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Pasha A, Kumar K, Heena SK, Arnold Emerson I, Pawar SC. Inhibition of NF-kB and COX-2 by andrographolide regulates the progression of cervical cancer by promoting PTEN expression and suppressing PI3K/AKT signalling pathway. Sci Rep 2024; 14:12020. [PMID: 38797813 PMCID: PMC11128455 DOI: 10.1038/s41598-024-57304-7] [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: 11/18/2023] [Accepted: 03/16/2024] [Indexed: 05/29/2024] Open
Abstract
In the face of recent advances in Cervical cancer (CC) treatment, therapeutic and surgical procedures for CC management are still inadequate. In the current study for the first time Andrographolide (Andro) has been explored for its multitarget therapeutic efficacy on NF-kB, COX-2, and PI3K/AKT expressions together in CC. The expression levels of NF-kB, COX-2, PI3K and PTEN in the CC patient samples, both at mRNA and protein levels have shown significant association with poor survival and increased tumor aggressiveness. The binding efficacy of Andro was investigated using molecular docking and molecular dynamic simulations, and the protein and ligand complex for NF-kB and COX-2 has shown high binding energy. Andro displayed cytotoxicity by impeding the in-vitro proliferation of CC cells. Andro significantly supressed the NF-kB, COX-2, and PI3K expression and enhanced the expression levels of PTEN at protein levels in-vitro. Andro induced apoptosis in a dose dependent manner and significantly inhibited the migration and invasion of CC cells. Andro exhibited similar activity in-vivo and suppressed the CC tumor growth in xenograft C57BL/6 mice model. The anti-tumor activity of Andro, both in-vitro and in-vivo has shown considerable downregulation of NF-kB and COX-2 and induced apoptosis through impeding the PI3K/AKT signalling pathway. These findings from the above study projects, administration of Andro as an effective alternate safe compound to curtail and impede cervical cancer progression.
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Affiliation(s)
- Akbar Pasha
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, Telangana, 500007, India
| | - Kiran Kumar
- Department of Bioinformatics, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - S K Heena
- Department of Pathology, Osmania Medical College, Hyderabad, Telangana, 500095, India
| | - I Arnold Emerson
- Department of Bioinformatics, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Smita C Pawar
- Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, Telangana, 500007, India.
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Zhang Y, Tang N, Zhou H, Zhu Y. The role of microbial metabolites in endocrine tumorigenesis: From the mechanistic insights to potential therapeutic biomarkers. Biomed Pharmacother 2024; 172:116218. [PMID: 38308969 DOI: 10.1016/j.biopha.2024.116218] [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: 09/26/2023] [Revised: 12/28/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
Microbial metabolites have been indicated to communicate with the host's endocrine system, regulating hormone production, immune-endocrine communications, and interactions along the gut-brain axis, eventually affecting the occurrence of endocrine cancer. Furthermore, microbiota metabolites such as short-chain fatty acids (SCFAs) have been found to affect the tumor microenvironment and boost immunity against tumors. SCFAs, including butyrate and acetate, have been demonstrated to exert anti-proliferative and anti-protective activity on pancreatic cancer cells. The employing of microbial metabolic products in conjunction with radiation and chemotherapy has shown promising outcomes in terms of reducing treatment side effects and boosting effectiveness. Certain metabolites, such as valerate and butyrate, have been made known to improve the efficiency of CAR T-cell treatment, whilst others, such as indole-derived tryptophan metabolites, have been shown to inhibit tumor immunity. This review explores the intricate interplay between microbial metabolites and endocrine tumorigenesis, spanning mechanistic insights to the discovery of potential therapeutic biomarkers.
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Affiliation(s)
- Yiyi Zhang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Nie Tang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Hui Zhou
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
| | - Ying Zhu
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
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Di Ciaula A, Bonfrate L, Khalil M, Portincasa P. The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease. Intern Emerg Med 2023; 18:2181-2197. [PMID: 37515676 PMCID: PMC10635993 DOI: 10.1007/s11739-023-03343-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 06/08/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy.
| | - Mohamad Khalil
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
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Guo J, Pan Y, Chen J, Jin P, Tang S, Wang H, Su H, Wang Q, Chen C, Xiong F, Liu K, Li Y, Su M, Tang T, He Y, Sheng J. Serum metabolite signatures in normal individuals and patients with colorectal adenoma or colorectal cancer using UPLC-MS/MS method. J Proteomics 2023; 270:104741. [PMID: 36174955 DOI: 10.1016/j.jprot.2022.104741] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/19/2022] [Accepted: 09/06/2022] [Indexed: 02/01/2023]
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenoma to adenocarcinoma, which provides a long screening window for clinical detection. However, early diagnosis of sporadic colorectal adenoma (CRA) and CRC using serum metabolic screening remains unclear. The purpose of this study was to identify some promising signatures for distinguishing the different pathological metabolites of colorectal mucosal malignant transformation. A total of 238 endogenous metabolites were elected. We found that CRA and CRC patients had 72 and 73 different metabolites compared with healthy controls, respectively. There were 20 different metabolites between CRA and CRC patients. The potential metabolites of tumor growth (including patients with CRA and CRC) were found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, Sarcosine, TXB 2, 12-Hete, and chenodeoxycholic acid. Compared with CRA, 3,4,5-trimethoxybenzoic acid was significantly higher in CRC patients. There results prompt us to use the potential serum signatures to screen CRC as the novel strategy. Serum metabolite screening is useful for early detection of mucosal intestinal malignancy. We will further investigate the roles of these promising biomarkers during intestinal tumorigenesis in future. SIGNIFICANCE: CRC is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenomas to adenocarcinoma, which provides a long screening window for about 5-10 years. We adopt the metabolic analysis of extensive targeted metabolic technology. The main purpose of the metabolic group analysis is to detect and screen the different metabolites, thereby performing related functional prediction and analysis of the differential metabolites. In our study, 30 samples are selected, divided into 3 groups for metabolic analysis, and 238 metabolites are elected. In 238 metabolites, we find that CRA patients have 72 different metabolites compared with health control. Compared with health control, CRC have 73 different metabolites. Compared with CRA and CRC patients, there are 20 different metabolites. The annotation results of the significantly different metabolites are classified according to the KEGG pathway type. The potential metabolites of tumor growth stage (including patients with CRA and CRC) are found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, sarcosine, TXB 2, 12-Hete and chenodeoxycholic acid. Compared with CRA patients, CRC patients had significantly higher 3,4,5-trimethoxybenzoic acid level. It is prompted to use serum different metabolites to screen CRC to provide new possibilities.
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Affiliation(s)
- Jiachi Guo
- Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Yuanming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9 Beiguan Street, Tongzhou District, Beijing 101149, China
| | - Jigui Chen
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Peng Jin
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Shan Tang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Haihong Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Hui Su
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China
| | - Qian Wang
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Chao Chen
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Fei Xiong
- Department of Colorectal and Anal Surgery Wuhan, No. 8 Hospital. No. 1307 Zhongshan Avenue, Jiang'an District, Hankou, Wuhan City, Hubei 430010, China
| | - Kejia Liu
- DHC Mediway Technology Co., Ltd., 14F, Zijin Digital Park, Zhongguancun, Haidian District, Beijing 100190, China
| | - Yansheng Li
- DHC Mediway Technology Co., Ltd., 14F, Zijin Digital Park, Zhongguancun, Haidian District, Beijing 100190, China
| | - Mingliang Su
- DHC Mediway Technology Co., Ltd., 14F, Zijin Digital Park, Zhongguancun, Haidian District, Beijing 100190, China
| | - Tang Tang
- Wuhan Metwell Biotechnology Co., Ltd., Building B7/B8, Biological Industry Innovation Base, 666 Gaoxin Avenue, Donghu New Technology Development Zone, Wuhan City, Hubei 430075, China
| | - Yuqi He
- Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China; The Second School of Clinical Medicine, Southern Medical University, 253 Middle Industrial Avenue, Guangzhou City, Guangdong 510280, China; Department of Gastroenterology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9 Beiguan Street, Tongzhou District, Beijing 101149, China.
| | - Jianqiu Sheng
- Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road Haidian District, Beijing 100853, China; Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing 100700, China.
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Interplay between Dysbiosis of Gut Microbiome, Lipid Metabolism, and Tumorigenesis: Can Gut Dysbiosis Stand as a Prognostic Marker in Cancer? DISEASE MARKERS 2022; 2022:2941248. [PMID: 35178126 PMCID: PMC8847007 DOI: 10.1155/2022/2941248] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/11/2022] [Indexed: 02/07/2023]
Abstract
The gut bacterial community is involved in the metabolism of bile acids and short-chain fatty acids (SCFAs). Bile acids are involved in the absorption of fat and the regulation of lipid homeostasis through emulsification and are transformed into unconjugated bile acids by the gut microbiota. The gut microbiota is actively involved in the production of bile acid metabolites, such as deoxycholic acid, lithocholic acid, choline, and SCFAs such as acetate, butyrate, and propionate. Metabolites derived from the gut microbiota or modified gut microbiota metabolites contribute significantly to host pathophysiology. Gut bacterial metabolites, such as deoxycholic acid, contribute to the development of hepatocellular carcinoma and colon cancer by factors such as inflammation and oxidative DNA damage. Butyrate, which is derived from gut bacteria such as Megasphaera, Roseburia, Faecalibacterium, and Clostridium, is associated with the activation of Treg cell differentiation in the intestine through histone acetylation. Butyrate averts the action of class I histone deacetylases (HDAC), such as HDAC1 and HDAC3, which are responsible for the transcription of genes such as p21/Cip1, and cyclin D3 through hyperacetylation of histones, which orchestrates G1 cell cycle arrest. It is essential to identify the interaction between the gut microbiota and bile acid and SCFA metabolism to understand their role in gastrointestinal carcinogenesis including colon, gastric, and liver cancer. Metagenomic approaches with bioinformatic analyses are used to identify the bacterial species in the metabolism of bile acids and SCFAs. This review provides an overview of the current knowledge of gut microbiota-derived bile acid metabolism in tumor development and whether it can stand as a marker for carcinogenesis. Additionally, this review assesses the evidence of gut microbiota-derived short-chain fatty acids including butyric acid in antitumor activity. Future research is required to identify the beneficial commensal gut bacteria and their metabolites which will be considered to be therapeutic targets in inflammation-mediated gastrointestinal cancers.
