Abnormal trophoblast invasion function is an important cause of recurrent spontaneous abortion (RSA). Recent research has revealed a connection between glutamine metabolism and RSA. However, the interplay between these three factors and their related mechanisms remains unclear. To address this issue, we collected villus tissues from 10 healthy women with induced abortion and from 10 women with RSA to detect glutamine metabolism. Then, the trophoblast cell line HTR-8/SVneo was used in vitro to explore the effect of glutamine metabolism on trophoblast cells invasion, which was tested by transwell assay. We found that the concentration of glutamine in the villi of the normal pregnancy group was significantly higher than that in the RSA group. Correspondingly, the expression levels of key enzymes involved in glutamine synthesis and catabolism, including glutamine synthetase and glutaminase, were significantly higher in the villi of the normal pregnancy group. Regarding trophoblast cells, glutamine markedly enhanced the proliferative and invasive abilities of HTR-8/SVneo cells. Additionally, collagen type I alpha 1 (COL1A1) was confirmed to be a downstream target of glutamine, and glutamine also activated the PI3K-AKT pathway in HTR-8/SVneo cells. These findings indicate that glutamine metabolism facilitates the invasion of trophoblasts by up-regulating COL1A1 expression through the activation of the PI3K-AKT pathway, but the specific mechanism of COL1A1 requires further study.

Leukemia is an abnormal proliferation of white blood cells that occurs in bone marrow and expands through the blood. It arises from dysregulated differentiation, uncontrolled growth, and inhibition of apoptosis. Glutamine (GLN) is a \"conditionally essential\" amino acid that promotes growth and proliferation of leukemic cells. Recently, details about the role of GLN and its metabolism in the diagnosis and treatment of acute myeloid, chronic lymphocytic, and acute lymphoblastic leukemia have emerged. The uptake of GLN by leukemia cells and the dynamic changes of glutamine-related indexes in leukemia patients may be able to assist in determining whether the condition of leukemia is in a state of progression, remission or relapse. Utilizing the possible differences in GLN metabolism in different subtypes of leukemia may help to differentiate between different subtypes of leukemia, thus providing a basis for accurate diagnosis. Targeting GLN metabolism in leukemia requires simultaneous blockade of multiple metabolic pathways without interfering with the normal cellular and immune functions of the body to achieve effective leukemia therapy. The present review summarizes recent advances, possible applications, and clinical perspectives of GLN metabolism in leukemia. In particular, it focuses on the prospects of GLN metabolism in the diagnosis and treatment of acute myeloid leukemia. The review provides new directions and hints at potential roles for future clinical treatments and studies.

The ischemia-reperfusion process of a donor heart during heart transplantation leads to severe mitochondrial dysfunction, which may be the main cause of donor heart dysfunction after heart transplantation. Pyruvate carboxylase (PC), an enzyme found in mitochondria, is said to play a role in the control of oxidative stress and the function of mitochondria. This research examined the function of PC and discovered the signaling pathways controlled by PC in myocardial IRI. We induced IRI using a murine heterotopic heart transplantation model in vivo and a hypoxia-reoxygenation cell model in vitro and evaluated inflammatory responses, oxidative stress levels, mitochondrial function, and cardiomyocyte apoptosis. In both in vivo and in vitro settings, we observed a significant decrease in PC expression during myocardial IRI. PC knockdown aggravated IRI by increasing MDA content, LDH activity, TUNEL-positive cells, serum cTnI level, Bax protein expression, and the level of inflammatory cytokines and decreasing SOD activity, GPX activity, and Bcl-2 protein expression. PC overexpression yielded the opposite findings. Additional research indicated that reducing PC levels could block the Wnt/β-catenin pathway and glutamine metabolism by hindering the movement of β-catenin to the nucleus and reducing the activity of complex I and complex II, as well as ATP levels, while elevating the ratios of NADP+/NADPH and GSSG/GSH. Overall, the findings indicated that PC therapy can shield the heart from IRI during heart transplantation by regulating glutamine metabolism through the Wnt/β-catenin pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is a fatal disease with metabolic abnormalities. The dysregulation of S100 calcium-binding protein A2 (S100A2), a member of the S100 protein family, is connected to the development of various cancers. The impact of S100A2 on the LUAD occurrence and metastasis, however, has not yet been reported. The functional mechanism of S100A2 on LUAD cell metastasis was examined in this article.
METHODS: The expression of TFAP2A and S100A2 in LUAD tissues and cells was analyzed by bioinformatics and qRT-PCR, respectively. The enrichment pathway analysis was performed on S100A2. Bioinformatics analysis determined the binding relationship between TFAP2A and S100A2, and their interaction was validated through dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was determined using cell counting kit-8 (CCK-8). A transwell assay was performed to analyze the invasion and migration of cells. Immunofluorescence was conducted to obtain vimentin and E-cadherin expression, and a western blot was used to detect the expression of MMP-2, MMP-9, GLS, and GLUD1. The kits measured the NADPH/NADP ratio, glutathione (GSH)/glutathione disulfide (GSSG) levels, and the contents of glutamine, α-KG, and glutamate.
RESULTS: S100A2 was upregulated in LUAD tissues and cells, and S100A2 mediated glutamine metabolism to induce LUAD metastasis. Additionally, the transcriptional regulator TFAP2A was discovered upstream of S100A2, and TFAP2A expression was upregulated in LUAD, which indicated that TFAP2A promoted the S100A2 expression. The rescue experiment found that upregulation of S100A2 could reverse the inhibitory effects of silencing TFAP2A on glutamine metabolism and cell metastasis.
CONCLUSIONS: In conclusion, by regulating glutamine metabolism, the TFAP2A/S100A2 axis facilitated LUAD metastasis. This suggested that targeting S100A2 could be beneficial for LUAD treatment.

