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Anakha J, Prasad YR, Pande AH. Endostatin in disease modulation: From cancer to beyond. Vascul Pharmacol 2025; 158:107459. [PMID: 39708990 DOI: 10.1016/j.vph.2024.107459] [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: 10/09/2024] [Revised: 12/04/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Angiogenesis plays a pivotal role in various pathological conditions, making it a key target in therapeutic development. Anti-angiogenic therapies are gaining traction for their potential in treating a range of angiogenesis-dependent diseases. Among these, endogenous angiogenesis inhibitors, particularly endostatin, have garnered significant attention for their therapeutic potential. While extensively studied for its anti-angiogenic effects in cancer, endostatin also exhibits anti-atherosclerotic and anti-fibrotic properties, broadening its therapeutic scope. Despite the successful clinical use of recombinant human endostatin in China for nearly two decades, its broader therapeutic potential remains underexplored. Thus, this review delves into the multifaceted applications of endostatin, examining its role in ocular diseases, inflammation, reproductive disorders, and tumor angiogenesis. Furthermore, it provides a comprehensive overview of its emerging roles beyond angiogenesis, particularly in the context of atherosclerosis and fibroproliferative conditions.
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Affiliation(s)
- J Anakha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India.
| | - Yenisetti Rajendra Prasad
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India
| | - Abhay H Pande
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India.
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2
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Kumarapperuma H, Wang R, Little PJ, Kamato D. Mechanistic insight: Linking cardiovascular complications of inflammatory bowel disease. Trends Cardiovasc Med 2024; 34:203-211. [PMID: 36702388 DOI: 10.1016/j.tcm.2023.01.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/25/2023]
Abstract
Cardiovascular diseases (CVD) are the leading cause of mortality worldwide despite an aggressive reduction of traditional cardiovascular risk factors. Underlying inflammatory conditions such as inflammatory bowel disease (IBD) increase the risk of developing CVD. A broad understanding of the underlying pathophysiological processes between IBD and CVD is required to treat and prevent cardiovascular events in patients with IBD. This review highlights the commonality between IBD and CVD, including dysregulated immune response, genetics, environmental risk factors, altered gut microbiome, stress, endothelial dysfunction and abnormalities, to shed light on an essential area of modern medicine.
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Affiliation(s)
- Hirushi Kumarapperuma
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
| | - Ran Wang
- Mater Research Institute, The University of Queensland, Translational Research Institute, Queensland 4102, Australia
| | - Peter J Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia; School of Environment and Science, Griffith University, Nathan, Queensland 4111, Australia.
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3
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Liang Y, Hao Y, Xiong Y, Zhong M, Jain D. MYC overexpression in inflammatory bowel disease-associated conventional dysplasia and association of subsequent low-grade dysplasia in follow-up biopsies. Pathol Res Pract 2023; 248:154642. [PMID: 37379711 DOI: 10.1016/j.prp.2023.154642] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 06/30/2023]
Abstract
OBJECTIVE Diagnosis of inflammatory bowel disease (IBD)-associated dysplastic lesions can be challenging. This study aims to evaluate MYC immunohistochemistry (IHC) as a potential biomarker for IBD-associated dysplasia and compare its effectiveness with p53 IHC. METHODS The study cohort included resections from 12 IBD patients with carcinoma and concurrent conventional low-grade dysplasia (LGD), as well as biopsies from 21 patients with visible conventional LGD, which were followed up for 2 years with subsequent endoscopic examination. MYC and p53 IHC and MYC-FISH analysis were performed. RESULTS Sensitivity for LGD detection was 67% (8/12) and 50% (6/12) for MYC and p53, respectively, but the difference was not statistically significant (p = 0.2207). MYC and p53 overexpression were not always mutually exclusive, nor were they always present simultaneously. Patients who presented dysplasia in subsequent biopsies (7/21) were found to be more likely present with multiple LGD polyps and MYC-overexpressed LGD in the initial biopsies, compared to those without subsequent dysplasia (p < 0.05). These dysplastic lesions were commonly associated with chronic colitis (p = 0.0614). The distribution of LGD sites did not show a significant difference between patients with and without subsequent LGD. In MYC overexpressed cases, homogeneously strong nuclear expression was not identified in all dysplastic epithelial cells, and no MYC amplification was found in these cases by FISH. CONCLUSION MYC IHC can complement p53 IHC as an adjunct biomarker for diagnosing IBD-associated conventional LGD and can be used for the prediction of subsequent LGD in the follow-up biopsies combined with endoscopic features.
