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1
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Liu P, Wang Y, Yang G, Zhang Q, Meng L, Xin Y, Jiang X. The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis. Pharmacol Res 2021; 165:105420. [PMID: 33434620 DOI: 10.1016/j.phrs.2021.105420] [Citation(s) in RCA: 388] [Impact Index Per Article: 97.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/25/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
Short-chain fatty acids (SCFAs), mainly including acetate, propionate, and butyrate, are metabolites produced during the bacterial fermentation of dietary fiber in the intestinal tract. They are believed to be essential factors affecting host health. Most in vitro and ex vivo studies have shown that SCFAs affect the regulation of inflammation, carcinogenesis, intestinal barrier function, and oxidative stress, but convincing evidence in humans is still lacking. Two major SCFA signaling mechanisms have been identified: promotion of histone acetylation and activation of G-protein-coupled receptors. In this review, we introduce the production and metabolic characteristics of SCFAs, summarize the potential effects of SCFAs on the four aspects mentioned above and the possible mechanisms. SCFAs have been reported to exert a wide spectrum of positive effects and have a high potential for therapeutic use in human-related diseases.
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Affiliation(s)
- Pinyi Liu
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China.
| | - Yanbing Wang
- Department of Orthopedic, The Second Hospital of Jilin University, Changchun, 130041, China.
| | - Ge Yang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| | - Qihe Zhang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| | - Lingbin Meng
- Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China.
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2
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Pan DC, Krishnan V, Salinas AK, Kim J, Sun T, Ravid S, Peng K, Wu D, Nurunnabi M, Nelson JA, Niziolek Z, Guo J, Mitragotri S. Hyaluronic acid-doxorubicin nanoparticles for targeted treatment of colorectal cancer. Bioeng Transl Med 2021; 6:e10166. [PMID: 33532580 PMCID: PMC7823125 DOI: 10.1002/btm2.10166] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/04/2020] [Accepted: 05/09/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer, common in both men and women, occurs when tumors form in the linings of the colon. Common treatments of colorectal cancer include surgery, chemotherapy, and radiation therapy; however, many colorectal cancer treatments often damage healthy tissues and cells, inducing severe side effects. Conventional chemotherapeutic agents such as doxorubicin (Dox) can be potentially used for the treatment of colorectal cancer; however, they suffer from limited targeting and lack of selectivity. Here, we report that doxorubicin complexed to hyaluronic acid (HA) (HA-Dox) exhibits an unusual behavior of high accumulation in the intestines for at least 24 hr when injected intravenously. Intravenous administrations of HA-Dox effectively preserved the mucosal epithelial intestinal integrity in a chemical induced colon cancer model in mice. Moreover, treatment with HA-Dox decreased the expression of intestinal apoptotic and inflammatory markers. The results suggest that HA-Dox could effectively inhibit the development of colorectal cancer in a safe manner, which potentially be used a promising therapeutic option.
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Affiliation(s)
- Daniel C. Pan
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Vinu Krishnan
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Alyssa K. Salinas
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Jayoung Kim
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Tao Sun
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Sagi Ravid
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Kevin Peng
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Debra Wu
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Md Nurunnabi
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Jeffery A. Nelson
- Faculty of Arts and Sciences, Division of SciencesHarvard UniversityCambridgeMassachusettsUSA
| | - Zachary Niziolek
- Faculty of Arts and Sciences, Division of SciencesHarvard UniversityCambridgeMassachusettsUSA
| | - Junling Guo
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Samir Mitragotri
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
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3
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Vetter LE, Merkel S, Bénard A, Krautz C, Brunner M, Mittelstädt A, Schlegel N, Wiegering A, Germer CT, Weber K, Grützmann R, Weber GF. Colorectal cancer in Crohn's colitis is associated with advanced tumor invasion and a poorer survival compared with ulcerative colitis: a retrospective dual-center study. Int J Colorectal Dis 2021; 36:141-150. [PMID: 32918621 PMCID: PMC7782386 DOI: 10.1007/s00384-020-03726-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Colorectal cancer is a well-recognized complication of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's colitis (CC). In this study, we assess the clinico-pathological features and outcomes of patients with colorectal cancer from UC in comparison with CC. METHODS Data of all patients with colitis-associated cancer (CAC) who underwent surgery at Erlangen or Würzburg University Clinic between 1995 and 2015 were selected. Clinical, histopathological, and survival data were analyzed retrospectively. RESULTS Of all 88 patients with CAC, 20 patients had Crohn's colitis and 68 patients had ulcerative colitis. We observed a young median age at tumor diagnosis (49.5 years UC; 45.5 years CC, p = 0.208) in both diseases and a long median disease duration before CAC (19 years UC; 18 years CC; p = 0.840). Patients with CC suffered more often from rectal cancer (14 (70.0%) in CC; 23 (33.8%) in UC; p = 0.005) and advanced tumor stages (8 (47.0%) pT4 in CC; 14 (25.0%) pT4/ypT4 in UC; p = 0.008). Five-year overall survival rate was 39.3% for CC and 67.1% for UC (p = 0.009 for difference between the groups). Survival did not differ significantly between UC and CC in the multivariate analysis after correction for UICC tumor stage. CONCLUSION CAC in CC showed advanced tumor stages associated with reduced survival compared with CAC in UC. This may be explained by less intense surveillance in patients with CC leading to delayed cancer diagnosis.
