bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–04–30
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19.
  2. ASCT2-mediated glutamine uptake of epithelial cells facilitates CCL5-induced T cell infiltration via ROS-STAT3 pathway in oral lichen planus.
  3. Metabolomic Profiling of Asparagine Deprivation in Asparagine Synthetase Deficiency Patient-Derived Cells.
  4. Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.
  5. Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations.
  6. Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment.
  7. Glutamate dehydrogenase: Potential therapeutic targets for neurodegenerative disease.
  8. Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence.
  9. An integrated bioinformatic analysis of bulk and single-cell sequencing clarifies immune microenvironment and metabolic profiles of lung adenocarcinoma to predict immunotherapy efficacy.
  10. The protective effects of glutamine against bronchopulmonary dysplasia are associated with MKP-1/MAPK/cPLA2 signalingmediated NF-kappaB pathway.
  11. Decoding the Regulatory Roles of Non-coding RNAs in Cellular Metabolism and Disease.
  12. A Novel Nutrient Intervention of Probiotics, Glutamine, and Fish Oil in Psychological Distress: A Concurrent Multiple Baseline Design.
  13. Glutamate dehydrogenase1 supports HIF-1α stability to promote colorectal tumorigenesis under hypoxia.
  14. Glutamine coated titanium for synergistic sonodynamic and photothermal on tumor therapy upon targeted delivery.
  15. A novel Alzheimer's disease prognostic signature: identification and analysis of glutamine metabolism genes in immunogenicity and immunotherapy efficacy.
  16. Metabolic Rewiring in Adult-Type Diffuse Gliomas.
  17. Quercetin-Induced Glutathione Depletion Sensitizes Colorectal Cancer Cells to Oxaliplatin.
  18. The Warburg effect: a signature of mitochondrial overload.
  19. A novel prognostic related lncRNA signature associated with amino acid metabolism in glioma.
  20. Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis.
  21. Glutamine alleviated heat-stress-induced damage of porcine intestinal epithelium associated with the mitochondrial apoptosis pathway mediated by heat shock protein 70.
  22. H3 Lysine 4 Methylation Is Required for Full Activation of Genes Involved in α-Ketoglutarate Availability in the Nucleus of Yeast Cells after Diauxic Shift.
  1. Int J Mol Sci. 2023 Apr 20. pii: 7593. [Epub ahead of print]24(8):
    Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19.
    William Durante.
      The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19.
    Keywords:  COVID-19; ammonia; coagulopathy; glutaminase; glutamine; heme oxygenase-1; immune and endothelial dysfunction; vascular disease
    DOI:  https://doi.org/10.3390/ijms24087593
  2. Int Immunopharmacol. 2023 Apr 26. pii: S1567-5769(23)00537-4. [Epub ahead of print]119 110216
    ASCT2-mediated glutamine uptake of epithelial cells facilitates CCL5-induced T cell infiltration via ROS-STAT3 pathway in oral lichen planus.
    Jingyi Lu, Zhangci Su, Wei Li, Zihang Ling, Bin Cheng, Xi Yang, Xiaoan Tao.
       BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease characterized by T cell infiltration at lesion sites. T cell migration is greatly facilitated by chemokines produced by epithelial cells. Studies have noted the potential role of glutamine uptake in OLP and other inflammatory diseases. Here, we investigated the effect of altered glutamine uptake of epithelial cells on T cell infiltration and its underlying mechanisms in OLP.
    METHODS: Immunohistochemistry was used to identify the expressions of glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2) and C-C motif chemokine ligand 5 (CCL5) in oral tissues of OLP and healthy controls. Human gingival epithelial cells (HGECs) were treated with glutamine deprivation and ASCT2 inhibiter GPNA respectively to detect the expressions of CCL5 and its related signaling molecules. Additionally, we had determined the impact of epithelial cell-derived CCL5 on T-cell migration using a co-culture system in vitro.
    RESULTS: ASCT2 and CCL5 expressions in OLP were significantly higher than healthy controls and positively correlated with the density of inflammatory infiltrations. Glutamine supplement significantly increased CCL5 production in HGECs, which was effectively inhibited by GPNA. Besides, glutamine could inhibit reactive oxygen species (ROS) production to activate the signal transducer and activator of transcription 3 (STAT3) causing higher expression level of CCL5 in HGECs. Simultaneously, T cell migration could be blocked by anti-CCL5 neutralizing antibody and STAT3 inhibitor stattic in the co-culture system.