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Affiliation(s)
- Yuanxin Liang
- Department of Pathology, Yale University, New Haven, CT, USA.
| | - Yansheng Hao
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - Yiqin Xiong
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | - Minghao Zhong
- Department of Pathology, Yale University, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale University, New Haven, CT, USA
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Britzen-Laurent N, Weidinger C, Stürzl M. Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases. Int J Mol Sci 2023; 24:ijms24065517. [PMID: 36982601 PMCID: PMC10051397 DOI: 10.3390/ijms24065517] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD.
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Affiliation(s)
- Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Correspondence:
| | - Carl Weidinger
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Michael Stürzl
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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5
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Cao Q, Mertens RT, Sivanathan KN, Cai X, Xiao P. Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine. J Leukoc Biol 2022; 112:313-331. [PMID: 35593111 PMCID: PMC9543232 DOI: 10.1002/jlb.3ru0322-176r] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/06/2022] Open
Abstract
The intestinal tract is a complex ecosystem where numerous cell types of epithelial, immune, neuronal, and endothelial origin coexist in an intertwined, highly organized manner. The functional equilibrium of the intestine relies heavily on the proper crosstalk and cooperation among each cell population. Furthermore, macrophages are versatile, innate immune cells that participate widely in the modulation of inflammation and tissue remodeling. Emerging evidence suggest that macrophages are central in orchestrating tissue homeostasis. Herein, we describe how macrophages interact with epithelial cells, neurons, and other types of mesenchymal cells under the context of intestinal inflammation, followed by the therapeutic implications of cellular crosstalk pertaining to the treatment of inflammatory bowel disease.
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Affiliation(s)
- Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Randall Tyler Mertens
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kisha Nandini Sivanathan
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xuechun Cai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.,The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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6
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Dickson K, Malitan H, Lehmann C. Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation. BIOLOGY 2020; 9:E418. [PMID: 33255906 PMCID: PMC7760140 DOI: 10.3390/biology9120418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022]
Abstract
Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.
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Affiliation(s)
- Kayle Dickson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Hajer Malitan
- Department of Anesthesia, Pain and Perioperative Management, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Christian Lehmann
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Anesthesia, Pain and Perioperative Management, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
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Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis. Biochem Pharmacol 2019; 166:264-273. [PMID: 31170375 DOI: 10.1016/j.bcp.2019.05.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 05/30/2019] [Indexed: 12/14/2022]
Abstract
Semaphorin 3E (SEMA3E) has emerged as an axon-guiding molecule that regulates various biological processes including the immune responses and apoptosis. However, its role in the pathophysiology of colitis remains elusive. We investigated the role of SEMA3E in intestinal epithelial cells (IECs) activation, using biopsies from patients with active ulcerative colitis (UC), a mouse model of UC, and an in-vitro model of intestinal mucosal healing. In this study, we confirmed that the mRNA level of SEMA3E is reduced significantly in patients with UC and demonstrated a negative linear association between SEMA3E mRNA and p53-associated genes. In mice, genetic deletion of Sema3e resulted in an increase onset and severity of colitis, p53-associated genes, apoptosis, and IL-1beta production. Recombinant SEMA3E treatment protected against colitis and decreased these effects. Furthermore, in stimulated epithelial cells, recombinant SEMA3E treatment enhanced wound healing, resistance to oxidative stress and decreased apoptosis and p53-associated genes. Together, these findings identify SEMA3E as a novel regulator in intestinal inflammation that regulates IECs apoptosis and suggest a potential novel approach to treat UC.
