI) (p < 0.05), higher incidence of prior irradiation (p < 0.001), and increased rate of tumor recurrence (p = 0.005) compared to group I. According to 1H-MRS, all metabolites, except lactate, displayed significantly higher median creatine (Cr) ratios in group II than group I: glutamine/Cr was 8.46, glutamate/Cr was 9.49, lipid/Cr was 11.36, and choline/Cr was 2.77. According to the receiver operating characteristic (ROC) analysis, glutamine had the largest area under the curve of 0.765 among 10 metabolites, and the cutoff value for distinguishing between group I and II was 5.76.
    CONCLUSIONS: In cases pathologically graded as WHO grade 2 or 3 meningiomas, metabolic products such as glutamine, glutamate, lipids, and choline increased significantly. These changes were correlated with elevation of the MIB-1 LI. In group II, the mean MIB-1 LI was 8.58, significantly higher than in group I, suggesting a strong association with pathological malignancy. Therefore, 1H-MRS may help to noninvasively predict tumor metabolic activity and tumor recurrence. Furthermore, the authors concluded from the ROC analysis that glutamine may be a potential indicator of future growth of meningioma and benefits of early surgery.
    Keywords:  1H-MRS; glutamate; glutamine; meningioma; tumor
    DOI:  https://doi.org/10.3171/2024.4.JNS24187
  13. Poult Sci. 2024 Jul 30. pii: S0032-5791(24)00704-1. [Epub ahead of print]103(10): 104125
    Effects of H9N2 avian influenza virus infection on metabolite content and gene expression in chick DF1 cells.
    Yijia Zhang, Li Li, Xin Xin, Lifeng Chang, Haowei Luo, Wenna Qiao, Jun Xia, Jihui Ping, Juan Su.
      After viral infection, the virus relies on the host cell's complex metabolic and biosynthetic machinery for replication. However, the impact of avian influenza virus (AIV) on metabolites and gene expression in poultry cells remains unclear. To investigate this, we infected chicken embryo fibroblasts DF1 cells with H9N2 AIV at an MOI of 3. Our aim was to explore how H9N2 AIV alters DF1 cells metabolic pathways to facilitate its replication. We employed metabolomics and transcriptomics techniques to analyze changes in metabolite content and gene expression. Metabolomics analysis revealed a significant increase in glutathione-related metabolites, including reduced glutathione (GSH), oxidized glutathione (GSSG) and total glutathione (T-GSH) upon H9N2 AIV infection in DF1 cells. Elisa results confirmed elevated levels of GSH, GSSG, and T-GSH consistent with metabolomics findings, noting a pronounced increase in GSSG compared to GSH. Transcriptomics showed significant alterations in genes involved in glutathione synthesis and metabolism post-H9N2 infection. However, adding the glutathione synthesis inhibitor BSO exogenously significantly promoted H9N2 replication in DF1 cells. This was accompanied by increased mRNA levels of pro-inflammatory cytokines (IL-1β, IFN-γ) and decreased mRNA levels of anti-inflammatory cytokines (TGF-β, IL-13). BSO also reduced catalase (CAT) gene expression and inhibited its activity, leading to higher reactive oxygen species (ROS) and malondialdehyde (MDA) level in DF1 cells. qPCR results indicated decreased mRNA levels of Nrf2, NQO1, and HO-1 with BSO, ultimately increasing oxidative stress in DF1 cells. Therefore, the above results indicated that H9N2 AIV infection in DF1 cells activated the glutathione metabolic pathway to enhance the cell's self-defense mechanism against H9N2 replication. However, when GSH synthesis is inhibited within the cells, it leads to an elevated oxidative stress level, thereby promoting H9N2 replication within the cells through Nrf2/HO-1 pathway. This study provides a theoretical basis for future rational utilization of the glutathione metabolic pathway to prevent viral replication.
    Keywords:  DF1 cell; GSH; H9N2; glutathione metabolism; oxidative stress
    DOI:  https://doi.org/10.1016/j.psj.2024.104125
  14. J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Aug 05. pii: S1570-0232(24)00279-4. [Epub ahead of print]1245 124270
    LC-MS analysis of chiral amino acids in human urine reveals D-amino acids as potential biomarkers for colorectal cancer.