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Affiliation(s)
- Leonie E Vetter
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Susanne Merkel
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Alan Bénard
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Christian Krautz
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Maximilian Brunner
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Anke Mittelstädt
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, Julius-Maximilians-University Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany
| | - Armin Wiegering
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, Julius-Maximilians-University Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany
| | - Christoph-Thomas Germer
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, Julius-Maximilians-University Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany
| | - Klaus Weber
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany
| | - Georg F Weber
- Department of Surgery, Friedrich-Alexander-University Erlangen, Krankenhausstraße 12, 91054, Erlangen, Germany.
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Chang J, Zhang W, Lin G, Tong D, Zhu D, Zhao J, Yu Q, Huang D, Li W. Tumor Response to Irinotecan is Associated with IL-10 Expression Level in Metastatic Colorectal Cancer-Results from mCRC Biomarker Study. Onco Targets Ther 2020; 13:11819-11826. [PMID: 33235468 PMCID: PMC7680186 DOI: 10.2147/ott.s275636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/06/2020] [Indexed: 11/23/2022] Open
Abstract
Purpose Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related death. Resistance to chemotherapy is the main reason for the failure of the treatment of mCRC. IL-10 has been reported to decrease after surgery and increase after mCRC reoccurrence. The role of IL-10 in chemotherapy drug resistance of mCRC is not well elucidated. Patients and Methods The retrospective study recruited 264 mCRC patients between January 2012 and December 2016 (NCT03532711). All the enrolled patients received an oxaliplatin-containing or irinotecan-containing regimen. The expression level of IL-10 in 232 patients’ plasma and 68 patients’ tumor tissue was examined. The relationships between IL-10 and clinicopathological characteristics were analyzed. Kaplan–Meier method and Cox regression were used to evaluate the prognostic impact of IL-10. Results The median concentration of IL-10 was 7.60 pg/mL before treatment and 11.08 pg/mL after treatment, which suggested that IL-10 level was significantly increased by treatment with a chemotherapeutic regimen (p = 0.000). By utilizing univariate and multivariate Cox proportional hazard analyses, we found that low IL-10 level in plasma was significantly associated with improved overall survival (OS) of mCRC patients treated with irinotecan-containing regimen-with optimal cutoff value of 5.525pg/mL, respectively (p =0.002). In addition, the low IL-10 expression level in tumor tissue was significantly associated with the improved OS for the irinotecan-containing regimen (p = 0.023). Conclusion Our study demonstrated that IL-10 could act as a prognostic biomarker for mCRC patients undergoing irinotecan-containing chemotherapy.
