bims-glucam 2026-01-04 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–01–04
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolites promote the progression of cervical cancer by inducing M2 macrophage polarization.
Nickel refining fumes Activate Glutamine Metabolism via the HIF-1α/Notch Pathway to Drive Epithelial-Mesenchymal Transition in Beas-2B Cells.
Identification of key genes related to glutamine metabolism in diabetic nephropathy by machine learning methods.
Integrative Single-Cell and Machine Learning Analysis Develops a Glutamine Metabolism-Based Prognostic Model and Identifies MSMO1 as a Therapeutic Target in Osteosarcoma.
Comprehensive bioinformatics analysis identified and validated KIT as a key gene associated with glutamine metabolism in thyroid carcinoma.
Redox-Amino Acid Metabolic Crosstalk in Ovarian Cancer Stem Cells: Integrating Metabolic Reprogramming, Signaling, and the Tumor Microenvironment.
CircRNA circdner mediates histone lactylation modification via glutamine metabolic reprogramming to regulate PD-L1 expression and promote immune evasion in lung cancer.
TGM2-P2RX7 loop promotes gemcitabine resistance in pancreatic cancer by modulating glutamine metabolism and mitophagy.
Target Discovery in Head-and-Neck Squamous Cell Carcinoma: Genome-Wide CRISPR Screens Illuminate Therapeutic Resistance and Actionable Dependencies.
Evaluation of Metabolic Characteristics of Cancer Cells.
BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.
Effect of perioperative glutamine-enriched nutritional support on patients with colorectal cancer: A systematic review and meta-analysis.
Glutamine synthetase sustains cortical circuit development via mTOR-mediated astrocyte maturation.
Melatonin Modulates Astrocyte Inflammatory Response and Nrf2/SIRT1 Signaling Pathways in Adult Rat Cortical Cultures.
Juglans regia L. attenuate Psoralea corylifolia L.-induced hepatotoxicity by regulating the Nrf2 pathway and amino acid metabolism.
The Efficacy and Safety of Nutritional Supplements for Cancer Supportive Care: An Umbrella Review and Hierarchical Evidence Synthesis.

Pathol Res Pract. 2025 Dec 29. pii: S0344-0338(25)00541-2. [Epub ahead of print]278 156348

Glutamine metabolites promote the progression of cervical cancer by inducing M2 macrophage polarization.

Tingting Liu, Lanyue Zhang, Yang Li, Wenxin Liao, Juexiao Deng, Hua Liang, Fujin Shen.

   BACKGROUND: Tumour-associated macrophages (TAMs) within the tumour microenvironment play crucial roles in tumour initiation, invasion, and metastasis. While glutamine synthetase (GS) is expressed predominantly in the tumour stroma, particularly in TAMs, the role of glutamine metabolism in regulating TAM polarization and function in cervical cancer (CC) remains poorly understood. This study aims to clarify this role and its implications for cancer progression.
METHODS: CD68 and GS expression in cervical tissues was detected using immunofluorescence staining. The effects of glutamine metabolism on TAM polarization were investigated via RTqPCR, flow cytometry, Western blotting and NAA treatment analyses. CCK8, colony formation, and Transwell assays were conducted to determine the effects of MSO-treated macrophages on tumour cell proliferation, migration, and invasion.
RESULTS: We observed a significant increase in GS expression in TAMs within cervical cancer (CC) tissues, particularly in M2-like TAMs. Glutamine synthesized by TAMs with high GS expression was found to increase the proliferation, migration, and invasion of CC cells. Inhibition of GS in TAMs notably reduced their tumour-promoting effects. Additionally, the byproducts of glutamine metabolism in CC cells contributed to the polarization of TAMs towards the M2 phenotype. This polarization was completely abrogated when SNAT1, a key glutamine transporter, was inhibited in CC cells.
CONCLUSIONS: Our findings demonstrate that glutamine synthesized by TAMs with high GS expression promotes tumour progression in CC. Furthermore, glutamine byproducts produced by CC cells induce TAM polarization towards the M2 phenotype, suggesting crucial metabolic crosstalk between tumour cells and macrophages that supports tumour progression. These results highlight the potential of targeting glutamine metabolism to modulate TAM function and inhibit tumour growth.

