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Laurindo LF, de Maio MC, Minniti G, de Góes Corrêa N, Barbalho SM, Quesada K, Guiguer EL, Sloan KP, Detregiachi CRP, Araújo AC, de Alvares Goulart R. Effects of Medicinal Plants and Phytochemicals in Nrf2 Pathways during Inflammatory Bowel Diseases and Related Colorectal Cancer: A Comprehensive Review. Metabolites 2023; 13:243. [PMID: 36837862 PMCID: PMC9966918 DOI: 10.3390/metabo13020243] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/02/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are related to nuclear factor erythroid 2-related factor 2 (Nrf2) dysregulation. In vitro and in vivo studies using phytocompounds as modulators of the Nrf2 signaling in IBD have already been published. However, no existing review emphasizes the whole scenario for the potential of plants and phytocompounds as regulators of Nrf2 in IBD models and colitis-associated colorectal carcinogenesis. For these reasons, this study aimed to build a review that could fill this void. The PubMed, EMBASE, COCHRANE, and Google Scholar databases were searched. The literature review showed that medicinal plants and phytochemicals regulated the Nrf2 on IBD and IBD-associated colorectal cancer by amplifying the expression of the Nrf2-mediated phase II detoxifying enzymes and diminishing NF-κB-related inflammation. These effects improve the bowel environment, mucosal barrier, colon, and crypt disruption, reduce ulceration and microbial translocation, and consequently, reduce the disease activity index (DAI). Moreover, the modulation of Nrf2 can regulate various genes involved in cellular redox, protein degradation, DNA repair, xenobiotic metabolism, and apoptosis, contributing to the prevention of colorectal cancer.
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Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Avenida Monte Carmelo, 800, Marília 17519-030, São Paulo, Brazil
| | - Mariana Canevari de Maio
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Avenida Monte Carmelo, 800, Marília 17519-030, São Paulo, Brazil
| | - Giulia Minniti
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
| | - Natália de Góes Corrêa
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília 17500-000, São Paulo, Brazil
| | - Karina Quesada
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília 17500-000, São Paulo, Brazil
| | - Elen Landgraf Guiguer
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília 17500-000, São Paulo, Brazil
| | | | - Claudia R. P. Detregiachi
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
| | - Ricardo de Alvares Goulart
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil
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Lei S, Feng Y, Huang P, Chen B, Bao K, Wu Q, Zhang H, Huang X. Ophiopogonin D'-induced mitophagy and mitochondrial damage are associated with dysregulation of the PINK1/Parkin signaling pathway in AC16 cells. Toxicology 2022; 477:153275. [PMID: 35905946 DOI: 10.1016/j.tox.2022.153275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/24/2022] [Accepted: 07/25/2022] [Indexed: 11/30/2022]
Abstract
Shenmai injection (SMI) is a patented traditional Chinese medicine that is extracted from Panax ginseng and Ophiopogon japonicus and is commonly used to treat cardiovascular diseases and tumors. The O. japonicus extract Ophiopogonin D' (OPD') is highly cardiotoxic. Mitochondria are central to OPD'-induced cardiotoxicity, although the precise mechanisms remain unclear. Excessive mitophagy activation and mitochondrial dysfunction lead to apoptosis, and the PTEN-induced kinase 1(PINK1)/Parkin pathway is critical in regulating mitophagy and mitochondrial function. We investigated the role of the PINK1/Parkin pathway in OPD'-induced mitochondrial damage and cardiotoxicity in AC16 cells. Concentrations of 2μM OPD' and above inhibited cardiomyocyte viability and increased lactate dehydrogenase (LDH) release in a concentration- and time-dependent manner. OPD' was toxic to cells and mitochondria and increased the rate of apoptosis, triggering pyknosis, decreasing mitochondrial membrane potential (MMP), and decreasing the protein expression of the biogenesis regulator peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α). The increased ratio of microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) in mitochondria indicated that OPD' induced mitophagy. OPD' significantly induced oxidative stress and apoptosis, including increased reactive oxygen species (ROS) generation and decreased nuclear factor erythroid-2 related factor 2 (Nrf2), heme oxygenase-1(HO-1), and B-cell lymphoma 2 (Bcl-2) protein expression. OPD' activated the PINK1/Parkin pathway and promoted PINK1/Parkin translocation to mitochondria. Inhibiting mitophagy attenuated OPD'-induced PINK1/Parkin pathway activation and preserved mitochondrial biogenesis, consequently mitigating OPD'-induced mitochondrial dysfunction and apoptosis. These findings suggest that OPD'-induced cardiomyocyte mitophagy and mitochondrial damage are at least partially mediated by dysregulation of the PINK1/Parkin pathway.