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Affiliation(s)
- Jinjia Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Wen Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Guangyi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Duo Tong
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Dan Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Jing Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Qihe Yu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Dan Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China
| | - Wenhua Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
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Alrafas HR, Busbee PB, Nagarkatti M, Nagarkatti PS. Resveratrol Downregulates miR-31 to Promote T Regulatory Cells during Prevention of TNBS-Induced Colitis. Mol Nutr Food Res 2019; 64:e1900633. [PMID: 31730734 DOI: 10.1002/mnfr.201900633] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/21/2019] [Indexed: 12/11/2022]
Abstract
SCOPE Colitis, an inflammatory bowel disease, is associated with aberrant regulation of the colonic mucosal immune system. Resveratrol, a natural plant product, has been found to exert anti-inflammatory properties and attenuate the development of murine colitis. In the current study, the role of microRNA (miR) in the ability of resveratrol to suppress colonic inflammation is examined. METHODS AND RESULTS BALB/C mice with 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS)-induced colitis, when treated with resveratrol, show improved clinical outcomes and reduce induction of inflammatory T cells (Th17 and Th1) while increasing CD4+Foxp3+ regulatory T cells (Tregs) and IL-10-producing CD4+ T cells. miR microarray analysis and polymerase chain reaction (PCR) validation from CD4+ T cells show treatment with resveratrol decreases the expression of several miRs (miR-31, Let7a, miR-132) that targets cytokines and transcription factors involved in anti-inflammatory T cell responses (Foxp3 and TGF-β). Transfection studies with miR-31 confirm that this miR directly regulates the expression of Foxp3. Lastly, analysis of public data from human patients with ulcerative colitis reveals that miR-31 expression is significantly increased when compared to controls. CONCLUSION Together, the current study demonstrates that resveratrol-mediated attenuation of colitis may be regulated by miR-31 through induction of Tregs and miR-31 may serve as a therapeutic target for human colitis.
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Affiliation(s)
- Haider Rasheed Alrafas
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
| | - Philip B Busbee
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
| | - Prakash S Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
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Wang CZ, Hou L, Wan JY, Yao H, Yuan J, Zeng J, Park CW, Kim SH, Seo DB, Shin KS, Zhang CF, Chen L, Zhang QH, Liu Z, Sava-Segal C, Yuan CS. Ginseng berry polysaccharides on inflammation-associated colon cancer: inhibiting T-cell differentiation, promoting apoptosis, and enhancing the effects of 5-fluorouracil. J Ginseng Res 2019; 44:282-290. [PMID: 32148410 PMCID: PMC7031751 DOI: 10.1016/j.jgr.2018.12.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 11/13/2018] [Accepted: 12/26/2018] [Indexed: 02/07/2023] Open
Abstract
Background Ginseng is a commonly used herbal medicine in treating various medical conditions. Chronic gut inflammation is a recognized factor for the development of colorectal cancer (CRC). In this project, Asian ginseng berry polysaccharide preparations were used to assess their effects on CRC and related immune regulation mechanisms. Methods Ginseng berry polysaccharide extract (GBPE) and purified ginseng berry polysaccharide portion (GBPP) were used to evaluate their activities on human HCT-116 and HT-29 CRC cell proliferation. Interleukin-8 secretion analysis was performed on HT-29 cells. Naive CD4 cell isolation and T-helper cell differentiation were performed and determined using flow cytometry for Th1 and Treg in addition to cell cycle and apoptotic investigation. Results GBPE and GBPP significantly inhibited interleukin-8 secretion and cancer cell proliferation, inhibited CD4+IFN-γ+ cell (Th1) differentiation, and decreased CD4+FoxP3+ cell (Treg) differentiation. Compared to the GBPE, GBPP showed more potent antiinflammatory activities on the malignant cells. This is consistent with the observation that GBPP can also inhibit Th1-cell differentiation better, suggesting that it has an important role in antiinflammation, whereas Treg cells hinder the body's immune response against malignancies. Supported by cell cycle and apoptosis data, GBPE and GBPP, at various degrees, remarkably enhanced the anticancer activities of 5-fluorouracil. Conclusion Data from this project suggested that Asian ginseng berry potentially has clinical utility in managing enteric inflammation and suppressing CRC through immunomodulation mechanisms.