Keywords:  Cervical cancer; GS; Glutamine; M2 polarization; Tumour-associated macrophages

DOI:  https://doi.org/10.1016/j.prp.2025.156348
Toxicology. 2025 Dec 30. pii: S0300-483X(25)00349-X. [Epub ahead of print] 154390

Nickel refining fumes Activate Glutamine Metabolism via the HIF-1α/Notch Pathway to Drive Epithelial-Mesenchymal Transition in Beas-2B Cells.

Qian-Qian Sun, Han-Nong Yu, Rui-Ze Wu, Bo Zhang, Wen-Xue Yao, Wei-Yang Liu, Jia Han, Li-Yan Ju, Yu-Lin Pan, Yong-Hui Wu.

  Occupational exposure to nickel refining fumes (NiRF) represents a critical risk factor for respiratory diseases; however, the molecular mechanisms governing NiRF-induced epithelial-mesenchymal transition (EMT) in bronchial epithelial cells remain incompletely elucidated. In vitro experiments using the human bronchial epithelial cell line Beas-2B as a model demonstrated that NiRF exposure robustly activated the hypoxia-inducible factor-1α (HIF-1α)/Notch signaling pathway, while concomitantly triggering glutamine metabolic reprogramming. This reprogramming phenotype was characterized by the upregulated expression of the glutamine transporter SLC1A5 and enhanced expression of glutaminase 1 (GLS1). Functional validation assays revealed that small interfering RNA (siRNA)-mediated silencing of HIF-1α (siHIF-1α) or Notch1 (siNotch1) significantly downregulated GLS1 expression, and reversed NiRF-induced glutamine metabolic activation. Furthermore, pharmacological inhibition of glutamine metabolism via treatment with a GLS1 inhibitor effectively abrogated the EMT process in Beas-2B cells, as evidenced by the upregulated expression of the epithelial marker E-cadherin and the downregulated expression of the mesenchymal markers N-cadherin and vimentin. In vivo experiments further confirmed that NiRF promoted EMT in lung tissue cells in a dose-dependent manner, accompanied by activation of the HIF-1α/Notch signaling pathway and enhanced glutamine metabolism (as reflected by the upregulated expression of both SLC1A5 and GLS1). Collectively, these findings verify that glutamine metabolic activation, mediated by the HIF-1α/Notch pathway, constitutes the core mechanism underlying NiRF-driven EMT in Beas-2B cells. This study provides novel theoretical insights and potential therapeutic targets for elucidating the pathogenesis of occupational NiRF-associated respiratory injury and developing targeted intervention strategies.

Keywords:  Beas-2B cells; Epithelial-mesenchymal transition; Glutamine metabolism; HIF-1α/Notch pathway; Nickel refining fumes; Respiratory injury

DOI:  https://doi.org/10.1016/j.tox.2025.154390
Sci Rep. 2025 Dec 29. 15(1): 45703

Identification of key genes related to glutamine metabolism in diabetic nephropathy by machine learning methods.

Yuanyuan Luo, Ruojing Bai.

  Diabetic nephropathy (DN) is a critical microvascular complication of diabetes. Increasing evidence suggests that dysregulation of glutamine metabolism contributes to DN pathogenesis. This study aimed to explore alterations in glutamine metabolism-related genes (GMRGs) in DN. Nine differentially expressed GMRGs (DE-GMRGs) were identified by intersecting 103 GMRGs with 2,281 DEGs from the GSE142153 dataset comparing normal and DN groups. Notably, DE-GMRGs located on autosomes were significantly enriched in pathways related to glutamine metabolism and the metabolism of alanine, aspartate, and glutamate. The Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) methods were employed to pinpoint key genes, SLC7A5 and SLC25A12. SLC7A5 was found to be upregulated in DN, whereas SLC25A12 showed decreased expression. The diagnostic potential of these genes was further validated by assessing the area under the receiver operating characteristic (ROC) curve. Correlation analysis revealed strong associations between these key genes and clinical markers such as glomerular filtration rate (GFR), serum creatinine, and immune cells, including mast cells and effector memory CD8 T cells. Drug prediction and molecular docking analyses indicated that valproic acid might serve as an effective therapeutic agent targeting these genes. Glutamine metabolism-related genes SLC7A5 and SLC25A12 were identified as potential diagnostic and therapeutic targets for DN. These findings offer valuable clinical insights for the diagnosis and management of DN.

