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Chen PT, Chien WC, Chung CH, Chen PJ, Huang TY, Chen HW. Risk of colon polyps and colorectal cancer in primary biliary cholangitis, a population-based retrospective cohort study in Taiwan. J Formos Med Assoc 2025:S0929-6646(25)00176-7. [PMID: 40253262 DOI: 10.1016/j.jfma.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/27/2025] [Accepted: 04/10/2025] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND & AIMS Bile acids are carcinogens causing mutations leading to colorectal cancer (CRC). Higher total bile acid concentrations in the serum of patients with primary biliary cholangitis (PBC), compared to healthy controls, have been reported in previous studies. However, the association between PBC and the risk for CRC remains controversial. We investigated the association between PBC and the development of colonic polyps leading to CRC overall in this study. METHODS The study enrolled 1,936,512 individuals from the Longitudinal Health Insurance Database spanning 2000 to 2017 for cohort analysis. Individuals assigned to ICD-9-CM and ICD-10-CM codes representing PBC were incorporated. A 1:4 control cohort was randomly selected. After adjusting for CRC risk factors using Cox regression analysis, we calculated the hazard ratios for developing colon polyps and CRC in PBC patients compared to the general population. RESULTS Within the study cohort, consisting of 2024 individuals meeting the inclusion criteria, 199 patients developed colon polyps or CRC. In contrast, among the 8096 individuals in the comparison cohort, 650 cases of colon polyps or CRC were observed during the 17-year-follow-up period. According to Cox regression analysis, the adjusted hazard ratio indicated that the risk was 1.678 times higher in the PBC group compared to the comparison group. CONCLUSIONS This population-based retrospective cohort study identified a 1.68-fold increased risk of colon polyps and CRC in patients with PBC, suggesting a potential association with colonic neoplasia. Further research is warranted to evaluate the role of endoscopic surveillance in patients with PBC.
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Affiliation(s)
- Pei-Tzu Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Medicine, Hualien Armed Forces General Hospital, Hualien City, Taiwan
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Hsiang Chung
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Peng-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tien-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsuan-Wei Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
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2
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Tang X, He M, Ren Y, Ji M, Yan X, Zeng W, Lv Y, Li Y, He Y. Traditional Chinese Medicine formulas-based interventions on colorectal carcinoma prevention: The efficacies, mechanisms and advantages. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:119008. [PMID: 39471879 DOI: 10.1016/j.jep.2024.119008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/08/2024] [Accepted: 10/26/2024] [Indexed: 11/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Traditional Chinese Medicine Formulas (TCMFs) represent a distinctive medical approach to disease treatment and have been utilized in clinical practice for treating intestinal diseases for thousands of years. Recently, TCMFs have received increasing attention due to their advantages of high efficiency, safety, as well as low toxicity, providing promising strategies for preventing colorectal carcinoma (CRC). Nonetheless, the potential mechanism of TCMFs in preventing CRC has not been fully elucidated. AIM OF THE STUDY The literature from the past three years was reviewed to highlight the therapeutic effects and underlying mechanisms of TCMFs in preventing CRC. MATERIALS AND METHODS The keywords have been searched, including "traditional Chinese medicine formulas," "herb pairs," "Herbal plant-derived nanoparticles," et al. in "PubMed" and "China National Knowledge Infrastructure (CNKI)," and screened published articles related to the treatment of intestinal precancerous lesions. This review primarily examined the effectiveness and mechanisms of TCMFs in treating intestinal precancerous lesions, highlighting their significant potential in preventing CRC. RESULTS Gegen Qinlian decoction, Shaoyao decoction, Wu Wei Wan, etc., exert substantial therapeutic effects on intestinal precancerous lesions. These therapeutic effects are demonstrated by a reduction in disease activity index scores, suppression of intestinal inflammation, and preservation of body weight and intestinal function, all of which contribute to the effective prevention of CRC. Besides, the classic Chinese herbal pairs and the extracellular vesicle-like nanoparticles of herbaceous plants have demonstrated superior efficacy in the treatment of intestinal precancerous lesions. Mechanistically, protecting the epithelial barrier, regulating gut microbiota as well as related metabolism, modulating macrophage polarization, and maintaining immune balance contribute to the role of TCMFs in CRC prevention. CONCLUSIONS This review demonstrates the great potential and mechanism of TCMFs in CRC prevention and provides a scientific basis for their utilization in CRC prevention.
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Affiliation(s)
- Xiaojuan Tang
- School of biomedical sciences, Hunan University, Changsha, 410012, Hunan, China; Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, 410006, Hunan, China; Hunan Academy of Chinese Medicine, Changsha, 410006, Hunan, China.
| | - Min He
- Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Yuan Ren
- Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Meng Ji
- Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Xiaoqi Yan
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, 410006, Hunan, China
| | - Wen Zeng
- Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Yuan Lv
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, 410006, Hunan, China; Hunan Academy of Chinese Medicine, Changsha, 410006, Hunan, China
| | - Yongmin Li
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, 410006, Hunan, China; Hunan Academy of Chinese Medicine, Changsha, 410006, Hunan, China
| | - Yongheng He
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, 410006, Hunan, China; Hunan Academy of Chinese Medicine, Changsha, 410006, Hunan, China; Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China.
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3
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Varanasi SK, Chen D, Liu Y, Johnson MA, Miller CM, Ganguly S, Lande K, LaPorta MA, Hoffmann FA, Mann TH, Teneche MG, Casillas E, Mangalhara KC, Mathew V, Sun M, Jensen IJ, Farsakoglu Y, Chen T, Parisi B, Deota S, Havas A, Lee J, Chung HK, Schietinger A, Panda S, Williams AE, Farber DL, Dhar D, Adams PD, Feng GS, Shadel GS, Sundrud MS, Kaech SM. Bile acid synthesis impedes tumor-specific T cell responses during liver cancer. Science 2025; 387:192-201. [PMID: 39787217 DOI: 10.1126/science.adl4100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 08/26/2024] [Accepted: 10/30/2024] [Indexed: 01/12/2025]
Abstract
The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.
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Affiliation(s)
- Siva Karthik Varanasi
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Dan Chen
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Yingluo Liu
- Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Melissa A Johnson
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Cayla M Miller
- Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Souradipta Ganguly
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Department of Medicine, School of Medicine, University of California, San Diego, CA, USA
| | - Kathryn Lande
- The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Michael A LaPorta
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Filipe Araujo Hoffmann
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Thomas H Mann
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Marcos G Teneche
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Eduardo Casillas
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Kailash C Mangalhara
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Varsha Mathew
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Ming Sun
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Isaac J Jensen
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Yagmur Farsakoglu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Timothy Chen
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Bianca Parisi
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Shaunak Deota
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Aaron Havas
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Jin Lee
- Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - H Kay Chung
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Andrea Schietinger
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
- Parker Institute for Cancer Immunotherapy, New York, NY, USA
| | - Satchidananda Panda
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - April E Williams
- The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Donna L Farber
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Debanjan Dhar
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Department of Medicine, School of Medicine, University of California, San Diego, CA, USA
| | - Peter D Adams
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Gen-Sheng Feng
- Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Gerald S Shadel
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Mark S Sundrud
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- Center for Digestive Health, Dartmouth Health, Lebanon, NH, USA
- Dartmouth Cancer Center, Dartmouth Health, Lebanon, NH, USA
| | - Susan M Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
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Kumar A, Gwalani P, Iyer PG, Wang KK, Falk GW, Ginsberg GG, Lightdale CJ, Del Portillo A, Lagana SM, Li Y, Li H, Genkinger J, Jin Z, Rustgi AK, Wang TC, Wang HH, Quante M, Abrams JA. Shifts in Serum Bile Acid Profiles Associated With Barrett's Esophagus and Stages of Progression to Esophageal Adenocarcinoma. Clin Transl Gastroenterol 2024; 15:e1. [PMID: 39166758 PMCID: PMC11500780 DOI: 10.14309/ctg.0000000000000762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024] Open
Abstract
INTRODUCTION Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11-3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.
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Affiliation(s)
- Aarti Kumar
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Pranav Gwalani
- Division of Internal Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Prasad G. Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kenneth K. Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gary W. Falk
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Gregory G. Ginsberg
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Charles J. Lightdale
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Armando Del Portillo
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
| | - Stephen M. Lagana
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
| | - Yun Li
- Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Hongzhe Li
- Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jeanine Genkinger
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York, USA
| | - Zhezhen Jin
- Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York, USA
| | - Anil K. Rustgi
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
- Digestive and Liver Disease Research Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Timothy C. Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
- Digestive and Liver Disease Research Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Harris H. Wang
- Digestive and Liver Disease Research Center, Columbia University Irving Medical Center, New York, New York, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New Yok, New York, USA
| | | | - Julian A. Abrams
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
- Digestive and Liver Disease Research Center, Columbia University Irving Medical Center, New York, New York, USA
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Ni M, Zhang Y, Sun Z, Zhou Q, Xiao J, Zhang B, Lin J, Gong B, Liu F, Meng F, Zheng G, Wang Y, Gu L, Li L, Shen W, Chen Y, Liu Y, Li L, Ling T, Cheng H. Efficacy and safety of Shenbai Granules for recurrent colorectal adenoma: A multicenter randomized controlled trial. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 127:155496. [PMID: 38471368 DOI: 10.1016/j.phymed.2024.155496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/25/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Colorectal adenoma is benign glandular tumor of colon, the precursor of colorectal cancer. But no pharmaceutical medication is currently available to treat and prevent adenomas. PURPOSE To evaluate efficacy of Shenbai Granules, an herbal medicine formula, in reducing the recurrence of adenomas. STUDY DESIGN This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted by eight hospitals in China. METHODS Patients who had received complete polypectomy and were diagnosed with adenomas within the recent 6 months were randomly assigned (1:1) to receive either Shenbai granules or placebo twice a day for 6 months. An annual colonoscopy was performed during the 2-year follow-up period. The primary outcome was the proportion of patients with at least one adenoma detected in the modified intention-to-treat (mITT) population during follow-up for 2 years. The secondary outcomes were the proportion of patients with sessile serrated lesions and other specified polypoid lesions. The data were analyzed using logistic regression. RESULTS Among 400 randomized patients, 336 were included in the mITT population. We found significant differences between treatment and placebo groups in the proportion of patients with at least one recurrent adenoma (42.5 % vs. 58.6 %; OR, 0.47; 95 % CI, 0.29-0.74; p = 0.001) and sessile serrated lesion (1.8 % vs. 8.3 %; OR, 0.20; 95 % CI, 0.06-0.72; p = 0.01). There was no significant difference in the proportion of patients developing polypoid lesions (70.7 % vs. 77.5 %; OR, 1.43; 95 % CI, 0.88-2.34; p = 0.15) or high-risk adenomas (9.0 % vs. 13.6 %; OR, 0.63; 95 % CI, 0.32-1.25; p = 0.18). CONCLUSION Shenbai Granules significantly reduced the recurrence of adenomas, indicating that they could be an effective option for adenomas. Future studies should investigate its effects in larger patient populations and explore its mechanism of action to provide more comprehensive evidence for the use of Shenbai Granules in adenoma treatment.