    Wenchan Deng, Chundan Ye, Wei Wang, Rongrong Huang, Cheng Guo, Yuanjiang Pan, Cuirong Sun.
      Colorectal cancer (CRC) is a common malignant tumor in the gastrointestinal tract. Changes in amino acid metabolites have been implicated in tumorigenesis and disease progression. Biomarkers on the basis of chiral amino acids, especially D-amino acids, have not been established for early diagnosis of CRC. Quantification of chiral amino acids, especially very low concentrations of endogenous D-amino acids, is technically challenging. We report here the quantification of L- and D-amino acids in urine samples collected from 115 CRC patients and 155 healthy volunteers, using an improved method. The method of chiral labeling, liquid chromatography, and tandem mass spectrometry enabled separation and detection of 28 amino acids (14 L-amino acids, 13 D-amino acids and Gly). Orthogonal partial least squares discriminant analysis identified 14 targeted variables among these chiral amino acids that distinguished the CRC from the healthy controls. Binary logistic regression analysis revealed that D-α-aminobutyric acid (D-AABA), L-alanine (L-Ala), D-alanine (D-Ala), D-glutamine (D-Gln) and D-serine (D-Ser) could be potential biomarkers for CRC. A receiver operating characteristic curve analysis of combined multi-variables contributed to an area under the curve (AUC) of 0.995 with 98.3 % sensitivity and 96.8 % specificity. A model constructed with D-AABA, D-Ala, D-Gln, and D-Ser achieved an AUC of 0.988, indicating important contributions of D-amino acids to the association with CRC. Further analysis also demonstrated that the metabolic aberration was associated with age and the development of CRC, D-methionine (D-Met) was decreased in CRC patients with age over 50, and D/L-Gln in patients at stage IV was higher than patients at stage I. This study provides the signature of D-amino acids in urine samples and offers a promising strategy for developing non-invasive diagnosis of CRC.
    Keywords:  Biomarkers; Colorectal cancer; D-amino acids; HPLC-MS/MS; Human urine; Metabolomics
    DOI:  https://doi.org/10.1016/j.jchromb.2024.124270
  15. Biol Reprod. 2024 Aug 16. pii: ioae124. [Epub ahead of print]
    Decreased glutathione synthesis in granulosa cells, but not oocytes, of growing follicles decreases fertility in mice.
    Rachel Cinco, Kelli Malott, Jinhwan Lim, Laura Ortiz, Christine Pham, Angelica Rosario, Jennifer Welch, Ulrike Luderer.
      Prior studies showed that mice deficient in the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in synthesis of the thiol antioxidant glutathione (GSH), have decreased ovarian GSH concentrations, chronic ovarian oxidative stress, poor oocyte quality resulting in early preimplantation embryonic mortality and decreased litter size, and accelerated age-related decline in ovarian follicle numbers. Global deficiency of the catalytic subunit of this enzyme, Gclc, is embryonic lethal. We tested the hypothesis that granulosa cell- or oocyte-specific deletion of Gclc recapitulates the female reproductive phenotype of global Gclm deficiency. We deleted Gclc in granulosa cells or oocytes of growing follicles using Gclc floxed transgenic mice paired with Amhr2-Cre or Zp3-Cre alleles respectively. We discovered that granulosa cell-specific deletion of Gclc in Amhr2Cre;Gclc(f/-) mice recapitulates the decreased litter size observed in Gclm-/- mice, but does not recapitulate the accelerated age-related decline in ovarian follicles observed in Gclm-/- mice. In addition to having lower GSH concentrations in granulosa cells, Amhr2Cre;Gclc(f/-) mice also had decreased GSH concentrations in oocytes. By contrast, oocyte-specific deletion of Gclc in Zp3Cre;Gclc(f/-) mice did not affect litter size or accelerate the age-related decline in follicle numbers, and these mice did not have decreased oocyte GSH concentrations, consistent with transport of GSH between cells via gap junctions. The results suggest that GSH deficiency at earlier stages of follicle development may be required to generate the accelerated follicle depletion phenotype observed in global Gclm null mice.
