Metabolomic analysis of the hippocampus in a rat model of chronic mild unpredictable stress-induced depression based on a pathway crosstalk and network module approach

Gao, Yao; Mu, Junfang; Xu, Teng; Linghu, Ting; Zhao, Huiliang; Tian, Jun-Sheng; Qin, Xuemei

doi:10.1016/j.jpba.2020.113755

Cited by 15 publications

(10 citation statements)

References 56 publications

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“…11 Glioblastoma is particular in that it is suspected to be derived from neural stem cells 15 and isoform 2 of IL4I1 is expressed in several neural cell types, 16 with a still undefined function that may involve control of the level of neurotransmitter amines. 17,18 In the same work, they demonstrate for the first time that IL4I1 promotes glioblastoma motility in vitro, an effect that may be highly relevant for metastatic processes. Finally, their work brings new insights by proposing that the immunosuppressive effect of IL4I1 in tumors is mediated by activation of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR).…”

Section: Introductionmentioning

confidence: 82%

What role for AHR activation in IL4I1-mediated immunosuppression ?

et al. 2021

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The amino-acid catabolizing enzyme Interleukin-4 induced gene 1 (IL4I1) remains poorly characterized despite it is emerging as a pertinent therapeutic target for cancer. IL4I1 is secreted in the synaptic cleft by antigen-presenting cells. It inhibits TCR signaling, modulates naïve T cell differentiation and limits effector T cell proliferation. IL4I1 expression in tumors shapes the tumor microenvironment and impairs the antitumor cytotoxic T cell response, thereby facilitating cancer immune escape. Several mechanisms participate in these effects. Recent data suggest a role of new IL4I1 metabolites in activation of the arylhydrocarbon receptor (AHR). Here, we observe that expression of IL4I1 is poorly correlated with that of validated targets of AHR in human cancers. Moreover, dendritic cells do not upregulate AHR target genes in relation with IL4I1 expression in vivo. Finally, IL4I1 activity toward tryptophan leading to production of AHR-activating products is very low, and should be negligible when tryptophan-degrading enzymes of higher affinity compete for the substrate. We recently showed that IL4I1 expression by dendritic cells directly regulates immune synapse formation and modulates the repertoire and memory differentiation of responding CD8 T cells after viral infection. Thus, IL4I1 may restrain tumor control through regulating the priming of tumor-specific CD8 T cells, independently of AHR activation.

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Section: Introductionmentioning

confidence: 82%

What role for AHR activation in IL4I1-mediated immunosuppression ?

et al. 2021

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“…As important paralogs, evidence has shown the correlation between CCBL1 (identical to KAT1 and GTK ) and pancreatic, prostate, and bladder cancers [ 28 ]. Furthermore, CCBL2 (identical to KAT2 ) plays an important role in several neurological diseases such as Huntington’s disease, Alzheimer’s disease and depression [ 15 , 18 , 29 ]. However, limited information is available regarding the expression of CCBL2 in tumors, especially BC.…”

Section: Discussionmentioning

confidence: 99%

“…And KYNA is a recognized neuroprotective and anticonvulsant agent involved in synaptic transmission and in the pathophysiology of various neurological disorders(11). Abnormal expression levels of CCBL2 are involved in the pathophysiological process of kidney injury, hospital-acquired VTE, depression and neurological disorders [ 12 , 15 , 18 – 22 ]. Recently, GTK (Glutamine Transaminase K, which is identical to KAT1 and CCBL1 ) has been reported to play an important role in pancreatic tumorigenesis through the glutamine pathway and cysteine conjugate beta-lyase ( CCBL ) had close relation with kidney cancer.…”

Section: Introductionmentioning

confidence: 99%

Cysteine conjugate beta-lyase 2 (CCBL2) expression as a prognostic marker of survival in breast cancer patients