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8
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Gu L, Ge Z, Wang Y, Shen M, Zhao P. Activating transcription factor 3 promotes intestinal epithelial cell apoptosis in Crohn’s disease. Pathol Res Pract 2018; 214:862-870. [DOI: 10.1016/j.prp.2018.04.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 04/06/2018] [Accepted: 04/17/2018] [Indexed: 12/15/2022]
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CDK8 regulates the angiogenesis of pancreatic cancer cells in part via the CDK8-β-catenin-KLF2 signal axis. Exp Cell Res 2018; 369:304-315. [PMID: 29856990 DOI: 10.1016/j.yexcr.2018.05.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 05/18/2018] [Accepted: 05/28/2018] [Indexed: 11/20/2022]
Abstract
BACKGROUND CDK8 is associated with the transcriptional Mediator complex and has been shown to regulate several transcription factors implicated in cancer. As a pancreatic cancer oncogene, the role of CDK8 in cancer angiogenesis remains unclear. Here, we investigated the contribution of CDK8 in pancreatic cancer angiogenesis and examined the underlying molecular mechanisms. METHODS CDK8 expression was evaluated via immunohistochemistry, western blotting, and qRT-PCR in relation to the clinicopathological characteristics of pancreatic cancer patients. The effects of silencing or overexpressing CDK8 on cancer angiogenesis were assessed in vitro by western blotting assays in pancreatic cancer cell lines and in vivo with nude mice xenograft models. RESULTS Compared with adjacent normal tissues, pancreatic cancer tissues showed upregulation of CDK8 expression, which was inversely correlated with T grade, liver metastasis, size, lymph node metastasis and poor survival. CDK8 overexpression promoted angiogenesis in pancreatic cancer via activation of the CDK8-β-catenin-KLF2 signaling axis, as demonstrated by the upregulation and downregulation of signals representing the rate-limiting steps in angiogenesis. Silencing CDK8 inhibited angiogenesis in pancreatic cancer in vitro. Additionally, these results were confirmed in nude mice xenograft models in vivo. CONCLUSIONS CDK8 promotes angiogenesis in pancreatic cancer via activation of the CDK8-β-catenin-KLF2 signaling axis, thus providing valid targets for the treatment of pancreatic cancer.
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10
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Gu L, Zhao J, Zhang S, Xu W, Ni R, Liu X. Runt-related transcription factor 2 (RUNX2) inhibits apoptosis of intestinal epithelial cells in Crohn's disease. Pathol Res Pract 2017; 214:245-252. [PMID: 29129496 DOI: 10.1016/j.prp.2017.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 10/26/2017] [Accepted: 11/03/2017] [Indexed: 01/04/2023]
Abstract
Apoptosis in intestinal epithelial cells (IECs) prevents the development of Crohn's disease (CD), a type of inflammatory bowel disease (IBD). Runt-related transcription factor 2 (Runx2) inhibits apoptosis in osteosarcoma-derived U2OS cells via down-regulating the transcriptional activity of p53. However, the expression and function of Runx2 in CD remain unclear. In this study, Runx2 protein levels were decreased in the intestinal epithelial cells (IECs) of CD patients and in a mouse 2, 4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model; in contrast, the expression levels of p53 and Bax, a p53-target gene, were increased. In a TNF-α-treated HT29 cell colitis model, the down-regulation of Runx2 was accompanied by the up-regulation of apoptotic markers, including cleaved caspase-3 and Bax. Furthermore, Runx2 overexpression effectively decreased TNF-α-induced Bax and cleaved caspase-3 expression levels. In conclusion, our data indicated that Runx2 might protect IECs from apoptosis in CD, thus revealing a novel molecular target for treating CD.
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Affiliation(s)
- Liugen Gu
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Juan Zhao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Shiqing Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Weisong Xu
- Department of Gastroenterology, The Secondary People's Hospital of Nantong, Nantong, 226001, Jiangsu, China
| | - Runzhou Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Xiaojuan Liu
- Department of Pathogen Biology, Nantong University, Nantong, 226001, Jiangsu, China.
