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Zhao X, Ye X, Gu Y, Lou Y, Zhou Z, Ji Y, Xu D. Oxymatrine for inflammatory bowel disease in preclinical studies: a systematic review and meta-analysis. Front Med (Lausanne) 2025; 12:1542953. [PMID: 40370726 PMCID: PMC12075229 DOI: 10.3389/fmed.2025.1542953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/15/2025] [Indexed: 05/16/2025] Open
Abstract
Background Inflammatory Bowel Disease (IBD) is a chronic, idiopathic inflammatory disorder of the intestines. Oxymatrine (OMT) is a naturally active substance found in the desiccated roots of Sophora flavescens. It possesses anti-tumor, antiviral, and anti-inflammatory properties. In recent years, its therapeutic role in IBD has gradually been discovered. This review aims to explore the impact of OMT on inflammatory bowel disease by animal models. Methods Conduct a systematic search in the PubMed, Embase, Web of Science, Cochrane, and Medline databases. Using SYRCLE's risk of bias tool to assess the bias risk and quality of the included studies. For some data presented as figures, Web Plot Digitizer 4.2 software was used to extract it. STATA 16.0 was selected for the final meta-analysis. Results After rigorous literature screening, 12 studies were included. The data analysis results indicated that the disease activity index (DAI), histopathological score (HS), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB), and myeloperoxidase (MPO) activity in the IBD animal models significantly decreased following intervention with oxymatrine. Furthermore, OMT also extended the colon length in the animal models and improved the expression level of zonula occludens-1(ZO-1) and occludin. These results suggested that OMT may improve the condition of IBD through anti-inflammatory, antioxidative stress and protecting the intestinal barrier. Conclusion Meta-analysis suggests oxymatrine positively affects IBD animal models. This provides new insights for the clinical treatment of inflammatory bowel disease. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD42024570580, identifier [CRD42024570580].
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Affiliation(s)
- Xuan Zhao
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaolu Ye
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuting Gu
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yijie Lou
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Zhanyi Zhou
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yunxi Ji
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Daogun Xu
- Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Taizhou, Zhejiang, China
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2
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Shi Y, Liu N, Bai Y, Li K, Li C, Hou Y. IL-37 attenuated HPV induced inflammation of oral epithelial cells via inhibiting PI3K/AKT/mTOR. Virol J 2024; 21:339. [PMID: 39736667 PMCID: PMC11684125 DOI: 10.1186/s12985-024-02615-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 12/17/2024] [Indexed: 01/01/2025] Open
Abstract
Human papillomavirus (HPV) is the most prevalent sexually transmitted infection globally, with significant implications for various anogenital cancers, such as vulval, vaginal, anal, penile, head and neck cancers. HPV infections have been linked to the induction of inflammation. In contrast, Interleukin-37 (IL-37) is recognized as an anti-inflammatory cytokine. In this study, two distinct types of oral epithelial cells were employed to investigate the impact of HPV on inflammation. The experimental outcomes unequivocally demonstrated that human papillomavirus (HPV) elicited a pronounced and statistically significant induction of inflammatory responses within both varieties of oral epithelial cells under investigation. Interestingly, IL-37 exhibited a mitigating effect, attenuating the HPV-induced inflammation in oral epithelial cells. Further exploration into the molecular mechanisms involved revealed that knockdown (KD) of PI3K compromised the anti-inflammatory effects of IL-37 in response to HPV. Similarly, KD of AKT was found to compromise the regulatory effects of IL-37 on HPV-induced inflammation. Notably, KD of mTOR was identified as a key factor, compromising the anti-inflammatory effects of IL-37 in the context of HPV-induced inflammation. Additionally, the study uncovered that the mTOR inhibitor, rapamycin, could effectively compromise the effects of IL-37 on HPV-induced inflammation. These findings contribute valuable insights into the intricate pathogenesis of HPV-induced inflammation and may pave the way for the development of innovative treatments for this condition.
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Affiliation(s)
- Yahong Shi
- Department of Stomatology, Second Hospital of Shijiazhuang, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Ning Liu
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yunfang Bai
- Department of Emergency, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Kunshan Li
- Department of Stomatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Chencong Li
- Physical Examination Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yujiao Hou
- Department of Stomatology, Affiliated Hospital of Hebei University, 212 Yuhua East Road, Baoding, 071000, Hebei, People's Republic of China.
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3
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Lin CI, Wang YW, Su KY, Chuang YH. Interleukin-37 exacerbates liver inflammation and promotes IFN-γ production in NK cells. Int Immunopharmacol 2024; 142:113086. [PMID: 39260304 DOI: 10.1016/j.intimp.2024.113086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/23/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024]
Abstract
Interleukin (IL)-37, a unique member of the IL-1 family, is known for its anti-inflammatory properties. However, its effects on immune-mediated liver diseases, such as primary biliary cholangitis (PBC) and acute immune-mediated hepatitis, remain unclear. Using mouse models of autoimmune cholangitis and hepatitis induced by 2-OA-OVA and concanavalin A (Con A) respectively, we introduced the human IL-37 gene via a liver-preferred adeno-associated virus vector (AAV-IL-37) to mice, as mice lack endogenous IL-37. Our findings reveal that IL-37 did not affect autoimmune cholangitis. Surprisingly, IL-37 exacerbated inflammation in Con A-induced hepatitis rather than mitigating it. Mechanistic insights suggest that this exacerbation involves the interferon (IFN)-γ pathway, supported by elevated serum IFN-γ levels in AAV-IL-37-treated Con A mice. Specifically, IL-37 heightened the number of hepatic NK and NKT cells, increased the production of the NK cell chemoattractant CCL5, and elevated the frequency of hepatic NK and NKT cells expressing IFN-γ. Moreover, IL-37 enhanced IFN-γ secretion from NK cells when combined with other proinflammatory cytokines, highlighting its synergistic effect in promoting IFN-γ production. These unexpected outcomes underscore a novel role for IL-37 in exacerbating liver inflammation during immune-mediated liver diseases, implicating its influence on NK cells and the production of IFN-γ by these cells.
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Affiliation(s)
- Chia-I Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Wen Wang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kang-Yi Su
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Genomic and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
| | - Ya-Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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4
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Teufel LU, Matzaraki V, Folkman L, Ter Horst R, Moorlag SJCFM, Mulders-Manders CM, Netea MG, Krausgruber T, Joosten LAB, Arts RJW. Insights into the multifaceted role of interleukin-37 on human immune cell regulation. Clin Immunol 2024; 268:110368. [PMID: 39307482 DOI: 10.1016/j.clim.2024.110368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Autoinflammatory diseases, while having a variety of underlying causes, are mediated by dysfunctional innate immune responses. Therefore, standard treatments target innate cytokines or block their receptors. Despite excellent responses in some patients, first-line treatments fail in others, for reasons which remain to be understood. We studied the effects of IL-37, an anti-inflammatory cytokine, on immune cells using multi-omics profiling of 325 healthy adults. Our findings show that IL-37 is associated with inflammation control and generally reduced immune cell activity. Further, genetic variants in IL37 are associated with impaired trained immunity, a memory phenotype of innate immune cells contributing to autoinflammation. To underpin the medical potential of IL-37, an explorative cohort of seven autoinflammatory disorders was built. In vitro stimulation experiments argue for recombinant IL-37 as a potential therapy in IL-6-, and IL-22-driven conditions. Concluding, IL-37 is highlighted as a cytokine with broad anti-inflammatory functions, implicating its potential as therapeutic intervention.
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Affiliation(s)
- Lisa U Teufel
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Vasiliki Matzaraki
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Lukas Folkman
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Austria
| | - Rob Ter Horst
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Simone J C F M Moorlag
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Catharina M Mulders-Manders
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Thomas Krausgruber
- Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Austria
| | - Leo A B Joosten
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Rob J W Arts
- Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
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5
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Li D, Xiong Y, Li M, Long L, Zhang Y, Yan H, Xiang H. STC2 knockdown inhibits cell proliferation and glycolysis in hepatocellular carcinoma through promoting autophagy by PI3K/Akt/mTOR pathway. Arch Biochem Biophys 2024; 761:110149. [PMID: 39271096 DOI: 10.1016/j.abb.2024.110149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 08/02/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND The pathogenesis exploration and timely intervention of hepatocellular carcinoma (HCC) are crucial due to its global impact on human health. As a general tumor biomarker, stanniocalcin 2 (STC2), its role in HCC remains unclear. We aimed to analyze the effect and mechanism of STC2 on HCC. METHODS STC2 expressions in HCC tissues and cell lines were measured. si-STC2 and oe-STC2 transfections were utilized to analyze how STC2 affected cell functions. Functional enrichment analysis of STC2 was performed by Gene Set Enrichment Analysis (GSEA). The regulatory mechanism of STC2 on HCC was investigated using 2-DG, 3-MA, IGF-1, Rap, and LY294002. The impact of STC2 on HCC progression in vivo was evaluated by the tumor formation experiment. RESULTS Higher levels of STC2 expression were observed in HCC tissues and cell lines. Besides, STC2 knockdown reduced proliferation, migration, and invasion, while inducing cell apoptosis. Further analysis indicated a positive correlation between STC2 and glycolysis. STC2 knockdown inhibited glycolysis progression and down-regulated the expressions of PKM2, GLUT1, and HK2 in HCC cells. However, treatment with glycolysis inhibitor (2-DG) prevented oe-STC2 from promoting the growth of HCC cells. Additionally, STC2 knockdown up-regulated the levels of LC3II/LC3I and Beclin1 and reduced the phosphorylation of PI3K, AKT, and mTOR. Treatment with 3-MA, IGF-1, Rap, and LY294002 altered the function of STC2 on proliferation and glycolysis in HCC cells. Tumor formation experiment results revealed that STC2 knockdown inhibited HCC progression. CONCLUSIONS STC2 knockdown inhibited cell proliferation and glycolysis in HCC through the PI3K/Akt/mTOR pathway-mediated autophagy induction.
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Affiliation(s)
- Ding Li
- Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Yuanyuan Xiong
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Muzi Li
- Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Lin Long
- Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Yongjin Zhang
- Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China
| | - Huifeng Yan
- The Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Hua Xiang
- Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha, 410005, Hunan, China.
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Liu S, Ba Y, Li C, Xing M, Zhang T, Liu Y, Gao Y, Xu G. Interleukin 37 inhibits the migration and invasion of Glioma cells. Biotechnol Genet Eng Rev 2024; 40:926-942. [PMID: 36951225 DOI: 10.1080/02648725.2023.2191084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 03/08/2023] [Indexed: 03/24/2023]
Abstract
Glioma is a medical term that describes a tumor originating in the brain. Several risk factors could develop glioma such as occupational exposure, gene mutation and ionizing radiation. Therefore, we aim to determine the expression and biological function of interleukin 37 (IL-37) in gliomas with different pathological grades. We used 95 participants with different pathological grades of glioma as our data subjects. We used CCK-8 assay and transwell assay to explore the proliferation of U251 over-expressing IL-37 and migration and invasion of U251. We found that IL-37 expression in tumor tissues was significantly higher than in normal tissue. The reduced IL-37 expression in gliomas was significantly associated with a higher WHO grade and lower Karnofsky Performance Status score. IL-37 expression in glioma tissues showed a decline with the increase of the WHO glioma grade. Patients with low IL-37 expression showed a shorter median survival. Transwell assay indicated that migration and invasion of U251 over-expressing IL-37 was significantly lower than that of the control at 24 h. Our findings showed that low IL-37 expression was negatively correlated with pathological grade and was positively correlated with survival time.