Keywords:  Diabetic nephropathy; Drug; Glutamine metabolism; Machine learning

DOI:  https://doi.org/10.1038/s41598-025-28169-1
Biomolecules. 2025 Nov 28. pii: 1664. [Epub ahead of print]15(12):

Integrative Single-Cell and Machine Learning Analysis Develops a Glutamine Metabolism-Based Prognostic Model and Identifies MSMO1 as a Therapeutic Target in Osteosarcoma.

Hui Ma, Haiyang Zhang, Johny Bajgai, Md Habibur Rahman, Thu Thao Pham, Chaodeng Mo, Buchan Cao, Yeong-Eun Choi, Cheol-Su Kim, Kyu-Jae Lee.

  Although metabolic pathways profoundly influence disease behavior, osteosarcoma (OS) still lacks a glutamine metabolism-based framework for patient stratification. By integrating single-cell RNA sequencing with bulk cohorts, we delineated a glutamine-associated transcriptional program and translated it into an externally validated, clinically oriented risk model. After rigorous quality control and doublet removal, 19 clusters were annotated into 10 cell types. Glutamine metabolism-related gene (GRG) scores, quantified by five orthogonal algorithms (AUCell, UCell, singscore, ssGSEA, and AddModuleScore), revealed pronounced intratumoral heterogeneity, particularly within osteoblastic cells. A composite GRG score correlated with 641 genes, defining 188 differentially expressed genes; intersecting positively correlated and up-regulated genes yielded 91 candidates. Through a 10-fold cross-validated benchmark of 10 machine-learning algorithms and 101 combinations, Step-Cox [forward] + Ridge emerged as the optimal pipeline, producing a five-gene prognostic model (GPX7, COL11A2, CPE, MSMO1, SGMS2) with moderate yet reproducible performance in independent cohorts. Functionally, stable MSMO1 knockdown in U2OS cells suppressed proliferation, migration, and invasion; increased apoptosis; altered GS, GLS, and α-ketoglutarate; and dampened Wnt/β-catenin signaling. Clinically, the model stratifies OS patients into molecular risk subgroups with distinct outcomes, supporting identification of high-risk individuals and informing personalized glutamine-targeted or combination therapies. Mechanistically, glutamine metabolism shapes the OS tumor microenvironment by modulating immune-evasion and angiogenic cues, underscoring its dual role in metabolic adaptation and immune-metabolic crosstalk. Collectively, this study establishes a single-cell-anchored, glutamine-coupled state in OS, introduces an externally validated prognostic tool with translational promise but modest discriminative power, and positions MSMO1 as a metabolic-signaling node warranting further mechanistic and in-vivo investigation.

Keywords:  MSMO1; Wnt/β-catenin signaling; glutamine metabolism; osteosarcoma; prognostic model; single-cell RNA sequencing; tumor microenvironment

DOI:  https://doi.org/10.3390/biom15121664
Medicine (Baltimore). 2025 Dec 26. 104(52): e46769

Comprehensive bioinformatics analysis identified and validated KIT as a key gene associated with glutamine metabolism in thyroid carcinoma.

Xinxiong Li, Lizhen Qiu, Enyu Gu, Naizhuo Ke, Miao Fang.