Meng

Yang

et al. 2022

PLoS ONE

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Objective Cysteine conjugate beta-lyase 2 (CCBL2), also known as kynurenine aminotransferase 3 (KAT3) or glutamine transaminase L (GTL), plays an essential role in transamination and cytochrome P450. Its correlation with some other cancers has been explored, but breast cancer (BC) not yet. Methods The mRNA and protein expression of CCBL2 in BC cell lines and patient samples were detected by RT-qPCR and immunohistochemistry (IHC). BC patients’ clinical information and RNA-Seq expression were acquired via The Cancer Genome Atlas (TCGA) database. Patients were categorized into high/low CCBL2 expression groups based on the optimal cutoff value (8.973) determined by receiver operating characteristic (ROC) curve. We investigated CCBL2 and clinicopathological characteristics’ relationship using Chi-square tests, estimated diagnostic capacity using ROC curves and drew survival curves using Kaplan–Meier estimate. We compared survival differences using Cox regression and externally validated using Gene Expression Omnibus (GEO) database. We evaluated enriched signaling pathways using gene set enrichment analysis (GSEA), explored CCBL2 and relevant genes’ relationship using tumor immunoassay resource (TIMER) databases and used the human protein atlas (HPA) for pan-cancer analysis and IHC. Results CCBL2 was overexpressed in normal human cell lines and tissues. CCBL2 expression was lower in BC tissues (n = 1104) than in normal tissues (n = 114), validated by GEO database. Several clinicopathologic features were related to CCBL2, especially estrogen receptor (ER), progesterone receptor (PR) and clinical stages. The low expression group exhibited poor survival. CCBL2’s area under curve (AUC) analysis showed finite diagnostic capacity. Multivariate cox-regression analysis indicated CCBL2 independently predicted BC survival. GSEA showed enriched pathways: early estrogen response, MYC and so on. CCBL2 positively correlated with estrogen, progesterone and androgen receptors. CCBL2 was downregulated in most cancers and was associated with their survival, including renal and ovarian cancers. Conclusions Low CCBL2 expression is a promising poor BC survival independent prognostic marker.

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“…Moreover, SLC6A4 was involved in the pathway of the serotonergic synapse, and SLC6A3 was involved in the pathway of the dopaminergic synapse. Metabolomic analysis of the hippocampus in a rat model of CUMS-induced depression demonstrated that some altered metabolites were related to the serotonergic synapse, dopaminergic synapse, and glutamatergic synapse, which were involved in the pathology of depression ( Gao et al, 2021 ). SLC6A4 (a serotonin transporter gene) is one of the major determinants of serotonergic neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

Integrated Network Pharmacology and GC-MS–Based Metabolomics to Investigate the Effect of Xiang-Su Volatile Oil Against Menopausal Depression

Yang

Chen

et al. 2021

Front. Pharmacol.

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Menopausal depression perplexes a great number of women in later life. Xiangfu-Zisu (Xiang-Su), a traditional Chinese herbal pair composed of rhizomes of Cyperus rotundus L. (Xiangfu) and leaves of Perilla frutescens (L.) Britt. (Zisu), is frequently reported with antidepressant-like effects. The volatile oil from Xiangfu and Zisu has shown good antidepressant action, but its mechanism is still unclear. This study aimed to investigate the pharmacological mechanism of Xiang-Su (XS) volatile oil against menopausal depression through gas chromatography–mass spectrometry (GC-MS)-based network pharmacology and metabolomics. First, ADME screening was performed on actual detected components of XS volatile oil to obtain active constituents, and then duplicates of active constituent–related targets and menopausal depression–related targets were collected. These duplicates were considered as targets for XS volatile oil against menopausal depression, followed by GO and KEGG enrichment analyses. It showed that a total of 64 compounds were identified in XS volatile oil, and 38 active compounds were screened out. 42 overlapping genes between 144 compound-related genes and 780 menopausal depression–related genes were obtained. Results showed that targets of SLC6A4 and SLC6A3, regulation of serotonergic and dopaminergic synapses, were involved in the antidepressant mechanism of XS volatile oil. Next, antidepressant-like effect of XS volatile oil was validated in menopausal rats by ovariectomy (OVX) combined with chronic unpredictable mild stress (CUMS). Behavioral tests, biochemical analysis, and GC-MS–based non-targeted plasma metabolomics were employed to validate the antidepressant effect of XS volatile oil. Experimental evidence demonstrated that XS volatile oil reversed behavioral parameters in the sucrose preference test (SPT), open-field test (OFT), forced swim test (FST), and serum estradiol levels in OVX rats. Furthermore, results of metabolomics indicated that XS volatile oil mainly acts on regulating metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, tyrosine metabolism, and tryptophan metabolism, which were corresponding with the above-predicted results. These data suggest that network pharmacology combined with metabolomics provides deep insight into the antidepressant effect of XS volatile oil, which includes regulating key targets like SLC6A4 and SLC6A3, and pathways of serotonergic and dopaminergic synapses.

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Metabolomic analysis of the hippocampus in a rat model of chronic mild unpredictable stress-induced depression based on a pathway crosstalk and network module approach

Cited by 15 publications

References 56 publications

What role for AHR activation in IL4I1-mediated immunosuppression ?

What role for AHR activation in IL4I1-mediated immunosuppression ?

Cysteine conjugate beta-lyase 2 (CCBL2) expression as a prognostic marker of survival in breast cancer patients

Integrated Network Pharmacology and GC-MS–Based Metabolomics to Investigate the Effect of Xiang-Su Volatile Oil Against Menopausal Depression

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