    Keywords:  Fertility; Glutamate cysteine ligase; Glutathione; Ovarian follicle; Ovary; Oxidative stress
    DOI:  https://doi.org/10.1093/biolre/ioae124
  16. Int J Biol Macromol. 2024 Aug 12. pii: S0141-8130(24)05466-7. [Epub ahead of print]278(Pt 1): 134661
    Hyaluronic acid-coated porphyrin nanoplatform with oxygen sustained supplying and glutathione depletion for enhancing photodynamic/ion/chemo synergistic cancer treatment.
    Shaochen Wang, Ningning Xu, Shuling Yu, Wen Si, Miaojie Yang, Yu Liu, Yan Zheng, Shuang Zhao, Jiahua Shi, Jintao Yuan.
      Hypoxia and high concentration of glutathione (GSH) in tumor seriously hinder the role of reactive oxygen species (ROS) and oxygen-dependence strategy in tumor treatment. In this work, a self-generating oxygen and self-consuming GSH hyaluronic acid (HA)-coated porphyrin nanoplatform (TAPPP@CaO2/Pt(IV)/HA) is established for enhancing photodynamic/ion/chemo targeting synergistic therapy of tumor. During the efforts of ROS production by nanosystems, a GSH consuming strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. CaO2 in the nanosystems is decomposed into O2 and H2O2 in an acidic environment, which alleviates hypoxia and enhances the photodynamic therapy (PDT) effect. Calcium overload causes mitochondria dysfunction and induces apoptosis. Pt (IV) reacts with GSH to produce Pt (II) for chemotherapy and reduce the concentration of GSH, protecting ROS from scavenging for augmenting ROS-induced oxidative damage. In vitro and in vivo results demonstrated the self-generating oxygen and self-consuming GSH strategy can enhance ROS-dependent PDT coupled with ion/chemo synergistic therapy. The proposed strategy not only solves the long-term problem that hypoxia limits therapeutic effect of PDT, but also ameliorates the highly reducing environment of tumors. Thus the preparation of TAPPP@CaO2/Pt(IV)/HA provided a novel strategy for the effective combined therapy of cancers.
    Keywords:  Calcium overload; GSH depletion; Porphyrin nanosystem; Self-produced oxygen; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.134661
  17. Mol Carcinog. 2024 Aug 13.
    SIRT1 promotes doxorubicin-induced breast cancer drug resistance and tumor angiogenesis via regulating GSH-mediated redox homeostasis.
    Shashikanta Sahoo, Sunita Kumari, Sriravali Pulipaka, Yogesh Chandra, Srigiridhar Kotamraju.
      Sirtuin 1 (SIRT1), a member of histone deacetylase III family, plays a pivotal role in mediating chemoresistance in several cancers, including breast cancer. However, the molecular mechanism by which the deregulated SIRT1 promotes doxorubicin (Dox) resistance is still elusive. Here, we showed that the cell proliferation rates and invasive properties of MDA-MB-231 breast cancer cells were increased from low- to high-Dox-resistant cells. In agreement, severe combined immunodeficiency disease (SCID) mice bearing labeled MDA-MB-231high Dox-Res cells showed significantly higher tumor growth, angiogenesis, and metastatic ability than parental MDA-MB-231 cells. Interestingly, the levels of SIRT1 and glutathione (GSH) were positively correlated with the degree of Dox-resistance. Dox-induced SIRT1 promoted NRF2 nuclear translocation with an accompanying increase in the antioxidant response element promotor activity and GSH levels. In contrast, inhibition of SIRT1 by EX527 greatly reversed these events. More so, Dox-resistance-induced pro-proliferative, proangiogenic, and invasive effects were obviated with depletion of either SIRT1 or GSH. Together, Dox-induced SIRT1 promotes dysregulation of redox homeostasis leading to breast cancer chemoresistance, tumor aggressiveness, angiogenesis, and metastasis.
    Keywords:  GSH; SIRT1; breast cancer; doxorubicin; drug resistance
    DOI:  https://doi.org/10.1002/mc.23809
  18. Int J Mol Sci. 2024 Jul 29. pii: 8284. [Epub ahead of print]25(15):
    Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments.
    Jianda Yue, Yekui Yin, Xujun Feng, Jiawei Xu, Yaqi Li, Tingting Li, Songping Liang, Xiao He, Zhonghua Liu, Ying Wang.
      In the development and progression of cervical cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and reactive oxygen species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical cancer both in vitro and in silico.