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Affiliation(s)
- Sisi Lei
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Yuchao Feng
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Peiying Huang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China
| | - BoJun Chen
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Kun Bao
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
| | - Qihua Wu
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Haobo Zhang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Xiaoyan Huang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Research on Emergency in Traditional Chinese Medicine, Clinical Research Team of Prevention and Treatment of Cardiac Emergencies with Traditional Chinese Medicine, Guangzhou, 510120, China.
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Zhang H, Gu H, Jia Q, Zhao Y, Li H, Shen S, Liu X, Wang G, Shi Q. Syringin protects against colitis by ameliorating inflammation. Arch Biochem Biophys 2020; 680:108242. [DOI: 10.1016/j.abb.2019.108242] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/26/2019] [Accepted: 12/29/2019] [Indexed: 02/07/2023]
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Fan H, Chen W, Zhu J, Zhang J, Peng S. Toosendanin alleviates dextran sulfate sodium-induced colitis by inhibiting M1 macrophage polarization and regulating NLRP3 inflammasome and Nrf2/HO-1 signaling. Int Immunopharmacol 2019; 76:105909. [PMID: 31520988 DOI: 10.1016/j.intimp.2019.105909] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/06/2019] [Accepted: 09/08/2019] [Indexed: 12/22/2022]
Abstract
Toosendanin (TSN), a triterpenoid extracted from the bark of fruit of Melia toosendan Sieb et Zucc, has been proven to have various biological activities including anti-inflammatory activity. But its effects on experimental colitis remain unreported. Herein, we investigated the role and potential mechanisms of TSN in dextran sulfate sodium (DSS) induced colitis in mice. The results showed that, TSN reduced colitis-associated disease activity index (DAI), shortened colon length, and weakened the pathological damage of the colon tissues in murine colitis models. Further studies disclosed that, TSN inhibited the secretion of proinflammatory cytokines and oxidative stress, and suppressed M1 macrophage polarization and the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome, but upregulated HO-1/Nrf2 expression in murine colitis. In addition, TSN maintained intestinal barrier by regulating zonula occludens-1 (ZO-1) and occludin expression. In conclusion, our findings demonstrated that, TSN alleviates DSS-induced experimental colitis by inhibiting M1 macrophage polarization and regulating NLRP3 inflammasome and Nrf2/HO-1 signaling, and may provide a novel Chinese patent medicine for the treatment of murine colitis.
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Affiliation(s)
- Huining Fan
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Wei Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Jinshui Zhu
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Jing Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Shiqiao Peng
- Department of Endocrinology and metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11001, PR China.