  The increasing incidence and mortality of thyroid cancer (THCA) exacerbates the global cancer burden. Glutamine metabolism is a hallmark metabolic feature of tumors, but its impact on the pathogenesis and progression of THCA remains unclear. Studies retrieved THCA data from TCGA and GEO databases. Cluster analysis, differential expression analysis, and weighted gene co-expression network analysis were used to identify key glutamine metabolism-related genes (GMRGs) in THCA. Identification of key genes through protein-protein interaction network construction, based on expression and diagnosis of internal and external datasets. Their functional role was systematically evaluated by competitive endogenous RNA network analysis, genomic alteration analysis, immune-related studies, and immune checkpoint analysis. Using GMRGs and differentially expressed genes in THCA, 6 markers (NOS2, OTC, NOS1, GLS2, UCP2, RIMKLA) were selected as references for THCA clustering. Differential analysis combined with weighted gene co-expression network analysis identified 173 GMRGs in THCA. The CytoHubba algorithm in the protein-protein interaction network identified 4 hub genes: MUC1, KIT, COMP, and MMP7. Subsequent validation showed a significant decrease in the expression of KIT in tumor samples (P < .05). Receiver operating characteristic curve (ROC) analysis showed excellent diagnostic performance with area under the curve values of 0.925, 0.945, 0.965, and 0.996 in the internal and external validation cohorts. Notably, KIT expression showed a significant difference between T and N phases (P < .05). In addition, we delineate a regulatory network of competitive endogenous RNAs that control KIT expression. Genomic alteration analysis reveals frequent KIT modifications in anaplastic thyroid carcinoma. Tumors with low KIT expression exhibited enhanced immune infiltration and significant correlation with immune checkpoint genes, including PDCD1LG2 and PDCD1 (P < .05). This study identifies KIT as a key GMRG in THCA, positioning it as a novel diagnostic biomarker and a potential therapeutic evaluation marker for tumor progression.

Keywords:  KIT; bioinformatics; glutamine metabolism; thyroid carcinoma; tumor markers

DOI:  https://doi.org/10.1097/MD.0000000000046769
Antioxidants (Basel). 2025 Nov 27. pii: 1413. [Epub ahead of print]14(12):

Redox-Amino Acid Metabolic Crosstalk in Ovarian Cancer Stem Cells: Integrating Metabolic Reprogramming, Signaling, and the Tumor Microenvironment.

Dan Liu, Huawei Yi, Cunjian Yi.

  Ovarian cancer stem cells (OCSCs) possess stemness; differentiation capacity; and tolerance to oxidative, metabolic, and therapeutic stress, driving recurrence and chemoresistance. Emerging evidence highlights a synergistic interplay between redox homeostasis and amino acid metabolism in maintaining stemness and treatment resistance. This review integrates redox regulation, amino acid metabolic reprogramming, and tumor microenvironment (TME) signals into a unified "redox-amino acid-TME" framework. OCSCs balance signal transduction and antioxidant defense by fine-tuning reactive oxygen species (ROS) levels. Glutamine, serine/glycine, and sulfur amino acid metabolism collectively generate NADPH and glutathione, sustaining the GPX4/TRX antioxidant systems and suppressing ferroptosis. Branched-chain amino acid (BCAA)-mTOR and tryptophan (Trp)-aryl hydrocarbon receptor (AhR) axes couple amino acid sensing to redox signaling, stabilizing the stem-like phenotype. Under TME stress, including hypoxia, acidity, and nutrient competition, exosomes and stromal components reinforce stemness and immune evasion through metabolic and redox crosstalk. Therapeutically, targeting glutamine metabolism (ASCT2/GLS), serine biosynthesis (PHGDH/SHMT), or antioxidant defenses (xCT/GPX4) disrupts reducing power, increases oxidative stress, and enhances the efficacy of chemotherapy, PARP inhibition, and immunotherapy. Biomarkers such as xCT/GPX4 expression, PHGDH levels, Nrf2 activity, and GSH/NADPH ratios may guide patient stratification and response prediction. Overall, understanding the redox-amino acid metabolic network provides a mechanistic basis and translational opportunities for precision metabolic therapies in ovarian cancer.

Keywords:  amino acid metabolism; ferroptosis; ovarian cancer stem cells; redox homeostasis; tumor microenvironment

DOI:  https://doi.org/10.3390/antiox14121413
World J Surg Oncol. 2025 Dec 29.

CircRNA circdner mediates histone lactylation modification via glutamine metabolic reprogramming to regulate PD-L1 expression and promote immune evasion in lung cancer.

Shi-Wei Xu, Tong Liu, Shi-Yin Liu, Ming-Long Li, Wei-Min Zhang, Yuan Weng, Gu-Ye Lu, Hai-Feng Wang, Jin-You Li.