    CONCLUSION: The upregulated ASCT2-mediated glutamine uptake in epithelial cells promotes CCL5 production via ROS-STAT3 signaling, which boosts the T-cell infiltration in OLP lesion.
    Keywords:  CCL5; Glutamine; OLP; ROS; STAT3
    DOI:  https://doi.org/10.1016/j.intimp.2023.110216
  3. Nutrients. 2023 Apr 18. pii: 1938. [Epub ahead of print]15(8):
    Metabolomic Profiling of Asparagine Deprivation in Asparagine Synthetase Deficiency Patient-Derived Cells.
    Mario C Chang, Stephen J Staklinski, Vinay R Malut, Geraldine L Pierre, Michael S Kilberg, Matthew E Merritt.
      The natural amino acid asparagine (Asn) is required by cells to sustain function and proliferation. Healthy cells can synthesize Asn through asparagine synthetase (ASNS) activity, whereas specific cancer and genetically diseased cells are forced to obtain asparagine from the extracellular environment. ASNS catalyzes the ATP-dependent synthesis of Asn from aspartate by consuming glutamine as a nitrogen source. Asparagine Synthetase Deficiency (ASNSD) is a disease that results from biallelic mutations in the ASNS gene and presents with congenital microcephaly, intractable seizures, and progressive brain atrophy. ASNSD often leads to premature death. Although clinical and cellular studies have reported that Asn deprivation contributes to the disease symptoms, the global metabolic effects of Asn deprivation on ASNSD-derived cells have not been studied. We analyzed two previously characterized cell culture models, lymphoblastoids and fibroblasts, each carrying unique ASNS mutations from families with ASNSD. Metabolomics analysis demonstrated that Asn deprivation in ASNS-deficient cells led to disruptions across a wide range of metabolites. Moreover, we observed significant decrements in TCA cycle intermediates and anaplerotic substrates in ASNS-deficient cells challenged with Asn deprivation. We have identified pantothenate, phenylalanine, and aspartate as possible biomarkers of Asn deprivation in normal and ASNSD-derived cells. This work implies the possibility of a novel ASNSD diagnostic via targeted biomarker analysis of a blood draw.
    Keywords:  ASNSD; GC-MS; amino acids; asparagine; biogenic; cancer metabolism; deprivation; high-throughput; metabolomics; translational
    DOI:  https://doi.org/10.3390/nu15081938
  4. Int J Mol Sci. 2023 Apr 18. pii: 7463. [Epub ahead of print]24(8):
    Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.
    Beatrice Foglia, Marc Beltrà, Salvatore Sutti, Stefania Cannito.
      Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.
    Keywords:  HCC; TCA cycle; amino acid metabolism; fatty acid metabolism; glucose metabolism; glutamine; immune response; metabolic reprogramming; tumor microenvironment; urea cycle
    DOI:  https://doi.org/10.3390/ijms24087463
  5. Redox Biol. 2023 Apr 14. pii: S2213-2317(23)00100-3. [Epub ahead of print]62 102699
    Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations.
    Hong Yan, Ronan Talty, Abhishek Jain, Yuping Cai, Jie Zheng, Xinyi Shen, Engjel Muca, Philip B Paty, Marcus W Bosenberg, Sajid A Khan, Caroline H Johnson.
      Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that only in male patients, tumors with KRAS mutations had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO)), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppress ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Additionally, low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.
    Keywords:  Colorectal cancer; Ferroptosis; KRAS; Metabolomics; Sex differences
    DOI:  https://doi.org/10.1016/j.redox.2023.102699
  6. Front Oncol. 2023 ;13 1155621
    Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment.
    María Matamala Montoya, Gijs J J van Slobbe, Jung-Chin Chang, Esther A Zaal, Celia R Berkers.
      Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance. Metabolic reprogramming is emerging as a hallmark of cancer that can potentially be exploited for cancer treatment. Recent studies show that metabolism is further adjusted in MM cells during the development of drug resistance. However, little is known about the role of BMSCs in inducing metabolic changes that are associated with drug resistance. In this Perspective, we summarize current knowledge concerning the metabolic reprogramming of MM, with a focus on those changes associated with drug resistance to the proteasome inhibitor Bortezomib (BTZ). In addition, we present proof-of-concept fluxomics (glucose isotope-tracing) and Seahorse data to show that co-culture of MM cells with BMSCs skews the metabolic phenotype of MM cells towards a drug-resistant phenotype, with increased oxidative phosphorylation (OXPHOS), serine synthesis pathway (SSP), TCA cycle and glutathione (GSH) synthesis. Given the crucial role of BMSCs in conveying drug resistance, insights into the metabolic interaction between MM and BMSCs may ultimately aid in the identification of novel metabolic targets that can be exploited for therapy.
    Keywords:  Bortezomib; bone marrow stromal cell (BMSC); cancer metabolism; drug resistance; fluxomics; metabolomics; multiple myeloma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1155621
  7. Eur J Pharmacol. 2023 Apr 26. pii: S0014-2999(23)00244-3. [Epub ahead of print] 175733
    Glutamate dehydrogenase: Potential therapeutic targets for neurodegenerative disease.
    Chuqiao Pan, Shijie Mao, Zeping Xiong, Zhao Chen, Ning Xu.
      Glutamate dehydrogenase (GDH) is a key enzyme in mammalian glutamate metabolism. It is located at the intersection of multiple metabolic pathways and participates in a variety of cellular activities. GDH activity is strictly regulated by a variety of allosteric compounds. Here, we review the unique distribution and expressions of GDH in the brain nervous system. GDH plays an essential role in the glutamate-glutamine-GABA cycle between astrocytes and neurons. The dysfunction of GDH may induce the occurrence of many neurodegenerative diseases, such as Parkinson's disease, epilepsy, Alzheimer's disease, schizophrenia, and frontotemporal dementia. GDH activators and gene therapy have been found to protect neurons and improve motor disorders in neurodegenerative diseases caused by glutamate metabolism disorders. To date, no medicine has been discovered that specifically targets neurodegenerative diseases, although several potential medicines are used clinically. Targeting GDH to treat neurodegenerative diseases is expected to provide new insights and treatment strategies.
    Keywords:  Glutamate dehydrogenase; Glutamate-glutamine-GABA cycle; Neurodegenerative diseases; Neuroprotection
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175733
  8. Metabolites. 2023 Apr 15. pii: 560. [Epub ahead of print]13(4):
    Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence.
    Roopak Murali, Vaishnavi Balasubramaniam, Satish Srinivas, Sandhya Sundaram, Ganesh Venkatraman, Sudha Warrier, Arun Dharmarajan, Rajesh Kumar Gandhirajan.
      Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.
    Keywords:  oncogenes; ovarian cancer; tumor metabolism; tumor suppressor genes
    DOI:  https://doi.org/10.3390/metabo13040560
  9. Front Cell Dev Biol. 2023 ;11 1163314
    An integrated bioinformatic analysis of bulk and single-cell sequencing clarifies immune microenvironment and metabolic profiles of lung adenocarcinoma to predict immunotherapy efficacy.
    Mengling Li, Baosen Zhou, Chang Zheng.