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Affiliation(s)
- Sheng Liu
- Department of Neurosurgery, Shandong Provincial Hospital, Shandong University, Jinan, China
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Ying Ba
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, China
| | - Chenglong Li
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Mengyang Xing
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Tao Zhang
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yongliang Liu
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yang Gao
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Guangming Xu
- Department of Neurosurgery, Shandong Provincial Hospital, Shandong University, Jinan, China
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7
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Mei Y, Zhu Y, Yong KSM, Hanafi ZB, Gong H, Liu Y, Teo HY, Hussain M, Song Y, Chen Q, Liu H. IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment. Cell Rep 2024; 43:113835. [PMID: 38412100 DOI: 10.1016/j.celrep.2024.113835] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/18/2023] [Accepted: 02/06/2024] [Indexed: 02/29/2024] Open
Abstract
Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.
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Affiliation(s)
- Yu Mei
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Ying Zhu
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Kylie Su Mei Yong
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore 138673, Singapore
| | - Zuhairah Binte Hanafi
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Huanle Gong
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, P.R. China
| | - Yonghao Liu
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Huey Yee Teo
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Muslima Hussain
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Yuan Song
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore 138673, Singapore.
| | - Haiyan Liu
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
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Wang Y, Mang X, Li D, Wang Z, Chen Y, Cai Z, Tan F. Cold atmospheric plasma sensitizes head and neck cancer to chemotherapy and immune checkpoint blockade therapy. Redox Biol 2024; 69:102991. [PMID: 38103343 PMCID: PMC10764269 DOI: 10.1016/j.redox.2023.102991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/01/2023] [Accepted: 12/07/2023] [Indexed: 12/19/2023] Open
Abstract
Head and neck cancer (HNC) is the seventh most prevalent cancer globally, often characterized by chemo-resistance and immunosuppression, which significantly hampers treatment efficacy. Cold atmospheric plasma (CAP) has recently emerged as a promising adjuvant oncotherapy with substantial potential and advantages. In this study, Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. We aimed to investigate the effects of CAPPZ2 on various types of HNC cells and elucidate the underlying mechanisms. In addition, we endeavored to examine the efficacy of combining CAPPZ2 with chemotherapy drugs (i.e., cisplatin) or immune checkpoint blockade (ICB, i.e., PD1 antibody) in HNC treatment. Firstly, the results demonstrated that CAPPZ2 exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promoting apoptosis and autophagy. Secondly, using transcriptomic sequencing, Western blotting, and quantitative real-time PCR, the mechanisms underlying CAPPZ2 treatment in vitro was presumed to be a multitargeted blockade of major cancer survival pathways, such as redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling. Lastly, combinatorial thearpy containing CAPPZ2 and cisplatin or PD-1 antibody significantly suppressed tumor growth and prolonged recipient survival in vivo. Collectively, the synergistic effects of CAPPZ2 and cisplatin or PD-1 antibody could serve as a promising solution to enhance head and neck tumor elimination.
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Affiliation(s)
- Yanhong Wang
- Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200432, China
| | - Xinyu Mang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Danni Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200432, China
| | - Zhao Wang
- Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200432, China
| | - Yiliang Chen
- Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Zhenyu Cai
- Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Fei Tan
- Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200432, China; The Royal College of Surgeons in Ireland, Dublin, Ireland; The Royal College of Surgeons of England, London, UK.
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9
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Amer OE, Sabico S, Khattak MNK, Alnaami AM, Saadawy GM, Al-Daghri NM. Circulating Interleukins-33 and -37 and Their Associations with Metabolic Syndrome in Arab Adults. Int J Mol Sci 2024; 25:699. [PMID: 38255771 PMCID: PMC10815042 DOI: 10.3390/ijms25020699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/27/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Interleukins (ILs) are a group of cytokines known to have immunomodulatory effects; they include ILs-33 and -37 whose emerging roles in the pathogenesis of metabolic syndrome (MetS) remain under investigated. In this study, we compared circulating IL-33 and IL-37 in Arab adults with and without MetS to determine its associations with MetS components. A total of 417 Saudi participants (151 males, 266 females; mean age ± SD 41.3 ± 9.0 years; mean body mass index ± SD 30.7 ± 6.3 kg/m2) were enrolled and screened for MetS using the ATP III criteria. Anthropometrics and fasting blood samples were taken for the assessment of fasting glucose and lipids. Circulating levels of IL-33 and IL-37 were measured using commercially available assays. The results showed higher levels of serum IL-33 and IL-37 in participants with MetS than those without (IL-33, 3.34 3.42 (2.3-3.9) vs. (1-3.9), p = 0.057; IL-37, 5.1 (2.2-8.3) vs. 2.9 (2.1-6.1), p = 0.01). Additionally, having elevated levels of IL-33 was a risk factor for hypertension, low HDL-c, and hypertriglyceridemia. A stratification of the participants according to sex showed that males had higher IL-33 levels than females [3.7 (3.0-4.1) vs. 3.15 (1.4-3.8), p < 0.001], while females had higher levels of IL-37 than males [3.01 (2.2-7.0) vs. 2.9 (2.1-5.6), p = 0.06]. In conclusion, the presence of MetS substantially alters the expression of ILs-33 and -37. IL-33 in particular can be potentially used as a therapeutic target to prevent MetS progression. Longitudinal and interventional studies are warranted to confirm present findings.
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Affiliation(s)
| | | | | | | | | | - Nasser M. Al-Daghri
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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10
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Cao J, Hou S, Chen Z, Yan J, Chao L, Qian Y, Li J, Yan X. Interleukin-37 relieves PM2.5-triggered lung injury by inhibiting autophagy through the AKT/mTOR signaling pathway in vivo and in vitro. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 269:115816. [PMID: 38091678 DOI: 10.1016/j.ecoenv.2023.115816] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 11/27/2023] [Accepted: 12/09/2023] [Indexed: 01/12/2024]
Abstract
Autophagy mediates PM2.5-related lung injury (LI) and is tightly linked to inflammation and apoptosis processes. IL-37 has been demonstrated to regulate autophagy. This research aimed to examine the involvement of IL-37 in the progression of PM2.5-related LI and assess whether autophagy serves as a mediator for its effects.To create a model of PM2.5-related LI, this research employed a nose-only PM2.5 exposure system and utilized both human IL-37 transgenic mice and wild-type mice. The hIL-37tg mice demonstrated remarkable reductions in pulmonary inflammation and pathological LI compared to the WT mice. Additionally, they exhibited activation of the AKT/mTOR signaling pathway, which served to regulate the levels of autophagy and apoptosis.Furthermore, in vitro experiments revealed a dose-dependent upregulation of autophagy and apoptotic proteins following exposure to PM2.5 DMSO extraction. Simultaneously, p-AKT and p-mTOR expression was found to decrease. However, pretreatment with IL-37 demonstrated a remarkable reduction in the levels of autophagy and apoptotic proteins, along with an elevation of p-AKT and p-mTOR. Interestingly, pretreatment with rapamycin, an autophagy inducer, weakened the therapeutic impact of IL-37. Conversely, the therapeutic impact of IL-37 was enhanced when treated with 3-MA, a potent autophagy inhibitor. Moreover, the inhibitory effect of IL-37 on autophagy was successfully reversed by administering AKT inhibitor MK2206. The findings suggest that IL-37 can inhibit both the inflammatory response and autophagy, leading to the alleviation of PM2.5-related LI. At the molecular level, IL-37 may exert its anti autophagy and anti apoptosis effects by activating the AKT/mTOR signaling pathway.
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Affiliation(s)
- Jing Cao
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China
| | - Shujie Hou
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China
| | - Zixiao Chen
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China
| | - Jie Yan
- Department of Cardiovascular Medicine,The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Lingshan Chao
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China
| | - Yuxing Qian
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China
| | - Jingwen Li
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China
| | - Xixin Yan
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Respiratory Critical Care Medicine, Hebei Institute of Respiratory Diseases, Shijiazhuang, Hebei 050000, China.
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11
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Gu M, Jin Y, Gao X, Xia W, Xu T, Pan S. Novel insights into IL-37: an anti-inflammatory cytokine with emerging roles in anti-cancer process. Front Immunol 2023; 14:1278521. [PMID: 37928545 PMCID: PMC10623001 DOI: 10.3389/fimmu.2023.1278521] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
Interleukin-37 (IL-37) is a newly discovered member of IL-1 family. The cytokine was proved to have extensive protective effects in infectious diseases, allergic diseases, metabolic diseases, autoimmune diseases and tumors since its discovery. IL-37 was mainly produced by immune and some non-immune cells in response to inflammatory stimulus. The IL-37 precursors can convert into the mature forms after caspase-1 cleavage and activation intracellularly, and then bind to Smad-3 and transfer to the nucleus to inhibit the production and functions of proinflammatory cytokines; extracellularly, IL-37 binds to cell surface receptors to form IL-37/IL-18Rα/IL-1R8 complex to exert immunosuppressive function via inhibiting/activating multiple signal pathways. In addition, IL-37 can attenuate the pro-inflammatory effect of IL-18 through directly or forming an IL-37/IL-18BP/IL-18Rβ complex. Therefore, IL-37 has the ability to suppress innate and acquired immunity of the host, and effectively control inflammatory stimulation, which was considered as a new hallmark of cancer. Specifically, it is concluded that IL-37 can inhibit the growth and migration of tumor cells, prohibit angiogenesis and mediate the immunoregulation in tumor microenvironment, so as to exert effective anti-tumor effects. Importantly, latest studies also showed that IL-37 may be a novel therapeutic target for cancer monitoring. In this review, we summarize the immunoregulation roles and mechanisms of IL-37 in anti-tumor process, and discuss its progress so far and potential as tumor immunotherapy.
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Affiliation(s)
- Min Gu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Yuexinzi Jin
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Xun Gao
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Wenying Xia
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Ting Xu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Shiyang Pan
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
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12
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Siapoush S, Rezaei R, Alavifard H, Hatami B, Zali MR, Vosough M, Lorzadeh S, Łos MJ, Baghaei K, Ghavami S. Therapeutic implications of targeting autophagy and TGF-β crosstalk for the treatment of liver fibrosis. Life Sci 2023; 329:121894. [PMID: 37380126 DOI: 10.1016/j.lfs.2023.121894] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/19/2023] [Accepted: 06/25/2023] [Indexed: 06/30/2023]
Abstract
Liver fibrosis is characterized by the excessive deposition and accumulation of extracellular matrix components, mainly collagens, and occurs in response to a broad spectrum of triggers with different etiologies. Under stress conditions, autophagy serves as a highly conserved homeostatic system for cell survival and is importantly involved in various biological processes. Transforming growth factor-β1 (TGF-β1) has emerged as a central cytokine in hepatic stellate cell (HSC) activation and is the main mediator of liver fibrosis. A growing body of evidence from preclinical and clinical studies suggests that TGF-β1 regulates autophagy, a process that affects various essential (patho)physiological aspects related to liver fibrosis. This review comprehensively highlights recent advances in our understanding of cellular and molecular mechanisms of autophagy, its regulation by TGF-β, and the implication of autophagy in the pathogenesis of progressive liver disorders. Moreover, we evaluated crosstalk between autophagy and TGF-β1 signalling and discussed whether simultaneous inhibition of these pathways could represent a novel approach to improve the efficacy of anti-fibrotic therapy in the treatment of liver fibrosis.