Keywords:  CircRNA circdner; Glutamine metabolic reprogramming; Histone lactylation modification; Immune evasion; Lung cancer; PD-L1

DOI:  https://doi.org/10.1186/s12957-025-04152-y
Cell Death Discov. 2025 Dec 30.

TGM2-P2RX7 loop promotes gemcitabine resistance in pancreatic cancer by modulating glutamine metabolism and mitophagy.

Ke Ye, Shuhua Zhou, Xuejun Gong, Zhongcheng Zhu, Moyan Xiao, Shuai Liang.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer with poor diagnosis and prognosis, and overcoming gemcitabine-resistant (Gem-R) is a major obstacle in its treatment. Given the important role of glutamine (Glu) metabolism in tumor drug resistance, we investigated the role and exact mechanism of transglutaminase type 2 (TGM2) in influencing PDAC sensitivity to gemcitabine. In this study, we found that TGM2 exhibited elevated expression levels in Gem-R cells and tissue samples from patients with clinically resistant PDAC. Mechanistically, downregulation of TGM2 suppressed the proliferation of Gem-R PDAC cells both in vitro and in vivo by modulating Glu metabolism. RNA sequencing analysis revealed that the mechanism by which targeting TGM2 inhibits drug resistance in Gem-R PDAC cells may be associated with purinergic receptor P2X7 (P2RX7) within the GO:0014049 pathway (positive regulation of glutamate secretion). P2RX7 is highly expressed in Gem-R PDAC cells and tissue samples, and it participates in Glu metabolism and mitophagy in Gem-R PDAC cells. Furthermore, Glu has also been found to induce mitophagy. Lastly, TGM2 and P2RX7 form a positive feedback regulatory loop, jointly regulating Glu metabolism and mitophagy, thereby promoting drug resistance in Gem-R PDAC cells. These data suggest that the TGM2-P2RX7 loop promotes Gem-R in PDAC by improving Glu metabolism and mitophagy, highlighting its potential as a crucial therapeutic target for PDAC.

DOI: https://doi.org/10.1038/s41420-025-02922-x
Biomedicines. 2025 Dec 08. pii: 3012. [Epub ahead of print]13(12):

Target Discovery in Head-and-Neck Squamous Cell Carcinoma: Genome-Wide CRISPR Screens Illuminate Therapeutic Resistance and Actionable Dependencies.

Vui King Vincent-Chong.

  Head-and-neck squamous cell carcinoma (HNSCC) remains a lethal malignancy with stagnant survival despite advances in surgery, radiotherapy, and systemic therapy. Beyond cetuximab and PD-1 inhibitors, there are only a few targeted options, which benefit only a minority of patients, underscoring the need for new biomarkers and druggable dependencies. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 screening now enables systematic, high-specificity investigation of gene function to reveal determinants of tumor proliferation, survival, and therapy response. Compared with RNA interference, CRISPR provides cleaner on-target knockout and more interpretable phenotypes, allowing efficient discovery of essential genes and synthetic-lethal interactions. Although the Cancer Dependency Map profiled 89 OSCC/HNSCC lines to nominate baseline dependencies, drug-perturbed states critical for understanding platinum resistance remain underexplored. Only a handful of HNSCC studies have applied genome-wide CRISPR cas9 screening: two mapped core essential genes; two mapped cisplatin resistance and radiation resistance; and others uncovered synthetic-lethal targets, including vulnerabilities to mTOR inhibition, EGFR inhibition, glutamine metabolism inhibition, and host determinants of oncolytic HSV-1 efficacy. This review synthesizes these findings, highlights methodological considerations (library design, coverage, and treatment duration), and integrates complementary functional data to prioritize targets for rational combinations. This review also provides information on the TCGA database and in vivo CRISPR screening that can accelerate precision therapeutics for patients with HNSCC.

Keywords:  HNSCC; OSCC; cisplatin; genome-wide CRISPR cas9 knockout screen; head-and-neck squamous cell carcinoma; oral squamous cell carcinoma; preclinical model; radiation; resistance; vulnerabilities

DOI:  https://doi.org/10.3390/biomedicines13123012
Methods Mol Biol. 2026 ;2983 159-167

Evaluation of Metabolic Characteristics of Cancer Cells.

