bims-glucam 2024-03-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒03‒24
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.
Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer.
Inhibition of glutamine metabolism increases sensitivity to plasma-activated medium-induced cytotoxicity.
Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer.
Metabolic reprogramming in the CLL TME; potential for new therapeutic targets.
SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
The role of amino acid metabolism in autoimmune hepatitis.
Mitochondrial Raf1 Regulates Glutamine Catabolism.
GLUT and HK: two primary and essential key players in Tumor glycolysis.
MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma.
Identification of different subtypes of ovarian cancer and construction of prognostic models based on glutamine-metabolism associated genes.
A metabolomics approach reveals metabolic disturbance of human cholangiocarcinoma cells after parthenolide treatment.
Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.
Glutamine mitigates oxidative stress-induced matrix degradation, ferroptosis, and pyroptosis in nucleus pulposus cells via deubiquitinating and stabilizing Nrf2.
Hypoxia-inducible factor-2α promotes fibrosis in non-alcoholic fatty liver disease by enhancing glutamine catabolism and inhibiting yes-associated protein phosphorylation in hepatic stellate cells.
Clinical and biochemical assessment of the effect of glutamine in management of radiation induced oral mucositis in patients with head and neck cancer: Randomized controlled clinical trial.
Protocol for analyzing energy metabolic pathway dependency in human liver cancer cell lines.
An insight into role of amino acids as antioxidants via NRF2 activation.

Front Pharmacol. 2024 ;15 1345522

Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.

Yuxin Fan, Han Xue, Zhimin Li, Mingge Huo, Hongxia Gao, Xingang Guan.

  Cancer cells have adapted to rapid tumor growth and evade immune attack by reprogramming their metabolic pathways. Glutamine is an important nitrogen resource for synthesizing amino acids and nucleotides and an important carbon source in the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathway. In this review, we summarize the significant role of glutamine metabolism in tumor development and highlight the vulnerabilities of targeting glutamine metabolism for effective therapy. In particular, we review the reported drugs targeting glutaminase and glutamine uptake for efficient cancer treatment. Moreover, we discuss the current clinical test about targeting glutamine metabolism and the prospective direction of drug development.

Keywords:  cancer therapy; combination therapy; glutamine; glutamine metabolism; glutamine uptake

DOI:  https://doi.org/10.3389/fphar.2024.1345522
Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2319429121

Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer.

Xinlu Han, Deyu Wang, Liao Yang, Ning Wang, Jianliang Shen, Jinghan Wang, Lei Zhang, Li Chen, Shenglan Gao, Wei-Xing Zong, Yongbo Wang.

  Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer.

Keywords:  SAT1; glutamine metabolism; lung cancer; polyamine catabolism

DOI:  https://doi.org/10.1073/pnas.2319429121
Free Radic Res. 2024 Mar 21. 1-10

Inhibition of glutamine metabolism increases sensitivity to plasma-activated medium-induced cytotoxicity.

Shu Tanaka, Sae Hayashi, Tomohiro Otsuka, Tetsuro Kamiya, Kenji Ishikawa, Hirokazu Hara.

  Non-thermal atmospheric pressure plasma (NTP), an ionized gas containing electrons, ions, radicals, and photons, has various biological effects, including wound healing and anticancer effects. Plasma-activated medium (PAM), which is prepared by irradiating medium with NTP, preferentially kills cancer cells. Large amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS) included in PAM are closely related to its anticancer effects. The precise mechanism of PAM-induced cytotoxicity is not fully understood; however, PAM exposure has been reported to reduce cellular energy metabolism. Glutamine (Gln) is an important amino acid as an energy source in cancer cells. Gln is converted to glutamate by glutaminase (GLS), and is utilized to synthesize ATP and glutathione (GSH). Expression levels of GLS have been shown to be higher in certain types of cancers. In this study, we examined the effects of GLS inhibition on PAM cytotoxicity using breast cancer MDA-MB-231 cells. Pretreatment with BPTES, a glutaminase 1 (GLS1) inhibitor, dose-dependently enhanced PAM-induced cell death. PAM-induced ROS production and γ-H2AX formation, a DNA damage marker, were increased in cells pretreated with BPTES compared with PAM alone. BPTES pretreatment enhanced a PAM-induced decrease in intracellular GSH, indicating the possibility that BPTES reduces the antioxidant capacity of MDA-MB-231 cells. In addition, BPTES pretreatment enhanced PAM-induced loss of the mitochondrial membrane potential and reduction of ATP production. Moreover, GLS1 knockdown promoted PAM-induced cell death. Taken together, the combination of GLS1 inhibitors such as BPTES is considered to be useful for enhancing the cytotoxic effects of PAM against cancer cells.