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Liu T, Song X, Khan S, Li Y, Guo Z, Li C, Wang S, Dong W, Liu W, Wang B, Cao H. The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing. Int J Cancer 2019; 146:1780-1790. [DOI: 10.1002/ijc.32563] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Tianyu Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Xueli Song
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Samiullah Khan
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Yun Li
- Department of Pharmacy, General HospitalTianjin Medical University Tianjin China
| | - Zixuan Guo
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Chuqiao Li
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Wenxiao Dong
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Wentian Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
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Chuang SM, Lu JH, Lin KL, Long CY, Lee YC, Hsiao HP, Tsai CC, Wu WJ, Yang HJ, Juan YS. Epigenetic regulation of COX‑2 expression by DNA hypomethylation via NF‑κB activation in ketamine‑induced ulcerative cystitis. Int J Mol Med 2019; 44:797-812. [PMID: 31257475 PMCID: PMC6657979 DOI: 10.3892/ijmm.2019.4252] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 06/05/2019] [Indexed: 01/03/2023] Open
Abstract
The present study investigated the methylation of CpG sites in the cyclooxygenase (COX)-2 promoter via nuclear factor (NF)-κB transcriptional regulation and elucidated its effect on the COX-2 transcriptional expression in a ketamine-induced ulcerative cystitis (KIC) animal model. The results of the present study revealed that ketamine treatment induced NF-κB p65 translocation to nuclei and activated COX-2 expression and prostaglandin (PGE)2 production in bladder tissue, whereas COX-2 inhibitor suppressed the inflammatory effect. Moreover, DNA hypomethylation of the COX-2 promoter region located from -1,522 to -829 bp might contribute to transcriptional regulation of COX-2 expression and induce a pro-inflammatory response in KIC. Ketamine treatment increased the binding of NF-κB and permissive histone H3 lysine-4 (H3K4)m3, but caused a decrease in the repressive histone H3K27m3 and H3K36m3 on the COX-2 promoter ranging from -1,522 to -1,331 bp as determined by a chromatin immunoprecipitation assay. Moreover, in the ketamine group, the level of Ten-Eleven-Translocation methylcytosine dioxygenase for demethylation as determined by reverse transcription-quantitative PCR assay was increased in comparison with the control group, but that was not the case for the level of DNA methyltransferases for methylation. The present findings revealed that there was a hypomethylation pattern of the COX-2 promoter in association with the level of COX-2 transcription in KIC.
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Affiliation(s)
- Shu-Mien Chuang
- Translational Research Center, Cancer Center, Department of Medical Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Jian-He Lu
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Kun-Ling Lin
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C
| | - Cheng-Yu Long
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C
| | - Yung-Chin Lee
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Hui-Pin Hsiao
- Division of Genetics, Endocrinology and Metabolism, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C
| | - Chia-Chun Tsai
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Wen-Jeng Wu
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Hui-Jun Yang
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
| | - Yung-Shun Juan
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C
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Romagnolo DF, Donovan MG, Doetschman TC, Selmin OI. n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer. Nutrients 2019; 11:E171. [PMID: 30650553 PMCID: PMC6356359 DOI: 10.3390/nu11010171] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 01/03/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (n-6HFD) on CpG methylation of Fxr and prostaglandin-endoperoxide synthase-2 (Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (Apc) and proliferative cyclin D1 (Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the n-6HFD had reduced (60%) Fxr promoter CpG methylation and increased (~50%) Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (Ibabp), small heterodimer protein (Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The n-6HFD reduced Ptgs-2 CpG methylation, increased the expression of Cox-2, and increased Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of Apc was coupled to accumulation of c-JUN and Ccnd1, respectively cofactor and gene targets for the β-catenin/Wnt signaling pathway. Finally, the n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an n-6HFD epigenetically modifies Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of Ptsg-2 coupled with silencing of Apc and accumulation of C-JUN and Ccnd1 may increase the risk of inflammation and cancer of the colon.
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Affiliation(s)
- Donato F Romagnolo
- The University of Arizona Cancer Center, Tucson, AZ 85724, USA.
- Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA.
| | - Micah G Donovan
- Interdisciplinary Cancer Biology Graduate Program, University of Arizona, Tucson, AZ 85724, USA.
| | - Tom C Doetschman
- Department of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.
| | - Ornella I Selmin
- The University of Arizona Cancer Center, Tucson, AZ 85724, USA.
- Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA.
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Nguyen TT, Ung TT, Kim NH, Jung YD. Role of bile acids in colon carcinogenesis. World J Clin Cases 2018; 6:577-588. [PMID: 30430113 PMCID: PMC6232560 DOI: 10.12998/wjcc.v6.i13.577] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/15/2018] [Accepted: 10/11/2018] [Indexed: 02/05/2023] Open
Abstract
Bile acids (BAs) are cholesterol derivatives synthesized in the liver and then secreted into the intestine for lipid absorption. There are numerous scientific reports describing BAs, especially secondary BAs, as strong carcinogens or promoters of colon cancers. Firstly, BAs act as strong stimulators of colorectal cancer (CRC) initiation by damaging colonic epithelial cells, and inducing reactive oxygen species production, genomic destabilization, apoptosis resistance, and cancer stem cells-like formation. Consequently, BAs promote CRC progression via multiple mechanisms, including inhibiting apoptosis, enhancing cancer cell proliferation, invasion, and angiogenesis. There are diverse signals involved in the carcinogenesis mechanism of BAs, with a major role of epidermal growth factor receptor, and its down-stream signaling, involving mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor kappa-light-chain-enhancer of activated B cells. BAs regulate numerous genes including the human leukocyte antigen class I gene, p53, matrix metalloprotease, urokinase plasminogen activator receptor, Cyclin D1, cyclooxygenase-2, interleukin-8, and miRNAs of CRC cells, leading to CRC promotion. These evidence suggests that targeting BAs is an efficacious strategies for CRC prevention and treatment.
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Affiliation(s)
- Thi Thinh Nguyen
- Department of Biochemistry, Chonnam National University Medical School, Jeonnam 58138, South Korea
| | - Trong Thuan Ung
- Department of Biochemistry, Chonnam National University Medical School, Jeonnam 58138, South Korea
| | - Nam Ho Kim
- Department of Nephrology, Chonnam National University Medical School, Gwangju 501-190, South Korea
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Jeonnam 58138, South Korea
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The role of bile acids in cellular invasiveness of gastric cancer. Cancer Cell Int 2018; 18:75. [PMID: 29942193 PMCID: PMC5963058 DOI: 10.1186/s12935-018-0569-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 05/08/2018] [Indexed: 12/23/2022] Open
Abstract
Background Bile acids have been implicated in the development of digestive tract malignancy by epidemiological, clinical and animal studies. The growth and transformation signaling by most of the bile acids is thought to be related to the induced cyclooxygenase-2 (COX-2) expression and increased production of prostaglandin E2 (PGE2). The highly hydrophobic bile acids such as chenodeoxycholic acid (CD) and deoxycholic acid can promote carcinogenesis and stimulate the invasion of colon cancer cells. On the contrary, ursodeoxycholic acid (UDCA), a less hydrophobic stereoisomer of CD, inhibits proliferation and induces apoptosis in colon cancer cells. We examined the effects of bile acid on human gastric cancer cells MKN-74. Methods Early-passage human gastric cancer MKN-74 cells were used for drug treatment, preparation of whole cell lysates, subcellular extracts and Western blot analysis. The levels of PGE2 released by the cells were measured by enzyme inummoassay to indicate COX-2 enzymatic activity. Cellular invasion assay was performed in Boyden chamber. Results Exposure of CD led to activation of protein kinase C (PKC) alpha, increased COX-2 expression and increased PGE2 synthesis. The induced COX-2 protein expression could be detected within 4 h exposure of 200 μM CD, and it was dose- and time-dependent. PGE2 is the product of COX-2, and has been reported to cause tumor invasion and angiogenesis in animal study. Safingol (SAF), a PKC inhibitor, suppressed the COX-2 protein expression and PGE2 production by CD in MKN-74. Furthermore, UDCA suppressed PGE2 production by CD but did not affect COX-2 protein expression induced by CD. Using a Boyden chamber invasion assay, both SAF and UDCA impeded CD induced tumor invasiveness of MKN-74 by 30–50%. Conclusions Our results indicate that signaling of hydrophobic bile acid such as CD in gastric cancer cells is through PKC activation and COX-2 induction, which leads to increased cellular invasion. By perturbing the bile acid pool, UDCA attenuates CD-induced PGE2 synthesis and tumor invasiveness.
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Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity. Nutr Res Rev 2016; 29:234-248. [PMID: 27841104 DOI: 10.1017/s0954422416000159] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.