Riddhi Mehta, Pritpal Kaur, Fatema Zohra Sadia, Patricia Maziarz, Ales Vancura.

  Cancer cells undergo a complex rearrangement of metabolic pathways that allows them to satisfy the needs of increased proliferation. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS) have emerged as a potential therapeutic strategy. In this chapter, we describe a protocol that utilizes the Agilent Seahorse XFp Analyzer to assess mitochondrial respiration and glycolysis in ovarian cancer cells.

Keywords:  Cancer metabolism; Extracellular acidification; Glycolysis; Mitochondrial respiration; Ovarian cancer; Oxygen consumption rate

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_15
Nat Commun. 2025 Dec 29.

BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.

Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei.

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206+ myeloid cells and reduced effector CD8+ T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape.

DOI: https://doi.org/10.1038/s41467-025-68027-2
World J Gastrointest Surg. 2025 Dec 27. 17(12): 112256

Effect of perioperative glutamine-enriched nutritional support on patients with colorectal cancer: A systematic review and meta-analysis.

Yong Huang, Xiu-Zhi Yang, Song-Han Qin, Tao Zhang, Ming Xie, Ji-Wei Wang.

   BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor of the digestive system that poses a serious threat to human health. During the perioperative period, patients with CRC are prone to nutritional risks and malnutrition. Compared with traditional nutritional support, immunostimulatory nutrients, including glutamine (Gln), have attracted increasing attention. Although many previous studies have reported that perioperative Gln supplementation can improve short-term clinical outcomes in patients with CRC, some studies have not demonstrated a benefit. Resolution of Gln supplementation value thus requires further exploration.
AIM: To clarify the influence of perioperative Gln-enhanced nutritional support on postoperative outcomes including nutritional status, immune function, inflammation levels, morbidity due to complications, and length of hospital stay (LOS).
METHODS: A comprehensive literature search was conducted (inception to June 2025). PubMed, EMBASE, Web of Science, Cochrane Library, China Biomedical Database, CNKI, VIP, and the Wanfang Electronic Database were searched. This meta-analysis ultimately included 27 studies with a total of 1643 patients; 827 patients received perioperative Gln treatment and 816 received conventional nutritional therapy. A random-effects model was used to pool relative risks (RR) and mean differences (MD) with 95% confidence intervals (CI).
RESULTS: Pooled analysis showed that Gln intervention reduced morbidity associated with postoperative infectious complications (RR = 0.36; 95%CI: 0.24-0.54) and non-infectious complications (RR = 0.32; 95%CI: 0.19-0.55) and shortened the LOS by 2.31 days (MD = -2.31; 95%CI: -3.21 to -1.41) in CRC patients. Gln supplementation also increased serum albumin, prealbumin, peripheral blood lymphocyte count, and nitrogen balance levels and improved humoral and cellular immune function. We also found that postoperative tumor necrosis factor-α and C-reactive protein levels were lower in Gln-supplemented patients. By contrast, Gln supplementation did not improve CD8+ and CD4+/CD8+ levels.
CONCLUSION: Gln supplementation effectively improved short-term clinical outcomes in patients with CRC.

Keywords:  Colorectal cancer; Immune function; Inflammation levels; Length of stay; Nitrogen balance; Nutritional status; Postoperative complications

DOI:  https://doi.org/10.4240/wjgs.v17.i12.112256
Protein Cell. 2025 Dec 30. pii: pwaf112. [Epub ahead of print]

Glutamine synthetase sustains cortical circuit development via mTOR-mediated astrocyte maturation.

Pifang Gong, Xiaoli Chen, Wei Cong, Wentong Hong, Yitong Liu, Guibo Qi, Xuan Song, Zhenru Wang, Zhanmeng Leng, Shumin Duan, Jun Gao, Woo-Ping Ge, Song Qin.

DOI: https://doi.org/10.1093/procel/pwaf112
Biomedicines. 2025 Dec 02. pii: 2967. [Epub ahead of print]13(12):

Melatonin Modulates Astrocyte Inflammatory Response and Nrf2/SIRT1 Signaling Pathways in Adult Rat Cortical Cultures.