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Affiliation(s)
- Chong-Zhi Wang
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Lifei Hou
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, USA
| | - Jin-Yi Wan
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA.,Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Haiqiang Yao
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Jinbin Yuan
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Jinxiang Zeng
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Chan Woong Park
- Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea.,Department of Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Su Hwan Kim
- Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea
| | - Dae Bang Seo
- Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea
| | - Kwang-Soon Shin
- Department of Food Science and Biotechnology, Kyonggi University, Suwon, Republic of Korea
| | - Chun-Feng Zhang
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Lina Chen
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Qi-Hui Zhang
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Zhi Liu
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Clara Sava-Segal
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
| | - Chun-Su Yuan
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA.,Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, USA
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7
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Neurath MF. IL-23 in inflammatory bowel diseases and colon cancer. Cytokine Growth Factor Rev 2018; 45:1-8. [PMID: 30563755 DOI: 10.1016/j.cytogfr.2018.12.002] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 12/11/2018] [Indexed: 02/07/2023]
Abstract
Studies in recent years have identified a pivotal role of the cytokine IL-23 in the pathogenesis of inflammatory bowel diseases (IBD: Crohn´s disease, ulcerative colitis) and colitis-associated colon cancer. Genetic studies revealed that subgroups of IBD patients have single nucleotide polymorphisms in the IL-23R gene suggesting that IL-23R signaling affects disease susceptibility. Furthermore, increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients. Moreover, in several murine models of colitis, suppression of IL-12/IL-23 p40, IL-23 p19 or IL-23R function led to marked suppression of gut inflammation. This finding was associated with reduced activation of IL-23 target cells such as T helper 17 cells, innate lymphoid cells type 3, granulocytes and natural killer cells as well as with impaired production of proinflammatory cytokines. Based on these findings, targeting of IL-23 emerges as important concept for suppression of gut inflammation and inflammation-associated cancer growth. Consistently, neutralizing antibodies against IL-12/IL-23 p40 and IL-23 p19 have been successfully used in clinical trials for therapy of Crohn´s disease and pilot studies in ulcerative colitis are ongoing. These findings underline the crucial regulatory role of IL-23 in chronic intestinal inflammation and colitis-associated cancer and indicate that therapeutic strategies aiming at IL-23 blockade may be of key relevance for future therapy of IBD patients.
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Affiliation(s)
- Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nürnberg, Kussmaul Research Campus & Ludwig Demling Endoscopy Center of Excellence, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), University of Erlangen-Nürnberg, Germany.
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8
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Gagné-Sansfaçon J, Coulombe G, Langlois MJ, Langlois A, Paquet M, Carrier J, Feng GS, Qu CK, Rivard N. SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development. Oncotarget 2018; 7:65676-65695. [PMID: 27582544 PMCID: PMC5323184 DOI: 10.18632/oncotarget.11601] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 08/13/2016] [Indexed: 02/07/2023] Open
Abstract
A major risk factor of developing colorectal cancer (CRC) is the presence of chronic inflammation in the colon. In order to understand how inflammation contributes to CRC development, the present study focused on SHP-2, a tyrosine phosphatase encoded by PTPN11 gene in which polymorphisms have been shown to be markers of colitis susceptibility. Conversely, gain-of-function mutations in PTPN11 gene (E76 residue) have been found in certain sporadic CRC. Results shown herein demonstrate that SHP-2 expression was markedly increased in sporadic human adenomas but not in advanced colorectal tumors. SHP-2 silencing inhibited proliferative, invasive and tumoral properties of both intestinal epithelial cells (IECs) transformed by oncogenic KRAS and of human CRC cells. IEC-specific expression of a SHP-2E76K activated mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the ApcMin/+ background. Conversely, mice with a conditional deletion of SHP-2 in IECs developed colitis-associated adenocarcinomas with age, associated with sustained activation of Wnt/β-catenin, NFκB and STAT3 signalings in the colonic mucosae. Moreover, SHP-2 epithelial deficiency considerably increased tumor load in ApcMin/+ mice, shifting tumor incidence toward the colon. Overall, these results reveal that SHP-2 can exert opposing functions in the large intestine: it can promote or inhibit tumorigenesis depending of the inflammatory context.