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Juan YS, Lee YL, Long CY, Wong JH, Jang MY, Lu JH, Wu WJ, Huang YS, Chang WC, Chuang SM. Translocation of NF-κB and Expression of Cyclooxygenase-2 Are Enhanced by Ketamine-Induced Ulcerative Cystitis in Rat Bladder. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:2269-85. [DOI: 10.1016/j.ajpath.2015.04.020] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 04/14/2015] [Accepted: 04/16/2015] [Indexed: 02/07/2023]
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Verbeke KA, Boobis AR, Chiodini A, Edwards CA, Franck A, Kleerebezem M, Nauta A, Raes J, van Tol EAF, Tuohy KM, on behalf of the ILSI Europe Prebiotics Task Force Expert Group ‘Microbial metabolism and fermentation’. Towards microbial fermentation metabolites as markers for health benefits of prebiotics. Nutr Res Rev 2015; 28:42-66. [PMID: 26156216 PMCID: PMC4501371 DOI: 10.1017/s0954422415000037] [Citation(s) in RCA: 220] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Available evidence on the bioactive, nutritional and putative detrimental properties of gut microbial metabolites has been evaluated to support a more integrated view of how prebiotics might affect host health throughout life. The present literature inventory targeted evidence for the physiological and nutritional effects of metabolites, for example, SCFA, the potential toxicity of other metabolites and attempted to determine normal concentration ranges. Furthermore, the biological relevance of more holistic approaches like faecal water toxicity assays and metabolomics and the limitations of faecal measurements were addressed. Existing literature indicates that protein fermentation metabolites (phenol, p-cresol, indole, ammonia), typically considered as potentially harmful, occur at concentration ranges in the colon such that no toxic effects are expected either locally or following systemic absorption. The endproducts of saccharolytic fermentation, SCFA, may have effects on colonic health, host physiology, immunity, lipid and protein metabolism and appetite control. However, measuring SCFA concentrations in faeces is insufficient to assess the dynamic processes of their nutrikinetics. Existing literature on the usefulness of faecal water toxicity measures as indicators of cancer risk seems limited. In conclusion, at present there is insufficient evidence to use changes in faecal bacterial metabolite concentrations as markers of prebiotic effectiveness. Integration of results from metabolomics and metagenomics holds promise for understanding the health implications of prebiotic microbiome modulation but adequate tools for data integration and interpretation are currently lacking. Similarly, studies measuring metabolite fluxes in different body compartments to provide a more accurate picture of their nutrikinetics are needed.
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Affiliation(s)
- Kristin A. Verbeke
- Translational Research in Gastrointestinal Disorders (TARGID), KU Leuven and Leuven Food Science and Nutrition Research Center (LFoRCe), Leuven, Belgium
| | - Alan R. Boobis
- Department of Medicine, Imperial College London, London, UK
| | - Alessandro Chiodini
- Formerly ILSI Europe, Box 6, Avenue Emmanuel Mounier 83, BE-1200, Brussels, Belgium; now European Commission, Research Executive Agency (REA) Unit B2, Brussels, Belgium
| | - Christine A. Edwards
- Human Nutrition School of Medicine, College of MVLS, University of Glasgow, Glasgow, Scotland
| | | | - Michiel Kleerebezem
- Host Microbe Interactomics, Wageningen University, Wageningen, The Netherlands
| | - Arjen Nauta
- FrieslandCampina, Amersfoort, The Netherlands
| | - Jeroen Raes
- Microbiology and Immunology, Rega Institute, KU Leuven, Leuven; VIB, Leuven; DBIT, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Kieran M. Tuohy
- Nutrition and Nutrigenomics, Research and Innovation Centre-Fondazione Edmund Mach, Trento, Italy
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García-París M, López-Estrada EK. First records of Eupompha imperialis (Wellman, 1912) (Coleoptera: Meloidae) in Mexico. GRAELLSIA 2015. [DOI: 10.3989/graellsia.2015.v71.131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis. Int J Colorectal Dis 2011; 26:575-82. [PMID: 21243500 PMCID: PMC3077743 DOI: 10.1007/s00384-010-1127-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/22/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIM In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. METHODS Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. RESULTS Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. CONCLUSION Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect.
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Pearson JR, Gill CIR, Rowland IR. Diet, fecal water, and colon cancer--development of a biomarker. Nutr Rev 2009; 67:509-26. [PMID: 19703259 DOI: 10.1111/j.1753-4887.2009.00224.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer incidence worldwide. Lifestyle factors, especially dietary intake, affect the risk of CRC development. Suitable risk biomarkers are required in order to assess the effect that specific dietary components have on CRC risk. The relationship between dietary intake and indicators of fecal water activity has been assessed using cell and animal models as well as human studies. This review summarizes the literature on fecal water and dietary components with a view to establishing further the potential role of fecal water as a source of CRC risk biomarkers. The literature indicates that fecal water activity markers are affected by specific dietary components linked with CRC risk: red meat, saturated fats, bile acids, and fatty acids are associated with an increase in fecal water toxicity, while the converse appears to be true for calcium, probiotics, and prebiotics. However, it must be acknowledged that the study of fecal water is still in its infancy and a number of issues need to be addressed before its usefulness can be truly gauged.
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Affiliation(s)
- Jennifer R Pearson
- Northern Ireland Centre for Food and Health (NICHE), University of Ulster-Coleraine, Cromore Road, Coleraine, Northern Ireland, UK.
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Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells. Br J Nutr 2009; 102:201-6. [PMID: 19586571 DOI: 10.1017/s0007114508162110] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Oligomers and polymers of flavan-3-ols (proanthocyanidins) are very abundant in the Mediterranean diet, but are poorly absorbed. However, when these polyphenols reach the colon, they are metabolised by the intestinal microbiota into various phenolic acids, including phenylpropionic, phenylacetic and benzoic acid derivatives. Since the biological properties of these metabolites are not completely known, in the present study, we investigated the effect of the following microbial phenolic metabolites: 3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 3-hydroxyphenylpropionic acid, 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid (4-HHA), on modulation of the production of the main pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6). The production of these cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) pre-treated with the phenolic metabolites was studied in six healthy volunteers. With the exception of 4-HHA for TNF-alpha secretion, only the dihydroxylated compounds, 3,4-DHPPA and 3,4-DHPAA, significantly inhibited the secretion of these pro-inflammatory cytokines in LPS-stimulated PBMC. Mean inhibition of the secretion of TNF-alpha by 3,4-DHPPA and 3,4-DHPAA was 84.9 and 86.4 %, respectively. The concentrations of IL-6 in the culture supernatant were reduced by 88.8 and 92.3 % with 3,4-DHPPA and 3,4-DHPAA pre-treatment, respectively. Finally, inhibition was slightly higher for IL-1beta, 93.1 % by 3,4-DHPPA and 97.9 % by 3,4-DHPAA. These results indicate that dihydroxylated phenolic acids derived from microbial metabolism present marked anti-inflammatory properties, providing additional information about the health benefits of dietary polyphenols and their potential value as therapeutic agents.
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Targeted metabolic profiling of phenolics in urine and plasma after regular consumption of cocoa by liquid chromatography-tandem mass spectrometry. J Chromatogr A 2009; 1216:7258-67. [PMID: 19671472 DOI: 10.1016/j.chroma.2009.07.058] [Citation(s) in RCA: 139] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Revised: 07/17/2009] [Accepted: 07/29/2009] [Indexed: 11/23/2022]
Abstract
The biological properties of cocoa (Theobroma cacao L.) polyphenols are strictly dependent on their bioavailability. A long-term cocoa feeding trial was performed with subjects at high risk for cardiovascular disease. Subjects (n=42) received two sachets of 20 g of cocoa powder/day with 250 mL of skimmed milk each, or only 500 mL/day of skimmed milk, both for two 4-week periods. The phenolic metabolic profile including phase II conjugated metabolites and phenolic acids derived from the intestinal microbiota was determined by LC-MS/MS in both 24-h urine and fasting plasma. The analysis of 24-h urine revealed significant increases of phase II metabolites, including glucuronides and sulfate conjugates of (-)-epicatechin, O-methyl-epicatechin, 5-(3',4'-dihydroxyphenyl)-gamma-valerolactone and 5-(3'-methoxy-4'-hydroxyphenyl)-gamma-valerolactone, after regular cocoa intake. In the case of plasma, only glucuronide conjugates of dihydroxyphenylvalerolactones increased. Regular consumption of cocoa also resulted in a significant increase in the urinary excretion of colonic microbial-derived phenolic metabolites, including vanillic, 3,4-dihydroxyphenylacetic and 3-hydroxyphenylacetic acids, and particularly 5-(3',4'-dihydroxyphenyl)-gamma-valerolactone, whereas only the two latter metabolites showed a significant increase in fasting plasma. The results found herein indicate that 5-(3',4'-dihydroxyphenyl)-gamma-valerolactone and hydroxyphenylacetic acids could be good biomarkers of the regular consumption of cocoa and therefore, of flavanol-rich foods.
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Cui G, Yuan A, Vonen B, Florholmen J. Progressive cellular response in the lamina propria of the colorectal adenoma-carcinoma sequence. Histopathology 2009; 54:550-60. [PMID: 19413637 DOI: 10.1111/j.1365-2559.2009.03273.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
AIMS The lamina propria is inevitably involved in epithelial transformation. The aim was to evaluate the dynamic cellular changes in the tumour lamina propria throughout the colorectal adenoma-carcinoma sequence. METHODS AND RESULTS Using immunohistochemistry and double immunohistochemistry, we examined lamina propria cellular changes in 41 colorectal adenomas, 25 colorectal cancers and 15 control tissues. The results showed that the proliferation labelling index in lamina propria cells began to increase in the precancerous lesions (adenomas) and became even higher in the colorectal cancers; these proliferative cells were primarily identified as myofibroblasts and lymphocytes. Phenotypic analysis revealed gradually increasing lymphocytic infiltration in both the lamina propria and adenomatous epithelium, as well as myofibroblasts in the lamina propria. However, the intraepithelial macrophage density also showed a tendency to increase gradually. Furthermore, cyclooxygenase-2-expressing cell density and microvessel density gradually increased in the tumour lamina propria throughout the adenoma-carcinoma sequence. CONCLUSIONS Progressive cellular responses in the lamina propria could be involved in the adenoma-carcinoma transition.
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Affiliation(s)
- Guanglin Cui
- Laboratory of Gastroenterology, Institute of Clinical Medicine, Faculty of Medicine, University of Tromsø, Tromsø, Norway.