      Targeting the tumor microenvironment is increasingly recognized as an effective treatment of advanced lung adenocarcinoma (LUAD). However, few studies have addressed the efficacy of immunotherapy for LUAD. Here, a novel method for predicting immunotherapy efficacy has been proposed, which combines single-cell and bulk sequencing to characterize the immune microenvironment and metabolic profile of LUAD. TCGA bulk dataset was used to cluster two immune subtypes: C1 with "cold" tumor characteristics and C2 with "hot" tumor characteristics, with different prognosis. The Scissor algorithm, which is based on these two immune subtypes, identified GSE131907 single cell dataset into two groups of epithelial cells, labeled as Scissor_C1 and Scissor_C2. The enrichment revealed that Scissor_C1 was characterized by hypoxia, and a hypoxic microenvironment is a potential inducing factor for tumor invasion, metastasis, and immune therapy non-response. Furthermore, single cell analysis was performed to investigate the molecular mechanism of hypoxic microenvironment-induced invasion, metastasis, and immune therapy non-response in LUAD. Notably, Scissor_C1 cells significantly interacted with T cells and cancer-associated fibroblasts (CAF), and exhibited epithelial-mesenchymal transition and immunosuppressive features. CellChat analysis revealed that a hypoxic microenvironment in Scissor_C1elevated TGFβ signaling and induced ANGPTL4 and SEMA3C secretion. Interaction with endothelial cells with ANGPTL4, which increases vascular permeability and achieves distant metastasis across the vascular endothelium. Additionally, interaction of tumor-associated macrophages (TAM) and Scissor_C1 via the EREG/EFGR pathway induces tyrosine kinase inhibitor drug-resistance in patients with LAUD. Thereafter, a subgroup of CAF cells that exhibited same features as those of Scissor_C1 that exert immunosuppressive functions in the tumor microenvironment were identified. Moreover, the key genes (EPHB2 and COL1A1) in the Scissor_C1 gene network were explored and their expressions were verified using immunohistochemistry. Finally, the metabolism dysfunction in cells crosstalk was determined, which is characterized by glutamine secretion by TAM and uptake by Scissor_C1 via SLC38A2 transporter, which may induce glutamine addiction in LUAD cells. Overall, single-cell sequencing clarifies how the tumor microenvironment affects immunotherapy efficacy via molecular mechanisms and biological processes, whereas bulk sequencing explains immunotherapy efficacy based on clinical information.
    Keywords:  cancer-associated fibroblasts; epithelia-mesenchymal transition; immunotherapy; lung adenocarcinoma; metabolism; single-cell multi-omics
    DOI:  https://doi.org/10.3389/fcell.2023.1163314
  10. Gen Physiol Biophys. 2023 May;42(3): 229-239
    The protective effects of glutamine against bronchopulmonary dysplasia are associated with MKP-1/MAPK/cPLA2 signalingmediated NF-kappaB pathway.
    Chouhui Xuan, Can Jin, Zhengyong Jin, Yongxue Chi.
      Glutamine is proven to have potential therapeutic effects on decreasing hyperoxia-induced acute pulmonary injury. The aim of this study is to investigate the effects and mechanism of glutamine on bronchopulmonary dysplasia (BPD) induced by hyperoxia in rat alveolar type II epithelial cells (AECIIs) RLE-6TN. Following hyperoxia induction and glutamine treatment, ROS levels were detected by DCFH-DA assay and TUNEL staining was performed to detect cell apoptosis. The levels of inflammatory indicators and expression of apoptosis-related proteins were detected through ELISA and Western blot, respectively. Besides, the expression of related proteins in mitogen-activated protein kinase phosphatase-1 (MKP-1)/mitogen-activated protein kinases (MAPK)/cytoplasmic phospholipase A2 (cPLA2) signaling was also detected by Western blot. To further analyze the role of MKP-1/MAPK/cPLA2 signaling, MKP-1 was silenced and anisomycin was used to treat cells, respectively. It was shown that glutamine significantly decreased inflammation, oxidative stress and apoptosis in hyperoxia-induced cells while MKP-1 interference and anisomycin were able to reverse these effects, suggesting that the protective effects of glutamine on BPD induced by hypoxia were related to MKP-1/MAPK/cPLA2 signaling. To sum up, glutamine protected against BPD by decreasing inflammation, oxidative stress and apoptosis via MKP-1/MAPK/cPLA2 signaling.
    DOI:  https://doi.org/10.4149/gpb_2023006
  11. Mol Ther. 2023 Apr 26. pii: S1525-0016(23)00210-1. [Epub ahead of print]
    Decoding the Regulatory Roles of Non-coding RNAs in Cellular Metabolism and Disease.
    Yuru Zong, Xuliang Wang, Bing Cui, Xiaowei Xiong, Andrew Wu, Chunru Lin, Yaohua Zhang.