Osteoarthritis is a chronic, age-related joint disease. Previous studies have shown that osteoarthritis develops during intrauterine development. Prednisone is frequently used to treat pregnancies complicated by autoimmune diseases. However, limited research has been conducted on the enduring effects of prednisone use during pregnancy on the offspring. In this study, we investigated the effect of excessive prednisone exposure on cartilage development and susceptibility to osteoarthritis in the offspring. We found that prenatal prednisone exposure (PPE) impaired cartilage extracellular matrix (ECM) synthesis, resulting in poor cartilage pathology in female offspring during the adult period, which was further exacerbated after long-distance running stimulation. Additionally, PPE suppressed cartilage development during the intrauterine period. Tracing back to the intrauterine period, we found that Pred, rather than prednisone, decreased glutamine metabolic flux, which resulted in increased oxidative stress, and decreased histone acetylation, and expression of cartilage phenotypic genes. Further, PGC-1α-mediated mitochondrial biogenesis, while PPE caused hypermethylation in the promoter region of PGC-1α and decreased its expression in fetal cartilage by activating the glucocorticoid receptor, resulting in a reduction of glutamine flux controlled by mitochondrial biogenesis. Additionally, overexpression of PGC-1α (either pharmacological or through lentiviral transfection) reversed PPE- and Pred-induced cartilage ECM synthesis impairment. In summary, this study demonstrated that PPE causes chondrodysplasia in female offspring and increases their susceptibility to postnatal osteoarthritis. Hence, targeting PGC-1α early on could be a potential intervention strategy for PPE-induced osteoarthritis susceptibility.

BACKGROUND: Reprogramming of glutamine metabolism in Gastric Cancer (GC) can significantly affect the tumor immune microenvironment and immunotherapy. This study examines the role of glutamine metabolism in the microenvironment and prognosis of gastric cancer.
METHODS: We obtained gene expression data and clinical information of patients from the TCGA database. The patients were divided into two metabolic subtypes based on consistent clustering. A prognostic risk model containing three glutamine metabolism-related genes (GMRGs) was developed using Lasso-Cox. It was validated by the GEO validation cohort. Additionally, the immune microenvironment composition of the highand low-risk groups was assessed using ESTIMATE, CIBERSORT, and ssGSEA. Drug sensitivity analysis was conducted using the \"oncoPredict\" R package.
RESULTS: We outlined the distinct clinical characteristics of two subtypes and developed a prognostic risk model. The high-risk group has a poorer prognosis due to an increased expression of immune checkpoints and immunosuppressive cellular infiltration. Our analysis, which included Cox risk regression, ROC curves, and nomogram, demonstrated that this risk model is an independent prognostic factor. The TIDE score was higher in the high-risk group than in the low-risk group. Additionally, the high-risk group did not respond well to chemotherapeutic drug treatment.
CONCLUSIONS: This study shows that modelling glutamine metabolism is a good predictor of prognosis and immunotherapy efficacy in gastric cancer. Thus, we can better understand the role of glutamine metabolism in the development of cancer and use these insights to develop more targeted and effective treatments.

Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation.

Cancer is characterized by metabolic reprogramming in cancer cells, which is crucial for tumorigenesis. The highly deregulated chromatin remodeler MORC2 contributes to cell proliferation, invasion, migration, DNA repair, and chemoresistance. MORC2 also plays a key role in metabolic reprogramming, including lipogenesis, glucose, and glutamine metabolism. A recent study showed that MORC2-regulated glucose metabolism affects the expression of E-cadherin, a crucial protein in the epithelial-to-mesenchymal transition. This review discusses recent developments in MORC2 regulated cancer cell metabolism and its role in cancer progression.

OBJECTIVE: Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma.
METHODS: In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance.
RESULTS: Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO\'s anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO.
CONCLUSIONS: Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an \"One-two Punch\" therapy of metastatic and recurrent osteosarcoma.

Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignancies. While PD-1 immune checkpoint inhibitors have demonstrated promising therapeutic efficacy in HCC, not all patients exhibit a favorable response to these treatments. Glutamine is a crucial immune cell regulatory factor, and tumor cells exhibit glutamine dependence. In this study, HCC patients were divided into two subtypes (C1 and C2) based on glutamine metabolism-related genes via consensus clustering. The C1 pattern, in contrast to C2, was associated with a lower survival probability among HCC patients. Additionally, the C1 pattern exhibited higher proportions of patients with advanced tumor stages. The activity of C1 in glutamine metabolism and transport is significantly enhanced, while its oxidative phosphorylation activity is reduced. And, C1 was mainly involved in the progression-related pathway of HCC. Furthermore, C1 exhibited high levels of immunosuppressive cells, cytokine-receptor interactions and immune checkpoint genes, suggesting C1 as an immunosuppressive subtype. After stepwise selection based on integrated four machine learning methods, SLC1A5 was finally identified as the pivotal gene that distinguishes the subtypes. The expression of SLC1A5 was significantly positively correlated with immunosuppressive status. SLC1A5 showed the most significant correlation with macrophage infiltration, and this correlation was confirmed through the RNA-seq data of CLCA project and our cohort. Low-SLC1A5-expression samples had better immunogenicity and responsiveness to immunotherapy. As expected, SubMap and survival analysis indicated that individuals with low SLC1A5 expression were more responsive to anti-PD1 therapy. Collectively, this study categorized HCC patients based on glutamine metabolism-related genes and proposed two subclasses with different clinical traits, biological behavior, and immune status. Machine learning was utilized to identify the hub gene SLC1A5 for HCC classification, which also could predict immunotherapy response.