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Affiliation(s)
- Samaneh Siapoush
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramazan Rezaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100 Gliwice, Poland; Autophagy Research Center, Department of Biochemistry; Shiraz University of Medical Sciences, Shiraz, Iran; LinkoCare Life Sciences AB, Linkoping, Sweden
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada.
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13
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Li C, Zhang Y, Zhao X, Li L, Kong X. Autophagy regulation of virus infection in aquatic animals. REVIEWS IN AQUACULTURE 2023; 15:1405-1420. [DOI: 10.1111/raq.12785] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 01/04/2023] [Indexed: 01/04/2025]
Abstract
AbstractAutophagy is a conserved intracellular degradation process that is required to maintain host homeostasis and cope with invading pathogens. Over the past few decades, studies on mammals have greatly increased our understanding of the relationship between autophagy and virus infection. Autophagy may convey the invader to lysosomes to degrade or activate the host immune response against virus replication. However, many viruses have developed some strategies that evade the degradative nature of autophagy or hijack this pathway for their gain. It follows that autophagy during viral infection is a double‐edged sword. In contrast to mammals, the review on autophagy modulated by the aquatic animal virus is limited. Here, after a brief description of the main information about autophagy, we highlight current progress on the interplays between autophagy and virus infection in aquatic animals, including the phenomenon of autophagy upon virus infection, the effect of modulating autophagy on virus replication, and the crosstalk between autophagy and immune response during virus infection. This review will help us better understand the pathogenic mechanism of aquatic animal viruses and develop proper antiviral countermeasures aimed at modulating autophagy.
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Affiliation(s)
- Chen Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Yunli Zhang
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Xianliang Zhao
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Li Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Xianghui Kong
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
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14
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Liang Q, Liu S, Yin F, Liu M, Wang L, Guo E, Lei L, Wu L, Yang Y, Zhang D, Zeng X. Low expression of GOT2 promotes tumor progress and predicts poor prognosis in hepatocellular carcinoma. Biomark Med 2023; 17:755-765. [PMID: 38095985 DOI: 10.2217/bmm-2023-0236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024] Open
Abstract
Background: To explore the biological function and the underlying mechanisms of GOT2 in hepatocellular carcinoma (HCC). Materials & methods: The expression level and prognostic value of GOT2 were examined using International Cancer Genome Consortium and International Cancer Proteogenome Consortium databases. The cell counting kit-8 method, clone formation, Transwell® assays and western blotting were used to evaluate the effects of GOT2 on the biological function and autophagy of HCC cells. Results: The expression of GOT2 was downregulated in HCC tissues and correlated with poor prognosis of HCC patients. Knockdown of GOT2 promoted proliferation, migration and invasion of HCC cells and promoted cells' proliferation by inducing autophagy. Conclusion: GOT2 plays a tumor-inhibitory role in HCC and may be a potential therapeutic target for HCC.
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Affiliation(s)
- Qiuli Liang
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Nanning Center for Disease Control & Prevention, Nanning, Guangxi, 530002, China
| | - Shun Liu
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Fuqiang Yin
- Life Sciences Institute Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Meiliang Liu
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Lijun Wang
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Erna Guo
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- School of International Education, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Lei Lei
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Liuyu Wu
- Department of Hospital Infection Control, Liuzhou People's Hospital, Liuzhou, Guangxi, 545026, China
| | - Yu Yang
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Di Zhang
- Department of Scientific Research, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, China
| | - Xiaoyun Zeng
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
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15
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Zhou T, Liu L, Lan H, Fang D. Effects of LAIR-1 on hepatocellular carcinoma cell proliferation and invasion via PI3K-AKT-mTOR pathway regulation. Immun Inflamm Dis 2023; 11:e982. [PMID: 37647449 PMCID: PMC10465992 DOI: 10.1002/iid3.982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/17/2023] [Accepted: 07/31/2023] [Indexed: 09/01/2023] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is one of the common malignant tumors. Although surgical resection is the best treatment for HCC, many patients with HCC are found to have metastases at the time of initial diagnosis and lose the opportunity for radical treatment. Therefore, the study of the invasion and metastasis of HCC has always been the focus of HCC research. This study aimed to assess the influence of LAIR-1 on HCC cell proliferation and invasion and the relevant mechanisms involved in this process. METHODS Immunocytochemical staining assay, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were used to detect the expression of LAIR-1mRNA and protein in healthy human hepatocyte LO2 and the HCC cell lines HepG2, Bel-7402, MHCC97-H, and Huh-7. Then, we evaluated the cell viability, colony formation, and invasion of MHCC97-H and Huh-7 cells in each group by silencing or overexpressing LAIR-1 expression in MHCC97-H and Huh-7 cells, respectively. WB was used to detect the expression levels of PI3K-AKT-mTOR pathway related proteins. RESULTS Our findings showed that LAIR-1 can inhibit cell viability, colony formation and invasion in vitro. Meanwhile, LAIR-1 significantly downregulated the expression of PI3K, p-AKT and p-mTOR, which were abolished by the PI3K inhibitor, LY294002. CONCLUSIONS Our study revealed that LAIR-1 inhibited cell proliferation and invasion, probably via suppressing the PI3K-AKT-mTOR pathway.
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Affiliation(s)
- Ti Zhou
- Department of General SurgeryThe First People's Hospital of Lin ping DistrictHangzhouZhejiangChina
| | - Luqing Liu
- Department of General SurgeryThe People's Hospital of Guannan CountyLianyungangJiangsuChina
| | - Haibin Lan
- Department of General SurgeryThe First People's Hospital of Lin ping DistrictHangzhouZhejiangChina
| | - Donglin Fang
- Department of General SurgeryThe First People's Hospital of Lin ping DistrictHangzhouZhejiangChina
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16
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Jiang B, Zhou Y, Liu Y, He S, Liao B, Peng T, Yao L, Qi L. Research Progress on the Role and Mechanism of IL-37 in Liver Diseases. Semin Liver Dis 2023; 43:336-350. [PMID: 37582401 PMCID: PMC10620037 DOI: 10.1055/a-2153-8836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/17/2023]
Abstract
Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury, and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.
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Affiliation(s)
- Baoyi Jiang
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Yulin Zhou
- Department of Clinical Laboratory, Shunde New Rongqi Hospital, Foshan, China
| | - Yanting Liu
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Siqi He
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Baojian Liao
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Tieli Peng
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Leyi Yao
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Ling Qi
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
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17
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Abdalla MMI. Serum resistin and the risk for hepatocellular carcinoma in diabetic patients. World J Gastroenterol 2023; 29:4271-4288. [PMID: 37545641 PMCID: PMC10401662 DOI: 10.3748/wjg.v29.i27.4271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC’s development and progression, as well as identify possible avenues for prevention and therapy.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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18
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Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, Bungau AF, Radu AF. Evaluation of the association of chronic inflammation and cancer: Insights and implications. Biomed Pharmacother 2023; 164:115015. [PMID: 37321055 DOI: 10.1016/j.biopha.2023.115015] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/02/2023] [Accepted: 06/11/2023] [Indexed: 06/17/2023] Open
Abstract
Among the most extensively researched processes in the development and treatment of cancer is inflammatory condition. Although acute inflammation is essential for the wound healing and reconstruction of tissues that have been damaged, chronic inflammation may contribute to the onset and growth of a number of diseases, including cancer. By disrupting the signaling processes of cells, which result in cancer induction, invasion, and development, a variety of inflammatory molecules are linked to the development of cancer. The microenvironment surrounding the tumor is greatly influenced by inflammatory cells and their subsequent secretions, which also contribute significantly to the tumor's growth, survivability, and potential migration. These inflammatory variables have been mentioned in several publications as prospective diagnostic tools for anticipating the onset of cancer. Targeting inflammation with various therapies can reduce the inflammatory response and potentially limit or block the proliferation of cancer cells. The scientific medical literature from the past three decades has been studied to determine how inflammatory chemicals and cell signaling pathways related to cancer invasion and metastasis are related. The current narrative review updates the relevant literature while highlighting the specifics of inflammatory signaling pathways in cancer and their possible therapeutic possibilities.
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Affiliation(s)
- Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Abhay Prakash Mishra
- Department of Pharmacology, Faculty of Health Science, University of Free State, 9300 Bloemfontein, South Africa.
| | - Vishal Kumar Deb
- Dietetics and Nutrition Technology Division, CSIR Institute of Himalayan Bioresource Technology, 176061 Palampur, Himanchal Pradesh, India
| | - Deen Bandhu Dimri
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Vinod Tiwari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology BHU, Varanasi 221005, Uttar Pradesh, India
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
| | - Alexa Florina Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Andrei-Flavius Radu
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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19
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Xiao S, Song X, Zheng M, Cao X, Ai G, Li B, Zhao G, Yuan H. Interleukin-37 ameliorates atherosclerosis by regulating autophagy-mediated endothelial cell apoptosis and inflammation. Int Immunopharmacol 2023; 118:110098. [PMID: 37023695 DOI: 10.1016/j.intimp.2023.110098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/18/2023] [Accepted: 03/23/2023] [Indexed: 04/07/2023]
Abstract
Atherosclerosis is a lipid-driven chronic inflammatory disease. Endothelial dysfunction is the initiating factor of atherosclerosis. Although much work has been done on the antiatherosclerotic effects of interleukin-37 (IL-37), the exact mechanism is still not fully understood. The aim of this study was to investigate whether IL-37 attenuates atherosclerosis by protecting endothelial cells and to confirm whether autophagy plays a role in this effect. In apolipoprotein E knockout (ApoE-/-) mice fed with a high fat diet, IL-37 treatment significantly attenuated progression of atherosclerotic plaques, reduced endothelial cell apoptosis and inflammasome activation. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to establish an endothelial dysfunction model. We observed that IL-37 alleviated ox-LDL-induced endothelial cell inflammation and dysfunction, as evidenced by decreased nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation, ROS production, apoptosis rate and secretion of inflammatory cytokines IL-1β and TNF-α. Furthermore, IL-37 could activate autophagy in endothelial cells, which is characterized by the upregulation of LC3II/LC3I, the downregulation of p62 and an increase in autophagosomes. The autophagy inhibitor 3-Methyladenine (3-MA) dramatically reversed the promotion of autophagy and the protective effect of IL-37 against endothelial injury. Our data illustrate that IL-37 alleviated inflammation and apoptosis of atherosclerotic endothelial cells by enhancing autophagy. The current study provides new insights and promising therapeutic strategies for atherosclerosis.