Keywords:  Non-thermal plasma; cancer; glutamine; glutathione; reactive oxygen species

DOI:  https://doi.org/10.1080/10715762.2024.2332343
J Cell Mol Med. 2024 Apr;28(7): e18198

Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer.

Lingling Gao, Zheng Wei, Feiquan Ying, Lin Huang, Jingni Zhang, Si Sun, Zehua Wang, Jing Cai, Yuan Zhang.

  Mounting evidence has highlighted the multifunctional characteristics of glutamine metabolism (GM) in cancer initiation, progression and therapeutic regimens. However, the overall role of GM in the tumour microenvironment (TME), clinical stratification and therapeutic efficacy in patients with ovarian cancer (OC) has not been fully elucidated. Here, three distinct GM clusters were identified and exhibited different prognostic values, biological functions and immune infiltration in TME. Subsequently, glutamine metabolism prognostic index (GMPI) was constructed as a new scoring model to quantify the GM subtypes and was verified as an independent predictor of OC. Patients with low-GMPI exhibited favourable survival outcomes, lower enrichment of several oncogenic pathways, less immunosuppressive cell infiltration and better immunotherapy responses. Single-cell sequencing analysis revealed a unique evolutionary trajectory of OC cells from high-GMPI to low-GMPI, and OC cells with different GMPI might communicate with distinct cell populations through ligand-receptor interactions. Critically, the therapeutic efficacy of several drug candidates was validated based on patient-derived organoids (PDOs). The proposed GMPI could serve as a reliable signature for predicting patient prognosis and contribute to optimising therapeutic strategies for OC.

Keywords:  metabolism reprogramming; molecular subtype; ovarian tumour; patient-derived organoids (PDOs); single-cell RNA transcriptome

DOI:  https://doi.org/10.1111/jcmm.18198
Semin Hematol. 2024 Feb 15. pii: S0037-1963(24)00016-7. [Epub ahead of print]

Metabolic reprogramming in the CLL TME; potential for new therapeutic targets.

Helga Simon-Molas, Chiara Montironi, Anna Kabanova, Eric Eldering.

  Chronic lymphocytic leukemia (CLL) cells circulate between peripheral (PB) blood and lymph node (LN) compartments, and strictly depend on microenvironmental factors for proliferation, survival and drug resistance. All cancer cells display metabolic reprogramming and CLL is no exception - though the inert status of the PB CLL cells has hampered detailed insight into these processes. We summarize previous work on reactive oxygen species (ROS), oxidative stress, and hypoxia, as well as the important roles of Myc, and PI3K/Akt/mTor pathways. In vitro co-culture systems and gene expression analyses have provided a partial picture of CLL LN metabolism. New broad omics techniques allow to obtain molecular and also single-cell level understanding of CLL plasticity and metabolic reprogramming. We summarize recent developments and describe the new concept of glutamine addiction for CLL, which may hold therapeutic promise.

Keywords:  glutamine; metabolism; oncogenes; transporters; tumor microenvironment

DOI:  https://doi.org/10.1053/j.seminhematol.2024.02.001
Cell Rep. 2024 Mar 19. pii: S2211-1247(24)00303-6. [Epub ahead of print]43(4): 113975

SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.

Sarah A Tucker, Song-Hua Hu, Sejal Vyas, Albert Park, Shakchhi Joshi, Aslihan Inal, Tiffany Lam, Emily Tan, Kevin M Haigis, Marcia C Haigis.