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11
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Lu X, Yu Y, Tan S. p53 expression in patients with ulcerative colitis - associated with dysplasia and carcinoma: a systematic meta-analysis. BMC Gastroenterol 2017; 17:111. [PMID: 29070013 PMCID: PMC5655860 DOI: 10.1186/s12876-017-0665-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 10/03/2017] [Indexed: 02/08/2023] Open
Abstract
Background Tumor suppressor gene p53 expression has been reported in patients with ulcerative colitis (UC). However, the correlation between p53 expression and UC remains controversial. The aim of this meta-analysis was to investigate the association between p53 expression and different pathological types of UC. Methods Publications were searched in the PubMed, Embase, EBSCO, Wangfang, and CNKI databases. The overall odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were summarized in this study. Results Final 19 papers were identified in this meta-analysis, including 1068 patients with UC and 130 normal tissue samples. Immunohistochemical p53 expression was significantly higher in UC without dysplasia and carcinoma (UC group) compared to normal tissue samples (OR = 3.14, P = 0.001), higher in UC with dysplasia than in UC group (OR = 10.76, P < 0.001), and higher in UC with colorectal cancer (CRC) than in UC with dysplasia (OR = 1.69, P = 0.035). Subgroup analysis of ethnicity (UC group vs. normal tissues) showed that p53 expression was correlated with UC in Asians, but not in Caucasians. When UC with dysplasia was compared to UC group, p53 expression was linked to UC with dysplasia among both Asians and Caucasians. When UC-CRC was compared to UC with dysplasia, p53 expression was not associated with UC-CRC in both Caucasians and Asians. Conclusions p53 expression was closely associated with UC-CRC development. p53 expression showed different ethnic characteristics among different pathological types of UC. Electronic supplementary material The online version of this article (10.1186/s12876-017-0665-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaohong Lu
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.
| | - Yuanjie Yu
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Shiyun Tan
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
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Pileczki V, Pop L, Braicu C, Budisan L, Bolba Morar G, Del C Monroig-Bosque P, Sandulescu RV, Berindan-Neagoe I. Double gene siRNA knockdown of mutant p53 and TNF induces apoptosis in triple-negative breast cancer cells. Onco Targets Ther 2016; 9:6921-6933. [PMID: 27956838 PMCID: PMC5113913 DOI: 10.2147/ott.s110719] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Apoptosis is the major downregulated pathway in cancer. Simultaneous inhibition using specific small interfering RNA (siRNA) of two key player genes, p53 and TNF, is an interesting and feasible strategy when it comes to investigating various molecular pathways and biological processes in triple-negative breast cancer (TNBC), which is one of the most aggressive and therapeutically unresponsive forms of breast cancers. Our present research focuses on evaluating the impact of double p53-siRNA and TNF-siRNA knockdown at a cellular level, and also evaluating cell proliferation, apoptosis, induction of autophagy, and gene expression by using reverse transcription polymerase chain reaction array approaches. Simultaneous inhibition of p53 and TNF in Hs578T TNBC human cell line revealed a panel of up- and downregulated genes involved in apoptosis. Furthermore, the effects of double gene knockdown were validated in a second TNBC cell line, MDA-MB-231, by using reverse transcription polymerase chain reaction TaqMan assay. All our findings help in understanding the functional mechanisms of extrinsic apoptosis, cell signaling pathways, and the mechanisms involved in tumor cell survival, growth, and death in TNBC.
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Affiliation(s)
- Valentina Pileczki
- The Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; Department of Analytical Chemistry, Faculty of Pharmacy, "Iuliu Hatieganu" University of Medicine and Pharmacy
| | - Laura Pop
- The Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cornelia Braicu
- The Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Livia Budisan
- The Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Gabriela Bolba Morar
- Department of Senology, the Oncology Institute "Prof Dr Ion Chiricuta", Cluj-Napoca, Romania
| | | | - Robert V Sandulescu
- Department of Analytical Chemistry, Faculty of Pharmacy, "Iuliu Hatieganu" University of Medicine and Pharmacy
| | - Ioana Berindan-Neagoe
- The Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; MedFuture Research Center for Advanced Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; Department of Functional Genomics and Experimental Pathology, the Oncology Institute "Prof Dr Ion Chiricuta", Cluj-Napoca, Romania
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Angiogenesis in Inflammatory Bowel Disease. Int J Inflam 2015; 2015:970890. [PMID: 26839731 PMCID: PMC4709626 DOI: 10.1155/2015/970890] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/07/2015] [Accepted: 12/08/2015] [Indexed: 12/24/2022] Open
Abstract
Angiogenesis is an important component of pathogenesis of inflammatory bowel disease (IBD). Chronic inflammation and angiogenesis are two closely related processes. Chronic intestinal inflammation is dependent on angiogenesis and this angiogenesis is modulated by immune system in IBD. Angiogenesis is a very complex process which includes multiple cell types, growth factors, cytokines, adhesion molecules, and signal transduction. Lymphangiogenesis is a new research area in the pathogenesis of IBD. While angiogenesis supports inflammation via leukocyte migration, carrying oxygen and nutrients, on the other hand, it has a major role in wound healing. Angiogenic molecules look like perfect targets for the treatment of IBD, but they have risk for serious side effects because of their nature.