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Affiliation(s)
- Shengyang Xiao
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiaoning Song
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Man Zheng
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xinran Cao
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Guo Ai
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Baona Li
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Gang Zhao
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
| | - Haitao Yuan
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
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20
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Zhang Z, Cui Y, Ouyang H, Zhu W, Feng Y, Yao M, Yang S. Radix Pueraria lobata polysaccharide relieved DSS-induced ulcerative colitis through modulating PI3K signaling. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023] Open
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21
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Zeng F, Wang X, Hu Y, Wang Z, Li Y, Hu J, Yu J, Zhou P, Teng X, Zhou H, Zheng H, Zhao F, Gu L, Yue C, Chen S, Cheng J, Hao Y, Zhao Q, Zhang C, Zou S, Hu Z, Wei X, Liu X, Li G, Huang N, Wu W, Zhou Y, Li W, Cui K, Li J. Interleukin-37 promotes DMBA/TPA skin cancer through SIGIRR-mediated inhibition of glycolysis in CD103 +DC cells. MedComm (Beijing) 2023; 4:e229. [PMID: 36891351 PMCID: PMC9986080 DOI: 10.1002/mco2.229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 02/05/2023] [Accepted: 02/08/2023] [Indexed: 03/07/2023] Open
Abstract
Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.
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Affiliation(s)
- Fan‐lian Zeng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Xiao‐yan Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Ya‐wen Hu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Zhen Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
- Department of Liver Surgery and Liver TransplantationWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Ya Li
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Jing Hu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Jia‐dong Yu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Pei Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Xiu Teng
- Laboratory of Human Disease and ImmunotherapiesWest China HospitalSichuan UniversityChengduChina
| | - Hong Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Hua‐ping Zheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Fu‐lei Zhao
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Lin‐na Gu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Cheng‐cheng Yue
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Shu‐wen Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Juan Cheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yan Hao
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Qi‐xiang Zhao
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Chen Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Song Zou
- Department of CardiologyWest China HospitalSichuan UniversityChengduChina
| | - Zhong‐lan Hu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Xiao‐qiong Wei
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Xiao Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Guo‐lin Li
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Nong‐yu Huang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Wen‐ling Wu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yi‐fan Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Wei Li
- Department of DermatovenereologyWest China HospitalSichuan UniversityChengduChina
| | - Kaijun Cui
- Department of CardiologyWest China HospitalSichuan UniversityChengduChina
| | - Jiong Li
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
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Lauritano D, Mastrangelo F, D’Ovidio C, Ronconi G, Caraffa A, Gallenga CE, Frydas I, Kritas SK, Trimarchi M, Carinci F, Conti P. Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines. Int J Mol Sci 2023; 24:ijms24054811. [PMID: 36902240 PMCID: PMC10002992 DOI: 10.3390/ijms24054811] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.
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Affiliation(s)
- Dorina Lauritano
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Filiberto Mastrangelo
- Department of Clinical and Experimental Medicine, School of Dentistry, University of Foggia, 71100 Foggia, Italy
| | - Cristian D’Ovidio
- Section of Legal Medicine, Department of Medicine and Aging Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Gianpaolo Ronconi
- Clinica dei Pazienti del Territorio, Fondazione Policlinico Gemelli, 00185 Rome, Italy
| | | | - Carla E. Gallenga
- Section of Ophthalmology, Department of Biomedical Sciences and Specialist Surgery, University of Ferrara, 44121 Ferrara, Italy
| | - Ilias Frydas
- Department of Parasitology, Aristotle University, 54124 Thessaloniki, Greece
| | - Spyros K. Kritas
- Department of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Macedonia, Greece
| | - Matteo Trimarchi
- Centre of Neuroscience of Milan, Department of Medicine and Surgery, University of Milan, 20122 Milano, Italy
| | - Francesco Carinci
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Pio Conti
- Immunology Division, Postgraduate Medical School, University of Chieti, 66100 Chieti, Italy
- Correspondence:
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23
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Teufel LU, van der Made CI, Klück V, Simons A, Hoischen A, Vernimmen V, Joosten LAB, Arts RJW. Effect of exogenous IL-37 on immune cells from a patient carrying a potential IL37 loss-of-function variant: A case study. Cytokine 2023; 162:156102. [PMID: 36476991 DOI: 10.1016/j.cyto.2022.156102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 11/04/2022] [Accepted: 11/25/2022] [Indexed: 12/09/2022]
Abstract
INTRODUCTION Chronic inflammatory or autoimmune diseases are commonly treated with immunosuppressive medication such as NSAIDs, corticosteroids, or antibodies against specific cytokines (TNF, IL-1 IL-17, IL-23, etc.) or signalling cascades (e.g. JAK-STAT inhibitors). Using sequencing data to locate genetic mutations in relevant genes allows the identification of alternative targets in a patient-tailored therapy setting. Interleukin (IL)-37 is an anti-inflammatory cytokine with broad effects on innate and adaptive immune cell function. Dysfunctional IL-37 expression or signalling is linked to various autoinflammatory disorders. The administration of recombinant IL-37 to hyperinflammatory patients that are non-responsive to standard treatment bears the potential to alleviate symptoms. METHODS In this case study, the (hyper)responsiveness of immune cell subsets was investigated in a single patient with a seronegative autoimmune disorder who carries a heterozygous stop-gain variant in IL37 (IL37 Chr2(GRCh37):g.113670640G > A NM_014439.3:c.51G > A p.(Trp17*)). As the patient has been non-responsive to blockage of TNF or IL-1 by Etanercept or Anakinra, respectively, additional in-vitro experiments were set out to elucidate whether treatment with recombinant IL-37 could normalise observed immune cell functions. FINDINGS Characterisation of immune cell function showed no elevated overall production of acute-phase pro-inflammatory cytokines by patient PBMCs and neutrophils at baseline or upon stimulation. T-cell responses were elevated, as was the metabolic activity and IL-1Ra production of PBMCs at baseline. The identified stop-gain variant in IL37 does not result in the absence of the protein in circulation. In line with this, treatment with recombinant IL-37 did overall not dampen immune responses with the exception of the complete suppression of IL-17. CONCLUSION The heterozygous stop-gain variant in IL37 (IL37 NM_014439.3:c.51G > A p.(Trp17*)) is not of functional relevance as we observed no clear pro-inflammatory phenotype in immune cells of a patient carrying this variant.
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Affiliation(s)
- Lisa U Teufel
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Caspar I van der Made
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Viola Klück
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Annet Simons
- Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Alexander Hoischen
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Vivian Vernimmen
- Department of Genetics, Maastricht UMC+, Maastricht, the Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Strada Victor Babes 8, 400000 Cluj-Napoca, Romania
| | - Rob J W Arts
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
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24
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Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, Razzazan M, Mirzaei S, Entezari M, Goharrizi MASB, Salimimoghadam S, Aref AR, Kalbasi A, Rajabi R, Rashidi M, Taheriazam A, Sethi G. Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges. Pharmacol Res 2023; 187:106553. [PMID: 36400343 DOI: 10.1016/j.phrs.2022.106553] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022]
Abstract
Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Ghadyani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Abbaspour
- Cellular and Molecular Research Center,Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhossein Zabolian
- Resident of department of Orthopedics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc. 6, Tide Street, Boston, MA 02210, USA
| | - Alireza Kalbasi
- Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
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25
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Huang K, Lin Y, Wang K, Shen J, Wei D. ARFIP2 Regulates EMT and Autophagy in Hepatocellular Carcinoma in Part Through the PI3K/Akt Signalling Pathway. J Hepatocell Carcinoma 2022; 9:1323-1339. [PMID: 36573219 PMCID: PMC9789708 DOI: 10.2147/jhc.s392056] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose ARFIP2, a canonical BAR domain-containing protein, is closely associated with regulating cargo exit from the Golgi. However, the potential biological functions of ARFIP2 in hepatocellular carcinoma (HCC) have not been well investigated. This study aimed to explore the critical role of ARFIP2 in HCC cells. Methods The expression of proteins related to epithelial to mesenchymal transition (EMT) and cell autophagy in HCC cells and tissues was assayed by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The ability of cells to proliferate, migrate and invade was detected by Cell Counting Kit-8, Transwell migration and invasion assays. In addition, the function of ARFIP2 in vivo was assessed using a tumour xenograft model. Results ARFIP2 expression is significantly upregulated in early recurrent and metastatic HCC patients and was positively correlated with a poor prognosis. ARFIP2 overexpression promoted cell proliferation, migration, and invasion by inducing EMT and inhibiting autophagy in vitro. Furthermore, the regulatory effects of ARFIP2 on autophagy and EMT were partially attributed to its regulation of the PI3K/AKT signalling pathway. The in vivo results also showed that ARFIP2 modulates HCC progression. Conclusion Our results substantiate a novel mechanism by which ARFIP2 can regulate the activity/phosphorylation of Akt to promote EMT and inhibit autophagy in part via the PI3K/Akt signalling pathway. The ARFIP2/PI3K/Akt axis may be a potential diagnostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Kaida Huang
- Department of Oncology, Xiamen Haicang Hospital, Xiamen, People’s Republic of China
| | - Yubiao Lin
- Department of Oncology, Xiamen Haicang Hospital, Xiamen, People’s Republic of China
| | - Keyin Wang
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
| | - Jianfen Shen
- Department of Central Laboratory, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
| | - Dahai Wei
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China,Department of Central Laboratory, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China,Institute of Hepatology, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China,Correspondence: Dahai Wei, Institute of Hepatology, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China, Tel/Fax +86-573-89975669, Email
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McCurdy S, Yap J, Irei J, Lozano J, Boisvert WA. IL-37-a putative therapeutic agent in cardiovascular diseases. QJM 2022; 115:719-725. [PMID: 33486516 PMCID: PMC12116290 DOI: 10.1093/qjmed/hcab011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/17/2020] [Accepted: 12/22/2020] [Indexed: 11/13/2022] Open
Abstract
Although it is a member of the Interleukin (IL)-1 family, IL-37 is unique in that it has wide-ranging anti-inflammatory characteristics. It was originally thought to prevent IL-18-mediated inflammation by binding to the IL-18-binding protein. However, upon discovery that it binds to the orphan receptor, IL-1R8, further studies have revealed an expanded role of IL-37 to include several intracellular and extracellular pathways that affect various aspects of inflammation. Its potential role specifically in cardiovascular diseases (CVD) stemmed initially from the discovery of elevated plasma IL-37 levels in human patients with acute coronary syndrome and atrial fibrillation. Other studies using mouse models of ischemia/reperfusion injury, vascular calcification and myocardial infarction have revealed that IL-37 can have a beneficial role in these conditions. This review will explore recent research on the effects of IL-37 on the pathogenesis of CVD.