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Khare S, Mustafi R, Cerda S, Yuan W, Jagadeeswaran S, Dougherty U, Tretiakova M, Samarel A, Cohen G, Wang J, Moore C, Wali R, Holgren C, Joseph L, Fichera A, Li YC, Bissonnette M. Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein. Nutr Cancer 2008; 60:389-400. [PMID: 18444174 DOI: 10.1080/01635580701883003] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the azoxymethane (AOM) model of experimental rodent colon cancer, cholic acid and its colonic metabolite deoxycholic acid (DCA) strongly promote tumorigenesis. In contrast, we showed that ursodeoxycholic acid (UDCA), a low abundance bile acid, inhibited AOM tumorigenesis. Dietary UDCA also blocked the development of tumors with activated Ras and suppressed cyclooxygenase-2 (Cox-2) upregulation in AOM tumors. In this study, we compared the effect of dietary supplementation with tumor-promoting cholic acid to chemopreventive UDCA on Cox-2 expression in AOM tumors. Cholic acid enhanced Cox-2 upregulation in AOM tumors, whereas UDCA inhibited this increase and concomitantly decreased CCAAT/enhancer binding protein beta (C/EBPbeta), a transcriptional regulator of Cox-2. In HCA-7 colon cancer cells, DCA activated Ras and increased C/EBPbeta and Cox-2 by a mechanism requiring the mitogen-activated protein kinase p38. UDCA inhibited DCA-induced p38 activation and decreased C/EBPbeta and Cox-2 upregulation. Using transient transfections, UDCA inhibited Cox-2 promoter and C/EBP reporter activation by DCA. Transfection with dominant-negative (17)N-Ras abolished DCA-induced p38 activation and C/EBPbeta and Cox-2 upregulation. Taken together, these studies have identified a transcriptional pathway regulating Cox-2 expression involving Ras, p38, and C/EBPbeta that is inhibited by UDCA. These signal transducers are novel targets of UDCA's chemopreventive actions.
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Affiliation(s)
- Sharad Khare
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA.
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Fukase K, Ohtsuka H, Onogawa T, Oshio H, Ii T, Mutoh M, Katayose Y, Rikiyama T, Oikawa M, Motoi F, Egawa S, Abe T, Unno M. Bile acids repress E-cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma. Cancer Sci 2008; 99:1785-92. [PMID: 18691339 PMCID: PMC11160067 DOI: 10.1111/j.1349-7006.2008.00898.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Although some kinds of bile acids have been implicated in colorectal cancer development, the mechanism of cancer progression remains unexplored in hepatobiliary cancer. From our personal results using complementary DNA microarray, we found that chenodeoxycholic acid (CDCA) induced Snail expression in human carcinoma cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. Snail expression plays an important role in the regulation of E-cadherin and in the acquisition of invasive potential in many types of human cancers including hepatocellular carcinoma. We found that CDCA and lithocholic acid (LCA) induced Snail expression in a concentration-dependent manner and down-regulated E-cadherin expression in hepatocellular carcinoma and cholangiocarcinoma cell lines. Moreover, Snail short interference RNA (siRNA) treatment reduced the down-regulation of E-cadherin by CDCA or LCA. Luciferase analysis demonstrated that the promoter region from -111 to -24 relative to the transcriptional start site was necessary for this induction and, at least in part, nuclear factor Y (NF-Y) and stimulating protein 1 (Sp1) might be an inducer of Snail expression in response to bile acids. In addition, using an in vitro wound healing assay and invasion assay, we observed that CDCA and LCA induced cell migration and invasion. These results suggest that bile acids repress E-cadherin through the induction of transcription factor Snail and increase cancer invasiveness in human hepatocellular carcinoma and cholangiocarcinoma. Inhibition of this bile acid-stimulated pathway may prove useful as an adjuvant in the therapy of hepatocellular carcinoma.
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Affiliation(s)
- Koji Fukase
- Department of Surgery, Tohoku University Graduate School of Medical Science, Sendai 980-8574, Japan
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Pettersson J, Karlsson PC, Choi YH, Verpoorte R, Rafter JJ, Bohlin L. NMR metabolomic analysis of fecal water from subjects on a vegetarian diet. Biol Pharm Bull 2008; 31:1192-8. [PMID: 18520053 DOI: 10.1248/bpb.31.1192] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A vegetarian diet rich in phytochemicals may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Compounds passing the digestive system reaching the colon could potentially be detected in fecal water. We previously reported that intact fecal water samples from human volunteers significantly decreased prostaglandin production and COX-2 protein expression in colonic cells. The aim with the present study was to further study the composition of the fecal waters, using NMR spectroscopy and multivariate data analysis, and to trace the COX-2 inhibiting activity. Intact fecal water samples and fractions thereof were analyzed for their ability to inhibit prostaglandin E2 production in the human colon cell line HT-29. The majority of the tested aqueous phases derived from intact fecal water showed ability to inhibit prostaglandin production in cells (13.8+/-1.34% inhibition, p=0.01). NMR analysis indicated the presence of significant quantities of amino acids and fatty acids. Major metabolites included; acetic acid, butanoic acid, propanoic acid, glutamic acid and alanine. Smaller amounts of glycine and fumaric acid, which are known to have anti-inflammatory and anti-tumorigenic properties, were also detected. This study describes for the first time NMR metabolomic analysis of fecal water from subjects on a vegetarian diet.
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Affiliation(s)
- Jenny Pettersson
- Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Uppsala, Sweden
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Rafter J, Bennett M, Caderni G, Clune Y, Hughes R, Karlsson PC, Klinder A, O'Riordan M, O'Sullivan GC, Pool-Zobel B, Rechkemmer G, Roller M, Rowland I, Salvadori M, Thijs H, Van Loo J, Watzl B, Collins JK. Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am J Clin Nutr 2007; 85:488-96. [PMID: 17284748 DOI: 10.1093/ajcn/85.2.488] [Citation(s) in RCA: 320] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Animal studies suggest that prebiotics and probiotics exert protective effects against tumor development in the colon, but human data supporting this suggestion are weak. OBJECTIVE The objective was to verify whether the prebiotic concept (selective interaction with colonic flora of nondigested carbohydrates) as induced by a synbiotic preparation-oligofructose-enriched inulin (SYN1) + Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (BB12)-is able to reduce the risk of colon cancer in humans. DESIGN The 12-wk randomized, double-blind, placebo-controlled trial of a synbiotic food composed of the prebiotic SYN1 and probiotics LGG and BB12 was conducted in 37 colon cancer patients and 43 polypectomized patients. Fecal and blood samples were obtained before, during, and after the intervention, and colorectal biopsy samples were obtained before and after the intervention. The effect of synbiotic consumption on a battery of intermediate bio-markers for colon cancer was examined. RESULTS Synbiotic intervention resulted in significant changes in fecal flora: Bifidobacterium and Lactobacillus increased and Clostridium perfringens decreased. The intervention significantly reduced colorectal proliferation and the capacity of fecal water to induce necrosis in colonic cells and improve epithelial barrier function in polypectomized patients. Genotoxicity assays of colonic biopsy samples indicated a decreased exposure to genotoxins in polypectomized patients at the end of the intervention period. Synbiotic consumption prevented an increased secretion of interleukin 2 by peripheral blood mononuclear cells in the polypectomized patients and increased the production of interferon gamma in the cancer patients. CONCLUSIONS Several colorectal cancer biomarkers can be altered favorably by synbiotic intervention.
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Affiliation(s)
- Joseph Rafter
- Department of Medical Nutrition, Karolinska Institutet, Huddinge, Sweden, University College Cork, Cork, Ireland
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German JB, Dillard CJ. Composition, structure and absorption of milk lipids: a source of energy, fat-soluble nutrients and bioactive molecules. Crit Rev Food Sci Nutr 2006; 46:57-92. [PMID: 16403683 DOI: 10.1080/10408690590957098] [Citation(s) in RCA: 176] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Milkfat is a remarkable source of energy, fat-soluble nutrients and bioactive lipids for mammals. The composition and content of lipids in milkfat vary widely among mammalian species. Milkfat is not only a source of bioactive lipid components, it also serves as an important delivery medium for nutrients, including the fat-soluble vitamins. Bioactive lipids in milk include triacylglycerides, diacylglycerides, saturated and polyunsaturated fatty acids, and phospholipids. Beneficial activities of milk lipids include anticancer, antimicrobial, anti-inflammatory, and immunosuppression properties. The major mammalian milk that is consumed by humans as a food commodity is that from bovine whose milkfat composition is distinct due to their diet and the presence of a rumen. As a result of these factors bovine milkfat is lower in polyunsaturated fatty acids and higher in saturated fatty acids than human milk, and the consequences of these differences are still being researched. The physical properties of bovine milkfat that result from its composition including its plasticity, make it a highly desirable commodity (butter) and food ingredient. Among the 12 major milk fatty acids, only three (lauric, myristic, and palmitic) have been associated with raising total cholesterol levels in plasma, but their individual effects are variable-both towards raising low-density lipoproteins and raising the level of beneficial high-density lipoproteins. The cholesterol-modifying response of individuals to consuming saturated fats is also variable, and therefore the composition, functions and biological properties of milkfat will need to be re-evaluated as the food marketplace moves increasingly towards more personalized diets.
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Affiliation(s)
- J Bruce German
- Department of Food Science and Technology, University of California, Davis, CA, 95616, USA.
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Lee YK, Hao W, Ho PS, Nordling MM, Low CS, de Kok TMCM, Rafter J. Human fecal water modifies adhesion of intestinal bacteria to Caco-2 cells. Nutr Cancer 2006; 52:35-42. [PMID: 16091002 DOI: 10.1207/s15327914nc5201_5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The aqueous phase of feces (fecal water) has been suggested to mediate the effects of diet on colon carcinogenesis. We determined whether human fecal water samples, of varying genotoxic potential, had the capacity to alter adhesion of intestinal bacteria to intestinal (Caco-2) cells. Genotoxicity of fecal water samples was measured using the single-cell gel electrophoresis assay ("comet" assay), and bacterial adhesion was measured using a well-established model system. Fecal water genotoxicity was found to correlate positively with inhibition of adhesion of Escherichia coli strains, Salmonella species, and Enterococcus faecium to Caco-2 cells. The presence of fecal water samples did not interfere with adhesion of Bacteroides and Lactobacillus species. Inhibition of adhesion by fecal water was not due to cytotoxicity to Caco-2 cells as cytotoxicities of most fecal water samples were similar, nor was the inhibitory effect due to bacteriotoxicity as toxicity of fecal waters in the 10 strains of bacteria studied was not detected. Results indicate that components in fecal water may alter adhesion of intestinal bacteria to intestinal cell surfaces and that this effect may be correlated to the genotoxic potential of fecal water. This may have consequences for dietary effects on colon carcinogenesis.