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Electroacupuncture at ST-36 ameliorates DSS-induced acute colitis via regulating macrophage polarization induced by suppressing NLRP3/IL-1β and promoting Nrf2/HO-1. Mol Immunol 2019; 106:143-152. [PMID: 30610999 DOI: 10.1016/j.molimm.2018.12.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 12/05/2018] [Accepted: 12/21/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND Electroacupuncture (EA) at ST-36 can attenuate acute experimental colitis, but the mechanisms are unclear. We investigated the role of macrophages in the anti-inflammatory effects of EA and its molecular mechanisms. METHODS Male C57BL/6 mice were randomized into five groups: normal control, dextran sulfate sodium (DSS)-induced acute colitis (DSS), DSS with sham EA (SEA), DSS with high-frequency EA (HEA) and DSS with low-frequency EA (LEA). Body weight, colon length, DAI score and histological score were evaluated during colitis progression. Serum and colonic levels of pro- and anti-inflammatory cytokines were detected with ELISA, cytometric beads array, RT-PCR and western blotting analysis. Colonic macrophage subsets were determined using flow cytometry. Magnetic-activated cell sorting was applied to isolate colonic macrophages, and molecular mechanisms were explored with western blotting, RT-PCR and immunofluorescence. RESULTS (1) Compared with the DSS group, HEA and LEA attenuated body weight loss and decreased DAI and histological scores. (2) Serum levels and colonic protein and mRNA levels of IL-1β, TNFα, IL-6, IL-12 and IL17 were markedly decreased with HEA and LEA. IL-10 level was increased with HEA. (3) M1 macrophage percentage increased, while M2 macrophage percentage decreased in the DSS group; HEA and LEA reversed these proportions. (4) NLRP3/IL-1β protein and mRNA levels in isolated macrophages decreased with HEA and LEA compared with the DSS treatment group; (5) HEA increased Nrf2/HO-1 levels compared with levels in DSS mice. CONCLUSION The anti-inflammatory effects of EA on DSS-induced acute colitis may rely on regulating macrophage polarization, NLRP3/IL-1β suppression and Nrf2/HO-1 promotion.
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Liang N, Kitts DD. Amelioration of Oxidative Stress in Caco-2 Cells Treated with Pro-inflammatory Proteins by Chlorogenic Acid Isomers via Activation of the Nrf2-Keap1-ARE-Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:11008-11017. [PMID: 30259744 DOI: 10.1021/acs.jafc.8b03983] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Understanding the potential effects of chlorogenic acid (CGA) isomers on the intestinal epithelium is important because coffee intake exposes consumers to the six major CGA isomers: 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), 5-caffeoylquinic acid (5-CQA), 3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and 4,5-dicaffeoylquinic acid (4,5-diCQA). The present study determined the relative effects of CGA isomers on the antioxidant status of inflamed Caco-2 intestinal cells by investigating the oxidative-stress-responsive pathway and nuclear-factor-erythroid-derived-2-like 2 (Nrf2) signaling. Differentiated Caco-2 cells were challenged with the inflammatory mediators PMA and IFNγ, as a model of intestinal inflammation in vitro. Significant redox ( p < 0.05) responses to these mediators were assessed by indirect measurement of induced generation of reactive oxygen species (ROS), as well as the expression of reduced (GSH) and oxidized (GSSG) glutathione. This translated to a 40% reduction in the GSH/GSSG ratio. We found that responses in these parameters were associated with increased Nrf2 activation ( p < 0.05). ROS generation and increased IL-8 secretion were found in challenged cells, indicating an association between induced oxidation and inflammatory status. Oxidative stress was ameliorated by CGA isomers, which scavenged intracellular ROS, increased GSH, and activated Nrf2 signaling. diCQA isomers were relatively more effective at reducing IL-8 ( p < 0.05). The observed increase in Nrf2 signaling led to upregulated expression of some Nrf2 target genes ( GPX2, KEAP1, and NFE2L2) in Caco-2 cells and activated the Nrf2-Keap1-ARE-signaling pathway. These findings indicate that CGA isomers present in coffee have bioactivity toward alleviating oxidative stress associated with intestinal inflammation.