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Affiliation(s)
- S McCurdy
- Department of Medicine, University of California San Diego, San Diego, CA, USA
| | - J Yap
- Department of Medicine, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - J Irei
- Department of Medicine, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - J Lozano
- Department of Medicine, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - W A Boisvert
- Department of Medicine, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlevskaya Str., Kazan, 420008, Russia
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27
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Huang X, Zhang S, Wang W. Artesunate restrains the malignant progression of human cutaneous squamous cell carcinoma cells via the suppression of the PI3K/AKT pathway. Tissue Cell 2022; 76:101789. [DOI: 10.1016/j.tice.2022.101789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 03/03/2022] [Accepted: 03/16/2022] [Indexed: 10/18/2022]
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28
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Shen Z, Xue D, Wang K, Zhang F, Shi J, Jia B, Yang D, Zhang Q, Zhang S, Jiang H, Luo D, Li X, Zhong Q, Zhang J, Peng Z, Han Y, Sima C, He X, Hao L. Metformin exerts an antitumor effect by inhibiting bladder cancer cell migration and growth, and promoting apoptosis through the PI3K/AKT/mTOR pathway. BMC Urol 2022; 22:79. [PMID: 35610639 PMCID: PMC9131696 DOI: 10.1186/s12894-022-01027-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 05/12/2022] [Indexed: 02/08/2023] Open
Abstract
Background To observe and explore the effect of metformin on the migration and proliferation of bladder cancer T24 and 5637 cells in vitro. Methods Bladder cancer T24 and 5637 cell lines were cultured in vitro, and were divided into group A (blank control group) and group B (metformin group: 5, 10, 15, and 20 mmol/L); both groups were plated on 6-well plates at the same time. Culture in 24-well plates was used for wound healing assays and in 96-well plates for Transwell migration and invasion, and Cell Counting Kit-8 proliferation experiments. We observed and detected the cell migration and proliferation ability of each group at 48 h, and calculated the cell migration area and survival rate. Flow cytometry was used to detect cell apoptosis in the groups. The apoptosis-related proteins, cleaved-caspase 3, cleaved-PARP, and the PI3K/AKT/mTOR signaling pathway member proteins PI3K, phosphorylated (p)-PI3K, AKT, p-AKT, mTOR, and p-mTOR were detected using western blotting. Results After 48 h of treatment with different concentrations of metformin, the cell migration and proliferation capabilities were significantly lower than those in the blank control group. The proliferation and migration abilities of T24 and 5637 cells decreased in a metformin concentration-dependent manner (P < 0.05). The apoptosis rate under different concentrations of metformin, as detected by flow cytometry, showed a significantly higher rate in the metformin group than in the control group (P < 0.05). Compared with that in the control group, the level of cleaved-caspase 3 and cleaved-PARP protein in the metformin group was increased in each treatment group, and the levels of p-mTOR, p-AKT, and p-PI3K decreased significantly compared with those in the control group (P < 0.05). Conclusion Metformin inhibited bladder cancer T24 and 5637 cell migration and proliferation, and induced their apoptosis. The mechanism might involve inhibition of the activation of the PI3K/AKT/mTOR signaling pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12894-022-01027-2.
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Affiliation(s)
- Zhiyong Shen
- Department of Urology, The Third Affiliated Hospital of Soochow University, No.185, Juqian Street, Tianning District, Changzhou, 213000, Jiangsu Province, China.,Department of Urology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Dong Xue
- Department of Urology, The Third Affiliated Hospital of Soochow University, No.185, Juqian Street, Tianning District, Changzhou, 213000, Jiangsu Province, China
| | - Kun Wang
- Department of Urology, The Third Affiliated Hospital of Soochow University, No.185, Juqian Street, Tianning District, Changzhou, 213000, Jiangsu Province, China
| | - Facai Zhang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.,Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Jiaqi Shi
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Benzhong Jia
- Department of Urology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Dan Yang
- Department of Clinic Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Qianjin Zhang
- Department of Urology, The Third Affiliated Hospital of Soochow University, No.185, Juqian Street, Tianning District, Changzhou, 213000, Jiangsu Province, China.,Department of Urology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Nanjing, China
| | - Shuai Zhang
- Laboratory of the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Hongyu Jiang
- Laboratory of the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Daiqin Luo
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China.,Laboratory of the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Xueying Li
- Laboratory of the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Quliang Zhong
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Junhao Zhang
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Zheng Peng
- Department of Urology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Yu Han
- Department of Urology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Chongyang Sima
- Department of Urology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, No.185, Juqian Street, Tianning District, Changzhou, 213000, Jiangsu Province, China.
| | - Lin Hao
- Department of Urology, Xuzhou Central Hospital, No. 199 Jiefang Street, Quanshan District, Xuzhou, 221009, Jiangsu, China.
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Teng YJ, Deng Z, Ouyang ZG, Zhou Q, Mei S, Fan XX, Wu YR, Long HP, Fang LY, Yin DL, Zhang BY, Guo YM, Zhu WH, Huang Z, Zheng P, Ning DM, Tian XF. Xihuang pills induce apoptosis in hepatocellular carcinoma by suppressing phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin pathway. World J Gastrointest Oncol 2022; 14:872-886. [PMID: 35582102 PMCID: PMC9048534 DOI: 10.4251/wjgo.v14.i4.872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/30/2021] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin (PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills (XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma (HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHP-associated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.
AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.
METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Cell-based experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP (0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay. Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction (RT-qPCR), respectively. Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway. Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.
RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry: Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625 mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose- and time-dependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract (0.625 mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins (e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.
CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3. Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
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Affiliation(s)
- Yong-Jie Teng
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhe Deng
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhao-Guang Ouyang
- Department of Preventive Dentistry, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510132, Guangdong Province, China
| | - Qing Zhou
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xing-Xing Fan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
| | - Yong-Rong Wu
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Hong-Ping Long
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Le-Yao Fang
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Dong-Liang Yin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Bo-Yu Zhang
- College of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yin-Mei Guo
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Wen-Hao Zhu
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhen Huang
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Piao Zheng
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Di-Min Ning
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xue-Fei Tian
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
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IL-1 family cytokines as drivers and inhibitors of trained immunity. Cytokine 2021; 150:155773. [PMID: 34844039 DOI: 10.1016/j.cyto.2021.155773] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022]
Abstract
Trained immunity is the long-term memory of innate immune cells, characterised by increased pro-inflammatory responses towards homo- and heterologous secondary stimuli. Interleukin (IL)-1 signalling plays an essential role in the induction of trained immunity, also called innate immune memory. As such, certain anti-inflammatory members of the IL-1 family of cytokines (IL-1F) which interfere with the inflammatory process have the potential to regulate the induction of a trained phenotype. The aim of this review is to provide an update on the role of IL-1F members in the context of trained immunity, emphasising the role of anti-inflammatory cytokines from the IL-1F to inhibit the induction of trained immunity, and touching upon their potential as therapeutics in IL-1-driven inflammatory disorders.
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Zhu Y, Qin H, Ye K, Sun C, Qin Y, Li G, Wang H, Wang H. Dual role of IL-37 in the progression of tumors. Cytokine 2021; 150:155760. [PMID: 34800851 DOI: 10.1016/j.cyto.2021.155760] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/17/2021] [Accepted: 11/01/2021] [Indexed: 01/05/2023]
Abstract
Interleukin (IL)-37 is a novel defined cytokine that belongs to IL-1 family, which possesses potent anti-inflammatory and immunosuppressive properties. The IL-37 protein mainly exists in the cytoplasm of monocytes and is also expressed in epithelial cells and T cells. IL-37 is produced as a precursor which works in mature or immature isoforms without a classic signal peptide, and negatively regulates TLR agonist- mediated signaling pathway, proinflammatory cytokines, and IL-1R ligands. IL-37 has been found to be elevated and plays an anti-tumor role in various types of tumors, such as hepatocellular carcinoma, non-small cell lung cancer, and cervical cancer. The tumor microenvironment (TME) refers to the cellular environment where the tumor or cancer stem cells exist. At present, growing evidence shows that changes in TME can regulate metabolism, immunity, secretion, and function, so as to inhibit or promote the progression of the tumor. Therefore, a thorough understanding of the TME is essential for the occurrence and development of tumors. In this review, we will summarize the role of IL-37 in the microenvironment of different tumors, hoping to provide novel perspectives towards the mechanism, prevention, and treatment of tumors.
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Affiliation(s)
- Yanglin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Kui Ye
- Department of Vascular Surgery, Tianjin Fourth Central Hospital, Tianjin 300140, China
| | - Chenglu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Extracellular IL-37 promotes osteogenic and odontogenic differentiation of human dental pulp stem cells via autophagy. Exp Cell Res 2021; 407:112780. [PMID: 34411610 DOI: 10.1016/j.yexcr.2021.112780] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/02/2021] [Accepted: 08/07/2021] [Indexed: 01/08/2023]
Abstract
The osteogenic and odontogenic differentiation of dental pulp stem cells (DPSCs) contribute to restoration and regeneration of dental tissue. Previous study indicated that interleukin-37 (IL-37) was an anti-inflammatory factor that affected other pro-inflammatory signals. The aim of this study was to explore the effects of IL-37 on the differentiation of DPSCs. DPSCs were cultured in growth medium with different concentrations of IL-37. We selected the optimal concentration for the following experiments by alkaline phosphatase (ALP) activity analysis, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot. Cell counting kit assay (CCK-8) and 5-Ethynyl-2'-Deoxyuridine (EdU) assay were conducted to assess the effects of IL-37 on the proliferation of DPSCs. ALP activity assay and staining, alizarin red S (ARS) staining, qRT-PCR, Western blot as well as immunofluorescence staining were conducted to assess differentiation ability of DPSCs. Western blot, immunofluorescence staining and transmission electron microscopy (TEM) were utilized to examine cell autophagy. Results showed that IL-37 enhanced the osteogenic and odontogenic differentiation ability of DPSCs with no significant influence on the proliferation of DPSCs. Autophagy in DPSCs was activated by IL-37. Activation of autophagy enhanced osteogenesis and odontogenesis of DPSCs, whereas inhibition of autophagy suppressed DPSCs osteogenic and odontogenic differentiation. In conclusion, IL-37 increased osteogenic and odontogenic differentiation via autophagy.
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Rico Montanari N, Anugwom CM, Boonstra A, Debes JD. The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13194876. [PMID: 34638361 PMCID: PMC8508513 DOI: 10.3390/cancers13194876] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Non-homeostatic cytokine expression during hepatocellular carcinogenesis, together with simple and inexpensive cytokine detection techniques, has opened up its use as potential biomarkers, from cancer detection to prognosis. However, carcinogenic programs during cancer progression are not linear. Therefore, cytokines with prognostic potential in one stage may not be relevant in another. Here, we reviewed cytokines with clinical potential in different settings during hepatocellular carcinoma progression. Abstract Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a leading cause of cancer-related death worldwide. Early detection remains the most effective strategy in HCC management. However, the spectrum of underlying liver diseases preceding HCC, its genetic complexity, and the lack of symptomatology in early stages challenge early detection. Regardless of underlying etiology, unresolved chronic inflammation is a common denominator in HCC. Hence, many inflammatory molecules, including cytokines, have been investigated as potential biomarkers to predict different stages of HCC. Soluble cytokines carry cell-signaling functions and are easy to detect in the bloodstream. However, its biomarkers’ role remains limited due to the dysregulation of immune parameters related to the primary liver process and their ability to differentiate carcinogenesis from the underlying disease. In this review, we discuss and provide insight on cytokines with clinical relevance for HCC differentiating those implicated in tumor formation, early detection, advanced disease, and response to therapy.