Ester Rezena, Matheus Sinhorelli Cioccari, Aline Daniel Moreira de Moraes, Giancarlo Tomazzoni de Oliveira, Vanessa-Fernanda Da Silva, Izaviany Schmitz, Guilhian Leipnitz, Carlos-Alberto Gonçalves, Carmem Gottfried, Larissa Daniele Bobermin, André Quincozes-Santos.

  Background/Objectives: The cerebral cortex is critical for neurological functions that are strongly affected by the aging process. Astrocytes play a central role in maintaining neurotransmitter balance and regulating antioxidant and anti-inflammatory responses, but these physiological functions may also decline with age. This study aimed to investigate the effects of melatonin, a molecule with known antioxidant, anti-inflammatory and neuroprotective properties, on astrocytes of mature cortical tissue obtained from adult Wistar rats. Methods: Primary cortical astrocyte cultures were obtained from neonatal and 90-day-old Wistar rats and treated with melatonin (300 µM for 24 h). We assessed cell viability and metabolism (MTT and extracellular lactate levels), glutamine synthetase (GS) activity, glutathione (GSH) content, release of cytokines, and the expression of genes and proteins associated with oxidative stress and inflammation by RT-qPCR and Western blotting. Results: Melatonin did not affect cell viability or lactate production. Moreover, there were no changes in GS activity, a key enzyme in glutamate metabolism, or in GSH levels, an antioxidant defense molecule synthesized by astrocytes. However, melatonin significantly reduced the expression of the nuclear factor NFκB, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS), while increasing interleukin 6 and 10 levels. Melatonin also upregulated the gene expression of the transcriptional factors Nrf2 and sirtuin 1 (SIRT1) and downregulated AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), while PGC-1α protein levels remained unchanged. A complementary analysis of astrocytes obtained from neonatal rats showed that melatonin did not change metabolic or redox parameters under basal conditions. Conclusions: Melatonin exerted anti-inflammatory effects on adult astrocyte cultures, likely through modulation of protective signaling pathways, such as Nrf2/SIRT1. These findings highlight the potential role of melatonin in preserving astrocytic function and mitigating age-related neuroinflammatory processes.

Keywords:  astrocytes; cerebral cortex; glioprotection; melatonin

DOI:  https://doi.org/10.3390/biomedicines13122967
J Ethnopharmacol. 2025 Dec 31. pii: S0378-8741(25)01813-6. [Epub ahead of print] 121120

Juglans regia L. attenuate Psoralea corylifolia L.-induced hepatotoxicity by regulating the Nrf2 pathway and amino acid metabolism.

Yu Wu, Meimei Luo, Letao Hu, Li Wu, Xingyu Zhu, Hui Zhu, Shen Shen, Yuwei Zhao, Xin Li, Jinhua Tao, Weidong Li.