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Affiliation(s)
- Mingxin Ni
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China
| | - Ye Zhang
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China; Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Zhenzhen Sun
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China
| | - Qing Zhou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Jun Xiao
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Beiping Zhang
- Department of Spleen and Stomach Disease, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China
| | - Jiang Lin
- Department of Spleen and Stomach Diseases, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Biao Gong
- Department of Digestive Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Fengbin Liu
- Department of Gastroenterology, the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, China
| | - Fandong Meng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Guoyin Zheng
- Department of Traditional Chinese Medicine, Affiliated Hospital of Naval Military Medical University, Shanghai 200433, China
| | - Yan Wang
- Digestive Endoscopy Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Limei Gu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Liu Li
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China
| | - Weixing Shen
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China
| | - Yugen Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Yanmei Liu
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ling Li
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Tingsheng Ling
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
| | - Haibo Cheng
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China.
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Abstract
Colorectal cancer (CRC) is a substantial source of global morbidity and mortality in dire need of improved prevention and treatment strategies. As our understanding of CRC grows, it is becoming increasingly evident that the gut microbiota, consisting of trillions of microorganisms in direct interface with the colon, plays a substantial role in CRC development and progression. Understanding the roles that individual microorganisms and complex microbial communities play in CRC pathogenesis, along with their attendant mechanisms, will help yield novel preventive and therapeutic interventions for CRC. In this Review, we discuss recent evidence concerning global perturbations of the gut microbiota in CRC, associations of specific microorganisms with CRC, the underlying mechanisms by which microorganisms potentially drive CRC development and the roles of complex microbial communities in CRC pathogenesis. While our understanding of the relationship between the microbiota and CRC has improved in recent years, our findings highlight substantial gaps in current research that need to be filled before this knowledge can be used to the benefit of patients.
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Affiliation(s)
- Maxwell T White
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cynthia L Sears
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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7
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Tan S, Ou Y, Yang Y, Huang S, Chen S, Gao Q. Preventive effects of chemical drugs on recurrence of colorectal adenomas: systematic review and Bayesian network meta-analysis. Eur J Gastroenterol Hepatol 2024; 36:62-75. [PMID: 37942763 DOI: 10.1097/meg.0000000000002676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
BACKGROUND The onset of colorectal adenomas (CRAs) is significantly associated with colorectal cancer. The preventive effects of chemical drugs on the recurrence of CRAs have been evaluated in a large number of randomized controlled trials (RCTs). However, there are still uncertainties about the relative effectiveness of such chemical drugs. METHODS We searched relevant RCTs published in six databases up to February 2023. The quality of the included studies was assessed by using the Cochrane risk of bias assessment tool and Review Manager 5.4. Pairwise comparison and network meta-analysis (NMA) were conducted using RStudio to compare the effects of chemical drugs on the recurrence of CRAs. RESULTS Forty-five high-quality RCTs were included. A total of 35 590 (test group: 20 822; control group: 14 768) subjects with a history of CRAs have been enrolled and randomized to receive placebo treatment or one of 24 interventions. Based on surface under the cumulative ranking values and NMA results, difluoromethylornithine (DFMO) + Sulindac significantly reduced the recurrence of CRAs, followed by berberine and nonsteroidal antiinflammatory drugs. CONCLUSION DFMO + Sulindac is more effective in reducing the recurrence of CRAs but has a high risk of adverse events. Considering drug safety, tolerance, and compliance, berberine has a brighter prospect of clinical development. However, further studies are needed to verify our findings.
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Affiliation(s)
- Shufa Tan
- Shaanxi University of Traditional Chinese Medicine, Xianyang
| | - Yan Ou
- Shaanxi University of Traditional Chinese Medicine, Xianyang
| | - Yunyi Yang
- Shanghai University of Traditional Chinese Medicine, Shanghai
| | - Shuilan Huang
- Shaanxi University of Traditional Chinese Medicine, Xianyang
| | - Shikai Chen
- Shaanxi University of Traditional Chinese Medicine, Xianyang
| | - Qiangqiang Gao
- Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang, China
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8
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Nenkov M, Shi Y, Ma Y, Gaßler N, Chen Y. Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy. Int J Mol Sci 2023; 25:6. [PMID: 38203175 PMCID: PMC10778939 DOI: 10.3390/ijms25010006] [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: 11/08/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed.
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Affiliation(s)
- Miljana Nenkov
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Yihui Shi
- California Pacific Medical Center Research Institute, Sutter Bay Hospitals, San Francisco, CA 94107, USA;
| | - Yunxia Ma
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Nikolaus Gaßler
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Yuan Chen
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
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9
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Feng T, Hou P, Mu S, Fang Y, Li X, Li Z, Wang D, Chen L, Lu L, Lin K, Wang S. Identification of cholesterol metabolism-related subtypes in nonfunctioning pituitary neuroendocrine tumors and analysis of immune infiltration. Lipids Health Dis 2023; 22:127. [PMID: 37563740 PMCID: PMC10413501 DOI: 10.1186/s12944-023-01883-3] [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: 03/29/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the role of cholesterol metabolism-related genes in nonfunctioning pituitary neuroendocrine tumors (NF-PitNETs) invading the cavernous sinus and analyze the differences in immune cell infiltration between invasive and noninvasive NF-PitNETs. METHODS First, a retrospective analysis of single-center clinical data was performed. Second, the immune cell infiltration between invasive and noninvasive NF-PitNETs in the GSE169498 dataset was further analyzed, and statistically different cholesterol metabolism-related gene expression matrices were obtained from the dataset. The hub cholesterol metabolism-related genes in NF-PitNETs were screened by constructing machine learning models. In accordance with the hub gene, 73 cases of NF-PitNETs were clustered into two subtypes, and the functional differences and immune cell infiltration between the two subtypes were further analyzed. RESULTS The clinical data of 146 NF-PitNETs were evaluated, and the results showed that the cholesterol (P = 0.034) between invasive and noninvasive NF-PitNETs significantly differed. After binary logistic analysis, cholesterol was found to be an independent risk factor for cavernous sinus invasion (CSI) in NF-PitNETs. Bioinformatics analysis found three immune cells between invasive and noninvasive NF-PitNETs were statistically significant in the GSE169498 dataset, and 34 cholesterol metabolism-related genes with differences between the two groups were obtained 12 hub genes were selected by crossing the two machine learning algorithm results. Subsequently, cholesterol metabolism-related subgroups, A and B, were obtained by unsupervised hierarchical clustering analysis. The results showed that 12 immune cells infiltrated differentially between the two subgroups. The chi-square test revealed that the two subgroups had statistically significance in the invasive and noninvasive samples (P = 0.001). KEGG enrichment analysis showed that the differentially expressed genes were mainly enriched in the neural ligand-receptor pathway. GSVA analysis showed that the mTORC signaling pathway was upregulated and played an important role in the two-cluster comparison. CONCLUSION By clinical data and bioinformatics analysis, cholesterol metabolism-related genes may promote the infiltration abundance of immune cells in NF-PitNETs and the invasion of cavernous sinuses by NF-PitNETs through the mTOR signaling pathway. This study provides a new perspective to explore the pathogenesis of cavernous sinus invasion by NF-PitNETs and determine potential therapeutic targets for this disease.
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Grants
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019Y9045 the Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
- 2020QH2040 Startup Fund for scientific research at Fujian Medical University
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Affiliation(s)
- Tianshun Feng
- Department of Neurosurgery, Dongfang Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Fuzhou, China
| | - Pengwei Hou
- Department of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Shuwen Mu
- Department of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yi Fang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinxiong Li
- Department of General Surgery, School of Medicine, Dongfang Affiliated Hospital of Xiamen University, Xiamen University, Fuzhou, China
| | - Ziqi Li
- Department of Neurosurgery, Dongfang Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Fuzhou, China
| | - Di Wang
- Department of Molecular Pathology, Fujian Cancer Hospital, Clinical Oncology School of Fujian Medical University, Fuzhou, China
| | - Li Chen
- Department of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Lingling Lu
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Kunzhe Lin
- Department of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Shousen Wang
- Department of Neurosurgery, Dongfang Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Fuzhou, China.
- Department of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China.