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Affiliation(s)
- Noe Rico Montanari
- Department of Medicine, Division of Gastroenterology & Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA; (N.R.M.); (C.M.A.)
- Department of Gastroenterology and Hepatology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Chimaobi M. Anugwom
- Department of Medicine, Division of Gastroenterology & Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA; (N.R.M.); (C.M.A.)
- Health Partners Digestive Care, Saint Paul, MN 55130, USA
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
| | - Jose D. Debes
- Department of Medicine, Division of Gastroenterology & Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA; (N.R.M.); (C.M.A.)
- Department of Gastroenterology and Hepatology, Erasmus MC, 3015 CE Rotterdam, The Netherlands;
- Correspondence:
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Deng Y, Chen QS, Huang WF, Dai JW, Wu ZJ. XPA serves as an autophagy and apoptosis inducer by suppressing hepatocellular carcinoma in a PI3K/Akt/mTOR dependent manner. J Gastrointest Oncol 2021; 12:1797-1810. [PMID: 34532129 DOI: 10.21037/jgo-21-310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/26/2021] [Indexed: 12/15/2022] Open
Abstract
Background To explore the potential biological function of XPA (Xeroderma pigmentosum group A) in hepatic neoplasms and the underlying molecular mechanisms. Methods Liver cells were used as experimental models to establish HCC (hepatocellular carcinoma) in vitro. Protein extractions were subjected to Western blotting to detect the proteins expression. The lentivirus transfection efficiency was confirmed by Western blot and RT-qPCR, Tunnel staining was used to detect apoptosis, and Transwell assays were used to observe cell migration and invasion. Cell proliferation was detected with colony formation and CCK-8 (cell counting kit-8) assays. Results XPA expression was obviously lower in HCC tissue and liver cancer cell lines. XPA overexpression induced autophagy and apoptosis by increasing LC3B II/I, Beclin1, cleaved-caspase-3, and Bax expression and decreasing p62 and Bcl2 protein levels. XPA also suppressed HCC EMT (Epithelial-Mesenchymal Transition) by increasing E-cadherin and decreasing N-cadherin and vimentin protein expression. Cell proliferation, migration and invasion in vivo were significantly inhibited by the overexpression of XPA, and p-PI3K, p-Akt, and p-mTOR expression were decreased in LV-XPA cells. In general, XPA inhibited HCC by inducing autophagy and apoptosis and by modulating the expression of PI3K/Akt/mTOR proteins. Conclusions XPA overexpression was found to suppress HCC by inducing autophagy and apoptosis and repressing EMT and proliferation. Each of these effects may be involved in modulating the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Yi Deng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Qing-Song Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Traumatology, Chongqing University Central Hospital, Chongqing, China
| | - Wei-Feng Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiang-Wen Dai
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Chengdu Fifth People's Hospital, Chengdu, China
| | - Zhong-Jun Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Chen QS, Shen A, Dai JW, Li TT, Huang WF, Shi K, Deng Y, Pan L, Wei XF, Wu ZJ. IL37 overexpression inhibits autophagy and apoptosis induced by hepatic ischemia reperfusion injury via modulating AMPK/mTOR/ULLK1 signalling pathways. Life Sci 2021; 276:119424. [PMID: 33785334 DOI: 10.1016/j.lfs.2021.119424] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/10/2021] [Accepted: 03/13/2021] [Indexed: 02/07/2023]
Abstract
AIM To investigate the potential role of IL37 in hepatic ischemia reperfusion injury and its underlying molecular mechanism. METHODS C57BL/6 mouse and hepatocytes were used to establish the hepatic ischemia reperfusion (IR) and the hypoxia reoxygenation (HR) injury model in vivo and in vitro, separately. Total extraction of tissue and cell protein expressions of LC3B, Beclin1, p62, cleaved caspase3, caspase3, bax, bcl2, AMPK, mTOR, ULK1 were detected by western blot. IL37 mRNA and protein level were detected by RT-qPCR and western blot. ALT and AST serum level were measured by microplate readers. H&E staining was used to assess the tissue sections. Autophagy was measured by TEM and confocal laser microscopy. Apoptosis in tissue and cell were detected by TUNEL staining. RESULTS Autophagy was aberrantly activated by H2R6 and I1R12. Both exogenous IL37 and endogenous IL37 exerted protective effects on hepatocytes by affecting both autophagy-related proteins, specifically, by suppressing LC3B II and Beclin1 expression and increasing p62 levels and apoptosis-related proteins specifically, by inhibiting cleaved caspase3 and Bax expression and increasing Bcl2 expression during HR. Furthermore, endogenous IL37 inactivated AMPK and ULK1 phosphorylation and promoted mTOR phosphorylation in hepatocytes. Furthermore, in vivo experiments, serum liver enzyme measurements, TUNEL assays, and histological assessments, as well as other typical evaluations, showed the protective effect of IL37 overexpression in mice. CONCLUSION Endogenous and exogenous IL37 were found to ameliorate hepatic ischemia reperfusion injury by inhibiting excessive autophagy and apoptosis, these effects may be connected with the modulation of AMPK/mTOR/ULK1 signalling complex.
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Affiliation(s)
- Qing-Song Chen
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ai Shen
- Department of hepatobiliary pancreatic Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Jiang-Wen Dai
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ting-Ting Li
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei-Feng Huang
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kun Shi
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Deng
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of oncology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Long Pan
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xu-Fu Wei
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Zhong-Jun Wu
- Department of hepatobiliary surgery, the first affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Wang X, Wei Z, Tang Z, Xue C, Yu H, Zhang D, Li Y, Liu X, Shi Y, Zhang L, Chen G, Zhou H, Wang J, Wang X. IL-37bΔ1-45 suppresses the migration and invasion of endometrial cancer cells by targeting the Rac1/NF-κB/MMP2 signal pathway. J Transl Med 2021; 101:760-774. [PMID: 33753880 DOI: 10.1038/s41374-021-00544-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 01/16/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
Endometrial carcinoma is one of the most common malignancies in the female reproductive system. Interleukin-37 (IL-37) is a newly discovered anti-inflammatory factor belonging to the IL-1 family. IL-37 has five different isoforms, and IL-37b is the most biologically functional subtype. In recent years, the protective roles of IL-37 in different cancers, including lung and liver cancers, have been successively reported. IL-37 also plays an important role in some gynecological diseases such as endometriosis, adenomyosis, and cervical cancer. However, the role and mechanism of IL-37b, especially the mature form of IL-37b, in endometrial carcinoma have not been elucidated. The present study demonstrated that IL-37 protein was downregulated in endometrial carcinoma cells compared with the control endometrium. IL-37b did not affect the proliferation and colony-forming ability of endometrial cancer cells. A mature form of IL-37b (IL-37bΔ1-45) effectively suppressed the migration and invasion of endometrial cancer cells by decreasing the expression of matrix metalloproteinase 2 (MMP2) via Rac1/NF-κB signal pathway. However, it did not affect epithelial-mesenchymal transition (EMT) or filamentous actin (F-actin) depolymerization of endometrial cancer cells. IL-37bΔ1-45 attenuated tumor metastasis in a peritoneal metastatic xenograft model of endometrial cancer. To sum up, these results suggested IL-37b could be involved in the pathogenesis of endometrial carcinoma and provide a novel target for the diagnosis and treatment of endometrial carcinoma.
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Affiliation(s)
- Xishuang Wang
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Zengtao Wei
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
- Department of Gynecology and Obstetrics, Clinical Medical School, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Zhongyun Tang
- Department of Gynecology and Obstetrics, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Chenyue Xue
- Department of Gynecology and Obstetrics, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Huayun Yu
- Department of Gynecology and Obstetrics, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Derui Zhang
- Department of Gynecology and Obstetrics, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Yulan Li
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Xihong Liu
- Department of Pathology, The Fourth People's Hospital of Jinan, Jinan, Shandong, PR China
| | - Yongyu Shi
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Lining Zhang
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Guoling Chen
- Department of Ophthalmology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Huaiyu Zhou
- Department of Microbiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Jianing Wang
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China
| | - Xiaoyan Wang
- Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
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Zhu PL, Lam DF, Li JK, Fu XQ, Yin CL, Chou JY, Wang YP, Liu YX, Chen YJ, Wu JY, Wu Y, Bai JX, Liang C, Yu ZL. Gomisin N Exerts Anti-liver Cancer Effects and Regulates PI3K-Akt and mTOR-ULK1 Pathways in Vitro. Biol Pharm Bull 2021; 43:1267-1271. [PMID: 32741948 DOI: 10.1248/bpb.b20-00030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N (GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K-Akt pathway and regulates the mTOR-ULK1 pathway in liver cancer cells.
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Affiliation(s)
- Pei-Li Zhu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Dick Fai Lam
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University
| | - Jun-Kui Li
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Xiu-Qiong Fu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Cheng-Le Yin
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Ji-Yao Chou
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Ya-Ping Wang
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Yu-Xi Liu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Ying-Jie Chen
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Jia-Ying Wu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Ying Wu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | - Jing-Xuan Bai
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
| | | | - Zhi-Ling Yu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University.,Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University.,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education
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He Y, Xiong T, Guo F, Du Z, Fan Y, Sun H, Feng Z, Zhang G. Interleukin-37b inhibits the growth of murine endometriosis-like lesions by regulating proliferation, invasion, angiogenesis and inflammation. Mol Hum Reprod 2021; 26:240-255. [PMID: 32119739 DOI: 10.1093/molehr/gaaa014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 01/28/2020] [Accepted: 02/06/2020] [Indexed: 12/17/2022] Open
Abstract
Endometriosis is a gynecological disease with abnormal expression of interleukin (IL)-37 which can suppress inflammation and the immune system. Here we investigated the role of the IL-37b splice variant in endometriosis in vivo and in vitro. In a murine model of endometriosis, in vivo administration of IL-37b significantly inhibited the development of lesions judged by the number (P = 0.0213), size (P = 0.0130) and weight (P = 0.0152) of lesions. IL-37b had no effect on the early stage of lesion formation, however administration in the growth stage of lesions decreased the number (P = 0.0158), size (P = 0.0158) and weight (P = 0.0258) of lesions compared with PBS control, an effect that was not reversed by macrophage depletion. Expressions of inflammatory factors, matrix metalloproteinases and vascular endothelial growth factor-A mRNA/protein were significantly inhibited in ectopic lesions following IL-37b administration, and in uterine segments treated in vitro. In vitro treatment of uterine segments with IL-37b inhibited phosphorylation of Akt and Erk1/2 in uterine segments. Isolated mouse endometrial stromal treated with IL-37b and transfected with pIL-37b plasmid got suppressed cell proliferation, invasion, angiogenesis and the expression of inflammatory factors. In addition, transfection with pIL-37b significantly decreased the phosphorylation of Akt and Erk1/2. IL-37b also inhibited proliferation and the expression of inflammatory and angiogenesis factors in epithelial cell line RL95-2. These findings suggest that IL-37b may inhibit the growth of lesions by regulating proliferation, invasion, angiogenesis and inflammation through Akt and Erk1/2 signaling pathway.
