Paroxetine combined with fluorouracil plays a therapeutic role in mouse models of colorectal cancer with depression through inhibiting IL‑22 expression to regulate the MAPK signaling pathway

Zhang, Huijie; Chen, Meixv; Liu, Ying; Dong, Xiaomei; Zhang, Chan; Jiang, Han; Xue, Chen

doi:10.3892/etm.2020.9370

Cited by 15 publications

(12 citation statements)

References 58 publications

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“…As IL-22 is involved in the induction of inflammatory responses in other tissues, we investigated its effects on the production of inflammatory cytokines [ 41 , 51 ], and found that treatment of BV2 and HT22 cells with IL-22 increased the levels of TNF-α ( Figure 2 A) and IL-6 ( Figure S1 ). Previous studies have shown that binding of IL-22 to IL-22Rα induces the JAK1, STAT3, and STAT5 pathways, as well as the MAP kinase pathways [ 17 , 52 , 53 ]. In line with these reports, we found that pretreatment of BV2 cells with SP600125 (a specific inhibitor of JNK) and pretreatment of HT22 cells with S3I-201 (a specific inhibitor of STAT3) attenuated the IL-22-induced increase in TNF-α ( Figure 3 A,B).…”

Section: Discussionmentioning

confidence: 99%

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

Lee

et al. 2022

IJMS

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Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rβ subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.

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Section: Discussionmentioning

confidence: 99%

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

Lee

et al. 2022

IJMS

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“…Regulating the CUMS-induced MAPK pathway and NF-κB protein complex activation can alleviate depression-like behavior in mice (Su et al 2017 ). Paroxetine combined with fluorouracil, ketamine and ghrelin and other drugs can show antidepressant-like effects via the MAPK signaling pathway (Zhang et al 2020 ; Humo et al 2020 ; Han et al 2019 ). Cui et al found that HL can alleviate inflammation by regulating the expression of pro-inflammatory cytokines through MAPK signaling pathway, thereby inhibiting the occurrence and development of IR and diabetes (Cui et al 2018 ).…”

Section: Discussionmentioning

confidence: 99%

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

Tang

Wang

et al. 2021

Mol Med

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Background The incidence of diabetes mellitus (DM) and depression is increasing year by year around the world, bringing a serious burden to patients and their families. Jiao-tai-wan (JTW), a well-known traditional Chinese medicine (TCM), has been approved to have hypoglycemic and antidepressant effects, respectively, but whether JTW has such dual effects and its potential mechanisms is still unknown. This study is to evaluate the dual therapeutic effects of JTW on chronic restraint stress (CRS)-induced DM combined with depression mice, and to explore the underlying mechanisms through network pharmacology. Methods CRS was used on db/db mice for 21 days to induce depression-like behaviors, so as to obtain the DM combined with depression mouse model. Mice were treated with 0.9% saline (0.1 ml/10 g), JTW (3.2 mg/kg) and Fluoxetine (2.0 mg/kg), respectively. The effect of JTW was accessed by measuring fasting blood glucose (FBG) levels, conducting behavioral tests and observing histopathological change. The ELISA assay was used to evaluate the levels of inflammatory cytokines and the UHPLC-MS/MS method was used to determine the depression-related neurotransmitters levels in serum. The mechanism exploration of JTW against DM and depression were performed via a network pharmacological method. Results The results of blood glucose measurement showed that JTW has a therapeutic effect on db/db mice. Behavioral tests and the levels of depression-related neurotransmitters proved that JTW can effectively ameliorate depression-like symptoms in mice induced by CRS. In addition, JTW can also improve the inflammatory state and reduce the number of apoptotic cells in the hippocampus. According to network pharmacology, 28 active compounds and 484 corresponding targets of JTW, 1407 DM targets and 1842 depression targets were collected by screening the databases, and a total of 117 targets were obtained after taking the intersection. JTW plays a role in reducing blood glucose level and antidepressant mainly through active compounds such as quercetin, styrene, cinnamic acid, ethyl cinnamate, (R)-Canadine, palmatine and berberine, etc., the key targets of its therapeutic effect include INS, AKT1, IL-6, VEGF-A, TNF and so on, mainly involved in HIF-1 signal pathway, pathways in cancer, Hepatitis B, TNF signal pathway, PI3K-Akt signal pathway and MAPK signaling pathway, etc. Conclusion Our experimental study showed that JTW has hypoglycemic and antidepressant effects. The possible mechanism was explored by network pharmacology, reflecting the characteristics of multi-component, multi-target and multi-pathway, which provides a theoretical basis for the experimental research and clinical application of JTW in the future.

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“…Regulating the CUMS-induced MAPK pathway and NF-κB protein complex activation can alleviate depression-like behavior in mice [108]. Paroxetine combined with uorouracil, ketamine and ghrelin and other drugs can show antidepressant-like effects via the MAPK signaling pathway [109][110][111]. In addition, resveratrol can attenuate cardiac dysfunction caused by diabetes, and the effects are related to down-regulation of AT1R-ERK/p38 MAPK signaling pathway [112].…”

Section: Discussionmentioning

confidence: 99%

Potential Molecular Mechanisms of JTW in the Treatment of Diabetes Mellitus and Depression Based on Network Pharmacology

Tang

et al. 2021

Preprint

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Background: The incidence of diabetes mellitus (DM) and depression is increasing year by year around the world, bringing a serious burden to patients and their families. As a well-known traditional Chinese medicine (TCM), Jiao-tai-wan (JTW) has obvious hypoglycemic and antidepressant effects, but its specific targets and mechanisms are still unclear.Methods: The active compounds and corresponding targets of JTW were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). The GeneCards, the Online Mendelian Inheritance in Man (OMIM), the DrugBank and the Therapeutic Target Database (TTD) were used to collect targets of DM and depression. After sorting out the intersection targets of drugs and diseases, the Cytoscape software was used to perform a "Drug-Compounds-Targets-Disease (D-C-T-D)" network to analyze the active compounds of JTW, and the protein-protein interaction (PPI) network was constructed by the STRING database to screen and analyze the key target proteins. Finally, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the intersection targets were carried out by the database for annotation, visualization and integrated discovery (DAVID). Results: 28 active compounds and 484 corresponding targets of JTW, 1407 DM targets and 1842 depression targets were collected by screening the above databases, and a total of 117 targets were obtained after taking the intersection. JTW plays a role in reducing blood glucose level and antidepressant mainly through active compounds such as quercetin, styrene, cinnamic acid, ethyl cinnamate, (R)-Canadine, palmatine and berberine, etc., the key targets of its therapeutic effect include insulin (INS), protein kinase B1 (AKT1), interleukin-6 (IL-6), vascular endothelial growth factor A (VEGF-A), tumor necrosis factor (TNF) and so on, mainly involved in HIF-1 signal pathway, pathways in cancer, Hepatitis B, TNF signal pathway, PI3K-Akt signal pathway and MAPK signaling pathway, etc.Conclusion: In this paper, the possible mechanism of JTW on DM and depression was explored by network pharmacology, reflecting the characteristics of multi-component, multi-target and multi-pathway, which provides a theoretical basis for the experimental research and clinical application of JTW in the future.

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Paroxetine combined with fluorouracil plays a therapeutic role in mouse models of colorectal cancer with depression through inhibiting IL‑22 expression to regulate the MAPK signaling pathway

Cited by 15 publications

References 58 publications

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

Potential Molecular Mechanisms of JTW in the Treatment of Diabetes Mellitus and Depression Based on Network Pharmacology

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