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10
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Luu HN, Tran CTD, Wang R, Nguyen MVT, Tran MT, Tuong TTV, Tran QH, Le LC, Pham HTT, Vu HH, Bui NC, Ha HTT, Trinh DT, Thomas CE, Adams-Haduch J, Velikokhatnaya L, Schoen RE, Xie G, Jia W, Boffetta P, Clemente JC, Yuan JM. Associations between Ileal Juice Bile Acids and Colorectal Advanced Adenoma. Nutrients 2023; 15:2930. [PMID: 37447256 DOI: 10.3390/nu15132930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/23/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND There is an urgent need to identify biomarkers for advanced adenoma, an important precursor of colorectal cancer (CRC). We aimed to determine alterations in ileal juice bile acids associated with colorectal advanced adenoma. METHODS We quantified a comprehensive panel of primary and secondary bile acids and their conjugates using an ultraperformance liquid chromatography triple-quadrupole mass spectrometric assay in ileal juice collected at colonoscopy from 46 study subjects (i.e., 14 biopsy-confirmed advanced adenomas and 32 controls free of adenoma or cancer). Using analysis of covariance (ANCOVA), we examined the differences in bile acid concentrations by disease status, adjusting for age, sex, body mass index, smoking status and type 2 diabetes. RESULTS The concentrations of hyodeoxycholic acid (HCA) species in ileal juice of the advanced adenoma patients (geometric mean = 4501.9 nM) were significantly higher than those of controls (geometric mean = 1292.3 nM, p = 0.001). The relative abundance of ursodeoxycholic acid (UDCA) in total bile acids was significantly reduced in cases than controls (0.73% in cases vs. 1.33% in controls; p = 0.046). No significant difference between cases and controls was observed for concentrations of total or specific primary bile acids (i.e., cholic acid (CA), chenodeoxycholic acid (CDCA) and their glycine- and taurine-conjugates) and total and specific major secondary bile acids (i.e., deoxycholic acid and lithocholic acid). CONCLUSIONS Colorectal advanced adenoma was associated with altered bile acids in ileal juice. The HCA species may promote the development of colorectal advanced adenoma, whereas gut microbiota responsible for the conversion of CDCA to UDCA may protect against it. Our findings have important implications for the use of bile acids as biomarkers in early detection of colorectal cancer.
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Affiliation(s)
- Hung N Luu
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Chi Thi-Du Tran
- Vietnam Colorectal Cancer and Polyps Research, Vinmec Healthcare System, Hanoi 10000, Vietnam
- College of Health Sciences, VinUniversity (VinUni), Hanoi 10000, Vietnam
- Center of Applied Sciences, Regenerative Medicine and Advanced Technologies, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Renwei Wang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
| | - Mai Vu-Tuyet Nguyen
- Vietnam Colorectal Cancer and Polyps Research, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Mo Thi Tran
- Vietnam Colorectal Cancer and Polyps Research, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Thuy Thi-Van Tuong
- Vietnam Colorectal Cancer and Polyps Research, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Quang Hong Tran
- Vietnam Colorectal Cancer and Polyps Research, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Linh Cu Le
- College of Health Sciences, VinUniversity (VinUni), Hanoi 10000, Vietnam
| | - Huong Thi-Thu Pham
- Department of Gastroenterology, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Hien Huy Vu
- Department of Gastroenterology, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Nam Chi Bui
- Department of Gastroenterology, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Hien Thi-Thu Ha
- Department of Cytopathology, Vinmec Healthcare System, Hanoi 10000, Vietnam
| | - Dung Tuan Trinh
- Department of Cytopathology, Vinmec Healthcare System, Hanoi 10000, Vietnam
- Department of Cytopathology, Tam Anh General Hospital, Hanoi 10000, Vietnam
| | - Claire E Thomas
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | | | | | - Robert E Schoen
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Guoxiang Xie
- University of Hawai'i Cancer Center, University of Hawaii, Honolulu, HI 96813, USA
| | - Wei Jia
- University of Hawai'i Cancer Center, University of Hawaii, Honolulu, HI 96813, USA
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong
| | - Paolo Boffetta
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Jose C Clemente
- Icahn Institute for Genomics & Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jian-Min Yuan
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
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11
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Lepore Signorile M, Grossi V, Fasano C, Simone C. Colorectal Cancer Chemoprevention: A Dream Coming True? Int J Mol Sci 2023; 24:7597. [PMID: 37108756 PMCID: PMC10140862 DOI: 10.3390/ijms24087597] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the deadliest forms of cancer worldwide. CRC development occurs mainly through the adenoma-carcinoma sequence, which can last decades, giving the opportunity for primary prevention and early detection. CRC prevention involves different approaches, ranging from fecal occult blood testing and colonoscopy screening to chemoprevention. In this review, we discuss the main findings gathered in the field of CRC chemoprevention, focusing on different target populations and on various precancerous lesions that can be used as efficacy evaluation endpoints for chemoprevention. The ideal chemopreventive agent should be well tolerated and easy to administer, with low side effects. Moreover, it should be readily available at a low cost. These properties are crucial because these compounds are meant to be used for a long time in populations with different CRC risk profiles. Several agents have been investigated so far, some of which are currently used in clinical practice. However, further investigation is needed to devise a comprehensive and effective chemoprevention strategy for CRC.
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Affiliation(s)
- Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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12
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Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2023; 21:236-247. [PMID: 36253479 DOI: 10.1038/s41579-022-00805-x] [Citation(s) in RCA: 356] [Impact Index Per Article: 178.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/08/2022]
Abstract
Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.
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Affiliation(s)
- Stephanie L Collins
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - Jonathan G Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Public Health Sciences, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Health Liver Center, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jordan E Bisanz
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - C Denise Okafor
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
- Department of Chemistry, The Pennsylvania State University, University Park, PA, USA
| | - Andrew D Patterson
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
- Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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13
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Niekamp P, Kim CH. Microbial Metabolite Dysbiosis and Colorectal Cancer. Gut Liver 2023; 17:190-203. [PMID: 36632785 PMCID: PMC10018301 DOI: 10.5009/gnl220260] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/09/2022] [Accepted: 08/18/2022] [Indexed: 01/13/2023] Open
Abstract
The global burden of colorectal cancer (CRC) is expected to continuously increase. Through research performed in the past decades, the effects of various environmental factors on CRC development have been well identified. Diet, the gut microbiota and their metabolites are key environmental factors that profoundly affect CRC development. Major microbial metabolites with a relevance for CRC prevention and pathogenesis include dietary fiber-derived short-chain fatty acids, bile acid derivatives, indole metabolites, polyamines, trimethylamine-N-oxide, formate, and hydrogen sulfide. These metabolites regulate various cell types in the intestine, leading to an altered intestinal barrier, immunity, chronic inflammation, and tumorigenesis. The physical, chemical, and metabolic properties of these metabolites along with their distinct functions to trigger host receptors appear to largely determine their effects in regulating CRC development. In this review, we will discuss the current advances in our understanding of the major CRC-regulating microbial metabolites, focusing on their production and interactive effects on immune responses and tumorigenesis in the colon.
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Affiliation(s)
- Patrick Niekamp
- Department of Pathology and Mary H. Weiser Food Allergy Center, Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Chang H. Kim
- Department of Pathology and Mary H. Weiser Food Allergy Center, Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
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14
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Sfeir M, Jacobs ET, Kohler LN, Steck SE, Yung AK, Thomson CA. Characterizing Dietary Advanced Glycation End-Product (dAGE) Exposure and the Relationship to Colorectal Adenoma Recurrence: A Secondary Analysis. Nutrients 2023; 15:1126. [PMID: 36904125 PMCID: PMC10005122 DOI: 10.3390/nu15051126] [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: 01/12/2023] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Limited studies have evaluated the association between dietary advanced glycation end-product AGE (dAGEs) intake and cancer risk; however, no studies have addressed adenoma risk or recurrence. The objective of this study was to determine an association between dietary AGEs and adenoma recurrence. A secondary analysis was conducted using an existing dataset from a pooled sample of participants in two adenoma prevention trials. Participants completed a baseline Arizona Food Frequency Questionnaire (AFFQ) to estimate AGE exposure. NƐ- carboxymethyl-lysine (CML)-AGE values were assigned to quantify foods in the AFFQ using a published AGE database, and participants' exposure was evaluated as a CML-AGE (kU/1000 kcal) intake. Regression models were run to determine the relationship between CML-AGE intake and adenoma recurrence. The sample included 1976 adults with a mean age of 67.2 y ± 7.34. The average CML-AGE intake was 5251.1 ± 1633.1 (kU/1000 kcal), ranging between 4960 and 17032.4 (kU/1000 kcal). A higher intake of CML-AGE had no significant association with the odds of adenoma recurrence [OR(95% CI) = 1.02 (0.71,1.48)] compared to participants with a lower intake. In this sample, CML-AGE intake was not associated with adenoma recurrence. Future research is needed and should be expanded to examine the intake of different types of dAGEs with consideration for the direct measurement of AGE.
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Affiliation(s)
- Maren Sfeir
- School of Nutritional Science and Wellness, University of Arizona, 1177 E 4th St, Tucson, AZ 85719, USA
| | - Elizabeth T. Jacobs
- College of Mel and Enid Zuckerman, School of Public Health, University of Arizona, Tucson, AZ 85724, USA
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Lindsay N. Kohler
- College of Mel and Enid Zuckerman, School of Public Health, University of Arizona, Tucson, AZ 85724, USA
| | - Susan E. Steck
- School of Public Health, University of South Carolina Arnold, Columbia, SC 29208, USA
| | - Angela K. Yung
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Cynthia A. Thomson
- College of Mel and Enid Zuckerman, School of Public Health, University of Arizona, Tucson, AZ 85724, USA
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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15
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He Q, Wu J, Ke J, Zhang Q, Zeng W, Luo Z, Gong J, Chen Y, He Z, Lan P. Therapeutic role of ursodeoxycholic acid in colitis-associated cancer via gut microbiota modulation. Mol Ther 2023; 31:585-598. [PMID: 38556635 PMCID: PMC9931610 DOI: 10.1016/j.ymthe.2022.10.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 09/21/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a predisposing factor for colitis-associated cancer (CAC). The association between bile acids and the gut microbiota has been demonstrated in colon neoplasia; however, the effect of ursodeoxycholic acid (UDCA) on gut microbiota alteration in development of colitis and CAC is unknown. Our analysis of publicly available datasets demonstrated the association of UDCA treatment and accumulation of Akkermansia. UDCA-mediated alleviation of DSS-induced colitis was microbially dependent. UDCA treatment significantly upregulated Akkermansia colonization in a mouse model. Colonization of Akkermansia was associated with enhancement of the mucus layer upon UDCA treatment as well as activation of bile acid receptors in macrophages. UDCA played a role in CAC prevention and treatment in the AOM-DSS and ApcMin/+-DSS models through downregulation of inflammation and accumulation of Akkermansia. This study suggests that UDCA intervention could reshape intestinal gut homeostasis, facilitating colonization of Akkermansia and preventing and treating colitis and CAC.