  The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.

Keywords:  CP: Cancer; SIRT4; glutamine; intestinal organoids; irradiation; nucleotide biosynthesis; nucleotide metabolism; sirtuin

DOI:  https://doi.org/10.1016/j.celrep.2024.113975
Biomed Pharmacother. 2024 Mar 18. pii: S0753-3322(24)00336-6. [Epub ahead of print]173 116452

The role of amino acid metabolism in autoimmune hepatitis.

Xiaorong Xiang, Qihong Li, Jiajia Wan, Chao Chen, Mengmeng Guo, Zhixu He, Donghong Wang, Xu Zhao, Lin Xu.

  Autoimmune hepatitis (AIH) is an inflammatory chronic liver disease with persistent and recurrent immune-mediated liver injury. The exact cause of AIH is still not fully understood, but it is believed to be primarily due to an abnormal activation of the immune system, leading to autoimmune injury caused by the breakdown of autoimmune tolerance. Although the pathogenesis of AIH remains unclear, recent studies have shown that abnormalities in amino acid metabolism play significant roles in its development. These abnormalities in amino acid metabolism can lead to remodeling of metabolic processes, activation of signaling pathways, and immune responses, which may present new opportunities for clinical intervention in AIH. In this paper, we first briefly outline the recent progress of clinically relevant research on AIH, focusing on the role of specific amino acid metabolism (including glutamine, cysteine, tryptophan, branched-chain amino acids, etc.) and their associated metabolites, as well as related pathways, in the development of AIH. Furthermore, we discuss the scientific issues that remain to be resolved regarding amino acid metabolism, AIH development and related clinical interventions, with the aim of contributing to the future development of amino acid metabolism-based as a new target for the clinical diagnosis and treatment of AIH.

Keywords:  Amino acid metabolic dysregulation; Autoimmune hepatitis; Cysteine; Glutamine; Tryptophan

DOI:  https://doi.org/10.1016/j.biopha.2024.116452
bioRxiv. 2024 Mar 09. pii: 2024.03.08.581297. [Epub ahead of print]

Mitochondrial Raf1 Regulates Glutamine Catabolism.

Ronald L Shanderson, Ian D Ferguson, Zurab Siprashvili, Luca Ducoli, Albert M Li, Weili Miao, Suhas Srinivasan, Mary Grace Velasco, Yang Li, Jiangbin Ye, Paul A Khavari.

Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

DOI: https://doi.org/10.1101/2024.03.08.581297
Semin Cancer Biol. 2024 Mar 15. pii: S1044-579X(24)00020-8. [Epub ahead of print]

GLUT and HK: two primary and essential key players in Tumor glycolysis.

Dhiraj Yadav, Anubha Yadav, Sujata Bhattacharya, Akansha Dagar, Vinit Kumar, Reshma Rani.

  Cancer cells reprogram their metabolism to become "glycolysis-dominant," which enables them to meet their energy and macromolecule needs and enhancing their rate of survival. This glycolytic-dominancy is known as the "Warburg effect", a significant factor in the growth and invasion of malignant tumors. Many studies confirmed that members of the GLUT family, specifically HK-II from the HK family play a pivotal role in the Warburg effect, and are closely associated with glucose transportation followed by glucose metabolism in cancer cells. Overexpression of GLUTs and HK-II correlates with aggressive tumor behaviour and tumor microenvironment making them attractive therapeutic targets. Several studies have proven that the regulation of GLUTs and HK-II expression improves the treatment outcome for various tumors. Therefore, small molecule inhibitors targeting GLUT and HK-II show promise in sensitizing cancer cells to treatment, either alone or in combination with existing therapies including chemotherapy, radiotherapy, immunotherapy, and photodynamic therapy. Despite existing therapies, viable methods to target the glycolysis of cancer cells are currently lacking to increase the effectiveness of cancer treatment. This review explores the current understanding of GLUT and HK-II in cancer metabolism, recent inhibitor developments, and strategies for future drug development, offering insights into improving cancer treatment efficacy.