      Non-coding RNAs, including long noncoding RNAs (lncRNA), microRNAs (miRNA), and circular RNAs (or circRNA), are being studied extensively in a variety of fields. Their roles in metabolism have received increasing attention in recent years but are not yet clear. The regulation of glucose, fatty acid, and amino acid metabolism is an imperative physiological process that occurs in living organisms that takes part in cancer and cardiovascular diseases. Here, we summarize the important roles played by non-coding RNAs in glucose metabolism, fatty acid metabolism, and amino acid metabolism, as well as the mechanisms involved. At the same time, we also summarize the therapeutic advances of non-coding RNAs in diseases such as obesity, cardiovascular disease, and some metabolic diseases. Overall, non-coding RNAs are indispensable factors of metabolism and have a significant role in the three major metabolisms, which may be exploited as therapeutic targets in the future.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.04.012
  12. J Integr Complement Med. 2023 Apr 28.
    A Novel Nutrient Intervention of Probiotics, Glutamine, and Fish Oil in Psychological Distress: A Concurrent Multiple Baseline Design.
    Sandra Grace, Joanne Bradbury, Cathy Avila, Liza Twohill, Samantha Morgan-Basnett.
      Objectives: The aim of this study was to investigate whether a combination of nutrients designed to promote gut and brain health also lowers psychological distress. The hypothesis is that a probiotic with fish oil, and glutamine supplement will reduce psychological distress. Design: A multiple baseline design was used to collect data from seven naturopathic patients in private naturopathic clinics in Australia. Patients were between 18 and 65 years of age, and had a Kessler-10 (K10) score between 16 and 30 and symptoms associated with mild gastrointestinal discomfort experienced several times most weeks for 3 months. They were randomized into one of three pathways to stagger the introduction of the intervention. Interventions: Participants received either a supplement incorporating a probiotic formulation (including Lactobacillus rhamnosus), a glutamine powder formulation, and fish oil, or matched placebos. The primary outcome measure was psychological distress as measured by the K10 scale of psychological distress. Results: The data showed a general trend toward lower K10 scores during the active phase compared with the baseline phase, with a marked reduction in the variances between phases. After controlling for time and baseline values, no significant difference between the phases for the K10 and the Perceived Stress Scale was found, but there was still a significant reduction in symptoms on the Gastrointestinal Symptom Rating Scale. Conclusions: A combination of a probiotic formulation, a glutamine powder formulation, and fish oil did not affect psychological distress and perceived stress, but had a significant beneficial effect on gastrointestinal symptoms in patients with high distress and concurrent gut symptomology. Clinical Trial: ACTRN12620000928910.
    Keywords:  digestive system; multiple baseline design; naturopathy; nutraceuticals; probiotics; stress
    DOI:  https://doi.org/10.1089/jicm.2022.0820
  13. EMBO J. 2023 Apr 24. e112675
    Glutamate dehydrogenase1 supports HIF-1α stability to promote colorectal tumorigenesis under hypoxia.
    Kunhua Hu, Yufeng Ding, Hongwen Zhu, Xiaoqian Jing, Weiling He, Hua Yu, Xiongjun Wang.
      Tumor cells surviving hypoxic stress acquire the ability to drive cancer progression. To explore the contribution of dehydrogenases to the low oxygen concentration response, we used siRNAs targeting 163 dehydrogenase-coding genes and discovered that glutamate dehydrogenase 1 (GDH1) plays a critical role in regulating colorectal cancer (CRC) cell survival under hypoxia. We observed that GDH1 deficiency had an inhibitory effect on CRC occurrence and impaired hypoxia-inducible factor 1-alpha (HIF-1α) stability even under hypoxia. Mechanistically, hypoxia triggered p300 recruitment to GDH1, promoting its acetylation at K503 and K527. GDH1 acetylation at K527 induced the formation of a GDH1 complex with EGLN1/HIF-1α; in contrast, GDH1 acetylation at K503 reinforced its affinity for α-ketoglutarate (αKG), and glutamate production. In line with this view, αKG is a product of GDH1 under normoxia, but hypoxia stimulation reversed GDH1 enzyme activity and αKG consumption by the EGLN1/HIF-1α complex, increasing HIF-1α stability and promoting CRC progression. Clinically, hypoxia-modulated GDH1 AcK503/527 can be used as a biomarker of CRC progression and is a potential target for CRC treatment.