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Affiliation(s)
- Qilang He
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Jinjie Wu
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Jia Ke
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Qiang Zhang
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Wanyi Zeng
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Zhanhao Luo
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Junli Gong
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Yuan Chen
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China
| | - Zhen He
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China.
| | - Ping Lan
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China.
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Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
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Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
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17
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Jiang X, Jiang Z, Cheng Q, Sun W, Jiang M, Sun Y. Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota. Front Med (Lausanne) 2022; 9:1000563. [PMID: 36213655 PMCID: PMC9540502 DOI: 10.3389/fmed.2022.1000563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/06/2022] [Indexed: 12/24/2022] Open
Abstract
The incidence and mortality of colorectal cancer (CRC) have been markedly increasing worldwide, causing a tremendous burden to the healthcare system. Therefore, it is crucial to investigate the risk factors and pathogenesis of CRC. Cholecystectomy is a gold standard procedure for treating symptomatic cholelithiasis and gallstone diseases. The rhythm of bile acids entering the intestine is altered after cholecystectomy, which leads to metabolic disorders. Nonetheless, emerging evidence suggests that cholecystectomy might be associated with the development of CRC. It has been reported that alterations in bile acid metabolism and gut microbiota are the two main reasons. However, the potential mechanisms still need to be elucidated. In this review, we mainly discussed how bile acid metabolism, gut microbiota, and the interaction between the two factors influence the development of CRC. Subsequently, we summarized the underlying mechanisms of the alterations in bile acid metabolism after cholecystectomy including cellular level, molecular level, and signaling pathways. The potential mechanisms of the alterations on gut microbiota contain an imbalance of bile acid metabolism, cellular immune abnormality, acid-base imbalance, activation of cancer-related pathways, and induction of toxin, inflammation, and oxidative stress.
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Affiliation(s)
- Xi Jiang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhongxiu Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qi Cheng
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- *Correspondence: Yan Sun,
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18
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Heer E, Ruan Y, Mah B, Nguyen T, Lyons H, Poirier A, Boyne DJ, O'Sullivan DE, Heitman SJ, Hilsden RJ, Forbes N, Brenner DR. The efficacy of chemopreventive agents on the incidence of colorectal adenomas: A systematic review and network meta-analysis. Prev Med 2022; 162:107169. [PMID: 35878711 DOI: 10.1016/j.ypmed.2022.107169] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 06/20/2022] [Accepted: 07/17/2022] [Indexed: 10/17/2022]
Abstract
Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs.
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Affiliation(s)
- Emily Heer
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Yibing Ruan
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada
| | - Brittany Mah
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Teresa Nguyen
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Hannah Lyons
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Abbey Poirier
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada
| | - Devon J Boyne
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Dylan E O'Sullivan
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Steven J Heitman
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert J Hilsden
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Nauzer Forbes
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Darren R Brenner
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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19
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Williams GJ, Hellerstedt ST, Scudder PN, Calderwood AH. Yield of Surveillance Colonoscopy in Older Adults with a History of Polyps: A Systematic Review and Meta-Analysis. Dig Dis Sci 2022; 67:4059-4069. [PMID: 34406584 PMCID: PMC10753972 DOI: 10.1007/s10620-021-07198-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 07/26/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND The benefit of surveillance colonoscopy in older adults is not well described. AIMS To quantify the detection of colorectal cancer (CRC) and advanced polyps during surveillance colonoscopy in older adults with a history of colon polyps. METHODS We conducted a systematic review (MEDLINE, Cochrane Library, Web of Science, and Embase) for all published studies through May 2020 in adults age > 70 undergoing surveillance colonoscopy. The main outcome was CRC and advanced polyps detection. We performed meta-analysis to pool results by age (>70 vs. 50-70). RESULTS The search identified 6239 studies, of which 569 underwent full-text review and 64 data abstraction, of which 19 were included. The risk of detecting CRC (N = 11) was higher in those >70 compared to 50-70 (risk ratio 1.5 (95% CI 1.1-2.2); risk difference 0.8% (95% CI -0.2%-1.8%)). Similarly, the risk of detecting advanced polyps (N = 8) was higher in those >70 compared to 50-70 (risk ratio 1.3 (95% CI 1.2-1.3), risk difference 2.7% (95% CI 1.3%-4.0%)). Most studies did not stratify results by baseline polyp risk. CONCLUSIONS The detection of CRC and advanced polyps during surveillance colonoscopy in older individuals was higher than in younger controls; however, the absolute risk increase for both was small. These differences must be weighed against competing medical problems and limited life expectancy in older adults when making decisions about surveillance colonoscopy. More primary data on the risks of CRC and advanced polyps accounting for number of past colonoscopies, prior polyp risk, and duration of time since last polyp are needed.
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Affiliation(s)
- Gregory J Williams
- The Dartmouth Institute of Health Policy and Clinical Practice, Lebanon, NH, USA
| | - Sage T Hellerstedt
- The Dartmouth Institute of Health Policy and Clinical Practice, Lebanon, NH, USA
| | - Paige N Scudder
- Dartmouth Biomedical Libraries, Dartmouth College, Hanover, NH, USA
| | - Audrey H Calderwood
- The Dartmouth Institute of Health Policy and Clinical Practice, Lebanon, NH, USA.
- Geisel School of Medicine At Dartmouth, Hanover, NH, USA.
- Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA.
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20
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Jang JY, Im E, Choi YH, Kim ND. Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review. Int J Mol Sci 2022; 23:7184. [PMID: 35806184 PMCID: PMC9266679 DOI: 10.3390/ijms23137184] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/22/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Bile acids are major signaling molecules that play a significant role as emulsifiers in the digestion and absorption of dietary lipids. Bile acids are amphiphilic molecules produced by the reaction of enzymes with cholesterol as a substrate, and they are the primary metabolites of cholesterol in the body. Bile acids were initially considered as tumor promoters, but many studies have deemed them to be tumor suppressors. The tumor-suppressive effect of bile acids is associated with programmed cell death. Moreover, based on this fact, several synthetic bile acid derivatives have also been used to induce programmed cell death in several types of human cancers. This review comprehensively summarizes the literature related to bile acid-induced programmed cell death, such as apoptosis, autophagy, and necroptosis, and the status of drug development using synthetic bile acid derivatives against human cancers. We hope that this review will provide a reference for the future research and development of drugs against cancer.
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Affiliation(s)
- Jung Yoon Jang
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Korea; (J.Y.J.); (E.I.)
| | - Eunok Im
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Korea; (J.Y.J.); (E.I.)
| | - Yung Hyun Choi
- Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Korea;
| | - Nam Deuk Kim
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Korea; (J.Y.J.); (E.I.)
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21
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Liu Y, Zhang S, Zhou W, Hu D, Xu H, Ji G. Secondary Bile Acids and Tumorigenesis in Colorectal Cancer. Front Oncol 2022; 12:813745. [PMID: 35574393 PMCID: PMC9097900 DOI: 10.3389/fonc.2022.813745] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 03/21/2022] [Indexed: 01/11/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and deadly cancers in the world and is a typical inflammatory tumor. In recent years, the incidence of CRC has been increasing year by year. There is evidence that the intake of high-fat diet and overweight are associated with the incidence of CRC, among which bile acids play a key role in the pathogenesis of the disease. Studies on the relationship between bile acid metabolism and the occurrence of CRC have gradually become a hot topic, improving the understanding of metabolic factors in the etiology of colorectal cancer. Meanwhile, intestinal flora also plays an important role in the occurrence and development of CRC In this review, the classification of bile acids and their role in promoting the occurrence of CRC are discussed, and we highlights how a high-fat diet affects bile acid metabolism and destroys the integrity of the intestinal barrier and the effects of gut bacteria.
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Affiliation(s)
- Yujing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengan Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Hu
- Department of Internal Medicine of Chinese Medicine, Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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22
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Režen T, Rozman D, Kovács T, Kovács P, Sipos A, Bai P, Mikó E. The role of bile acids in carcinogenesis. Cell Mol Life Sci 2022; 79:243. [PMID: 35429253 PMCID: PMC9013344 DOI: 10.1007/s00018-022-04278-2] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/03/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022]
Abstract
AbstractBile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.
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Affiliation(s)
- Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tünde Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
| | - Patrik Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Adrienn Sipos
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Péter Bai
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary.
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23
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Thomas JP, Modos D, Rushbrook SM, Powell N, Korcsmaros T. The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease. Front Immunol 2022; 13:829525. [PMID: 35185922 PMCID: PMC8850271 DOI: 10.3389/fimmu.2022.829525] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 01/14/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that arises due to complex interactions between host genetic risk factors, environmental factors, and a dysbiotic gut microbiota. Although metagenomic approaches have attempted to characterise the dysbiosis occurring in IBD, the precise mechanistic pathways interlinking the gut microbiota and the intestinal mucosa are still yet to be unravelled. To deconvolute these complex interactions, a more reductionist approach involving microbial metabolites has been suggested. Bile acids have emerged as a key class of microbiota-associated metabolites that are perturbed in IBD patients. In recent years, metabolomics studies have revealed a consistent defect in bile acid metabolism with an increase in primary bile acids and a reduction in secondary bile acids in IBD patients. This review explores the evolving evidence that specific bile acid metabolites interact with intestinal epithelial and immune cells to contribute to the inflammatory milieu seen in IBD. Furthermore, we summarise evidence linking bile acids with intracellular pathways that are known to be relevant in IBD including autophagy, apoptosis, and the inflammasome pathway. Finally, we discuss how novel experimental and bioinformatics approaches could further advance our understanding of the role of bile acids and inform novel therapeutic strategies in IBD.