Keywords:  Cancer cells reprograming; GLUT; Glucose transporter; Warburg effect; hexokinase

DOI:  https://doi.org/10.1016/j.semcancer.2024.03.001
iScience. 2024 Apr 19. 27(4): 109417

MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma.

Lama Hasan Bou Issa, Léa Fléchon, William Laine, Aicha Ouelkdite, Silvia Gaggero, Adeline Cozzani, Remi Tilmont, Paul Chauvet, Nicolas Gower, Romanos Sklavenitis-Pistofidis, Carine Brinster, Xavier Thuru, Yasmine Touil, Bruno Quesnel, Suman Mitra, Irene M Ghobrial, Jérôme Kluza, Salomon Manier.

  Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM.

Keywords:  Cancer; Metabolomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.109417
Heliyon. 2024 Mar 30. 10(6): e27358

Identification of different subtypes of ovarian cancer and construction of prognostic models based on glutamine-metabolism associated genes.

Xie Yaqing, Gao Yang, Yang Linlin, Ruan Youqing, Yang Henghui, Yang Ping, Yang Hongying, Wang Shaojia.

Ovarian cancer (OC) is common malignant tumor of female reproductive system. Glutamine metabolism-related genes (GMRGs) play a key role in ovarian cancer. Here, available database-- The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases were applied in our research. OC samples from TCGA were divided into different clusters based on Cox analysis, which filtering GMRGs with survival information. Then, differentially expressed genes (DEGs) between these clusters were intersected with DEGs between normal ovary samples and OC samples, and GMRGs in order to obtain GMRGs-related DEGs. Next, a risk model of OC was constructed and enrichment analysis of risk model was performed based on hallmark gene set. Besides, the immune cells ratio in OC samples were detected via Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT). Finally, we explored a series of potential biomarkers of OC. In this research, 9 GMRGs-related DEGs were obtained. GMRGs-related DEGs were enriched to canonical Wnt signaling pathway.NKD2, C2orf88, and KLHDC8A, which were significantly associated with prognosis, were retained for risk model construction. Based on the risk model, 18 hallmark pathways with significant difference were enriched. Fifteen types of immune cells (such as iDC, NK CD56dim cells, and neutrophils) enjoying significant difference between these 2 risk groups (high risk group vs. low risk group) were detected, which indicates possible disparate TME in different metabolic subtypes of ovarian cancer.

DOI: https://doi.org/10.1016/j.heliyon.2024.e27358
J Ethnopharmacol. 2024 Mar 19. pii: S0378-8741(24)00374-X. [Epub ahead of print] 118075

A metabolomics approach reveals metabolic disturbance of human cholangiocarcinoma cells after parthenolide treatment.

Yongping He, Qianxue Yu, Xiaoyu Ma, Diya Lv, Hui Wang, Weian Qiu, Xiao Fei Chen, Yang Jiao, Yue Liu.