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Nylund K, Jirik R, Mezl M, Leh S, Hausken T, Pfeffer F, Ødegaard S, Taxt T, Gilja OH. Quantitative contrast-enhanced ultrasound comparison between inflammatory and fibrotic lesions in patients with Crohn's disease. ULTRASOUND IN MEDICINE & BIOLOGY 2013; 39:1197-1206. [PMID: 23643057 DOI: 10.1016/j.ultrasmedbio.2013.01.020] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Revised: 01/25/2013] [Accepted: 01/27/2013] [Indexed: 06/02/2023]
Abstract
The aim of this study was to determine whether there are differences in absolute blood flow between patients with Crohn's disease with inflammation or fibrosis using contrast-enhanced ultrasound. Eighteen patients with fibrotic disease and 19 patients with inflammation were examined. Video sequences of contrast data were analyzed using a pharmacokinetic model to extract the arterial input and tissue residue functions with a custom software, enabling calculation of the absolute values for mean transit time, blood volume and flow. Feasibility of the examination was 89%. The fibrosis group had lower blood volume (0.9 vs. 3.4 mL per 100 mL tissue; p = 0.001) and flow (22.6 vs. 45.3 mL/min per 100 mL tissue; p = 0.003) compared with the inflammation group. There was no significant difference in mean transit time (3.9 vs. 5.5 s). In conclusion, absolute perfusion measurement in the gastrointestinal wall using contrast-enhanced ultrasound is feasible. There seems to be reduced blood volume and blood flow in patients with fibrotic disease.
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Affiliation(s)
- Kim Nylund
- Institute of Medicine, University of Bergen, Bergen, Norway.
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15
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Wohl P, Hucl T, Drastich P, Kamenar D, Spicak J, Honsova E, Sticova E, Lodererova A, Matous J, Hill M, Wohl P, Kucera M. Epithelial markers of colorectal carcinogenesis in ulcerative colitis and primary sclerosing cholangitis. World J Gastroenterol 2013; 19:2234-2241. [PMID: 23599650 PMCID: PMC3627888 DOI: 10.3748/wjg.v19.i14.2234] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 01/09/2013] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the expression of epithelial markers of colorectal carcinogenesis in patients with long-term ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) before and after transplantation.
METHODS: Eight patients with UC and PSC prior to liver transplantation (PSC-UC), 22 patients with UC after liver transplantation for PSC (OLT), 9 patients with active ulcerative colitis without PSC (UCA), 7 patients with UC in remission (UCR) and 10 controls (N) underwent colonoscopy with multiple biopsies. Specimens were analysed histologically and semi-quantitatively immunohistochemically for p53, Bcl-2 and cyclooxygenase-2 (COX-2) markers. Statistical analysis was performed by Kruskal-Wallis and Fisher’s exact tests.
RESULTS: PSC-UC had a statistically significantly higher expression of p53 in the nondysplastic mucosa as compared to OLT, UCA, UCR and N (P < 0.05). We also found a statistically significant positive correlation between the incidence of PSC and the expression of p53 (P < 0.001). UCA had a higher p53 expression as compared to UCR. OLT had a significantly lower expression of p53 as compared with PSC-UC (P < 0.001). Bcl-2 had a significant higher bcl-2 expression as compared with controls. No difference in COX-2 expression between PSC-UC, UCR and UCA was found. UCA had higher COX-2 expression as compared to UCR. We also found a statistically significant positive correlation between the expression of COX-2 and p53. Patients after liver transplantation for PSC had a statistically significantly lower expression of the p53 compared with PSC-UC (P < 0.001). PSC-UC had the same inflammatory endoscopic activity as OLT and UCR when evaluated with the Mayo score.