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Affiliation(s)
- Jessica Gagné-Sansfaçon
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Geneviève Coulombe
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marie-Josée Langlois
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Ariane Langlois
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marilene Paquet
- Département de microbiologie et pathologie, Université de Montréal, St-Hyacinthe, QC, Canada
| | - Julie Carrier
- Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Gen-Sheng Feng
- Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA
| | - Cheng-Kui Qu
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Nathalie Rivard
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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9
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Wan JY, Huang WH, Zheng W, Park CW, Kim SH, Seo DB, Shin KS, Zeng J, Yao H, Sava-Segal C, Wang CZ, Yuan CS. Multiple Effects of Ginseng Berry Polysaccharides: Plasma Cholesterol Level Reduction and Enteric Neoplasm Prevention. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:1293-1307. [PMID: 28830208 DOI: 10.1142/s0192415x17500719] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The root of Asian ginseng (Panax ginseng C.A. Meyer) has been used for centuries in Oriental medicine to improve general well-being and to relieve various medical conditions. It is commonly understood that ginsenosides are responsible for the pharmacological activities of ginseng. Compared to the root of ginseng, studies on the berry are considerably limited. In this study, we evaluated the effects of polysaccharides from Asian ginseng berries on plasma lipid levels, chemically-induced enteric inflammation and neoplasm, and cancer chemoprevention in different experimental models. We tested two polysaccharide preparations: regular ginseng berry polysaccharide extract (GBPE) and ginseng berry polysaccharide portion (GBPP, removed MV [Formula: see text]). We first observed that both oral GBPE and oral GBPP significantly reduced plasma cholesterol and triglycerides levels in a dose-related manner in ob/ob mice, without obvious body weight changes. Then, in AOM/DSS-induced acute colitis mice, GBPE and GBPP significantly ameliorated the increased gut disease activity index and inhibited the reduction of the colon length. Further, the berry polysaccharides significantly suppressed chemically-induced pro-inflammatory cytokine levels. This is consistent with the observation that GBPE and GBPP attenuated tumorigenesis in mice by significantly and dose-dependently reducing tumor load. Finally, in vitro HCT-116 and HT-29 human colon cancer cells were used. While these berry preparations had better antiproliferation effects on the HCT-116 than the HT-29 cells, the GBPE had significantly stronger inhibitory effects than GBPP. The observed in vitro GBPE's effect could contribute to the actions of its small-molecule non-polysaccharide compounds due to their direct antiproliferative activities. Results obtained from the present study suggest that ginseng berry polysaccharides may have a therapeutic role in the management of high lipid levels, enteric inflammation, and colon malignancies.
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Affiliation(s)
- Jin-Yi Wan
- * School of Pharmacy, Jiangsu University, Zhenjiang, P. R. China.,∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Wei-Hua Huang
- † Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China.,∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Wei Zheng
- ∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Chan Woong Park
- ‡ Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea.,¶ Department of Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Su Hwan Kim
- ‡ Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea
| | - Dae Bang Seo
- ‡ Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea
| | - Kwang-Soon Shin
- § Department of Food Science and Biotechnology, Kyonggi University, Suwon, Republic of Korea
| | - Jinxiang Zeng
- ∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Haiqiang Yao
- ∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Clara Sava-Segal
- ∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Chong-Zhi Wang
- ∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Chun-Su Yuan
- ∥ Tang Center for Herbal Medicine Research and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
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Weigmann B, Neurath MF. Th9 cells in inflammatory bowel diseases. Semin Immunopathol 2016; 39:89-95. [PMID: 27837255 DOI: 10.1007/s00281-016-0603-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 10/31/2016] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel diseases are chronic, relapsing, immunologically mediated disorders of the gastrointestinal tract. Emerging evidence suggests a critical functional role of transcription factors and T cell-related cytokines in ulcerative colitis and Crohn's disease. Gut-residing T cells from patients with inflammatory bowel disease produce high amounts of IL-9. Experimental models of colitis highlighted that IL-9-producing T cells critically interfered with an intact barrier function of the intestinal epithelium by impacting cellular proliferation and tight junction molecules. The blockade of IL-9 was suited to significantly ameliorate the disease activity and severity in experimental models of inflammatory bowel disease thereby suggesting that targeting IL-9 might function as a novel targeted approach for therapy.
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Affiliation(s)
- Benno Weigmann
- Department of Medicine 1, Kussmaul Campus for Medical Research, Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Kussmaul Campus for Medical Research, Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nürnberg, Erlangen, Germany.
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11
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Suzuki N, Murata-Kamiya N, Yanagiya K, Suda W, Hattori M, Kanda H, Bingo A, Fujii Y, Maeda S, Koike K, Hatakeyama M. Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein. Sci Rep 2015; 5:10024. [PMID: 25944120 PMCID: PMC4421872 DOI: 10.1038/srep10024] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/25/2015] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori cagA-positive strain delivers the CagA oncoprotein into gastric epithelial cells and at the same time elicits stomach inflammation. To experimentally investigate the pathophysiological interplay between CagA and inflammation, transgenic mice systemically expressing the bacterial cagA gene were treated with a colitis inducer, dextran sulfate sodium (DSS). Compared with control mice, DSS-induced colitis was markedly deteriorated in cagA-transgenic mice. In the colonic epithelia of cagA-transgenic mice, there was a substantial decrease in the level of IκB, which binds and sequesters NF-κB in the cytoplasm. This IκB reduction was due to CagA-mediated inhibition of PAR1, which may stimulate IκB degradation by perturbing microtubule stability. Whereas the CagA-mediated IκB reduction did not automatically activate NF-κB, it lowered the threshold of NF-κB activation by inflammogenic insults, thereby contributing to colitis exacerbation in cagA-transgenic mice. CagA also activates inflammasomes independently of NF-κB signaling, which further potentiates inflammation. The incidence of colonic dysplasia was elevated in DSS-treated cagA-transgenic mice due to a robust increase in the number of pre-cancerous flat-type dysplasias. Thus, CagA deteriorated inflammation, whereas inflammation strengthened the oncogenic potential of CagA. This work revealed that H. pylori CagA and inflammation reinforce each other in creating a downward spiral that instigates neoplastic transformation.