  ETHNOPHARMACOLOGICAL RELEVANCE: Tanacetum parthenium (L.) Schultz-Bip, commonly known as feverfew, has been traditionally used to treat fever, migraines, rheumatoid arthritis, and cancer. Parthenolide (PTL), the main bioactive ingredient isolated from the shoots of feverfew, is a sesquiterpene lactone with anti-inflammatory and antitumor properties. Previous studies showed that PTL exerts anticancer activity in various cancers, including hepatoma, cholangiocarcinoma, acute myeloid leukemia, breast, prostate, and colorectal cancer. However, the metabolic mechanism underlying the anticancer effect of PTL remains poorly understood.AIM OF THE STUDY: To explore the anticancer activity and underlying mechanism of PTL in human cholangiocarcinoma cells.
MATERIAL AND METHODS: In this investigation, the effects and mechanisms of PTL on human cholangiocarcinoma cells were investigated via a liquid chromatography/mass spectrometry (LC/MS)-based metabolomics approach. First, cell proliferation and apoptosis were evaluated using cell counting kit-8 (CCK-8), flow cytometry analysis, and western blotting. Then, LC/MS-based metabolic profiling along with orthogonal partial least-squares discriminant analysis (OPLS-DA) has been constructed to distinguish the metabolic changes between the negative control group and the PTL-treated group in TFK1 cells. Next, enzyme-linked immunosorbent assay (ELISA) was applied to investigate the changes of metabolic enzymes associated with significantly alerted metabolites. Finally, the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established using MetaboAnalyst 5.0 and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database.
RESULTS: PTL treatment could induce the proliferation inhibition and apoptosis of TFK1 in a concentration-dependent manner. Forty-three potential biomarkers associated with the antitumor effect of PTL were identified, which primarily related to glutamine and glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, nicotinate and nicotinamide metabolism, pyrimidine metabolism, fatty acid metabolism, phospholipid catabolism, and sphingolipid metabolism. Pathway analysis of upstream and downstream metabolites, we found three key metabolic enzymes, including glutaminase (GLS), γ-glutamyl transpeptidase (GGT), and carnitine palmitoyltransferase 1 (CPT1), which mainly involved in glutamine and glutamate metabolism, glutathione metabolism, and fatty acid metabolism. The changes of metabolic enzymes associated with significantly alerted metabolites were consistent with the levels of metabolites, and the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established. PTL may exert its antitumor effect against cholangiocarcinoma by disturbing metabolic pathways. Furthermore, we selected two positive control agents that are considered as first-line chemotherapy standards in cholangiocarcinoma therapy to verify the reliability and accuracy of our metabolomic study on PTL.
CONCLUSION: This research enhanced our comprehension of the metabolic profiling and mechanism of PTL treatment on cholangiocarcinoma cells, which provided some references for further research into the anti-cancer mechanisms of other drugs.

Keywords:  Cholangiocarcinoma cells; Liquid chromatography/mass spectrometry; Metabolic profiling; Metabolomics; Parthenolide

DOI:  https://doi.org/10.1016/j.jep.2024.118075
Cold Spring Harb Perspect Med. 2024 Mar 19. pii: a041536. [Epub ahead of print]

Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.

Daniel Peled, Ruth Casey, Eyal Gottlieb.

With the foundation pre-laid, research in the new millennium has readily excavated and expanded upon the architectural framework laid out by Otto Warburg's seminal work in a new wave of "westward expansion," ever widening our understanding of cancer metabolism beyond the telescopic vision seen over a century ago. On this path, the unique circuitry of the cancer metabolic program has been elucidated, illuminating mutations of conserved cellular pathways implicated in tumorigenesis. Paramount among these are mutations in tricarboxylic acid cycle enzymes, succinate dehydrogenase, and fumarate hydratase, leading to deleterious accumulations in metabolic intermediates, "oncometabolites," the pilots of the disease process. In this work, we seek to reflect on the advancements in the field in recent years, updating knowledge on the exact biochemical mechanisms at the helm of the tumor, providing rationale for clinical trials currently underway, and anticipating directions for the future on this expansive frontier.

DOI: https://doi.org/10.1101/cshperspect.a041536
Antioxid Redox Signal. 2024 Mar 19.

Glutamine mitigates oxidative stress-induced matrix degradation, ferroptosis, and pyroptosis in nucleus pulposus cells via deubiquitinating and stabilizing Nrf2.

Jiajun Wu, Weitao Han, Yangyang Zhang, Shuangxing Li, Tianyu Qin, Zhengqi Huang, Chao Zhang, Ming Shi, Yuliang Wu, Wanli Zheng, Bo Gao, Kang Xu, Wei Ye.