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Affiliation(s)
- Yongpei He
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
| | - Ting Xiong
- Department of Gynaecology and Obstetrics, Reproductive Medical center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The People's Republic of China
| | - Fang Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
| | - Zhenzhen Du
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
| | - Yixian Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
| | - Huanhuan Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
| | - Zuohua Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
| | - Guimei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The people's Republic of China
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Xu R, Zhang Y, Li A, Ma Y, Cai W, Song L, Xie Y, Zhou S, Cao W, Tang X. LY‑294002 enhances the chemosensitivity of liver cancer to oxaliplatin by blocking the PI3K/AKT/HIF‑1α pathway. Mol Med Rep 2021; 24:508. [PMID: 33982772 PMCID: PMC8134878 DOI: 10.3892/mmr.2021.12147] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Liver cancer remains one of the leading causes of cancer deaths worldwide. The therapeutic effect of oxaliplatin on liver cancer is often limited by acquired resistance of the cancer cells. Abnormal activation of the PI3K/AKT pathway plays an important role in the acquired resistance of oxaliplatin. The present study investigated the effects of the PI3K inhibitor LY-294002 and AKT inhibitor MK2206 on the chemosensitivity of oxaliplatin-resistant liver cancer cells and the molecular mechanism involved. An oxaliplatin-resistant liver cancer cell line HepG2R was developed. MTT assay, clone formation experiments, flow cytometry and Annexin V-FITC/PI staining were used to determine the proliferation, cycle and apoptosis of HepG2R cells when oxaliplatin was combined with LY-294002 or MK2206 treatment. The effects of LY-294002 and MK-2206 on the abnormal activation of PI3K/AKT pathway and hypoxia inducible factor (HIF)-1α protein level in HepG2R cells were detected using western blotting. The results indicated that the PI3K/AKT pathway is stably activated in HepG2R cells. Compared with the AKT inhibitor MK2206, the PI3K inhibitor LY-294002 more effectively downregulated the phosphorylation levels of p85, p110α, p110β, p110γ and AKT in the PI3K/AKT pathway in HepG2R cells, and more effectively inhibited the proliferation of the cells. LY-294002 enhanced the chemotherapy sensitivity of HepG2R cells to oxaliplatin by inducing G0/G1 phase arrest and increasing the proportion of apoptotic cells. In addition, LY-294002 reduced the level of HIF-1α, which is highly expressed in HepG2R cells. It was concluded that LY-294002 enhanced the chemosensitivity of liver cancer cells to oxaliplatin by inhibiting the PI3K/AKT signaling pathway, which may be related to the inhibition of HIF-1α expression. These findings may have clinical significance for the treatment of oxaliplatin-resistant liver cancer.
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Affiliation(s)
- Ruyue Xu
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Yinci Zhang
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Amin Li
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Yongfang Ma
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Wenpeng Cai
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Li Song
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Yinghai Xie
- Institute of Environmentally Friendly Materials and Occupational Health, Anhui University of Science and Technology, Wuhu, Anhui 241000, P.R. China
| | - Shuping Zhou
- Institute of Environmentally Friendly Materials and Occupational Health, Anhui University of Science and Technology, Wuhu, Anhui 241000, P.R. China
| | - Weiya Cao
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Xiaolong Tang
- Medical School, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
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40
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BEZ235 Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib by Inhibiting PI3K/AKT/mTOR and Inducing Autophagy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5556306. [PMID: 33987439 PMCID: PMC8079203 DOI: 10.1155/2021/5556306] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022]
Abstract
Acquired resistance of hepatocellular carcinoma (HCC) to sorafenib (SFB) is the main reason for the failure of SFB treatment of the cancer. Abnormal activation of the PI3K/AKT/mTOR pathway is important in the acquired resistance of SFB. Therefore, we investigated whether BEZ235 (BEZ) could reverse acquired sorafenib resistance by targeting the PI3K/mTOR pathway. A sorafenib-resistant HCC cell line Huh7R was established. MTT assay, clone formation assay, flow cytometry, and immunofluorescence were used to analyze the effects of BEZ235 alone or combined with sorafenib on cell proliferation, cell cycle, apoptosis, and autophagy of Huh7 and Huh7R cells. The antitumor effect was evaluated in animal models of Huh7R xenografts in vivo. Western blot was used to detect protein levels of the PI3K/AKT/mTOR pathway and related effector molecules. In vitro results showed that the Huh7R had a stronger proliferation ability and antiapoptosis effect than did Huh7, and sorafenib had no inhibitory effect on Huh7R. SFB + BEZ inhibited the activation of the PI3K/AKT/mTOR pathway caused by sorafenib. Moreover, SFB + BEZ inhibited the proliferation and cloning ability, blocked the cell cycle in the G0/G1 phase, and promoted apoptosis in the two cell lines. The autophagy level in Huh7R cells was higher than in Huh7 cells, and BEZ or SFB + BEZ further promoted autophagy in the two cell lines. In vivo, SFB + BEZ inhibited tumor growth by inducing apoptosis and autophagy. We concluded that BEZ235 enhanced the sensitivity of sorafenib through suppressing the PI3K/AKT/mTOR pathway and inducing autophagy. These observations may provide the experimental basis for sorafenib combined with BEZ235 in trial treatment of HCC.
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41
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Li H, Huang H, Li S, Mei H, Cao T, Lu Q. Long non-coding RNA ADAMTS9-AS2 inhibits liver cancer cell proliferation, migration and invasion. Exp Ther Med 2021; 21:559. [PMID: 33850531 PMCID: PMC8027749 DOI: 10.3892/etm.2021.9991] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
Long non-coding RNA (lncRNA) ADAM metallopeptidase with thrombospondin type 1 motif 9 antisense RNA 2 (ADAMTS9-AS2) is involved in various types of cancer, such as ovarian cancer, lung cancer and clear cell renal cell carcinoma. However, the roles of ADAMTS9-AS2 in liver cancer are not completely understood. The present study aimed to determine the functional role of ADAMTS9-AS2 in human liver cancer and investigate the potential underlying molecular mechanisms. The expression levels of ADAMTS9-AS2 and ADAMTS9 were determined following ADAMTS9-AS2 overexpression and knockdown. The results indicated that ADAMTS9-AS2 overexpression and knockdown increased and decreased ADAMTS9 mRNA and protein expression levels, respectively, indicating that alterations in ADAMTS9 expression corresponded with ADAMTS9-AS2 expression. Subsequently, the effects of ADAMTS9-AS2 on liver cancer cell proliferation, migration and invasion were analyzed by performing Cell Counting Kit-8, wound healing and Transwell assays, respectively. The results demonstrated that ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion. Finally, the effect of ADAMTS9 on PI3K/AKT/mTOR signaling pathway-associated proteins [AKT, phosphorylated-AKT, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit β (PIK3CB), mTOR and phosphorylated-mTOR], several key autophagy-related proteins [light chain 3-I/II (LC3-I/II), beclin 1 (BECN1) and sequestosome 1 (SQSTM1)] and apoptosis-related proteins (Bax and Bcl-2) was detected via western blotting. The results suggested that ADAMTS9-AS2 downregulated the phosphorylation of AKT and mTOR, the protein expression level of PIK3CB, as well as the expression levels of autophagy protein SQSTM1 and antiapoptotic protein Bcl-2. By contrast, ADAMTS9-AS2 upregulated the expression levels of autophagy proteins LC3-II and BECN1, and the proapoptotic protein Bax. Collectively, ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion via inhibiting the PI3K/AKT/mTOR signaling pathway. The present study provided a novel insight into the role of ADAMTS9-AS2 in liver cancer.
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Affiliation(s)
- Hanjun Li
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.,Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Hu Huang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.,Department of Oncology, The People's Liberation Army No. 161 Hospital, Wuhan, Hubei 430010, P.R. China
| | - Sha Li
- Department of Anesthesiology, General Hospital of Central Theater Command of The People's Liberation Army, Wuhan, Hubei 430070, P.R. China
| | - Hongliang Mei
- Department of General Surgery, General Hospital of Central Theater Command of The People's Liberation Army, Wuhan, Hubei 430070, P.R. China
| | - Tingjia Cao
- Department of General Surgery, General Hospital of Central Theater Command of The People's Liberation Army, Wuhan, Hubei 430070, P.R. China
| | - Qiping Lu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.,Department of General Surgery, General Hospital of Central Theater Command of The People's Liberation Army, Wuhan, Hubei 430070, P.R. China
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42
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Suares A, Medina MV, Coso O. Autophagy in Viral Development and Progression of Cancer. Front Oncol 2021; 11:603224. [PMID: 33763351 PMCID: PMC7982729 DOI: 10.3389/fonc.2021.603224] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
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Affiliation(s)
- Alejandra Suares
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Victoria Medina
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Omar Coso
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
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43
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Suares A, Medina MV, Coso O. Autophagy in Viral Development and Progression of Cancer. Front Oncol 2021. [DOI: 10.3389/fonc.2021.603224
expr 816899697 + 824303767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
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44
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de Graaf DM, Teufel LU, van de Veerdonk FL, Joosten LAB, Netea MG, Dinarello CA, Arts RJW. IL-38 prevents induction of trained immunity by inhibition of mTOR signaling. J Leukoc Biol 2021; 110:907-915. [PMID: 33620105 PMCID: PMC8380748 DOI: 10.1002/jlb.3a0220-143rrr] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 01/28/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Trained immunity is the acquisition of a hyperresponsive phenotype by innate immune cells (such as monocytes and macrophages) after an infection or vaccination, a de facto nonspecific memory dependent on epigenetic and metabolic reprogramming of these cells. We have recently shown that induction of trained immunity is dependent on IL‐1β. Here, we show that recombinant IL‐38, an anti‐inflammatory cytokine of the IL‐1‐family, was able to induce long‐term inhibitory changes and reduce the induction of trained immunity by β‐glucan in vivo in C57BL/6 mice and ex vivo in their bone marrow cells. IL‐38 blocked mTOR signaling and prevented the epigenetic and metabolic changes induced by β‐glucan. In healthy subjects, the IL1F10 associated single nucleotide polymorphism rs58965312 correlated with higher plasma IL‐38 concentrations and reduced induction of trained immunity by β‐glucan ex vivo. These results indicate that IL‐38 induces long‐term anti‐inflammatory changes and also inhibits the induction of trained immunity. Recombinant IL‐38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity.