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Affiliation(s)
- Nobumi Suzuki
- Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoko Murata-Kamiya
- Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kohei Yanagiya
- Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Wataru Suda
- Center for Omics and Bioinformatics, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan
| | - Masahira Hattori
- Center for Omics and Bioinformatics, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan
| | - Hiroaki Kanda
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsuhiro Bingo
- Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yumiko Fujii
- Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shin Maeda
- Gastroenterology Division, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masanori Hatakeyama
- Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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12
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American ginseng significantly reduced the progression of high-fat-diet-enhanced colon carcinogenesis in Apc (Min/+) mice. J Ginseng Res 2015. [PMID: 26199554 PMCID: PMC4506368 DOI: 10.1016/j.jgr.2014.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cause of death worldwide. Chronic gut inflammation is recognized as a risk factor for tumor development, including CRC. American ginseng is a very commonly used ginseng species in the West. METHODS A genetically engineered Apc (Min/+) mouse model was used in this study. We analyzed the saponin composition of American ginseng used in this project, and evaluated its effects on the progression of high-fat-diet-enhanced CRC carcinogenesis. RESULTS After oral ginseng administration (10-20 mg/kg/d for up to 32 wk), experimental data showed that, compared with the untreated mice, ginseng very significantly reduced tumor initiation and progression in both the small intestine (including the proximal end, middle end, and distal end) and the colon (all p < 0.01). This tumor number reduction was more obvious in those mice treated with a low dose of ginseng. The tumor multiplicity data were supported by body weight changes and gut tissue histology examinations. In addition, quantitative real-time polymerase chain reaction analysis showed that compared with the untreated group, ginseng very significantly reduced the gene expression of inflammatory cytokines, including interleukin-1α (IL-1α), IL-1β, IL-6, tumor necrosis factor-α, granulocyte-colony stimulating factor, and granulocyte-macrophage colony-stimulating factor in both the small intestine and the colon (all p < 0.01). CONCLUSION Further studies are needed to link our observed effects to the actions of the gut microbiome in converting the parent ginsenosides to bioactive ginseng metabolites. Our data suggest that American ginseng may have potential value in CRC chemoprevention.
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14
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Raine T. Vedolizumab for inflammatory bowel disease: Changing the game, or more of the same? United European Gastroenterol J 2014; 2:333-44. [PMID: 25360311 DOI: 10.1177/2050640614550672] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/09/2014] [Indexed: 12/11/2022] Open
Abstract
Two decades ago, the first reports of the use of monoclonal antibodies targeting tumour-necrosis factor α heralded a revolution in treatment options for moderate to severe Crohn's disease and ulcerative colitis. Nonetheless, patients with refractory disease or loss of treatment response are all too familiar to gastroenterologists. Preventing the infiltration of the gastrointestinal mucosa by circulating cells of the immune system using antibodies targeting the adhesion molecules involved represents an attractive new treatment option. Vedolizumab has recently received European and US regulatory approval for treatment of ulcerative colitis and Crohn's disease on the basis of encouraging results from one of the largest phase III trial programmes ever conducted in the field of inflammatory bowel diseases and promising safety data. Are we now seeing another revolution in the management of inflammatory bowel disease, and how can this new drug best be used in clinical practice?