CONCLUSION: Our study shows that the nondysplatic mucosa of UC patients with PSC is characterised by a higher expression of the tumour suppressor gene p53, suggesting a higher susceptibility of cancer. This p53 overexpression correlates with the presence of PSC whilst it is not present in patients with UC after liver transplantation for PSC.
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Goretsky T, Dirisina R, Sinh P, Mittal N, Managlia E, Williams DB, Posca D, Ryu H, Katzman RB, Barrett TA. p53 mediates TNF-induced epithelial cell apoptosis in IBD. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1306-15. [PMID: 22863952 DOI: 10.1016/j.ajpath.2012.06.016] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Revised: 06/07/2012] [Accepted: 06/27/2012] [Indexed: 12/12/2022]
Abstract
Chronic ulcerative colitis (CUC) is characterized by increased intestinal epithelial cell (IEC) apoptosis associated with elevated tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), and p53. We previously showed that p53 is increased in crypt IECs in human colitis and is needed for IEC apoptosis in chronic dextran sulfate sodium-colitis. Herein, we examined the roles of TNF and iNOS in regulating p53-induced IEC apoptosis in CUC. The IEC TUNEL staining, caspases 3, 8, and 9, and p53 protein levels, induced by anti-CD3 monoclonal antibody (mAb) activation of T cells, were markedly reduced in TNF receptor 1 and 2 gene knockout mice. Induction of IEC apoptosis correlated with increased p53, which was attenuated in iNOS(-/-) mice. IEC p53 levels and apoptosis were reduced in IL-10(-/-) colitic mice treated with neutralizing TNF mAb and the iNOS inhibitor, aminoguanidine, further suggesting that TNF and iNOS are upstream of p53 during colitis-induced IEC apoptosis. IEC apoptosis and p53 levels were assessed in control versus untreated or anti-TNF-treated CUC patients with equivalent levels of inflammation. Data indicated that IEC apoptosis and p53 levels were clearly higher in untreated CUC but markedly reduced in patients treated with anti-TNF mAb. Therefore, TNF-induced iNOS activates a p53-dependent pathway of IEC apoptosis in CUC. The inhibition of IEC apoptosis may be an important mechanism for mucosal healing in anti-TNF-treated CUC patients.
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Affiliation(s)
- Tatiana Goretsky
- Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
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A limited role of p53 on the ability of a Hexane fraction of American ginseng to suppress mouse colitis. J Biomed Biotechnol 2012; 2012:785739. [PMID: 22899889 PMCID: PMC3414200 DOI: 10.1155/2012/785739] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 05/25/2012] [Accepted: 06/11/2012] [Indexed: 01/26/2023] Open
Abstract
Ulcerative colitis (UC) is debilitating and carries a high colon cancer risk. Apoptosis of inflammatory cells is a key mechanism regulating UC. We have recently shown that American ginseng (AG), and to a greater extent, a Hexane fraction of AG (HAG) can cause apoptosis and suppress mouse colitis through a p53-mediated mechanism. Here, we tested the hypothesis that HAG suppresses colitis through a p53 mechanism. We found only a limited impact of p53 in the ability of HAG to induce inflammatory cell apoptosis and suppress mouse colitis in vitro and in vivo. Finally, we asked whether HAG could cause cell cycle arrest of HCT116 colon cancer cells in vitro. Interestingly, HAG caused a G1 arrest of such cells independent of p53 status. Findings are significant because HAG suppresses colitis and associated colon cancer, and mutation in p53 is observed in most colitis-driven colon cancers. Therefore, HAG might be very effective in targeting the inflammatory cells and cancer cells since it induces apoptosis of inflammatory cells and cell cycle arrest in both p53−/− and WT p53 colon cancer cells.