    Keywords:  GDH1; HIF1α; acetylation; colorectal cancer; α-ketoglutarate
    DOI:  https://doi.org/10.15252/embj.2022112675
  14. Front Bioeng Biotechnol. 2023 ;11 1139426
    Glutamine coated titanium for synergistic sonodynamic and photothermal on tumor therapy upon targeted delivery.
    Lina Zhang, Pengfeng Zhu, Ting Wan, Huaiyan Wang, Zhilei Mao.
      Introduction: The application of titanium dioxide nanoparticles (TiO2 NPs) for cancer therapy has been studied for decades; however, the targeted delivery of TiO2 NPs to tumor tissues is challenging, and its efficiency needs to be improved. Method: In this study, we designed an oxygen-deficient TiO2-x coated with glutamine layer for targeted delivery, as well as the enhanced separation of electrons (e-) and holes (h+) following the joint application of sonodynamic therapy (SDT) and photothermal therapy (PTT). Results: This oxygen-deficient TiO2-x possesses relatively high photothermal and sonodynamic efficiency at the 1064 nm NIR-II bio-window. The GL-dependent design eased the penetration of the TiO2-x into the tumor tissues (approximately three-fold). The in vitro and in vivo tests showed that the SDT/PTT-based synergistic treatment achieved more optimized therapeutic effects than the sole use of either SDT or PTT. Conclusion: Our study provided a safety targeted delivery strategy, and enhanced the therapeutic efficiency of SDT/PTT synergistic treatment.
    Keywords:  TiO2−x@GL; glutamine addiction; photothermal (PTT); sonodynamic (SDT); synergistic tumor therapy
    DOI:  https://doi.org/10.3389/fbioe.2023.1139426
  15. Sci Rep. 2023 Apr 27. 13(1): 6895
    A novel Alzheimer's disease prognostic signature: identification and analysis of glutamine metabolism genes in immunogenicity and immunotherapy efficacy.
    Zixuan Wu, Ping Liu, Baisheng Huang, Sisi Deng, Zhenyan Song, Xindi Huang, Jing Yang, Shaowu Cheng.
      Alzheimer's disease (AD) is characterized as a distinct onset and progression of cognitive and functional decline associated with age, as well as a specific neuropathology. It has been discovered that glutamine (Gln) metabolism plays a crucial role in cancer. However, a full investigation of its role in Alzheimer's disease is still missing. This study intended to find and confirm potential Gln-related genes associated with AD using bioinformatics analysis. The discovery of GlnMgs was made possible by the intersection of the WGCNA test and 26 Gln-metabolism genes (GlnMgs). GlnMgs' putative biological functions and pathways were identified using GSVA. The LASSO method was then used to identify the hub genes as well as the diagnostic efficiency of the four GlnMgs in identifying AD. The association between hub GlnMgs and clinical characteristics was also studied. Finally, the GSE63060 was utilized to confirm the levels of expression of the four GlnMgs. Four GlnMgs were discovered (ATP5H, NDUFAB1, PFN2, and SPHKAP). For biological function analysis, cell fate specification, atrioventricular canal development, and neuron fate specification were emphasized. The diagnostic ability of the four GlnMgs in differentiating AD exhibited a good value. This study discovered four GlnMgs that are linked to AD. They shed light on potential new biomarkers for AD and tracking its progression.
    DOI:  https://doi.org/10.1038/s41598-023-33277-x
  16. Int J Mol Sci. 2023 Apr 16. pii: 7348. [Epub ahead of print]24(8):
    Metabolic Rewiring in Adult-Type Diffuse Gliomas.
    Jong-Whi Park.
      Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma's complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
    Keywords:  glioma metabolism; isocitrate dehydrogenases (IDH); therapeutic strategies
    DOI:  https://doi.org/10.3390/ijms24087348
  17. Foods. 2023 Apr 21. pii: 1733. [Epub ahead of print]12(8):
    Quercetin-Induced Glutathione Depletion Sensitizes Colorectal Cancer Cells to Oxaliplatin.
    Jinkyung Lee, Chan Ho Jang, Yoonsu Kim, Jisun Oh, Jong-Sang Kim.