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Affiliation(s)
- Yuan-Kun Lee
- Department of Microbiology, Faculty of Medicine, National University of Singapore
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Hull MA. Cyclooxygenase-2: how good is it as a target for cancer chemoprevention? Eur J Cancer 2005; 41:1854-63. [PMID: 16002278 DOI: 10.1016/j.ejca.2005.04.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2005] [Accepted: 04/01/2005] [Indexed: 01/20/2023]
Abstract
There is now substantial evidence for a role for cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) signalling during carcinogenesis in a number of tissues and selective COX-2 inhibitors (coxibs) were considered attractive candidate chemoprevention agents. However, recent concerns over the toxicity of systemic selective COX-2 inhibition and the realisation that COX-1 may also contribute to carcinogenesis have cast some doubt on COX-2 inhibition as a safe and effective chemoprevention strategy. This review will describe the available evidence relating to the known benefits (preventive efficacy in rodent tumorigenesis models and limited human data from small randomised, controlled trials and epidemiological studies) and risks (cardiovascular and renal toxicity) of coxib therapy for cancer chemoprevention. Potential, alternative strategies for inhibition of COX-PG signalling that minimise or avoid systemic selective COX-2 inhibition will also be discussed.
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Affiliation(s)
- Mark A Hull
- Molecular Medicine Unit, Clinical Sciences Building, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
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Merchant NB, Rogers CM, Trivedi B, Morrow J, Coffey RJ. Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells. Surgery 2005; 138:415-21. [PMID: 16213893 DOI: 10.1016/j.surg.2005.06.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2005] [Revised: 06/13/2005] [Accepted: 06/16/2005] [Indexed: 12/31/2022]
Abstract
BACKGROUND Secondary bile acids such as deoxycholic acid (DCA) are known to promote colorectal cancer (CRC). Increasing evidence suggests that DCA-induced signaling is mediated by activation of the epidermal growth factor receptor (EGFR). We have shown that activation of the EGFR induces up-regulation of cyclooxygenase 2, basolateral release of prostaglandins (PGs), and mitogenesis in a polarizing human colon cancer cell line, HCA-7. The purpose of this study was to determine the mechanism by which DCA activates EGFR in human polarizing CRC cell lines HCA-7 and HCT-8. METHODS A primary, non-tumor-promoting bile acid (cholic acid [CA]) and a secondary, tumor-promoting bile acid, DCA, were added to the apical and basolateral compartment of polarized HCA-7 and HCT-8 cells. These cells were pretreated with monoclonal antibody 528, a monoclonal antibody that inhibits ligand binding to EGFR, or with WAY-022, a selective inhibitor of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease-17 (TACE/ADAM-17), which cleaves amphiregulin (AR) to its mature, soluble form from the basolateral cell membrane. AR levels were measured in the apical and basolateral medium and cell lysates by radioimmunoassay. PGs were measured in the apical and basolateral medium by gas chromatography/mass spectrometry. RESULTS Basolateral delivery of DCA, but not CA, preferentially stimulated release of AR into the basolateral medium compared with cell lysates of polarized HCA-7 and HCT-8 cells. Basolateral delivery of DCA resulted in increased basolateral PGE2 levels (P < .05), and this effect was attenuated by pretreatment with monoclonal antibody 528 (P < .05). Inhibiting cell surface cleavage of AR with WAY-022 before DCA treatment reduced AR (P < .05) and PGE2 (P < .05) levels in the basolateral medium. CONCLUSION DCA, but not CA, results in compartment-specific, ligand-dependent activation of EGFR and subsequent increased basolateral PGE2 levels. The mechanism of DCA-induced EGFR activation is ligand-dependent and is controlled, at least in part, at the level of AR release from the basolateral cell membrane.
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Affiliation(s)
- Nipun B Merchant
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232-8680, USA.
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Karlsson PC, Huss U, Jenner A, Halliwell B, Bohlin L, Rafter JJ. Human fecal water inhibits COX-2 in colonic HT-29 cells: role of phenolic compounds. J Nutr 2005; 135:2343-9. [PMID: 16177193 DOI: 10.1093/jn/135.10.2343] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The inducible enzyme cyclooxygenase-2 (COX-2) plays a major role in the regulation of inflammation and possibly in the development of colon cancer. The aim of the present study was to screen for COX-2 inhibitors in samples of fecal water (the aqueous phase of feces) and investigate whether phenolic compounds are responsible for any observed effects on COX-2. Volunteers (n = 20) were recruited and asked to supply a 24-h stool sample. Fecal water samples were prepared and analyzed by GC-MS for their content of phenolic compounds. These samples were also evaluated for their effects on COX-2 protein levels (Western blot) and prostaglandin (PG)E2 production in tumor necrosis-alpha-stimulated HT-29 cells and pure enzymatic activity in a COX-2-catalyzed prostaglandin biosynthesis in vitro assay. The major phenolic compounds identified were phenylpropionic acid, phenylacetic acid, cinnamic acid, and benzoic acid derivatives. Of 13 fecal water samples analyzed, 12 significantly decreased PGE2 production (range 5.4-39.7% inhibition, P-value < 0.05) compared with control cells and 13 of 14 samples analyzed decreased COX-2 protein levels in HT-29 cells (19-63% inhibition). Of the 20 fecal water samples, 2 also weakly inhibited enzymatic activity of purified COX-2 (22-24% inhibition). Three compounds identified in fecal water, 3-phenylpropionic acid, 3-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)-propionic acid, decreased the protein level at 250 micromol/L (15-62% inhibition). This study shows for the first time that human fecal water contains components that can affect both the COX-2 protein level and enzymatic activity.
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Affiliation(s)
- Pernilla C Karlsson
- Department of Medical Nutrition, Karolinska Institutet, Novum, S-141 86 Huddinge, Sweden
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Araki Y, Katoh T, Ogawa A, Bamba S, Andoh A, Koyama S, Fujiyama Y, Bamba T. Bile acid modulates transepithelial permeability via the generation of reactive oxygen species in the Caco-2 cell line. Free Radic Biol Med 2005; 39:769-80. [PMID: 16109307 DOI: 10.1016/j.freeradbiomed.2005.04.026] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2004] [Revised: 04/29/2005] [Accepted: 04/29/2005] [Indexed: 02/06/2023]
Abstract
The barrier functions in epithelial and endothelial cells seem to be very important for maintaining normal biological homeostasis. However, it is unclear whether or how bile acids affect the epithelial barrier. We examined the bile acid-induced disruption of the epithelial barrier. We measured the transepithelial electrical resistance (TEER) of Caco-2 cells as a marker of disruption of the epithelial barrier. Reactive oxygen species (ROS) generation was also measured. Cholic acid (CA) decreased the TEER and increased intracellular ROS generation. PLA2 (phospholipase A2), COX (cyclooxygenase), PKC (protein kinase), ERK 1/2 (extracellular signal-regulated kinase 1/2), PI 3 K (phosphatidylinositol 3-kinase), p38 MAPK (p38 mitogen-activated protein kinase), MLCK (myosin light-chain kinase), NADH dehydrogenase, and XO (xanthine oxidase) inhibitors or ROS scavengers prevented the CA-induced TEER decrease. PLA2, COX, PKC, NADH dehydrogenase, and XO inhibitors prevented the CA-induced ROS generation but not ERK 1/2, PI 3 K, p38 MAPK, and MLCK inhibitors. If the cells were treated with ROS generators such as superoxide dismutase, the TEER decreased. ERK 1/2, PI 3 K, p38 MAPK, and MLCK inhibitors prevent these ROS generators from inducing the TEER decrease. These results suggest that ROS play an important role. In addition, PLA2, COX, PKC, NADH dehydrogenase, and XO are located upstream of the ROS generation, but ERK 1/2, PI 3 K, p38 MAPK, and MLCK are downstream during the signaling of CA-induced TEER alterations.
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Affiliation(s)
- Yoshio Araki
- Department of Internal Medicine, Biwako Youikuin Hospital, 7-7-2 Ohgaya, Otsu 520-2144 Shiga, Japan.
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Yasuda H, Yamada M, Endo Y, Inoue K, Yoshiba M. Elevated cyclooxygenase-2 expression in patients with early gastric cancer in the gastric pylorus. J Gastroenterol 2005; 40:690-697. [PMID: 16082585 DOI: 10.1007/s00535-005-1612-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2004] [Accepted: 03/01/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND Duodenogastric reflux after surgery increases the risk of gastric carcinoma. To determine whether bile reflux influences the development of gastric cancer in patients who have not had surgery, we compared cyclooxygenase-2 (COX-2) immunoreactivity in early gastric cancer originating from the gastric pylorus and that originating from other locations. We also examined the effects of bile acids on the expression and activity of COX-2 in gastric cells in vitro. METHODS Tumor sections from 79 patients who underwent endoscopic mucosal resection for early intestinal-type gastric carcinoma were stained using a COX-2-specific monoclonal antibody. Immunoblotting of COX-2 was used to assess the effects of bile acids on COX-2 expression and activity in human gastric cell lines. RESULTS Among the 79 early gastric cancer lesions studied, 13 (16%) arose in the gastric pylorus. In this group, COX-2 immunoreactivity was negative to weak in 38% (5 of 13 lesions) and moderate to strong in 62% (8 of 13 lesions). In the control group, COX-2 immunoreactivity was negative to weak in 70% (46 of 66 lesions) and moderate to strong in 30% (20 of 66 lesions). COX-2 expression was significantly elevated in early gastric cancer located in the gastric pylorus, compared with that in the other locations. In human gastric cell lines, bile acids induced COX-2 expression, mediated by the ERK 1/2 mitogen-activated protein kinase pathway. CONCLUSIONS COX-2 expression is elevated in early gastric cancer of the gastric pylorus, a common site of gastric cancer. Bile acids induced COX-2 expression in human gastric cell lines, suggesting a role of bile reflux in gastric carcinogenesis.