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Affiliation(s)
- Tim Raine
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
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15
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Foersch S, Neurath MF. Colitis-associated neoplasia: molecular basis and clinical translation. Cell Mol Life Sci 2014; 71:3523-35. [PMID: 24830703 PMCID: PMC11113942 DOI: 10.1007/s00018-014-1636-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 04/07/2014] [Accepted: 04/28/2014] [Indexed: 02/07/2023]
Abstract
Crohn's disease and ulcerative colitis are both associated with an increased risk of inflammation-associated colorectal carcinoma. Colitis-associated cancer (CAC) is one of the most important causes for morbidity and mortality in patients with inflammatory bowel diseases (IBD). Colitis-associated neoplasia distinctly differs from sporadic colorectal cancer in its biology and the underlying mechanisms. This review discusses the molecular mechanisms of CAC and summarizes the most important genetic alterations and signaling pathways involved in inflammatory carcinogenesis. Then, clinical translation is evaluated by discussing new endoscopic techniques and their contribution to surveillance and early detection of CAC. Last, we briefly address different types of concepts for prevention (i.e., anti-inflammatory therapeutics) and treatment (i.e., surgical intervention) of CAC and give an outlook on this important aspect of IBD.
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Affiliation(s)
- Sebastian Foersch
- Department of Medicine 1, FAU Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany,
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16
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Feng ST, Li J, Luo Y, Yin T, Cai H, Wang Y, Dong Z, Shuai X, Li ZP. pH-sensitive nanomicelles for controlled and efficient drug delivery to human colorectal carcinoma LoVo cells. PLoS One 2014; 9:e100732. [PMID: 24964012 PMCID: PMC4071001 DOI: 10.1371/journal.pone.0100732] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Accepted: 05/29/2014] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The triblock copolymers PEG-P(Asp-DIP)-P(Lys-Ca) (PEALCa) of polyethylene glycol (PEG), poly(N-(N',N'-diisopropylaminoethyl) aspartamide) (P(Asp-DIP)), and poly (lysine-cholic acid) (P(Lys-Ca)) were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES), and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. METHODOLOGY/PRINCIPAL FINDINGS The anticancer drug Paclitaxel (PTX) and hydrophilic superparamagnetic iron oxide (SPIO) were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells), and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC) LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI) and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. CONCLUSIONS/SIGNIFICANCE These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy.
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Affiliation(s)
- Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jingguo Li
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, China
| | - Yanji Luo
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tinghui Yin
- Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Huasong Cai
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yong Wang
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, China
| | - Zhi Dong
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xintao Shuai
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, China
| | - Zi-Ping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail:
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Rutter MD, Riddell RH. Colorectal dysplasia in inflammatory bowel disease: a clinicopathologic perspective. Clin Gastroenterol Hepatol 2014; 12:359-67. [PMID: 23756224 DOI: 10.1016/j.cgh.2013.05.033] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 05/18/2013] [Accepted: 05/20/2013] [Indexed: 02/07/2023]
Abstract
Surveillance for neoplasia in colitis is the most challenging diagnostic colonoscopic procedure. The detection and treatment of colorectal dysplasia in inflammatory bowel disease remain problematic to the point that unsuspected colorectal cancers (CRCs) are still identified. Excellent bowel preparation and use of high-resolution colonoscopes with chromoendoscopy facilitate the detection and characterization of subtle neoplasia. This approach is superior to taking random biopsy specimens and should be the standard of care for surveillance but requires adequate training. Suspicious lesions should be assessed carefully and described using objective terminology. The terms dysplasia-associated lesions/masses and flat dysplasia are best avoided because they may be open to misinterpretation. Most suspicious lesions detected during surveillance can be removed endoscopically, precluding the need for surgery. Nevertheless, endotherapy in colitis can be difficult as a result of underlying inflammation and scarring. Lesions that are not endoscopically resectable need to be removed surgically, although the possibility that some lesions might be amenable to local resection (including lymphadenectomy) rather than subtotal colectomy may need to be re-evaluated. Despite surveillance programs, patients still present clinically with CRC. This may occur because lesions are missed (possibly because of the failure to use optimal techniques), lesions are not adequately removed, patients fail to return for colonoscopy, or CRCs arise rapidly in mucosa that is minimally dysplastic and the CRCs are not recognized as being potentially invasive even on biopsy. Future advances in, for example, stool DNA assays, use of confocal endomicroscopy, or use of endoscopic ultrasound, may help in the identification of high-risk patients and the assessment of dysplastic lesions.
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Affiliation(s)
- Matthew D Rutter
- Tees Bowel Cancer Screening Centre, University Hospital of North Tees, Stockton-on-Tees, Cleveland, United Kingdom; School of Medicine, Pharmacy and Health, Durham University, County Durham, United Kingdom; Northern Region Endoscopy Group, Northern England, United Kingdom.
| | - Robert H Riddell
- Department of Pathobiology and Laboratory Medicine, Mt Sinai Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
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Koehler BC, Jäger D, Schulze-Bergkamen H. Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives. World J Gastroenterol 2014; 20:1923-1934. [PMID: 24587670 PMCID: PMC3934462 DOI: 10.3748/wjg.v20.i8.1923] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/06/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.