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Affiliation(s)
- Dennis M de Graaf
- Department of Medicine, University of Colorado, Aurora, Colorado, USA.,Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lisa U Teufel
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frank L van de Veerdonk
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.,Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Charles A Dinarello
- Department of Medicine, University of Colorado, Aurora, Colorado, USA.,Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rob J W Arts
- Department of Medicine, University of Colorado, Aurora, Colorado, USA.,Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
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45
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Gipson CD, Rawls S, Scofield MD, Siemsen BM, Bondy EO, Maher EE. Interactions of neuroimmune signaling and glutamate plasticity in addiction. J Neuroinflammation 2021; 18:56. [PMID: 33612110 PMCID: PMC7897396 DOI: 10.1186/s12974-021-02072-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/05/2021] [Indexed: 02/28/2023] Open
Abstract
Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.
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Affiliation(s)
- Cassandra D Gipson
- Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB, Room 363, Lexington, KY, 40536-0509, USA.
| | - Scott Rawls
- Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Michael D Scofield
- Department of Anesthesiology, Medical University of South Carolina, Charleston, USA
- Department of Neuroscience, Medical University of South Carolina, Charleston, USA
| | - Benjamin M Siemsen
- Department of Anesthesiology, Medical University of South Carolina, Charleston, USA
| | - Emma O Bondy
- Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB, Room 363, Lexington, KY, 40536-0509, USA
| | - Erin E Maher
- Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB, Room 363, Lexington, KY, 40536-0509, USA
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46
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Liu J, Ming S, Song W, Meng X, Xiao Q, Wu M, Wu Y, Xie H, Zhou J, Zhong H, Huang X. B and T lymphocyte attenuator regulates autophagy in mycobacterial infection via the AKT/mTOR signal pathway. Int Immunopharmacol 2020; 91:107215. [PMID: 33348294 DOI: 10.1016/j.intimp.2020.107215] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/08/2020] [Accepted: 11/14/2020] [Indexed: 01/09/2023]
Abstract
The survivability of Mycobacterium tuberculosis (M.tb) in macrophages in granuloma is a predominant cause for tuberculosis (TB) infection and recurrence. However, the mechanism of mycobacterial clearance in macrophages still needs further study. Here, we explored a novel role of B and T lymphocyte Attenuator (BTLA) in macrophage-mediated host defense against mycobacterial infection. We found that the surface expression of BTLA was increased in CD14+ monocytes from active TB patients. The mRNA levels of BTLA were induced in human and mice monocytes/macrophages during Mycobacterium bovis BCG or M.tb H37Rv infection, as well as spleen and lung of H37Rv-infected mice. Furthermore, silencing of BTLA promoted the intracellular survival of BCG and H37Rv by suppressing the autophagy in macrophages but not effecting phagocytosis, reactive oxygen species (ROS) and apoptosis. Silence of BTLA reduced bacterial-autophagosome and bacterial-lysosome colocalization. Moreover, BTLA inhibited AKT and mTOR signaling substrates S6K and 4EBP1 phosphorylation in BCG and H37Rv infected macrophages, and BTLA-mediated AKT-mTOR signaling and intracellular BCG survival were reversed by PI3K inhibitors in macrophages. Finally, treatment with BTLA agonist ameliorated lung pathology and promoted autophagy and mycobacterial clearance during mycobacterial infection in vivo. These results demonstrate that BTLA promotes host defense against mycobacteria by enhancing autophagy, which may provide potential therapeutic interventions against tuberculosis.
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Affiliation(s)
- Jiao Liu
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China
| | - Siqi Ming
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China
| | - Weifeng Song
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Xiaojun Meng
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Qiang Xiao
- Respiratory and Critical Medicine, Shunde Hospital, Southern Medical University, Guangdong Province 528300, China
| | - Minhao Wu
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Yongjian Wu
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China
| | - Hanbin Xie
- The Third People's Hospital of Shantou, Guangdong Province 515073, China
| | - Jie Zhou
- The Forth People's Hospital of Foshan, Foshan 528000, China.
| | - Haibo Zhong
- The Third People's Hospital of Shantou, Guangdong Province 515073, China.
| | - Xi Huang
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China.
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Zhou GZ, Guo SS, Liu DX, Zhang L, Sun GC. Antiproliferative effect and autophagy induction of curcumin derivative ZYX02-Na on the human lung cancer cells A549. J Biochem Mol Toxicol 2020; 34:e22592. [PMID: 33176062 DOI: 10.1002/jbt.22592] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 05/19/2020] [Accepted: 07/14/2020] [Indexed: 11/09/2022]
Abstract
At present, a large number of curcumin derivatives had been produced and identified aiming to replace the curcumin in view of its low bioavailability and stability. Here, a novel curcumin derivative ZYX02-Na was first used to reduce the cell viability of human non-small cell lung cells A549, which was confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry and Western blot analysis showed that ZYX02-Na could lead to cell cycle arrest in G0/G1 phase, which demonstrated that ZYX02-Na inhibited the proliferation of A549 cells. Furthermore, the AMPK/mTOR/4E-BP1 signaling pathway was activated in ZYX02-Na-treated A549 cells. Besides, wounding healing and transwell experiments showed that ZYX02-Na could also inhibited the migration ability of A549 cells. Moreover, we also found that ZYX02-Na could induce autophagy of A549 cells by acridine orange staining, GFP-LC3 subcellular localization observation and Western blotting analysis, respectively. In short, our current studies indicated that ZYX02-Na possessed the antiproliferation effect and autophagy induction on A549 cells, while in vivo anticancer study of ZYX02-Na needs to be done in future.
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Affiliation(s)
- Guang-Zhou Zhou
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Shuang-Shuang Guo
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Deng-Xu Liu
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Lu Zhang
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Gang-Chun Sun
- Department of Applied Chemistry, College of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, China
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Xu T, Sun D, Chen Y, Ouyang L. Targeting mTOR for fighting diseases: A revisited review of mTOR inhibitors. Eur J Med Chem 2020; 199:112391. [DOI: 10.1016/j.ejmech.2020.112391] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/24/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
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Zhang X, Yi S, Xing G, Wu H, Zhu Y, Guo X, Zhang L. FOXCUT Promotes the Proliferation and Invasion by Activating FOXC1/PI3K/AKT Pathway in Colorectal Cancer. Cancer Manag Res 2020; 12:6269-6278. [PMID: 32801872 PMCID: PMC7399466 DOI: 10.2147/cmar.s259801] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 06/17/2020] [Indexed: 12/20/2022] Open
Abstract
Introduction Colorectal cancer (CRC) is the third most commonly diagnosed world cancer. Long noncoding RNAs (lncRNAs) serve important regulatory roles in tumorigenesis. However, the contributions of lncRNAs to human CRC remain largely unknown. Material and Methods FOXC1 and FOXCUT lncRNA expression levels were detected in a panel of paired specimens obtained from 48 patients’ tissues and cell lines with CRC using RT-qPCR. RNA interference was used to investigate potential correlations between FOXC1 and FOXCUT expression in HT29. Cell proliferation was assessed by MTT assay and EdU incorporation assay. The migration and invasion of CRC cells were detected by transwell assay. Western blot was applied to assess the protein expression and PI3K/AKT signaling pathway. Results In this study, a novel long noncoding RNA (FOXCUT) was frequently overexpressed in CRC tissues and cell lines. In addition, the expressions of FOXCUT and FOXC1 were positively correlated. When the expression of FOXCUT was downregulated by small interfering RNA (siRNA), the expression of FOXC1 was also decreased. Moreover, knockdown of FOXCUT significantly inhibited proliferation and invasion of CRC cell lines and resulted in downregulated expression of the matrix metalloproteinase 1 (MMP-1). Mechanistically, FOXCUT promotes the expression of FOXC1 to activate PI3K/AKT signaling pathway for its regulation of cell growth and proliferation. Conclusion In summary, our findings indicate that FOXCUT plays an important oncogenic role and may serve as a novel biomarker and therapeutic target in CRC progression.
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Affiliation(s)
- Xiaojie Zhang
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Shanyong Yi
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Guochen Xing
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Huili Wu
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Ying Zhu
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Xiaodan Guo
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
| | - Lei Zhang
- Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, People's Republic of China
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Zhang Z, Jia JP, Zhang YJ, Liu G, Zhou F, Zhang BC. Long Noncoding RNA ADAMTS9-AS2 Inhibits the Proliferation, Migration, and Invasion in Bladder Tumor Cells. Onco Targets Ther 2020; 13:7089-7100. [PMID: 32801743 PMCID: PMC7382762 DOI: 10.2147/ott.s245826] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/29/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Bladder tumor is the fifth most prevalent tumor in men, yet its pathogenesis remains to be fully identified. Albeit a host of long noncoding RNAs (lncRNA) are emerging as new players involved in bladder tumor, the functions of many lncRNAs are still enigmatic. Reports on the deluge of studies on lncRNA ADAMTS9-AS2 have been convincingly associated with various tumors, but without mention of its roles in bladder tumor. Therefore, the roles of ADAMTS9-AS2 in bladder tumor cells were explored in our study. MATERIALS AND METHODS Quantitative real-time PCR assays and bioinformatic tools were applied in bladder tumor cells to identify the ADAMTS9-AS2 and ADAMTS9 expression. Western blot assays were performed to obtain the protein levels of bladder tumor related key molecules. CCK8, clonogenic assay, scratch wound healing, and transwell assays were separately applied to identify the functional roles of ADAMTS9-AS2 on proliferation, migration, and invasion in bladder tumor cells. RESULTS First, ADAMTS9-AS2 downregulation in bladder tumor cells was identified. Overexpression and knockdown experiments showed that ADAMTS9-AS2 expression was positively related to ADAMTS9, which is in accordance with the results from GEO database. Second, ADAMTS9-AS2 contributed to the inhibition of proliferation, migration, and invasion in bladder tumor cells. Third, ADAMTS9-AS2 was linked with PI3K/AKT/mTOR pathway related-molecules, several key autophagy, and apoptotic proteins. CONCLUSION Conjointly, our findings suggested that ADAMTS9-AS2 might function as a tumor suppressor to restrain the proliferation, migration, and invasion in bladder tumor cells. The potential mechanism of ADAMTS9-AS2 related to PI3K/AKT/mTOR signal pathway was further identified. Of note, we found that ADAMTS9-AS2 has a significant effect on several key autophagy and apoptotic proteins. Therefore, these observations will provide supportive evidence to ADAMTS9-AS2 as a potential biomarker in patients with bladder tumor.
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Affiliation(s)
- Zhan Zhang
- Department of Rehabilitation Medicine, Changhai Hospital, Second Military Medical University, Shanghai200433, People’s Republic of China
| | - Jin-Peng Jia
- Department of Orthopaedics, General Hospital of Chinese People’s Liberation Army, Beijing100853, People’s Republic of China
| | - Yin-Jiang Zhang
- School of Pharmacy, Minzu University of China, Beijing100081, People’s Republic of China
| | - Gang Liu
- Department of Urology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi435000, Hubei, People’s Republic of China
- Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University, Huangshi435000, Hubei, People’s Republic of China
| | - Fan Zhou
- Department of Urology, Wuhan Fourth Hospital, Pu’ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan430033, Hubei, People’s Republic of China
| | - Bi-Cheng Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan430060, Hubei, People’s Republic of China
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