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Affiliation(s)
- Hiroshi Yasuda
- Division of Gastroenterology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Yokohama, 227-8501, Japan
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Wu J, Cheng Y, Jönsson BAG, Nilsson A, Duan RD. Acid sphingomyelinase is induced by butyrate but does not initiate the anticancer effect of butyrate in HT29 and HepG2 cells. J Lipid Res 2005; 46:1944-52. [PMID: 15961787 DOI: 10.1194/jlr.m500118-jlr200] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Butyric acid and sphingomyelin (SM) affect colonic tumorigenesis. We examined the potential link between butyrate stimulation and SM metabolism in colonic and hepatic cancer cell lines. After incubating HT29 and HepG2 cells with butyrate and other short-chain fatty acids, we found that butyrate increased acid but not neutral or alkaline sphingomyelinase (SMase) activity by 10- to 20-fold. The effects occurred after 16 h of incubation and were associated with reduced SM and phosphatidylcholine contents and increased ceramide levels. Northern blotting showed increased acid SMase mRNA levels in these cells after butyrate stimulation. Propionate was less potent, and acetate had no effect. No similar changes of acid phosphatase could be identified. At concentrations that increased acid SMase expression, butyrate inhibited cell proliferation, activated caspase 3, and induced apoptosis. However, the antiproliferative and apoptotic effects of butyrate preceded the changes of acid SMase and were not affected by knocking down acid SMase expression by small, interfering RNA. In addition, butyrate-induced acid SMase expression was not affected by blocking the caspase pathway. In conclusion, butyrate regulates SM metabolism by stimulating acid SMase expression in colon and liver cancer cells, but the increased acid SMase is not a critical mechanism for initiating the anticancer effects of butyrate.
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Affiliation(s)
- Jun Wu
- Gastroenterology Laboratory, Biomedical Center B11, Lund University, S-221 84 Lund, Sweden
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Looby E, Long A, Kelleher D, Volkov Y. Bile acid deoxycholate induces differential subcellular localisation of the PKC isoenzymes beta 1, epsilon and delta in colonic epithelial cells in a sodium butyrate insensitive manner. Int J Cancer 2005; 114:887-95. [PMID: 15645414 DOI: 10.1002/ijc.20803] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Elevated levels of bile acids have been implicated in the abnormal morphogenesis of the colonic epithelium thus contributing to colorectal cancer (CRC). Alternatively sodium butyrate (NaB) produced by anaerobic fermentation of dietary fibre is regarded as being protective against colon cancer. Bile acids such as deoxycholic acid (DCA) are thought to mediate some of their actions by differentially activating protein kinase C (PKC). We examined the effects of DCA on the subcellular localisation of PKC-beta(1), -epsilon and -delta and whether these responses could be modulated by NaB. HCT116 cells endogenously express PKC-epsilon and -delta but not PKC-beta. DCA treatment results in endogenous PKC-epsilon translocation but not PKC-delta after 1 hr. To study the subcellular localisation of PKC isoforms in response to DCA in real time, PKC-beta(1), PKC-epsilon and PKC-delta functionally intact green fluorescent protein (GFP) fusion constructs were used. Stimulation with 300 microM DCA induces rapid translocation of PKC-beta(1)-GFP and PKC-epsilon-GFP but not PKC-delta-GFP from the cytosol to the plasma membrane in 15 min. Interestingly, pretreatment with 4mM NaB does not modify the response of the PKC isoenzymes to DCA as PKC-beta(1)-GFP and PKC-epsilon-GFP translocates to the plasma membrane in 15 min whereas PKC-delta-GFP localisation remains unaltered. Immunofluorescence shows that PKC-beta(1)-GFP and PKC-epsilon-GFP cells treated with DCA colocalise with the cytoskeletal elements actin and tubulin adjacent to the plasma membrane. Our findings demonstrate that the differential activation of the PKC isoenzymes by DCA may be of critical importance for the functional responses of colonic epithelial cells. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.
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Affiliation(s)
- Eileen Looby
- Department of Clinical Medicine, Trinity College and Dublin Molecular Medicine Centre, Dublin, Ireland
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Halliwell B, Rafter J, Jenner A. Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not? Am J Clin Nutr 2005; 81:268S-276S. [PMID: 15640490 DOI: 10.1093/ajcn/81.1.268s] [Citation(s) in RCA: 428] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Foods and beverages rich in phenolic compounds, especially flavonoids, have often been associated with decreased risk of developing several diseases. However, it remains unclear whether this protective effect is attributable to the phenols or to other agents in the diet. Alleged health-promoting effects of flavonoids are usually attributed to their powerful antioxidant activities, but evidence for in vivo antioxidant effects of flavonoids is confusing and equivocal. This may be because maximal plasma concentrations, even after extensive flavonoid intake, may be low (insufficient to exert significant systemic antioxidant effects) and because flavonoid metabolites tend to have decreased antioxidant activity. Reports of substantial increases in plasma total antioxidant activity after flavonoid intake must be interpreted with caution; findings may be attributable to changes in urate concentrations. However, phenols might exert direct effects within the gastrointestinal tract, because of the high concentrations present. These effects could include binding of prooxidant iron, scavenging of reactive nitrogen, chlorine, and oxygen species, and perhaps inhibition of cyclooxygenases and lipoxygenases. Our measurements of flavonoids and other phenols in human fecal water are consistent with this concept. We argue that tocopherols and tocotrienols may also exert direct beneficial effects in the gastrointestinal tract and that their return to the gastrointestinal tract by the liver through the bile may be physiologically advantageous.
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Hoffmann D, Jogler C, Wildner O. Effects of the Ad5 upstream E1 region and gene products on heterologous promoters. J Gene Med 2005; 7:1356-66. [PMID: 15945123 DOI: 10.1002/jgm.771] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND All recombinant adenovirus vectors contain the upstream region of the E1A gene comprising the viral origin of replication, encapsidation signal, and cis-acting regulatory elements for transcription of the E1A and other early genes. Using different reporter genes, some previous studies demonstrated the maintenance of heterologous promoter specificity in the adenoviral context, while others reported that adenoviral sequences interfere with promoter activity. METHODS Plasmid DNA-based luciferase reporter gene assays and adenovirus type 5 (Ad5) infection were combined to examine the effect of the Ad5 (nt 1-353) element and/or adenoviral gene products on tissue-specific (Midkine (MK) and COX-2), cell cycle associated (Ki-67 and E2F1) and viral promoters (Ad5 E1, Ad5 E4 and SV40). As a proof of concept, data were verified in the setting of recombinant replication-defective and replication-competent adenoviral vectors. RESULTS Viral and E2F1 promoter activities were enhanced by the Ad5 (nt 1-353) segment by approximately 100% and 145%, respectively, regardless of its position. A polyadenylation sequence (polyA) upstream of the promoter had no effect, confirming an enhancer element within the Ad5 (nt 1-353) segment. Ad5 (nt 1-353) increased COX-2 promoter activity by 146% but was blocked by an upstream polyA, indicating a cryptic transcription start site. When placing the reporter gene cassette in a replication-defective adenovirus, similar data were obtained. In the plasmid vector-based system, adenoviral gene products transactivated the E2F1 and viral promoters by 194%, 19%, 67%, and 16%, respectively. Tissue-specific promoter activities were not significantly affected by the Ad5 (nt 1-353) segment, nor adenoviral gene products. In concert with these data, we were able to target replication-competent adenoviral vectors with the COX-2 promoter, but not with the cell cycle associated promotor. CONCLUSIONS The adenovirus E1A upstream regulatory region and gene products interact with some but not all heterologous promoters. Often, the basal promoter activity can be reduced with an upstream polyA. Since the data obtained in our plasmid vector-based assay with internal control and infection with adenovirus could be confirmed in the adenoviral setting, our system might be suitable to speed up the identification of promoters which maintain their specificity in the adenoviral context and circumvent the problems associated with determining infectious adenovirus titers.
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Affiliation(s)
- Dennis Hoffmann
- Ruhr-Universität Bochum, Abteilung für Molekulare und Medizinische Virologie, Bldg. MA, Rm. 6/40, D-44801 Bochum, Germany
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Jones R, Adel-Alvarez LA, Alvarez OR, Broaddus R, Das S. Arachidonic acid and colorectal carcinogenesis. Mol Cell Biochem 2004. [PMID: 14619964 DOI: 10.1023/a:10260604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Colorectal carcinoma is a leading cause of cancer related death worldwide. This deadly disease advances through a series of clinical and histopathological stages, initiated by single crypt lesions to small benign tumors and finally to malignancy. Although some progress has been made in elucidating the formation of colorectal tumors at molecular/genetic levels, the possible mechanisms of dietary lipids in inducing and promoting colorectal tumorigenesis are poorly understood. Recent epidemiological studies, however, indicate that lipid-rich diet containing omega-6 fatty acids (i.e. linoleic acid, arachidonic acid, etc.) may somehow be related with the disease process. Rapid metabolism of arachidonic acid, increased activities of phospholipases (i.e. phospholipase-A2s), and the elevated levels of cyclooxygenase (COX) and lipoxygenase (LOX) in colonic cells were reported in various stages of the malignancy, suggesting a possible link between dietary lipids and the incidence of colorectal cancer. The major focus of this review is to delineate the recent findings on enhanced arachidonic acid metabolism and its conversion into eicosanoids during the initiation and progression of colorectal carcinogenesis. In addition, the identification and participation of various phospholipases are also discussed. It is speculated that many of these phospholipases can be used as targets for developing new drugs against colorectal as well as other adenocarcinomas.