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Affiliation(s)
- John P Thomas
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Organisms and Ecosystem, Earlham Institute, Norwich, United Kingdom.,Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - Dezso Modos
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Organisms and Ecosystem, Earlham Institute, Norwich, United Kingdom
| | - Simon M Rushbrook
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom.,Department of Hepatology, University of East Anglia Medical School, Norwich, United Kingdom
| | - Nick Powell
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - Tamas Korcsmaros
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Organisms and Ecosystem, Earlham Institute, Norwich, United Kingdom.,Division of Digestive Diseases, Imperial College London, London, United Kingdom
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24
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Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
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25
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Yang R, Du C, Cao T, Wang G, Jiang X, Gao J, Lin T, Sun C, Ding R, Tian W, Chen H. Synthesis and Anti-Hepatoma Activities of U12 Derivatives Arresting G0/G1 Phase and Inducing Apoptosis by PI3K/AKT/mTOR Pathway. Pharmaceuticals (Basel) 2022; 15:ph15010107. [PMID: 35056164 PMCID: PMC8781819 DOI: 10.3390/ph15010107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/12/2022] [Accepted: 01/14/2022] [Indexed: 11/22/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma.
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26
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Lin W, Li S, Meng Y, Huang G, Liang S, Du J, Liu Q, Cheng B. UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell-Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling. Front Pharmacol 2021; 12:755394. [PMID: 34975472 PMCID: PMC8714963 DOI: 10.3389/fphar.2021.755394] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 11/23/2021] [Indexed: 12/29/2022] Open
Abstract
Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell-induced angiogenesis and the possible mechanisms. Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE). Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8-induced angiogenesis in vitro and in vivo through suppressing IL-8-induced phosphorylation of ERK. The levels of HIF-1α mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1α degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1α overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell-induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF. Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell-induced angiogenesis through suppressing HIF-1α/VEGF/IL-8-mediated intercellular signaling between HCC cells and endothelial cells.
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Affiliation(s)
- Wanfu Lin
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Shu Li
- Department of Gastroenterology, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yongbin Meng
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Guokai Huang
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Shufang Liang
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Juan Du
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Qun Liu
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai, China
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27
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Fang Y, Yan C, Zhao Q, Xu J, Liu Z, Gao J, Zhu H, Dai Z, Wang D, Tang D. The roles of microbial products in the development of colorectal cancer: a review. Bioengineered 2021; 12:720-735. [PMID: 33618627 PMCID: PMC8806273 DOI: 10.1080/21655979.2021.1889109] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A large number of microbes exist in the gut and they have the ability to process and utilize ingested food. It has been reported that their products are involved in colorectal cancer development. The molecular mechanisms which underlie the relationship between gut microbial products and CRC are still not fully understood. The role of some microbial products in CRC is particularly controversial. Elucidating the effects of gut microbiota products on CRC and their possible mechanisms is vital for CRC prevention and treatment. In this review, recent studies are examined in order to describe the contribution metabolites and toxicants which are produced by gut microbes make to CRC, primarily focusing on the involved molecular mechanisms.Abbreviations: CRC: colorectal cancer; SCFAs: short chain fatty acids; HDAC: histone deacetylase; TCA cycle: tricarboxylic acid cycle; CoA: cytosolic acyl coenzyme A; SCAD: short chain acyl CoA dehydrogenase; HDAC: histone deacetylase; MiR-92a: microRNA-92a; KLF4: kruppel-like factor; PTEN: phosphatase and tensin homolog; PI3K: phosphoinositide 3-kinase; PIP2: phosphatidylinositol 4, 5-biphosphate; PIP3: phosphatidylinositol-3,4,5-triphosphate; Akt1: protein kinase B subtype α; ERK1/2: extracellular signal-regulated kinases 1/2; EMT: epithelial-to-mesenchymal transition; NEDD9: neural precursor cell expressed developmentally down-regulated9; CAS: Crk-associated substrate; JNK: c-Jun N-terminal kinase; PRMT1: protein arginine methyltransferase 1; UDCA: ursodeoxycholic acid; BA: bile acids; CA: cholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; LCA: lithocholic acid; CSCs: cancer stem cells; MHC: major histocompatibility; NF-κB: NF-kappaB; GPR: G protein-coupled receptors; ROS: reactive oxygen species; RNS: reactive nitrogen substances; BER: base excision repair; DNA: deoxyribonucleic acid; EGFR: epidermal growth factor receptor; MAPK: mitogen activated protein kinase; ERKs: extracellular signal regulated kinases; AKT: protein kinase B; PA: phosphatidic acid; TMAO: trimethylamine n-oxide; TMA: trimethylamine; FMO3: flavin-containing monooxygenase 3; H2S: Hydrogen sulfide; SRB: sulfate-reducing bacteria; IBDs: inflammatory bowel diseases; NSAID: non-steroidal anti-inflammatory drugs; BFT: fragile bacteroides toxin; ETBF: enterotoxigenic fragile bacteroides; E-cadherin: extracellular domain of intercellular adhesive protein; CEC: colonic epithelial cells; SMOX: spermine oxidase; SMO: smoothened; Stat3: signal transducer and activator of transcription 3; Th17: T helper cell 17; IL17: interleukin 17; AA: amino acid; TCF: transcription factor; CDT: cytolethal distending toxin; PD-L1: programmed cell death 1 ligand 1.
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Affiliation(s)
- Yongkun Fang
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Cheng Yan
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Qi Zhao
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Jiaming Xu
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Zhuangzhuang Liu
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Jin Gao
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Hanjian Zhu
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Zhujiang Dai
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
- CONTACT Dong TangDepartment of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou225001, China
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Zhang H, Xu H, Zhang C, Tang Q, Bi F. Ursodeoxycholic acid suppresses the malignant progression of colorectal cancer through TGR5-YAP axis. Cell Death Discov 2021; 7:207. [PMID: 34365464 PMCID: PMC8349355 DOI: 10.1038/s41420-021-00589-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/20/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023] Open
Abstract
The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. This study means to explore relationship of UDCA and YAP in CRC. UDCA suppressed YAP signaling by activating the membrane G-protein-coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67. UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.
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Affiliation(s)
- Huan Zhang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Huanji Xu
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Chenliang Zhang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qiulin Tang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Feng Bi
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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29
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Peng Y, Nie Y, Yu J, Wong CC. Microbial Metabolites in Colorectal Cancer: Basic and Clinical Implications. Metabolites 2021; 11:metabo11030159. [PMID: 33802045 PMCID: PMC8001357 DOI: 10.3390/metabo11030159] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading cancers that cause cancer-related deaths worldwide. The gut microbiota has been proved to show relevance with colorectal tumorigenesis through microbial metabolites. By decomposing various dietary residues in the intestinal tract, gut microbiota harvest energy and produce a variety of metabolites to affect the host physiology. However, some of these metabolites are oncogenic factors for CRC. With the advent of metabolomics technology, studies profiling microbiota-derived metabolites have greatly accelerated the progress in our understanding of the host-microbiota metabolism interactions in CRC. In this review, we briefly summarize the present metabolomics techniques in microbial metabolites researches and the mechanisms of microbial metabolites in CRC pathogenesis, furthermore, we discuss the potential clinical applications of microbial metabolites in cancer diagnosis and treatment.
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Affiliation(s)
- Yao Peng
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, China; (Y.P.); (Y.N.)
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, China; (Y.P.); (Y.N.)
- Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou 510180, China
| | - Jun Yu
- Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou 510180, China
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (J.Y.); (C.C.W.)
| | - Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (J.Y.); (C.C.W.)
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30
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Hild B, Heinzow HS, Schmidt HH, Maschmeier M. Bile Acids in Control of the Gut-Liver-Axis. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:63-68. [PMID: 33429452 DOI: 10.1055/a-1330-9644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The liver and gut share an intimate relationship whose communication relies heavily on metabolites, among which bile acids play a major role. Beyond their function as emulsifiers, bile acids have been recognized for their influence on metabolism of glucose and lipids as well as for their impact on immune responses. Therefore, changes to the composition of the bile acid pool can be consequential to liver and to gut physiology. By metabolizing primary bile acids to secondary bile acids, the bacterial gut microbiome modifies how bile acids exert influence. An altered ratio of secondary to primary bile acids is found to be substantial in many studies. Thus, disease pathogenesis and progression could be changed by gut microbiome modification which influences the bile acid pool.
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Affiliation(s)
- Benedikt Hild
- Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
| | - Hauke S Heinzow
- Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
| | - Hartmut H Schmidt
- Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
| | - Miriam Maschmeier
- Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
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31
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Florea A, Harris RB, Klimentidis YC, Kohler LN, Jurutka PW, Jacobs ET. Circulating Fibroblast Growth Factor-21 and Risk of Metachronous Colorectal Adenoma. J Gastrointest Cancer 2020; 52:940-946. [PMID: 32918272 DOI: 10.1007/s12029-020-00515-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2020] [Indexed: 11/30/2022]
Abstract
PURPOSE Prior work has shown that higher circulating concentrations of fibroblast growth factor-21 (FGF-21) are associated with an increased likelihood of developing colorectal cancer. We conducted a prospective study to assess the relationship between circulating FGF-21 and odds of developing early neoplastic lesions in the colorectum. METHODS A total of 94 study participants were included from the ursodeoxycholic acid (UDCA) trial, a phase III, randomized, double-blind, placebo-controlled clinical trial of the effect of 8-10 mg/kg of body weight UDCA vs. placebo. Logistic regression analyses were conducted to evaluate the association between baseline FGF-21 concentrations and odds of developing a metachronous adenoma. RESULTS Of the characteristics compared across tertiles of FGF-21 concentrations, including age, race, sex, BMI, and other variables, only a previous personal history of colorectal polyps prior to entry into the UDCA trial was statistically significantly related to FGF-21 levels, with a proportion of 26.7%, 56.7%, and 50.0% across the first, second, and third tertiles, respectively (p < 0.05). Higher circulating concentrations of FGF-21 were statistically significantly associated with greater odds of developing a metachronous colorectal adenoma. After adjusting for potential confounders and when compared with the lowest tertile of FGF-21, the adjusted ORs (95% CIs) for metachronous colorectal adenoma in the second and third tertiles were 4.72 (95% CI, 1.42-15.72) and 3.82 (95% CI, 1.15-12.68), respectively (p trend < 0.05). CONCLUSION Our results reveal for the first time that, in addition to a recently discovered association with colorectal cancer, circulating FGF-21 concentrations are significantly and directly associated with odds of developing metachronous colorectal adenoma.