      Quercetin is an antioxidant phytochemical which belongs to the natural flavonoids group. Recently, the compound has been reported to inhibit glutathione reductase responsible for replenishing reduced forms of glutathione and thus leads to glutathione depletion, triggering cell death. In this study, we examined if quercetin sensitizes tumors to oxaliplatin by inhibiting glutathione reductase activity in human colorectal cancer cells, and thereby facilitates apoptotic cell death. A combined treatment with quercetin and oxaliplatin was found to synergistically inhibit glutathione reductase activity, lower intracellular glutathione level, increase reactive oxygen species production, and reduce cell viability, compared to treatment with oxaliplatin alone in human colorectal HCT116 cancer cells. Furthermore, the incorporation of sulforaphane, recognized for its ability to scavenge glutathione, in combination with quercetin and oxaliplatin, substantially suppressed tumor growth in an HCT116 xenograft mouse model. These findings suggest that the depletion of intracellular glutathione by quercetin and sulforaphane could strengthen the anti-cancer efficacy of oxaliplatin.
    Keywords:  anti-cancer; apoptosis; glutathione reductase; oxaliplatin; oxidative stress; quercetin; sulforaphane
    DOI:  https://doi.org/10.3390/foods12081733
  18. Trends Cell Biol. 2023 Apr 26. pii: S0962-8924(23)00070-3. [Epub ahead of print]
    The Warburg effect: a signature of mitochondrial overload.
    Yahui Wang, Gary J Patti.
      A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
    Keywords:  Warburg effect; aerobic fermentation; aerobic glycolysis; cancer metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.013
  19. Front Immunol. 2023 ;14 1014378
    A novel prognostic related lncRNA signature associated with amino acid metabolism in glioma.
    Qiang Lei, Bo Yuan, Kun Liu, Li Peng, Zhiwei Xia.
       Background: Glioma is one of the deadliest malignant brain tumors in adults, which is highly invasive and has a poor prognosis, and long non-coding RNAs (lncRNAs) have key roles in the progression of glioma. Amino acid metabolism reprogramming is an emerging hallmark in cancer. However, the diverse amino acid metabolism programs and prognostic value remain unclear during glioma progression. Thus, we aim to find potential amino-related prognostic glioma hub genes, elaborate and verify their functions, and explore further their impact on glioma.
    Methods: Glioblastoma (GBM) and low-grade glioma (LGG) patients' data were downloaded from TCGA and CCGA datasets. LncRNAs associated with amino acid metabolism were discriminated against via correlation analysis. LASSO analysis and Cox regression analysis were conducted to identify lncRNAs related to prognosis. GSVA and GSEA were performed to predict the potential biological functions of lncRNA. Somatic mutation data and CNV data were further built to demonstrate genomic alterations and the correlation between risk scores. Human glioma cell lines U251 and U87-MG were used for further validation in vitro experiments.
    Results: There were eight amino-related lncRNAs in total with a high prognostic value that were identified via Cox regression and LASSO regression analyses. The high risk-score group presented a significantly poorer prognosis compared with the low risk-score group, with more clinicopathological features and characteristic genomic aberrations. Our results provided new insights into biological functions in the above signature lncRNAs, which participate in the amino acid metabolism of glioma. LINC01561 is one of the eight identified lncRNAs, which was adopted for further verification. In in vitro experiments, siRNA-mediated LINC01561 silencing suppresses glioma cells' viability, migration, and proliferation.
    Conclusion: Novel amino-related lncRNAs associated with the survival of glioma patients were identified, and a lncRNA signature can predict glioma prognosis and therapy response, which possibly has vital roles in glioma. Meanwhile, it emphasized the importance of amino acid metabolism in glioma, particularly in providing deeper research at the molecular level.
    Keywords:  amino acid; glioma; lncRNA; prognostic; target
    DOI:  https://doi.org/10.3389/fimmu.2023.1014378
  20. Int J Mol Sci. 2023 Apr 11. pii: 7076. [Epub ahead of print]24(8):
    Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis.
    Nan Niu, Jinfeng Ye, Zhangli Hu, Junbin Zhang, Yun Wang.
      One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.