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19
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New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol 2014; 7:6-19. [PMID: 24084775 DOI: 10.1038/mi.2013.73] [Citation(s) in RCA: 252] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023]
Abstract
Healing of the inflamed mucosa (mucosal healing) is an emerging new goal for therapy and predicts clinical remission and resection-free survival in inflammatory bowel diseases (IBDs). The era of antitumor necrosis factor (TNF) antibody therapy was a remarkable progress in IBD therapy and anti-TNF agents led to mucosal healing in a subgroup of IBD patients; however, many patients do not respond to anti-TNF treatment highlighting the relevance of finding new targets for therapy of IBD. In particular, current studies are addressing the role of other anticytokine agents including antibodies against interleukin (IL)-6R, IL-13, and IL-12/IL-23 as well as new anti-inflammatory concepts (regulatory T cell therapy, Smad7 antisense, Jak inhibition, Toll-like receptor 9 stimulation, worm eggs). In addition, blockade of T-cell homing via the integrins α4β7 and the addressin mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) emerges as a promising new approach for IBD therapy. Here, new approaches for achieving mucosal healing are discussed as well as their implications for future therapy of IBD.
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20
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Xue Q, Sun K, Deng HJ, Lei ST, Dong JQ, Li GX. MicroRNA-338-3p inhibits colorectal carcinoma cell invasion and migration by targeting smoothened. Jpn J Clin Oncol 2013; 44:13-21. [PMID: 24277750 DOI: 10.1093/jjco/hyt181] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To investigate the regulative effect of microRNA-338-3p on colorectal carcinoma cell invasion and migration. METHODS The microRNA-338-3p expression pattern of colorectal carcinoma tissues and cell lines was detected by real-time reverse transcriptase polymerase chain reaction. The protein level of smoothened was detected by western blot analysis. Furthermore, colorectal carcinoma cells were pretreated with or without anti-smoothened-small interfering ribonucleic acid prior to the addition of pre-microRNA-338-3p or anti-microRNA-338-3p. The status of colorectal carcinoma cell invasion and that of migration were detected by transwell assay and wound healing assay, respectively. RESULTS The expression of microRNA-338-3p was significantly down-regulated in colorectal carcinoma tissues in comparison with those in the adjacent non-tumorous tissues, and the value was negatively related to advanced tumor, node, metastasis stage and local invasion. The expression of microRNA-338-3p in colorectal carcinoma cells transfected with pre-microRNA-338-3p p was significantly increased. Furthermore, over-expression of microRNA-338-3p inhibited the expression of smoothened protein in colorectal carcinoma cells, which showed obviously suppressed invasion and migration ability. The expression of microRNA-338-3p in colorectal carcinoma cells transfected with anti-microRNA-338-3p was significantly decreased. Moreover, the down-regulated expression of microRNA-338-3p caused the up-regulated expression of smoothened protein in colorectal carcinoma cells, which showed significantly enhanced invasion and migration ability. However, anti-smoothened-small interfering ribonucleic acid largely, but not completely, reversed the effects induced by blockage of microRNA-338-3p, suggesting that the regulative effect of microRNA-338-3p on colorectal carcinoma cell invasion and migration was indeed mediated by smoothened. Additionally, smoothened was identified as a direct target of microRNA-338-3p by luciferase assay. CONCLUSIONS MicroRNA-338-3p could inhibit colorectal carcinoma cell invasion and migration by inhibiting smoothened expression.
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Affiliation(s)
- Qi Xue
- *Department of General Surgery, Nanfang Hospital of Southern Medical University, Guangzhou 510515, Guangdong Province, China.
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Abstract
While barrier function and the effects of the intestinal microbiome have only recently moved into the focus of inflammatory bowel disease research, the role of the innate and the adaptive immune system in these gastrointestinal disorders has extensively been studied. Although still not completely understood, the increasing knowledge about the immune system's contribution to the pathophysiology of inflammatory bowel diseases has led to new diagnostic and therapeutic approaches. This review gives a compact overview on this important topic.
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Affiliation(s)
- Sebastian Foersch
- Department of Medicine 1, Friedrich Alexander University, Erlangen, Germany
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