   ETHNOPHARMACOLOGICAL RELEVANCE: The hepatotoxicity associated with the traditional herbal tonic Psoralea corylifolia L., also known as Psoraleae fructus (PF) in the Chinese Pharmacopoeia, is attenuated by compatibility with Juglans regia L., also known as Walnut kernels (WKs) in the Chinese Pharmacopoeia; however, the molecular mechanisms involved are unknown.
AIM OF THE STUDY: To elucidate the molecular mechanisms through which WKs attenuate PF-induced liver injury.
METHODS: Sprague-Dawley rats were randomly allocated to the control, low-dose PF (PL), high-dose PF (PH), low-dose PF+WKs (PJL), high-dose PF+WKs (PJH), and PJH+Nrf2 inhibitor (PJHM) groups. After 4 weeks of daily therapeutic intervention, serum and hepatic tissues were collected for hepatic biochemical profiling, inflammatory cytokine quantification, oxidative stress parameter evaluation, and histopathological and ultrastructural examinations.
RESULTS: WKs administration considerably attenuated hepatotoxicity biomarkers and proinflammatory mediators while enhancing the antioxidant capacity of hepatocytes compared to the effects observed in the PL and PH groups. Histopathological analysis revealed marked amelioration of hepatocellular swelling and reduced inflammatory infiltration. Ultrastructural examination confirmed the preservation of the mitochondrial cristae structure and suppression of apoptosis. Pharmacological inhibition of Nrf2 exacerbated hepatic damage, and effectively reversed the protective effects of WKs. Western blot analysis revealed that the Nrf2/HO-1 axis was activated in the PJH group and upregulated the expression of the downstream effectors HO-1 and NQO1, whereas a significant suppression of this pathway was observed in the PJHM group. HPLC-MS/MS profiling revealed enhanced norbakuchinic acid levels, coupled with substantial decreases in hepatotoxic psoralen derivatives (psoralen, isopsoralen, bavachinin, bavachalcone, and neobavaisoflavone) in the PJH group. Untargeted metabolomics revealed 33 dysregulated metabolites in the PH group, 23 of which were regulated back to a more normal expression in the PJH group. These metabolites are involved in pathways of arginine biosynthesis, glycine-serine-threonine metabolism, and pyruvate metabolism. Targeted metabolomics validated the metabolic reprogramming of the following amino acids: sarcosine, pyruvate, urea, lactate, and malate decreased, threonine, aspartate, fumarate, and glutamine were increased; and citrulline and glutamate showed an upward trend. Spearman's correlation network analysis revealed strong positive associations between hepatotoxic components (psoralidin, neobavaisoflavone, and bavachin) and liver injury indicators. Aspartate, citrulline, and pyruvate levels correlated most prominently with the components of liver injury.
CONCLUSIONS: WKs mitigated PF-induced liver injury through multiple pathways, particularly by reducing the levels of injury-causing components. Additionally, WKs activate the Nrf2/HO-1 signaling pathway and modulate amino acid metabolism.

Keywords:  Juglans regia L.; Psoralea corylifolia L.; chemical constituents; compatibility-attenuated toxicity; liver injury; metabolomics

DOI:  https://doi.org/10.1016/j.jep.2025.121120
Integr Cancer Ther. 2026 Jan-Dec;25:25 15347354251405267

The Efficacy and Safety of Nutritional Supplements for Cancer Supportive Care: An Umbrella Review and Hierarchical Evidence Synthesis.

Sarah Benna-Doyle, Suzanne Grant, Alison Maunder, Jing Liu, Melik Ibrahim, Adele Cave, Chhiti Pandey, Monica Tang, Eng-Siew Koh, Geoff Delaney, Deep Jyoti Bhuyan, Victoria Choi, Ki Kwon, Maria Gonzalez, Susannah Graham, Ashanya Malalasekera, Carolyn Ee.

  Cancer survivors experience a range of side effects during and after treatment. There is a need for a rigorous synthesis of the most recent and best available evidence on the role of nutritional supplements for supportive care in cancer, to inform shared decision-making. We searched 5 databases for umbrella reviews, meta-analyses and systematic reviews on nutritional supplements for supportive cancer care, excluding studies on pain, anxiety and depression, which are covered in recent guidelines. We found 52 reviews that reported on 250 RCTs on 18 supplements for 16 indications. Almost all reviews were of low/critically low quality (assessed using A MeaSurement Tool to Assess systematic Reviews version 2). There was moderate-certainty evidence for benefit from the following supplements: amino acids and oral proteolytic enzymes for severity of radiation-induced dermatitis, N-acetyl cysteine for prevention of chemotherapy-induced peripheral neuropathy (CIPN) in individuals with gastrointestinal cancers. There was low to very low certainty evidence that glutamine, zinc, probiotics and melatonin may be effective for oral mucositis; Vitamin E, omega-3 fatty acids, glutamine and other amino acids may be effective for preventing CIPN. Serious adverse events were reported for high-dose Vitamin A, and dose-related adverse events were reported with zinc and Vitamin E. However, the majority of nutritional supplements were associated with only minor adverse events. Due to the low to very low certainty of the majority of evidence, firm clinical recommendations cannot be made. Further research to conclusively evaluate benefit and harm, including potential impact on efficacy of standard treatments, should be conducted.

Keywords:  cancer supportive care; evidence synthesis; nutritional supplements; review

DOI:  https://doi.org/10.1177/15347354251405267