AIMS: Intervertebral disc degeneration (IDD) is closely related to low back pain (LBP), which is a prevalent age-related problem worldwide; however, the mechanism underlying IDD is unknown. Glutamine, a free amino acid prevalent in plasma, is recognized for its anti-inflammatory and antioxidant properties in various diseases, the current study aims to clarify the effect and mechanism of glutamine in IDD.RESULTS: A synergistic interplay was observed between pyroptosis and ferroptosis within degenerated human disc specimens. Glutamine exhibited significant efficacy in mitigating IDD in both ex-vivo and in-vivo experimental models. Moreover, glutamine protected nucleus pulposus (NP) cells after tert-butyl hydroperoxide (TBHP)-induced pyroptosis, ferroptosis, and extracellular matrix (ECM) degradation in vitro. Glutamine protected NP cells from TBHP-induced ferroptosis by promoting Nrf2 accumulation by inhibiting its ubiquitin-proteasome degradation and inhibiting lipid oxidation.
INNOVATION AND CONCLUSIONS: A direct correlation is evident in the progression of IDD between the processes of pyroptosis and ferroptosis. Glutamine suppressed oxidative stress-induced cellular processes, including pyroptosis, ferroptosis, and ECM degradation through deubiquitinating Nrf2 and inhibiting lipid oxidation in NP cells. Glutamine is a promising novel therapeutic target for the management of IDD.

DOI: https://doi.org/10.1089/ars.2023.0384
Front Endocrinol (Lausanne). 2024 ;15 1344971

Hypoxia-inducible factor-2α promotes fibrosis in non-alcoholic fatty liver disease by enhancing glutamine catabolism and inhibiting yes-associated protein phosphorylation in hepatic stellate cells.

Ranran Yan, Hao Cai, Xiaofeng Zhou, Guodan Bao, Zhenzhong Bai, Ri-Li Ge.

  Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence and affects approximately one-third of adults, owing to high-fat dietary habits and a sedentary lifestyle. The role of hypoxia-inducible factor 2α (HIF-2α) in NAFLD progression remains unknown. This study aimed to investigate the effects of chronic hypoxia on NAFLD progression by examining the role of hypoxia-inducible factor 2α (HIF-2α) activation and that of hepatic stellate cell (HSC)-derived myofibroblasts through glutaminolysis. We hypothesised that hypoxia exacerbates NAFLD by promoting HIF-2α upregulation and inhibiting phosphorylated yes-associated protein (YAP), and that increasing YAP expression enhances HSC-derived myofibroblasts. We studied patients with NAFLD living at high altitudes, as well as animal models and cultured cells. The results revealed significant increases in HSC-derived myofibroblasts and collagen accumulation caused by HIF-2α and YAP upregulation, both in patients and in a mouse model for hypoxia and NAFLD. HIF-2α and HIF-2α-dependent YAP downregulation reduced HSC activation and myofibroblast levels in persistent chronic hypoxia. Furthermore, hypoxia-induced HIF-2α upregulation promoted YAP and inhibited YAP phosphorylation, leading to glutaminase 1 (GLS1), SLC38A1, α-SMA, and Collagen-1 overexpression. Additionally, hypoxia restored mitochondrial adenosine triphosphate production and reactive oxygen species (ROS) overproduction. Thus, chronic hypoxia-induced HIF-2α activation enhances fibrosis and NAFLD progression by restoring mitochondrial ROS production and glutaminase-1-induced glutaminolysis, which is mediated through the inhibition of YAP phosphorylation and increased YAP nuclear translocation. In summary, HIF-2α plays a pivotal role in NAFLD progression during chronic hypoxia.

Keywords:  HIF-2α; NAFLD/NASH; YAP/p-YAP; glutaminolysis; hepatic stellate cells-derived myofibroblasts

DOI:  https://doi.org/10.3389/fendo.2024.1344971
J Stomatol Oral Maxillofac Surg. 2024 Mar 15. pii: S2468-7855(24)00063-6. [Epub ahead of print] 101827

Clinical and biochemical assessment of the effect of glutamine in management of radiation induced oral mucositis in patients with head and neck cancer: Randomized controlled clinical trial.

Suzan S Ibrahim, Fatma E A Hassanein, Hany W Zaky, Hadeel Gamal.