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Affiliation(s)
- Ana Florea
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. .,Department of Medicine, Division of Nephrology, College of Medicine, University of Arizona, Tucson, AZ, USA.
| | - Robin B Harris
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
| | - Yann C Klimentidis
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
| | - Lindsay N Kohler
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.,Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
| | - Peter W Jurutka
- School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ, USA.,Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - Elizabeth T Jacobs
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
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Donadelli RA, Pezzali JG, Oba PM, Swanson KS, Coon C, Varney J, Pendlebury C, Shoveller AK. A commercial grain-free diet does not decrease plasma amino acids and taurine status but increases bile acid excretion when fed to Labrador Retrievers. Transl Anim Sci 2020; 4:txaa141. [PMID: 32832860 PMCID: PMC7433909 DOI: 10.1093/tas/txaa141] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 07/17/2020] [Indexed: 12/21/2022] Open
Abstract
Grain-free diets tend to have greater inclusions of pulses in contrast to grain-based diets. In 2018, the Food and Drug Administration (FDA) released a statement that grain-free diets may be related to the development of canine dilated cardiomyopathy (DCM). However, all dog foods met regulatory minimums for nutrient inclusion recommended by the Association of American Feed Controls Official. In some FDA case reports, but not all, dogs diagnosed with DCM also had low concentrations of plasma or whole blood taurine; thus, we hypothesized that feeding these diets will result in reduced taurine status from baseline measures. The objective of this study was to determine the effects of feeding a grain-free diet to large-breed dogs on taurine status and overall health. Eight Labrador Retrievers (four males and four females; Four Rivers Kennel, MO) were individually housed and fed a commercial complete and balanced grain-free diet (Acana Pork and Squash formula; APS) for 26 wk. Fasted blood samples were collected prior to the start of the trial (baseline; week 0) and at weeks 13 and 26 for analyses of blood chemistry, hematology, plasma amino acids, and whole blood taurine. Urine was collected by free catch at weeks 0 and 26 for taurine and creatinine analyses. Fresh fecal samples were collected at weeks 0 and 26 for bile acid analyses. Data were analyzed using the GLIMMIX procedure with repeated measures in SAS (v. 9.4). Plasma His, Met, Trp, and taurine and whole blood taurine concentrations increased over the course of the study (P < 0.05). Urinary taurine to creatinine ratio was not affected by diet (P > 0.05). Fecal bile acid excretion increased after 26 wk of feeding APS to dogs. Despite the higher fecal excretion of bile acids, plasma and whole blood taurine increased over the 26-wk feeding study. These data suggest that feeding APS, a grain-free diet, over a 26-wk period improved taurine status in Labrador Retrievers and is not the basis for the incidence of DCM for dogs fed APS. Other factors that may contribute to the etiology of DCM should be explored.
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Affiliation(s)
- Renan A Donadelli
- Animal Biosciences Department, University of Guelph, Guelph, ON, Canada
| | - Julia G Pezzali
- Animal Biosciences Department, University of Guelph, Guelph, ON, Canada
| | - Patricia M Oba
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL
| | - Kelly S Swanson
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL
| | | | | | | | - Anna K Shoveller
- Animal Biosciences Department, University of Guelph, Guelph, ON, Canada
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Gao Y, Zhang S, Zhang Y, Qian J. Identification of MicroRNA-Target Gene-Transcription Factor Regulatory Networks in Colorectal Adenoma Using Microarray Expression Data. Front Genet 2020; 11:463. [PMID: 32508878 PMCID: PMC7248367 DOI: 10.3389/fgene.2020.00463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/15/2020] [Indexed: 12/18/2022] Open
Abstract
Objective The aim of the study was to find the key genes, microRNAs (miRNAs) and transcription factors (TFs) and construct miRNA-target gene-TF regulatory networks to investigate the underlying molecular mechanism in colorectal adenoma (CRA). Methods Four mRNA expression datasets and one miRNA expression dataset were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were identified between CRA and normal samples. Moreover, functional enrichment analysis for DEGs was carried out utilizing the Cytoscape-plugin, known as ClueGO. These DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, a miRNA-target gene regulatory network was established to screen key DEMs. In addition, similar workflow of the analyses were also performed comparing the CRC samples with CRA ones to screen key DEMs. Finally, miRNA-target gene-TF regulatory networks were constructed for these key DEMs using iRegulon plug-in in Cytoscape. Results We identified 514 DEGs and 167 DEMs in CRA samples compared to healthy samples. Functional enrichment analysis revealed that these DEGs were significantly enriched in several terms and pathways, such as regulation of cell migration and bile secretion pathway. A PPI network was constructed including 325 nodes as well as 890 edges. A total of 59 DEGs and 65 DEMs were identified in CRC samples compared to CRA ones. In addition, Two key DEMs in CRA samples compared to healthy samples were identified, such as hsa-miR-34a and hsa-miR-96. One key DEM, hsa-miR-29c, which was identified when we compared the differentially expressed molecules found in the comparison CRA versus normal samples to the ones obtained in the comparison CRC versus CRA, was also identified in CRC samples compared to CRA ones. The miRNA-target gene-TF regulatory networks for these key miRNAs included two TFs, one TF and five TFs, respectively. Conclusion These identified key genes, miRNA, TFs and miRNA-target gene-TF regulatory networks associated with CRA, to a certain degree, may provide some hints to enable us to better understand the underlying pathogenesis of CRA.
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Affiliation(s)
- Yadong Gao
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Shenglai Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Yan Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Junbo Qian
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
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Marchesi E, Chinaglia N, Capobianco ML, Marchetti P, Huang TE, Weng HC, Guh JH, Hsu LC, Perrone D, Navacchia ML. Dihydroartemisinin-Bile Acid Hybridization as an Effective Approach to Enhance Dihydroartemisinin Anticancer Activity. ChemMedChem 2020; 14:779-787. [PMID: 30724466 DOI: 10.1002/cmdc.201800756] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/02/2019] [Indexed: 12/29/2022]
Abstract
A series of hybrid compounds based on natural products-bile acids and dihydroartemisinin-were prepared by different synthetic methodologies and investigated for their in vitro biological activity against HL-60 leukemia and HepG2 hepatocellular carcinoma cell lines. Most of these hybrids presented significantly improved antiproliferative activities with respect to dihydroartemisinin and the parent bile acid. The two most potent hybrids of the series exhibited a 10.5- and 15.4-fold increase in cytotoxic activity respect to dihydroartemisinin alone in HL-60 and HepG2 cells, respectively. Strong evidence that an ursodeoxycholic acid hybrid induced apoptosis was obtained by flow cytometric analysis and western blot analysis.
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Affiliation(s)
- Elena Marchesi
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via L. Borsari 46, 44121, Ferrara, Italy
| | - Nicola Chinaglia
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via L. Borsari 46, 44121, Ferrara, Italy
| | - Massimo L Capobianco
- Institute of Organic Synthesis and Photoreactivity, National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy
| | - Paolo Marchetti
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via L. Borsari 46, 44121, Ferrara, Italy
| | - Tzu-En Huang
- School of Pharmacy, National Taiwan University, No. 33 Linsen South Road, Taipei, 10050, Taiwan
| | - Hao-Cheng Weng
- School of Pharmacy, National Taiwan University, No. 33 Linsen South Road, Taipei, 10050, Taiwan
| | - Jih-Hwa Guh
- School of Pharmacy, National Taiwan University, No. 33 Linsen South Road, Taipei, 10050, Taiwan
| | - Lih-Ching Hsu
- School of Pharmacy, National Taiwan University, No. 33 Linsen South Road, Taipei, 10050, Taiwan
| | - Daniela Perrone
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via L. Borsari 46, 44121, Ferrara, Italy
| | - Maria Luisa Navacchia
- Institute of Organic Synthesis and Photoreactivity, National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy
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Goossens JF, Bailly C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol Ther 2019; 203:107396. [DOI: 10.1016/j.pharmthera.2019.107396] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022]
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Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, Collier J, Dyson JK, Jones DE, Patanwala I, Thain C, Walmsley M, Pereira SP. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut 2019; 68:1356-1378. [PMID: 31154395 PMCID: PMC6691863 DOI: 10.1136/gutjnl-2018-317993] [Citation(s) in RCA: 172] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/21/2019] [Accepted: 03/24/2019] [Indexed: 12/11/2022]
Abstract
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
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Affiliation(s)
- Michael Huw Chapman
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | | | - Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | | | | | - Jessica K Dyson
- Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - David Ej Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Imran Patanwala
- Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | | | | | - Stephen P Pereira
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Institute for Liver & Digestive Health, University College London, London, UK
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Thompson PA. Finding the Responders in the Cancer Prevention Trials. J Natl Cancer Inst 2019; 111:639-640. [PMID: 30624679 DOI: 10.1093/jnci/djy205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 09/29/2018] [Indexed: 12/31/2022] Open
Affiliation(s)
- Patricia A Thompson
- Department of Pathology, Stony Brook School of Medicine, Stony Brook University, Stony Brook, NY
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Shen ML, Xiao A, Yin SJ, Wang P, Lin XQ, Yu CB, He GH. Associations between UGT2B7 polymorphisms and cancer susceptibility: A meta-analysis. Gene 2019; 706:115-123. [PMID: 31082503 DOI: 10.1016/j.gene.2019.05.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND UGT2B7 was recently acknowledged as a new critical enzyme involved in biotransformation of a variety of carcinogens, whose function was reported to be significantly associated with its encoding gene (UGT2B7) polymorphisms. However, results regarding the associations between single nucleotide polymorphisms (SNPs) of UGT2B7 and cancer risk still remained controversial. Therefore, a meta-analysis was conducted to further elucidate the role of UGT2B7 SNPs on cancer susceptibilities. METHODS PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang Database were searched for eligible studies until March 2019. All analysis was carried out using the Review Manager 5.3 software. Subgroup analyses were performed by cancer types, ethnicity or source of controls. RESULTS 13 studies with a total of 7688 cancer cases and 11,281 controls were included in this meta-analysis. The results showed that UGT2B7 rs7439366 increased the colorectal cancer risk in dominant model (OR = 0.76, 95% CI = 0.61-0.95, P = 0.02). However, as for the rs7435335 and rs12233719, we did not find their associations with cancer risk in all genetic models. In addition, the rs7441774 was found to be associated with breast cancer risk and significantly reduced papillary thyroid cancer risk in rs3924194 was also observed. Nevertheless, these findings remained to be further proven in future studies since these 2 SNPs were only respectively involved in 1 study. CONCLUSION This meta-analysis confirmed the association of UGT2B7 rs7439366 with colorectal cancer risk, which may be a potential promising biomarker for prediction of colorectal cancer risk.