    Keywords:  glycolysis; malignant proliferation; metabolic plasticity; mitochondrial oxidative phosphorylation; tumorigenesis
    DOI:  https://doi.org/10.3390/ijms24087076
  21. J Anim Sci. 2023 Apr 27. pii: skad127. [Epub ahead of print]
    Glutamine alleviated heat-stress-induced damage of porcine intestinal epithelium associated with the mitochondrial apoptosis pathway mediated by heat shock protein 70.
    Bolin Zhang, Huilei Sun, Zewei Sun, Ning Liu, Rujie Liu, Qingzhen Zhong.
      The present study aimed to investigate the effect of glutamine (Gln) addition on the damage of porcine intestinal epithelial cells (IPEC-J2) induced by heat stress (HS). IPEC-J2 cultured in logarithmic growth period in vitro were firstly exposed to 42°C for 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h for cell viability and cultured with 1, 2, 4, 6, 8 or 10 mmol Gln per L of culture media for heat-shock protein 70 (HSP70) expression to determine the optimal disposal strategy (HS, 42℃ for 12 h and HSP70 expression, 6 mmol/L Gln treatment for 24 h). Then IPEC-J2 cells were divided into three groups: control group (Con, cultured at 37 ℃), HS group (HS, cultured at 42 ℃ for 12 h) and glutamine group (Gln + HS, cultured at 42 ℃ for 12 h combined with 6 mmol/L Gln treatment for 24 h). The results showed that HS treatment for 12 h significantly decreased the cell viability of IPEC-J2 (P<0.05) and 6 mmol/L Gln treatment for 12 h increased HSP70 expression (P<0.05). HS treatment increased the permeability of IPEC-J2, evidenced by the increased the fluorescent yellow flux rates (P<0.05) and the decreased transepithelial electrical resistance (P<0.05). Moreover, the down-regulated protein expression of occluding, claudin-1 and ZO-1 were observed in HS group (P<0.05), but Gln addition alleviated the negative effects on permeability and the integrity of intestinal mucosal barrier induced by HS (P<0.05). In addition, HS resulted in the elevations in HSP70 expression, cell apoptosis, cytoplasmic Cytc potential expression and the protein expressions of apoptosis related factors (Apaf1, Caspase-3 and Caspase-9) (P<0.05), however, the reductions in mitochondrial membrane potential expression and Bcl-2 expression were induced by HS (P<0.05). But Gln treatment attenuated HS-induced adverse effects above mentioned (P<0.05). Taken together, Gln treatment exhibited protective effects in protecting IPEC-J2 from cell apoptosis and the damaged integrity of epithelial mucosal barrier induced by HS, which maybe associated with the mitochondrial apoptosis pathway mediated by HSP70.
    Keywords:  Glutamine; Heat shock protein 70; Heat stress; Intestinal barrier integrity; Mitochondrial apoptosis
    DOI:  https://doi.org/10.1093/jas/skad127
  22. Metabolites. 2023 Mar 31. pii: 507. [Epub ahead of print]13(4):
    H3 Lysine 4 Methylation Is Required for Full Activation of Genes Involved in α-Ketoglutarate Availability in the Nucleus of Yeast Cells after Diauxic Shift.
    Elena Di Nisio, Svetlana Danovska, Livia Condemi, Angela Cirigliano, Teresa Rinaldi, Valerio Licursi, Rodolfo Negri.
      We show that in S. cerevisiae the metabolic diauxic shift is associated with a H3 lysine 4 tri-methylation (H3K4me3) increase which involves a significant fraction of transcriptionally induced genes which are required for the metabolic changes, suggesting a role for histone methylation in their transcriptional regulation. We show that histone H3K4me3 around the start site correlates with transcriptional induction in some of these genes. Among the methylation-induced genes are IDP2 and ODC1, which regulate the nuclear availability of α-ketoglutarate, which, as a cofactor for Jhd2 demethylase, regulates H3K4 tri-methylation. We propose that this feedback circuit could be used to regulate the nuclear α-ketoglutarate pool concentration. We also show that yeast cells adapt to the absence of Jhd2 by decreasing Set1 methylation activity.
    Keywords:  H3K4 tri-methylation; diauxic shift; transcriptional regulation
    DOI:  https://doi.org/10.3390/metabo13040507
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