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Affiliation(s)
- Raymond Jones
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA
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Jones R, Adel-Alvarez LA, Alvarez OR, Broaddus R, Das S. Arachidonic acid and colorectal carcinogenesis. Mol Cell Biochem 2004; 253:141-9. [PMID: 14619964 DOI: 10.1023/a:1026060426569] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Colorectal carcinoma is a leading cause of cancer related death worldwide. This deadly disease advances through a series of clinical and histopathological stages, initiated by single crypt lesions to small benign tumors and finally to malignancy. Although some progress has been made in elucidating the formation of colorectal tumors at molecular/genetic levels, the possible mechanisms of dietary lipids in inducing and promoting colorectal tumorigenesis are poorly understood. Recent epidemiological studies, however, indicate that lipid-rich diet containing omega-6 fatty acids (i.e. linoleic acid, arachidonic acid, etc.) may somehow be related with the disease process. Rapid metabolism of arachidonic acid, increased activities of phospholipases (i.e. phospholipase-A2s), and the elevated levels of cyclooxygenase (COX) and lipoxygenase (LOX) in colonic cells were reported in various stages of the malignancy, suggesting a possible link between dietary lipids and the incidence of colorectal cancer. The major focus of this review is to delineate the recent findings on enhanced arachidonic acid metabolism and its conversion into eicosanoids during the initiation and progression of colorectal carcinogenesis. In addition, the identification and participation of various phospholipases are also discussed. It is speculated that many of these phospholipases can be used as targets for developing new drugs against colorectal as well as other adenocarcinomas.
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Affiliation(s)
- Raymond Jones
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA
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Chang MC, Wu HL, Lee JJ, Lee PH, Chang HH, Hahn LJ, Lin BR, Chen YJ, Jeng JH. The induction of prostaglandin E2 production, interleukin-6 production, cell cycle arrest, and cytotoxicity in primary oral keratinocytes and KB cancer cells by areca nut ingredients is differentially regulated by MEK/ERK activation. J Biol Chem 2004; 279:50676-83. [PMID: 15375172 DOI: 10.1074/jbc.m404465200] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
There are about 200-600 million betel quid (BQ) chewers in the world. BQ chewing is one of the major risk factor of hepatocarcinoma, oropharyngeal, and esophagus cancers in Taiwan, India, and Southeast Asian countries. Thus, the precise molecular mechanisms deserve investigation. We used cultured primary keratinocytes and KB cells, RT-PCR, flow cytometry, Western blotting, and ELISA to evaluate whether alterations in early gene expression is crucial in the carcinogenic processes of BQ. We observed the induction of c-Fos mRNA expression in human gingival keratinocyte (GK) and KB carcinoma cells by areca nut (AN) extract and arecoline. A maximal increment in c-fos gene expression was shown at about 30 min after challenge. AN extract (100-800 microg/ml) and arecoline (0.1-0.8 mM) also stimulated ERK1/ERK2 phosphorylation with a maximal stimulation at 5-10 min of exposure. Pretreatment by U0126 (30 microM), a MEK inhibitor, markedly inhibited the c-Fos, cyclooxygenase-2 (COX-2), and IL-6 mRNA expression of the KB epithelial cells. In addition, U0126 and PD98059 (50 microM) also decreased AN extract- and arecoline-associated PGE2 and IL-6 production in GK and KB cells. However, U0126 by itself arrested the cells in G0/G1 phase, but was not able to prevent AN- and arecoline-induced cell death or apoptosis. In contrast, U0126 enhanced the AN-induced apoptosis of KB cells. AN ingredients thus play a significant role in the pathogenesis of oropharyngeal cancer by activation of MEK1/ERK/c-Fos pathway, which promotes keratinocyte inflammation, cell survival, and affects cell cycle progression.
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Affiliation(s)
- Mei-Chi Chang
- Team of Biomedical Science, Chang-Gung Institute of Technology, Kwei-Shan, Taoyuan, Taiwan
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Wendum D, Masliah J, Trugnan G, Fléjou JF. Cyclooxygenase-2 and its role in colorectal cancer development. Virchows Arch 2004; 445:327-33. [PMID: 15340847 DOI: 10.1007/s00428-004-1105-2] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2004] [Accepted: 07/12/2004] [Indexed: 12/17/2022]
Abstract
Cyclooxygenase 2 (COX-2), also called prostaglandin endoperoxide synthase 2, is involved in colorectal tumor development. This review deals with particular questions raised in this field such as the mechanisms of COX-2 related tumor promotion, the role of the different types of cells (epithelial and interstitial) expressing COX-2, the factors that trigger COX-2 induction, and the clinical potential of selective COX-2 inhibitors to treat or prevent colorectal tumors. Several mechanisms of COX-2 related tumor promotion have been identified. Some are dependent on prostaglandin E(2) production (such as induction of cell proliferation, angiogenenis or local immunosuppression, inhibition of apoptosis, increase in cell motility) and others are not (such as carcinogen activation or malondialdehyde production). COX-2 expression has been demonstrated in epithelial cells of colorectal cancers and adenomas and also in interstitial cells. These cells correspond to macrophages and/or fibroblasts and endothelial cells. COX-2 expression in these interstitial cells participates in tumor development. Factors or events that trigger COX-2 expression include oncogene activation, antioncogene inactivation, cytokines, growth factors, some fatty acids, bile salts, and mucins. Finally, selective COX-2 inhibitors may be effective in preventing or treating colorectal adenomas or carcinomas. However, their real efficiency and the cost/benefit balance are currently evaluated, and no definite conclusion can be made at the moment.
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Affiliation(s)
- Dominique Wendum
- Service d'Anatomie Pathologique, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France.
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Ogawa H, Rafiee P, Fisher PJ, Johnson NA, Otterson MF, Binion DG. Butyrate modulates gene and protein expression in human intestinal endothelial cells. Biochem Biophys Res Commun 2003; 309:512-9. [PMID: 12963019 DOI: 10.1016/j.bbrc.2003.08.026] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We hypothesized that sodium butyrate, a product of enteric bacterial fermentation, modulates gene expression in gut microvascular endothelium which plays a central role in mucosal immunity. We examined sodium butyrate's effect on LPS-induced gene and protein expression in primary cultures of human intestinal microvascular endothelial cells. cDNA array analysis revealed that sodium butyrate augmented ICAM-1 mRNA expression, while it inhibited IL-6 and COX-2 expression in response to LPS stimulation. These results were confirmed at the protein level. Prostaglandin E2 production by LPS was also strongly inhibited by butyrate. The pattern of altered gene expression by butyrate was reproduced by the histone deacetylase inhibitor tricostatin A, suggesting that the regulatory mechanism of butyrate on HIMEC gene expression involves histone deacetylase inhibition. IkappaBalpha degradation and NF-kappaB activation were unaffected by butyrate. In addition to effects on epithelium, sodium butyrate modulates the innate mucosal immune response towards LPS through effects on microvascular endothelial function.
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Affiliation(s)
- Hitoshi Ogawa
- Department of Medicine, Digestive Disease Center, Free Radical Research Center, Froedtert Memorial Lutheran Hospital, Milwaukee Veterans Administration Medical Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Zeng H, Davis CD. Down-regulation of proliferating cell nuclear antigen gene expression occurs during cell cycle arrest induced by human fecal water in colonic HT-29 cells. J Nutr 2003; 133:2682-7. [PMID: 12888658 DOI: 10.1093/jn/133.8.2682] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Cancer is a disease in which the cell cycle is altered, and the elucidation of the mechanisms by which constituents of human fecal water influence the cell cycle can lead to noninvasive measurement of colon cancer risk. The purpose of the present study was to investigate the effect of human fecal water on HT-29 cell-cycle progression with sodium selenite as a reference for comparison. Both human fecal water (2.5-5.0%) and selenite (3-4 micro mol/L) significantly inhibited cell growth. Cell-cycle analysis revealed that human fecal water decreased the proportion of S + G2 phase cells and increased that of G1 phase cells. In contrast, selenite decreased G1 phase cells and increased proportions of S and G2 phase cells. Both 5% human fecal water and 4 micro mol/L selenite greatly increased the mRNA level of the cyclin-dependent kinase inhibitor gene p21(waf1). Interestingly, the mRNA levels of cyclin A and proliferating cell nuclear antigen (PCNA) were dramatically decreased by 69 and 62%, respectively, in HT-29 cells treated with fecal water but not selenite. In contrast, the mRNA level of DNA damage-inducible transcript 1, gadd45, was significantly increased by 2.28-fold in HT-29 cells treated with selenite but not fecal water. Furthermore, a PCNA gene promoter was cloned into a luciferase reporter construct and its activity was significantly reduced in a dose-dependent manner in cells treated with fecal water but not selenite. Collectively, these results suggest that human fecal water and selenite can differentially induce growth arrest genes, and that PCNA gene expression is uniquely and highly sensitive to human fecal water.
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Affiliation(s)
- Huawei Zeng
- U.S. Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034, USA.
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Abstract
Invasion causes cancer malignancy. We review recent data about cellular and molecular mechanisms of invasion, focusing on cross-talk between the invaders and the host. Cancer disturbs these cellular activities that maintain multicellular organisms, namely, growth, differentiation, apoptosis, and tissue integrity. Multiple alterations in the genome of cancer cells underlie tumor development. These genetic alterations occur in varying orders; many of them concomitantly influence invasion as well as the other cancer-related cellular activities. Examples discussed are genes encoding elements of the cadherin/catenin complex, the nonreceptor tyrosine kinase Src, the receptor tyrosine kinases c-Met and FGFR, the small GTPase Ras, and the dual phosphatase PTEN. In microorganisms, invasion genes belong to the class of virulence genes. There are numerous clinical and experimental observations showing that invasion results from the cross-talk between cancer cells and host cells, comprising myofibroblasts, endothelial cells, and leukocytes, all of which are themselves invasive. In bone metastases, host osteoclasts serve as targets for therapy. The molecular analysis of invasion-associated cellular activities, namely, homotypic and heterotypic cell-cell adhesion, cell-matrix interactions and ectopic survival, migration, and proteolysis, reveal branching signal transduction pathways with extensive networks between individual pathways. Cellular responses to invasion-stimulatory molecules such as scatter factor, chemokines, leptin, trefoil factors, and bile acids or inhibitory factors such as platelet activating factor and thrombin depend on activation of trimeric G proteins, phosphoinositide 3-kinase, and the Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of proinvasive fragments from cell surface glycoproteins.
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Affiliation(s)
- Marc Mareel
- Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Belgium.