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Affiliation(s)
- Ming-Li Shen
- Institute of Pharmacy and Chemistry, Dali University, Dali 671000, China; Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China
| | - An Xiao
- Department of Infectious Diseases, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650000, China
| | - Sun-Jun Yin
- Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China
| | - Ping Wang
- Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China
| | - Xiao-Qian Lin
- Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China
| | - Chen-Bin Yu
- Emergency Department, Taikang Xianlin Drum Tower Hospital affiliated to Nanjing University Medical School, Nanjing 210046, China.
| | - Gong-Hao He
- Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China.
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Pearson T, Caporaso JG, Yellowhair M, Bokulich NA, Padi M, Roe DJ, Wertheim BC, Linhart M, Martinez JA, Bilagody C, Hornstra H, Alberts DS, Lance P, Thompson PA. Effects of ursodeoxycholic acid on the gut microbiome and colorectal adenoma development. Cancer Med 2019; 8:617-628. [PMID: 30652422 PMCID: PMC6382922 DOI: 10.1002/cam4.1965] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/10/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022] Open
Abstract
It has been previously reported that ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduced risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colorectal cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies. Using banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal adenomatous polyps, we compared change in the microbiome composition after a 3-year intervention in a subset of participants randomized to oral UDCA at 8-10 mg/kg of body weight per day (n = 198) or placebo (n = 203). Study participants randomized to UDCA experienced compositional changes in their microbiome that were statistically more similar to other individuals in the UDCA arm than to those in the placebo arm. This reflected a UDCA-associated shift in microbial community composition (P < 0.001), independent of sex, with no evidence of a UDCA effect on microbial richness (P > 0.05). These UDCA-associated shifts in microbial community distance metrics from baseline to end-of-study were not associated with risk of any or advanced adenoma (all P > 0.05) in men or women. Separate analyses of microbial networks revealed an overrepresentation of Faecalibacterium prausnitzii in the post-UDCA arm and an inverse relationship between F prausnitzii and Ruminococcus gnavus. In men who received UDCA, the overrepresentation of F prausnitzii and underrepresentation of R gnavus were more prominent in those with no adenoma recurrence at follow-up compared to men with recurrence. This relationship was not observed in women. Daily UDCA use modestly influences the relative abundance of microbial species in stool and affects the microbial network composition with suggestive evidence for sex-specific effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk.
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Affiliation(s)
- Talima Pearson
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
- Department of Biological SciencesNorthern Arizona UniversityFlagstaffArizona
| | - J. Gregory Caporaso
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
- Department of Biological SciencesNorthern Arizona UniversityFlagstaffArizona
| | - Monica Yellowhair
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | | | - Megha Padi
- Department of Molecular and Cellular BiologyUniversity of ArizonaTucsonArizona
| | - Denise J. Roe
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Betsy C. Wertheim
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Mark Linhart
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
| | - Jessica A. Martinez
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
- Department of Nutritional SciencesUniversity of ArizonaTucsonArizona
| | - Cherae Bilagody
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
| | - Heidie Hornstra
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
| | - David S. Alberts
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Peter Lance
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Patricia A. Thompson
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
- Stony Brook School of MedicineStony BrookNew York
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Hanafi NI, Mohamed AS, Sheikh Abdul Kadir SH, Othman MHD. Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart. Biomolecules 2018; 8:E159. [PMID: 30486474 PMCID: PMC6316857 DOI: 10.3390/biom8040159] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 11/15/2018] [Accepted: 11/15/2018] [Indexed: 12/12/2022] Open
Abstract
Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP (cAMP) synthesis, and calcium mobilization. They are ligands for several nuclear hormone receptors, including farnesoid X-receptor (FXR). Recently, BAs have been shown to bind to muscarinic receptor and Takeda G-protein-coupled receptor 5 (TGR5), both G-protein-coupled receptor (GPCR), independent of the nuclear hormone receptors. Moreover, BA signals have also been elucidated in other nonclassical BA pathways, such as sphingosine-1-posphate and BK (large conductance calcium- and voltage activated potassium) channels. Hydrophobic BAs have been proven to affect heart rate and its contraction. Elevated BAs are associated with arrhythmias in adults and fetal heart, and altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile, in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase in serum bile acid concentrations. In contrast, the most hydrophilic BA, known as ursodeoxycholic acid (UDCA), has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury. This review provides an overview of BA signaling, with the main emphasis on past and present perspectives on UDCA signals in the heart.
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Affiliation(s)
- Noorul Izzati Hanafi
- Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia.
| | - Anis Syamimi Mohamed
- Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia.
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia.
| | - Mohd Hafiz Dzarfan Othman
- Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, Johor Bharu 81310, Johor, Malaysia.
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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: 10/12/2018] [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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Adherence to Nutrition and Physical Activity Cancer Prevention Guidelines and Development of Colorectal Adenoma. Nutrients 2018; 10:nu10081098. [PMID: 30115827 PMCID: PMC6115749 DOI: 10.3390/nu10081098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/09/2018] [Accepted: 08/13/2018] [Indexed: 01/27/2023] Open
Abstract
Adherence to the American Cancer Society’s (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines is associated with reductions in overall cancer incidence and mortality, including site-specific cancers such as colorectal cancer. We examined the relationship between baseline adherence to the ACS guidelines and (1) baseline adenoma characteristics and (2) odds of recurrent colorectal adenomas over 3 years of follow-up. Cross-sectional and prospective analyses with a pooled sample of participants from the Wheat Bran Fiber (n = 503) and Ursodeoxycholic Acid (n = 854) trials were performed. A cumulative adherence score was constructed using baseline self-reported data regarding body size, diet, physical activity and alcohol consumption. Multivariable logistic regression demonstrated significantly reduced odds of having three or more adenomas at baseline for moderately adherent (odds ratio [OR] = 0.67, 95% confidence intervals [CI]: 0.46–0.99) and highly adherent (OR = 0.50, 95% CI: 0.31–0.81) participants compared to low adherers (p-trend = 0.005). Conversely, guideline adherence was not associated with development of recurrent colorectal adenoma (moderate adherence OR = 1.16, 95% CI: 0.85–1.59, high adherence OR = 1.23, 95% CI: 0.85–1.79).
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Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK. Int J Mol Med 2018; 42:2551-2559. [PMID: 30106087 PMCID: PMC6192782 DOI: 10.3892/ijmm.2018.3807] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 07/18/2018] [Indexed: 01/03/2023] Open
Abstract
Sorafenib has been approved for the treatment of advanced stage hepatocellular carcinoma but has limited efficacy. Ursodeoxycholic acid exerts cytoprotective activities in hepatocytes and is believed to suppress tumorigenesis through cell cycle arrest and induction of apoptosis. The present study examined whether co-treatment with ursodeoxycholic acid has a synergistic effect on the antitumor activity of sorafenib in hepatocellular carcinoma cells. Notably, co-treatment with both agents more effectively inhibited cell proliferation than sorafenib or ursodeoxycholic acid alone. Furthermore, co-treatment inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and activated extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinase, accompanied by excessive intracellular reactive oxygen species generation in hepatocellular carcinoma cells. Thus, chemotherapy with sorafenib and ursodeoxycholic combination may be efficacious in hepatocellular carcinoma by inhibiting cell proliferation and inducing apoptosis through reactive oxygen species-dependent activation of ERK and dephosphorylation of STAT3. The present findings may represent a promising therapeutic strategy for patients with advanced hepatocellular carcinoma.
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Jacobs ET, Gupta S, Baron JA, Cross AJ, Lieberman DA, Murphy G, Martínez ME. Family history of colorectal cancer in first-degree relatives and metachronous colorectal adenoma. Am J Gastroenterol 2018; 113:899-905. [PMID: 29463834 PMCID: PMC8283793 DOI: 10.1038/s41395-018-0007-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Little is known about the relationship between having a first-degree relative (FDR) with colorectal cancer (CRC) and risk for metachronous colorectal adenoma (CRA) following polypectomy. METHODS We pooled data from seven prospective studies of 7697 patients with previously resected CRAs to quantify the relationship between having a FDR with CRC and risk for metachronous adenoma. RESULTS Compared with having no family history of CRC, a positive family history in any FDR was significantly associated with increased odds of developing any metachronous CRA (OR = 1.14; 95% CI = 1.01-1.29). Higher odds of CRA were observed among individuals with an affected mother (OR = 1.27; 95% CI = 1.05-1.53) or sibling (OR = 1.34; 95% CI = 1.11-1.62) as compared with those without, whereas no association was shown for individuals with an affected father. Odds of having a metachronous CRA increased with number of affected FDRs, with ORs (95% CIs) of 1.07 (0.93-1.23) for one relative and 1.39 (1.02-1.91) for two or more. Younger age of diagnosis of a sibling was associated with higher odds of metachronous CRA, with ORs (95% CIs) of 1.66 (1.08-2.56) for diagnosis at <54 years; 1.34 (0.89-2.03) for 55-64 years; and 1.10 (0.70-1.72) for >65 years (p-trend = 0.008). Although limited by sample size, results for advanced metachronous CRA were similar to those for any metachronous CRA. CONCLUSIONS A family history of CRC is related to a modestly increased odds of metachronous CRA. Future research should explore whether having a FDR with CRC, particularly at a young age, should have a role in risk stratification for surveillance colonoscopy.