    Keywords:  SLC7A11/xCT axis; cervical cancer; drug discovery; oxidative stress; virtual screening and molecular dynamics simulation
    DOI:  https://doi.org/10.3390/ijms25158284
  19. Eur J Med Chem. 2024 Aug 08. pii: S0223-5234(24)00632-9. [Epub ahead of print]277 116751
    Glutathione-dependent degradation of SMARCA2/4 for targeted lung cancer therapy with improved selectivity.
    Ming Ji, Dehao Yu, Xinmin Liu, Luo Wang, Dongli Zhang, Zhengduo Yang, Wanqiao Huang, Heli Fan, Lulu Wang, Huabing Sun.
      SMARCA2 and SMARCA4 are the mutually exclusive catalytic subunits of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, and have recently been considered as attractive synthetic lethal targets for PROTAC-based cancer therapy. However, the potential off-tissue toxicity towards normal tissues remains a concern. Here, we optimize a GSH-inducible SMARCA2/4-based PROTAC precursor with selective antitumor activity towards lung cancer cells and negligible cytotoxicity towards normal cells in both in vitro and in vivo studies. The precursor is not bioactive or cytotoxic, but preferentially responds to endogenous GSH in GSH-rich lung cancer cells, releasing active PROTAC to degrade SMARCA2/4 via PROTAC-mediated proteasome pathway. Subsequent xenograft model study reveals that selective SMARCA2/4 degradation in lung tumors triggers DNA damage and apoptosis, which significantly inhibits lung cancer cell proliferation without obvious adverse events towards normal tissues. This study exemplifies the targeted degradation of SMARCA2/4 in lung cancer cells by the GSH-responsive PROTAC precursor, highlighting its potential as an encouraging cancer therapeutic strategy.
    Keywords:  Glutathione-responsive; Lung cancer therapy; PROTACs; SMARCA2/4; Selective antitumor activity
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116751
  20. Nutrients. 2024 Jul 31. pii: 2476. [Epub ahead of print]16(15):
    Nebulized Glutathione as a Key Antioxidant for the Treatment of Oxidative Stress in Neurodegenerative Conditions.
    João Vitor Lana, Alexandre Rios, Renata Takeyama, Napoliane Santos, Luyddy Pires, Gabriel Silva Santos, Izair Jefthé Rodrigues, Madhan Jeyaraman, Joseph Purita, Jose Fábio Lana.
      Glutathione (GSH), a tripeptide synthesized intracellularly, serves as a pivotal antioxidant, neutralizing reactive oxygen species (ROS) and reactive nitrogen species (RNS) while maintaining redox homeostasis and detoxifying xenobiotics. Its potent antioxidant properties, particularly attributed to the sulfhydryl group (-SH) in cysteine, are crucial for cellular health across various organelles. The glutathione-glutathione disulfide (GSH-GSSG) cycle is facilitated by enzymes like glutathione peroxidase (GPx) and glutathione reductase (GR), thus aiding in detoxification processes and mitigating oxidative damage and inflammation. Mitochondria, being primary sources of reactive oxygen species, benefit significantly from GSH, which regulates metal homeostasis and supports autophagy, apoptosis, and ferroptosis, playing a fundamental role in neuroprotection. The vulnerability of the brain to oxidative stress underscores the importance of GSH in neurological disorders and regenerative medicine. Nebulization of glutathione presents a novel and promising approach to delivering this antioxidant directly to the central nervous system (CNS), potentially enhancing its bioavailability and therapeutic efficacy. This method may offer significant advantages in mitigating neurodegeneration by enhancing nuclear factor erythroid 2-related factor 2 (NRF2) pathway signaling and mitochondrial function, thereby providing direct neuroprotection. By addressing oxidative stress and its detrimental effects on neuronal health, nebulized GSH could play a crucial role in managing and potentially ameliorating conditions such as Parkinson's Disease (PD) and Alzheimer's Disease (AD). Further clinical research is warranted to elucidate the therapeutic potential of nebulized GSH in preserving mitochondrial health, enhancing CNS function, and combating neurodegenerative conditions, aiming to improve outcomes for individuals affected by brain diseases characterized by oxidative stress and neuroinflammation.
    Keywords:  aging; glutathione; nebulization; neurological disorders; oxidative stress; regenerative medicine
    DOI:  https://doi.org/10.3390/nu16152476
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