  BACKGROUND: This study aimed to evaluate the effect of oral glutamine suspension on salivary levels of transforming growth factor beta 1 (TGF-β1), a cytokine involved in inflammation and Tumor progression, and the severity of radiation-induced oral mucositis (RIOM) in head and neck cancer patients. This is the first study to investigate the impact of glutamine on TGF-β1 levels in head and neck cancer patients with radiation induced oral mucositis (RIOM).METHODS: In this randomized controlled clinical trial, 50 HNC patients were enrolled and received either glutamine oral suspension or maltodextrin as a placebo from the baseline of RIOM to the end of radiotherapy. Salivary TGF-β1 levels were measured at baseline and after treatment. Also, RIOM was assessed using the World Health Organization (WHO) Oral Toxicity Scale, the Oral Mucositis Assessment Scale (OMAS), the Pain Visual Analog Scale (Pain-VAS), the incidence of opioid use, and body mass index (BMI).
RESULTS: Glutamine significantly reduced salivary TGF-β1 levels and improved RIOM symptoms, such as pain, opioid use, and weight loss. The reduction of TGF-β1 levels was associated with the improvement of RIOM severity.
CONCLUSION: Glutamine may modulate the inflammatory response and enhance wound healing in RIOM by decreasing salivary TGF-β1 levels. These findings support the use of glutamine as a potential intervention for RIOM and nutritional support for improving radiation sensitivity.
TRIAL REGISTRATION: This study was registered on clinicalTrials.gov with identifier no. NCT05856188.

Keywords:  Glutamine; Head and neck cancer; Oral mucositis; TGF-β1; Transforming growth factor beta 1

DOI:  https://doi.org/10.1016/j.jormas.2024.101827
STAR Protoc. 2024 Mar 18. pii: S2666-1667(24)00129-1. [Epub ahead of print]5(2): 102964

Protocol for analyzing energy metabolic pathway dependency in human liver cancer cell lines.

Sk Ramiz Islam, Sebabrata Maity, Oishee Chakrabarti, Soumen Kanti Manna.

  Cellular energy metabolism analysis is complex, expensive, and indirect. We present a protocol to analyze relative contribution of metabolic pathways to ATP production by directly measuring ATP levels. We describe steps for cell counting and seeding in 96-well plate, treating with metformin, and systematic inhibition with metabolic inhibitors. We then detail procedures for a viability and ATP assay and calculating energy metabolism dependency. This high-throughput and accessible protocol works with any cell line and allows for flexible perturbation studies.

Keywords:  Cancer; Metabolism; Molecular Biology

DOI:  https://doi.org/10.1016/j.xpro.2024.102964
Amino Acids. 2024 Mar 20. 56(1): 23

An insight into role of amino acids as antioxidants via NRF2 activation.

Melford C Egbujor, Olugbemi T Olaniyan, Chigbundu N Emeruwa, Sarmistha Saha, Luciano Saso, Paolo Tucci.

  Oxidative stress can affect the protein, lipids, and DNA of the cells and thus, play a crucial role in several pathophysiological conditions. It has already been established that oxidative stress has a close association with inflammation via nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway. Amino acids are notably the building block of proteins and constitute the major class of nitrogen-containing natural products of medicinal importance. They exhibit a broad spectrum of biological activities, including the ability to activate NRF2, a transcription factor that regulates endogenous antioxidant responses. Moreover, amino acids may act as synergistic antioxidants as part of our dietary supplementations. This has aroused research interest in the NRF2-inducing activity of amino acids. Interestingly, amino acids' activation of NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway exerts therapeutic effects in several diseases. Therefore, the present review will discuss the relationship between different amino acids and activation of NRF2-KEAP1 signaling pathway pinning their anti-inflammatory and antioxidant properties. We also discussed amino acids formulations and their applications as therapeutics. This will broaden the prospect of the therapeutic applications of amino acids in a myriad of inflammation and oxidative stress-related diseases. This will provide an insight for designing and developing new chemical entities as NRF2 activators.

Keywords:  Amino acids; Anti-inflammatory; Antioxidant; NRF2-KEAP1 signaling; Oxidative stress

DOI:  https://doi.org/10.1007/s00726-024-03384-8