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Affiliation(s)
- Elizabeth T Jacobs
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Samir Gupta
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - John A Baron
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Amanda J Cross
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - David A Lieberman
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Gwen Murphy
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - María Elena Martínez
- University of Arizona Cancer Center, Tucson, AZ, USA. Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. Veteran Affairs San Diego System, San Diego, CA, USA. Department of Internal Medicine, Division of Gastroenterology, and the Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Imperial College London, London, UK. Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and Oregon Health and Science University, Portland, OR, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Department of Family Medicine and Public Health and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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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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Herstad KMV, Rønning HT, Bakke AM, Moe L, Skancke E. Changes in the faecal bile acid profile in dogs fed dry food vs high content of beef: a pilot study. Acta Vet Scand 2018; 60:29. [PMID: 29751815 PMCID: PMC5948804 DOI: 10.1186/s13028-018-0383-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 05/03/2018] [Indexed: 12/31/2022] Open
Abstract
Background Dogs are fed various diets, which also include components of animal origin. In humans, a high-fat/low-fibre diet is associated with higher faecal levels of bile acids, which can influence intestinal health. It is unknown how an animal-based diet high in fat and low in fibre influences the faecal bile acid levels and intestinal health in dogs. This study investigated the effects of high intake of minced beef on the faecal bile acid profile in healthy, adult, client-owned dogs (n = 8) in a 7-week trial. Dogs were initially adapted to the same commercial dry food. Thereafter, incremental substitution of the dry food by boiled minced beef over 3 weeks resulted in a diet in which 75% of each dog’s total energy requirement was provided as minced beef during week 5. Dogs were subsequently reintroduced to the dry food for the last 2 weeks of the study. The total taurine and glycine-conjugated bile acids, the primary bile acids chenodeoxycholic acid and cholic acid, and the secondary bile acids lithocholic acid, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) were analysed, using liquid chromatography–tandem mass spectrometry. Results The faecal quantities of DCA were significantly higher in dogs fed the high minced beef diet. These levels reversed when dogs were reintroduced to the dry food diet. The faecal levels of UDCA and taurine-conjugated bile acids had also increased in response to the beef diet, but this was only significant when compared to the last dry food period. Conclusions These results suggest that an animal-based diet with high-fat/low-fibre content can influence the faecal bile acids levels. The consequences of this for canine colonic health will require further investigation. Electronic supplementary material The online version of this article (10.1186/s13028-018-0383-7) contains supplementary material, which is available to authorized users.
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Wali RK, Bianchi L, Kupfer S, De La Cruz M, Jovanovic B, Weber C, Goldberg MJ, Rodriguez LM, Bergan R, Rubin D, Tull MB, Richmond E, Parker B, Khan S, Roy HK. Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial. PLoS One 2018; 13:e0193544. [PMID: 29617381 PMCID: PMC5884487 DOI: 10.1371/journal.pone.0193544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 01/02/2018] [Indexed: 11/18/2022] Open
Abstract
Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. TRIAL REGISTRATION ClinicalTrials.gov NCT00828984.
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Affiliation(s)
- Ramesh K. Wali
- Department of Medicine, Boston University Medical Center, Boston, MA, United States of America
| | - Laura Bianchi
- Department of Medicine, NorthShore University HealthSystem, Evanston, IL, United States of America
| | - Sonia Kupfer
- Department of Medicine, University of Chicago, Chicago, IL, United States of America
| | - Mart De La Cruz
- Department of Medicine, Boston University Medical Center, Boston, MA, United States of America
| | - Borko Jovanovic
- Department of Medicine, Northwestern University, Chicago, IL, United States of America
| | - Christopher Weber
- Department of Medicine, University of Chicago, Chicago, IL, United States of America
| | - Michael J. Goldberg
- Department of Medicine, NorthShore University HealthSystem, Evanston, IL, United States of America
| | - L. M. Rodriguez
- National Cancer Institute, Rockville, MD, United States of America
| | - Raymond Bergan
- Department of Medicine, Oregon Health & Science University, Portland, OR, United States of America
| | - David Rubin
- Department of Medicine, University of Chicago, Chicago, IL, United States of America
| | - Mary Beth Tull
- Department of Medicine, Northwestern University, Chicago, IL, United States of America
| | - Ellen Richmond
- National Cancer Institute, Rockville, MD, United States of America
| | - Beth Parker
- Department of Medicine, Boston University Medical Center, Boston, MA, United States of America
| | - Seema Khan
- Department of Medicine, University of Chicago, Chicago, IL, United States of America
| | - Hemant K. Roy
- Department of Medicine, Boston University Medical Center, Boston, MA, United States of America
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Lewis KN, Rubinstein ND, Buffenstein R. A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence. GeroScience 2018; 40:105-121. [PMID: 29679203 PMCID: PMC5964061 DOI: 10.1007/s11357-018-0014-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 03/15/2018] [Indexed: 12/23/2022] Open
Abstract
Mouse-sized naked mole-rats (Heterocephalus glaber), unlike other mammals, do not conform to Gompertzian laws of age-related mortality; adults show no age-related change in mortality risk. Moreover, we observe negligible hallmarks of aging with well-maintained physiological and molecular functions, commonly altered with age in other species. We questioned whether naked mole-rats, living an order of magnitude longer than laboratory mice, exhibit different plasma metabolite profiles, which could then highlight novel mechanisms or targets involved in disease and longevity. Using a comprehensive, unbiased metabolomics screen, we observe striking inter-species differences in amino acid, peptide, and lipid metabolites. Low circulating levels of specific amino acids, particularly those linked to the methionine pathway, resemble those observed during the fasting period at late torpor in hibernating ground squirrels and those seen in longer-lived methionine-restricted rats. These data also concur with metabolome reports on long-lived mutant mice, including the Ames dwarf mice and calorically restricted mice, as well as fruit flies, and even show similarities to circulating metabolite differences observed in young human adults when compared to older humans. During evolution, some of these beneficial nutrient/stress response pathways may have been positively selected in the naked mole-rat. These observations suggest that interventions that modify the aging metabolomic profile to a more youthful one may enable people to lead healthier and longer lives.
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Affiliation(s)
- Kaitlyn N Lewis
- Calico Life Sciences LLC, 1170 Veterans Blvd., South San Francisco, 94080, USA
| | - Nimrod D Rubinstein
- Calico Life Sciences LLC, 1170 Veterans Blvd., South San Francisco, 94080, USA
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Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells. Eur J Cancer Prev 2018; 25:368-79. [PMID: 26378497 DOI: 10.1097/cej.0000000000000198] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.
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Choi WS, Han DS, Eun CS, Park DI, Byeon JS, Yang DH, Jung SA, Lee SK, Hong SP, Park CH, Lee SH, Ji JS, Shin SJ, Keum B, Kim HS, Choi JH, Jung SH. Three-year colonoscopy surveillance after polypectomy in Korea: a Korean Association for the Study of Intestinal Diseases (KASID) multicenter prospective study. Intest Res 2018; 16:126-133. [PMID: 29422807 PMCID: PMC5797259 DOI: 10.5217/ir.2018.16.1.126] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/19/2017] [Accepted: 08/01/2017] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Colonoscopic surveillance is currently recommended after polypectomy owing to the risk of newly developed colonic neoplasia. However, few studies have investigated colonoscopy surveillance in Asia. This multicenter and prospective study was undertaken to assess the incidence of advanced adenoma based on baseline adenoma findings at 3 years after colonoscopic polypectomy. Methods A total of 1,323 patients undergoing colonoscopic polypectomy were prospectively assigned to 3-year colonoscopy surveillance at 11 tertiary endoscopic centers. Relative risks for advanced adenoma after 3 years were calculated according to baseline adenoma characteristics. Results Among 1,323 patients enrolled, 387 patients (29.3%) were followed up, and the mean follow-up interval was 31.0±9.8 months. The percentage of patients with advanced adenoma on baseline colonoscopy was higher in the surveillance group compared to the non-surveillance group (34.4% vs. 25.7%). Advanced adenoma recurrence was observed in 17 patients (4.4%) at follow-up. The risk of advanced adenoma recurrence was 2 times greater in patients with baseline advanced adenoma than in those with baseline non-advanced adenoma, though the difference was not statistically significant (6.8% [9/133] vs. 3.1% [8/254], P=0.09). Advanced adenoma recurrence was observed only in males and in subjects aged ≥50 years. In contrast, adenoma recurrence was observed in 187 patients (48.3%) at follow-up. Male sex, older age (≥50 years), and multiple adenomas (≥3) at baseline were independent risk factors for adenoma recurrence. Conclusions A colonoscopy surveillance interval of 3 years in patients with baseline advanced adenoma can be considered appropriate.
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Affiliation(s)
- Won Seok Choi
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Chang Soo Eun
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Dong Il Park
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hoon Yang
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Ae Jung
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sang Kil Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Pil Hong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Cheol Hee Park
- Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea
| | - Suck-Ho Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jeong-Seon Ji
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary's Hospital, Incheon, Korea
| | - Sung Jae Shin
- Department of Internal Medicine, Ajou University School of Medinie, Suwon, Korea
| | - Bora Keum
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyun Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Wonju, Korea
| | - Jung Hye Choi
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Sin-Ho Jung
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
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