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Davis CD. Low dietary copper increases fecal free radical production, fecal water alkaline phosphatase activity and cytotoxicity in healthy men. J Nutr 2003; 133:522-7. [PMID: 12566494 DOI: 10.1093/jn/133.2.522] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
One possible dietary factor that may increase susceptibility to colon cancer is inadequate copper intake. The objective of this study was to investigate the effects of low and adequate copper intakes on copper nutriture and putative risk factors for colon cancer susceptibility in healthy men. Seventeen healthy free-living nonsmoking men aged 21-52 y completed a 13-wk controlled feeding study in a randomized crossover design. The basal diet contained 0.59 mg Cu/13.65 MJ. After a 1-wk equilibration period in which the men consumed the basal diet supplemented with 1.0 mg Cu/d, they were randomly assigned to receive either the basal diet or the basal diet supplemented with 2 mg Cu/d for 6 wk. After the first dietary period, the men immediately began to consume the other level of Cu for the last 6 wk. They collected their feces during the equilibration period and during the last 2 wk of the two dietary periods for free radical and fecal water analysis. Low dietary copper significantly (P < 0.01) increased fecal free radical production and fecal water alkaline phosphatase activity. Low dietary copper significantly (P < 0.0001) decreased fecal water copper concentrations but did not affect fecal water volume, pH, iron or zinc concentrations. In contrast to the fecal analysis, hematological indicators of copper status were not significantly affected by the dietary treatments. These results suggest that low dietary copper adversely affects fecal free radical production and fecal water alkaline phosphatase activity, which are putative risk factors for colon cancer.
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Affiliation(s)
- Cindy D Davis
- U.S. Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034, USA.
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Nordling MM, Glinghammar B, Karlsson PC, T M C M de Kok, Rafter JJ. Effects on Cell Proliferation, Activator Protein-1 and Genotoxicity by Fecal Water from Patients with Colorectal Adenomas. Scand J Gastroenterol 2003; 38:549-555. [PMID: 28443764 DOI: 10.1080/00365520310002913] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The free water phase of feces (fecal water) may mediate the effects of diet on colon carcinogenesis. We examined the effects of fecal water from adenoma patients and controls on three parameters in colonocytes believed to be relevant to tumorigenesis, i.e. genotoxicity in intact cells and on isolated DNA, proliferative activity and activator protein-1 (AP-1) activity. METHODS Genotoxicity in intact colonic cells was assayed using the single-cell gel electrophoresis assay (`comet' assay) and on isolated DNA using double-stranded DNA from the X-174 RF plasmid. Cell proliferation was assessed using the commercially available `alamar blue' proliferation kit and AP-1 activity using cells transiently transfected with an AP-1-luciferase reporter construct. RESULTS The data showed that lipid extracts of fecal water samples from the adenoma patients had a significantly higher capacity to induce cell proliferation than those from controls, and that this effect could be explained to a large extent by the concentrations of deoxycholic and chenodeoxycholic acids in the fecal water using regression models. No difference between patients and controls was observed for induction of AP-1 activity or induction of DNA strand breaks in intact cells. However, induction of DNA strand breaks in isolated DNA was significantly higher for the fecal waters from patients than for those from controls, which could be explained in part in a regression model by concentrations of lithocholic acid in fecal water and fecapentaene-12 in feces. CONCLUSIONS Our results support the hypothesis that the biochemistry of fecal waters from adenoma patients and controls differs.
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Affiliation(s)
- M M Nordling
- a Dept. of Medical Nutrition Karolinska Institutet Novum Huddinge Sweden
| | - B Glinghammar
- b King Gustav V Research Institute Karolinska Hospital Stockholm Sweden
| | - P C Karlsson
- c Dept. of Health Risk Analysis and Toxicology University of Maastricht Maastricht The Netherlands
| | - T M C M de Kok
- a Dept. of Medical Nutrition Karolinska Institutet Novum Huddinge Sweden
| | - J J Rafter
- b King Gustav V Research Institute Karolinska Hospital Stockholm Sweden
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Debruyne PR, Bruyneel EA, Karaguni IM, Li X, Flatau G, Müller O, Zimber A, Gespach C, Mareel MM. Bile acids stimulate invasion and haptotaxis in human colorectal cancer cells through activation of multiple oncogenic signaling pathways. Oncogene 2002; 21:6740-50. [PMID: 12360401 DOI: 10.1038/sj.onc.1205729] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2002] [Revised: 05/16/2002] [Accepted: 06/07/2002] [Indexed: 12/19/2022]
Abstract
Bile acids are implicated in colorectal carcinogenesis as evidenced by epidemiological and experimental studies. We examined whether bile acids stimulate cellular invasion of human colorectal and dog kidney epithelial cells at different stages of tumor progression. Colon PC/AA/C1, PCmsrc, and HCT-8/E11 cells and kidney MDCKT23 cells were seeded on top of collagen type I gels and invasive cells were counted after 24 h incubation. Activation of the Rac1 and RhoA small GTPases was investigated by pull-down assays. Haptotaxis was analysed with modified Boyden chambers. Lithocholic acid, chenodeoxycholic acid, cholic acid and deoxycholic acid stimulated cellular invasion of SRC- and RhoA-transformed PCmsrc and MDCKT23-RhoAV14 cells, and of HCT-8/E11 cells originating from a sporadic tumor, but were ineffective in premalignant PC/AA/C1 and MDCKT23 cells. Bile acid-stimulated invasion occurred through stimulation of haptotaxis and was dependent on the RhoA/Rho-kinase pathway and signaling cascades using protein kinase C, mitogen-activated protein kinase, and cyclooxygenase-2. Accordingly, BA-induced invasion was associated with activation of the Rac1 and RhoA GTPases and expression of the farnesoid X receptor. We conclude that bile acids stimulate invasion and haptotaxis in colorectal cancer cells via several cancer invasion signaling pathways.
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Affiliation(s)
- P R Debruyne
- Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, B-9000 Ghent, Belgium
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Tian G, Yu JP, Luo HS, Yu BP, Yue H, Li JY, Mei Q. Effect of Nimesulide on proliferation and apoptosis of human hepatoma SMMC-7721 cells. World J Gastroenterol 2002; 8:483-7. [PMID: 12046075 PMCID: PMC4656426 DOI: 10.3748/wjg.v8.i3.483] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Cyclooxygenase-2 (COX-2) has been suggested to be associated with carcinogenesis. We sought to investigate the effect of the selective COX-2 inhibitor, Nimesulide on proliferation and apoptosis of SMMC-7721 human hepatoma cells.
METHODS: This study was carried out on the culture of hepatic carcinoma SMMC-7721 cell line. Various concentrations of Nimesulide (0, 200 μmol/L, 300 μmol/L, 400 μmol/L) were added and incubated. Cell proliferation was detected with MTT colorimetric assay, cell apoptosis by electron microscopy, flow cytometry and TUNEL.
RESULTS: Nimesulide could significantly inhibit SMMC-7721 cells proliferation dose-dependent and in a dependent manner compared with that of the control group. The duration lowest inhibition rate produced by Nimesulide in SMMC-7721 cells was 19.06%, the highest inhibition rate was 58.49%. After incubation with Nimesulide for 72 h, the most highest apoptosis rate and apoptosis index of SMMC-7721 cells comparing with those of the control were 21.20% ± 1.62% vs 2.24% ± 0.26% and 21.23 ± 1.78 vs 2.01 ± 0.23 (P < 0.05).
CONCLUSION: The selective COX-2 inhibitor, Nimesulide can inhibit the proliferation of SMMC-7721 cells and increase apoptosis rate and apoptosis index of SMMC-7721 cells. The apoptosis rate and the apoptosis index are dose-dependent. Under electron microscope SMMC-7721 cells incubated with 300 μmol and 400 μmol Nimesulide show apoptotic characteristics. With the clarification of the mechanism of selective COX-2 inhibitors, These COX-2 selective inhibitors can become the choice of prevention and treatment of cancers.
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Affiliation(s)
- Geng Tian
- Gastroenterology department. Renmin hospital of Wuhan university, 238 Jie-fang Road,Wuhan 430060,Hubei Province,China
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Dalgleish AG, O'Byrne KJ. Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. Adv Cancer Res 2002; 84:231-76. [PMID: 11883529 DOI: 10.1016/s0065-230x(02)84008-8] [Citation(s) in RCA: 130] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.
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Affiliation(s)
- Angus G Dalgleish
- Department of Oncology, St George's Hospital Medical School, London, United Kingdom
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Zhang F, Altorki NK, Wu YC, Soslow RA, Subbaramaiah K, Dannenberg AJ. Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids. Gastroenterology 2001; 121:1391-9. [PMID: 11729118 DOI: 10.1053/gast.2001.29781] [Citation(s) in RCA: 105] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND & AIMS Reflux of duodenal contents including bile acids is believed to contribute to esophageal injury and Barrett's esophagus. Cyclooxygenase (COX)-2, an inducible form of COX, has been implicated in both inflammation and carcinogenesis. In this study, we investigated the effects of bile acids and duodenal reflux on COX-2 expression in cultured esophageal cells and tissue, respectively. METHODS Immunoblotting and Northern blotting were used to assess the effects of bile acids on COX-2 expression in esophageal cell lines. Immunoblotting and immunohistochemistry were performed to evaluate the effects of duodenal reflux on COX-2 expression and cell proliferation in esophageal tissue. RESULTS Unconjugated bile acids were about fivefold more potent inducers of COX-2 messenger RNA, COX-2 protein, and prostaglandin synthesis than conjugated bile acids. Acidifying the culture medium sensitized esophageal cells to bile acid-mediated induction of COX-2. The induction of COX-2 by bile acids was mediated by phosphatidylinositol-3 kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. In experimental animals, duodenoesophageal reflux led to esophagitis, marked thickening of the esophageal mucosa, and enhanced expression of COX-2. Increased immunoreactivity for Ki-67 and cyclin D1 indicated that enhanced cell proliferation contributed to mucosal thickening. CONCLUSIONS Reflux of duodenal contents into the esophagus led to increased COX-2 expression and mucosal thickening. Bile acids are likely to contribute to these effects.
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Affiliation(s)
- F Zhang
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
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