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Paolillo R, Romano Carratelli C, Sorrentino S, Mazzola N, Mita L, Rizzo A. Expression of IL-23, VEGF and TLR2/TLR4 on mononuclear cells after exposure to Pseudomonas aeruginosa. Int J Immunopathol Pharmacol 2012; 24:961-73. [PMID: 22230402 DOI: 10.1177/039463201102400414] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Pseudomonas aeruginosa is a Gram-negative, aerobic bacillus causing infections of the respiratory and other organ systems in susceptible hosts. Although it does not cause pulmonary infections in immunocompetent individuals, P. aeruginosa causes chronic lung infection in individuals with cystic fibrosis and nosocomial pneumonia resulting in significant morbidity and mortality. Exogenous administration of an important P. aeruginosa virulence factor, lipase, present in P. aeruginosa culture supernatant, induces potent mononuclear cell activation leading to the production of numerous proinflammatory cytokines. In particular, P. aeruginosa culture supernatant stimulated increased proliferation of THP-1 cells and monocytes (MN). The addition of culture supernatant to THP-1 cells and MN also induced Interleukin (IL)-23 and vascular endothelial growth factor (VEGF) release in a time-dependent manner. To investigate whether any compounds present in the supernatant lipase contributed to releasing IL-23 and VEGF, the culture supernatant from P. aeruginosa containing lipase was treated with hexadecylsulfonylfluoride (AMSF). The AMSF-treated culture supernatant (CS) did not show any induction on the IL-23 and VEGF release compared to the cells treated with CS without AMSF. We also showed that Toll-like receptors (TLR)2/TLR4 are expressed in THP-1 cells and MN treated with P. aeruginosa CS in a time-dependent fashion. Flow cytometry analysis revealed a higher TLR4 and a lower TLR2 expression at 48 and 72 h of treatment. The treatment of cells with TLR4 neutralizing antibody, and to a lesser extent with TLR2 neutralizing antibody, resulted in a decrease in P. aeruginosa CS-induced IL-23 and VEGF production.
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Affiliation(s)
- R Paolillo
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
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19
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Alkim C, Sakiz D, Alkim H, Livaoglu A, Kendir T, Demirsoy H, Erdem L, Akbayir N, Sokmen M. Thrombospondin-1 and VEGF in inflammatory bowel disease. Libyan J Med 2012; 7:LJM-7-8942. [PMID: 22299021 PMCID: PMC3269884 DOI: 10.3402/ljm.v7i0.8942] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 12/20/2011] [Accepted: 12/29/2011] [Indexed: 12/17/2022] Open
Abstract
Background and aim Angiogenesis is an important process in the pathogenesis of chronic inflammation. We aimed to study the angiogeneic balance in inflammatory bowel disease (IBD) by evaluating the expression of vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) on colonic epithelial cells, together with the expression of inducible nitric oxide synthase (iNOS). Methods Twenty-one ulcerative colitis (UC), 14 Crohn's disease (CD), 11 colorectal cancer patients, and 11 healthy controls colonic biopsy samples were evaluated immunohistochemically. Results The expressions of TSP-1, VEGF, and iNOS in UC and CD groups were higher than expression in healthy control group, all with statistical significance. However, in colorectal cancer group, VEGF and iNOS expressions were increased importantly, but TSP-1 expression was not statistically different from healthy control group's expression. Both TSP-1 and VEGF expressions were correlated with iNOS expression distinctly but did not correlate with each other. Conclusions Both pro-angiogeneic VEGF and antiangiogeneic TSP-1 expressions were found increased in our IBD groups, but in colorectal cancer group, only VEGF expression was increased. TSP-1 increases in IBD patients as a response to inflammatory condition, but this increase was not enough to suppress pathologic angiogenesis and inflammation in IBD.
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Affiliation(s)
- Canan Alkim
- Department of Gastroenterology, Sisli Etfal Training and Research Hospital, Istanbul, Turkey
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Elevated Serum Level of IL-23 Correlates with Expression of VEGF in Human Colorectal Carcinoma. Arch Med Res 2010; 41:182-9. [DOI: 10.1016/j.arcmed.2010.02.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Accepted: 01/29/2010] [Indexed: 12/13/2022]
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Tumor necrosis factor alpha induces p53 up-regulated modulator of apoptosis expression in colorectal cancer cell lines. Dis Colon Rectum 2010; 53:257-63. [PMID: 20173470 DOI: 10.1007/dcr.0b013e3181c522c7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Inflammatory bowel disease (IBD)-associated colorectal carcinogenesis involves dysregulation of multiple cellular pathways, including p53 signaling and cytokine action. The purpose of the current study was to evaluate the effects of tumor necrosis factor alpha (TNF-alpha) on p53 and p53 up-regulated modulator of apoptosis (PUMA), a downstream effector of p53 in the apoptotic pathway in colorectal cancer cells. METHODS The cell lines HT29 (which express mutant p53) and HCT116 (which express wild-type p53) were treated with TNF-alpha (0, 50, 100, or 500 ng/mL) for 1, 12, 24, or 48 hours. Protein expression and subcellular localization of p53 and PUMA were determined by immunoblot and immunofluorescence. Changes in p53 and PUMA mRNA expression were determined by quantitative real time polymerase chain reaction. RESULTS Nuclear p53 expression was increased in TNF-alpha-treated HT29 cells; in contrast, expression was decreased or minimally changed in TNF-alpha-treated HCT116 cells, as determined by immunoblot and immunofluorescence. At 24 hours, p53 mRNA transcript levels were minimally increased in HT29 cells, whereas PUMA increased 34-fold. CONCLUSIONS TNF-alpha increased nuclear p53 expression in HT29 cells, which express p53 mutation, but not in HCT116 cells, which are wild type for p53. In addition, TNF-alpha markedly up-regulated PUMA mRNA levels in HT29 cells. Our findings suggest that TNF-alpha may be a factor in carcinogenesis in IBD in cells carrying a p53 mutation.
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Jin Y, Hofseth AB, Cui X, Windust AJ, Poudyal D, Chumanevich AA, Matesic LE, Singh NP, Nagarkatti M, Nagarkatti PS, Hofseth LJ. American ginseng suppresses colitis through p53-mediated apoptosis of inflammatory cells. Cancer Prev Res (Phila) 2010; 3:339-47. [PMID: 20179294 DOI: 10.1158/1940-6207.capr-09-0116] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ulcerative colitis is a dynamic, chronic inflammatory condition associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism regulating ulcerative colitis. American ginseng (AG) is a putative antioxidant that can suppress hyperactive immune cells. We have recently shown that AG can prevent and treat mouse colitis. Because p53 levels are elevated in inflammatory cells in both mouse and human colitis, we tested the hypothesis that AG protects from colitis by driving inflammatory cell apoptosis through a p53 mechanism. We used isogenic p53(+/+) and p53(-/-) inflammatory cell lines as well as primary CD4(+)/CD25(-) effector T cells from p53(+/+) and p53(-/-) mice to show that AG drives apoptosis in a p53-dependent manner. Moreover, we used a dextran sulfate sodium (DSS) model of colitis in C57BL/6 p53(+/+) and p53(-/-) mice to test whether the protective effect of AG against colitis is p53 dependent. Data indicate that AG induces apoptosis in p53(+/+) but not in isogenic p53(-/-) cells in vitro. In vivo, C57BL/6 p53(+/+) mice are responsive to the protective effects of AG against DSS-induced colitis, whereas AG fails to protect from colitis in p53(-/-) mice. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling of inflammatory cells within the colonic mesenteric lymph nodes is elevated in p53(+/+) mice consuming DSS + AG but not in p53(-/-) mice consuming DSS + AG. Results are consistent with our in vitro data and with the hypothesis that AG drives inflammatory cell apoptosis in vivo, providing a mechanism by which AG protects from colitis in this DSS mouse model.
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Affiliation(s)
- Yu Jin
- Department of Biomedical and Pharmaceutical Sciences, South Carolina College of Pharmacy, 770 Sumter Street, Coker Life Sciences, University of South Carolina, Columbia, SC 29208, USA
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