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Affiliation(s)
- Ningjian Liang
- Food, Nutrition, and Health Program, Faculty of Land and Food Systems , The University of British Columbia , 2205 East Mall , Vancouver , British Columbia V6T 1Z4 , Canada
| | - David D Kitts
- Food, Nutrition, and Health Program, Faculty of Land and Food Systems , The University of British Columbia , 2205 East Mall , Vancouver , British Columbia V6T 1Z4 , Canada
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Tekeli İO, Ateşşahin A, Sakin F, Aslan A, Çeribaşı S, Yipel M. Protective effects of conventional and colon-targeted lycopene and linalool on ulcerative colitis induced by acetic acid in rats. Inflammopharmacology 2018; 27:10.1007/s10787-018-0485-x. [PMID: 29736689 DOI: 10.1007/s10787-018-0485-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 04/21/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To compare the potential protective effects of conventional and colon-targeted lycopene (TLC) and linalool (TLN) on acetic acid (AA)-induced ulcerative colitis (UC) in rats. METHODS Conventional and colon-targeted LC (10 mg/kg) and LN (200 mg/kg) were administered in vivo orally for 7 days and sulfasalazine (100 mg/kg) was also used as reference drug. Then, 4% AA was administered intrarectally to induce UC. Subsequently, the colon tissues were taken as samples for biochemical and histopathological analysis. RESULTS Malondialdehyde (MDA), interleukin 1β (IL-1β), IL-6, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) levels were decreased (p < 0.05) in the targeted groups compared to the AA group, whereas nuclear factor-erythroid 2-related factor 2 (Nrf-2) level was increased (p < 0.05). Tumor necrosis factor α (TNF-α) level was also decreased (p < 0.05) and catalase activity (CAT) was increased (p < 0.05) in the TLC group compared to the AA group. IL-1β and IL-6 levels were lower in the TLC group compared to the conventional LC and sulfasalazine groups (p < 0.05). COX-2 and NF-κB levels were lower, while the Nrf-2 level was higher in the targeted groups compared to the conventional groups (p < 0.05). Furthermore, COX-2 level was lower and Nrf-2 level was higher in the targeted groups compared to the sulfasalazine group (p < 0.05). CONCLUSION As expected, sulfasalazine was effective on all parameters analyzed, but the colon-targeted pretreatments were more effective from sulfasalazine on some parameters. Therefore, colon-targeted plant-derived therapies might be alternative approaches to provide protection against UC, which deserves to be investigated further.
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Affiliation(s)
- İbrahim Ozan Tekeli
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Mustafa Kemal University, 31060, Hatay, Turkey.
| | - Ahmet Ateşşahin
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Fırat University, 23119, Elazığ, Turkey
| | - Fatih Sakin
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Mustafa Kemal University, 31060, Hatay, Turkey
| | - Abdullah Aslan
- Department of Biology, Faculty of Science, Fırat University, 23119, Elazığ, Turkey
| | - Songül Çeribaşı
- Department of Pathology, Faculty of Veterinary Medicine, Fırat University, 23119, Elazığ, Turkey
| | - Mustafa Yipel
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Namık Kemal University, 59030, Tekirdağ, Turkey
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Guan Y, Tan Y, Liu W, Yang J, Wang D, Pan D, Sun Y, Zheng C. NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-β1/SMADs Pathway. Dig Dis Sci 2018; 63:366-380. [PMID: 28815354 DOI: 10.1007/s10620-017-4710-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/01/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear. METHODS BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-β1 (TGF-β1), which transformed the cells into myofibroblasts. The main fibrosis markers such as α-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-β1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate. RESULTS tBHQ suppressed the intestinal fibrosis through the TGF-β1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-β1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-β1-stimulated CCD-18Co cells. Pretreatment with H2O2, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-β1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-β1 promoted by Nrf2 knockdown. CONCLUSIONS The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-β1/SMADs pathway in vivo and in vitro.
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Affiliation(s)
- Yadi Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Yue Tan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Weiyu Liu
- Department of Gastroenterology, The People's Hospital Liaoning Provincial, 33 Wenyi Road, Shenhe District, Shenyang, 110013, Liaoning Province, China
| | - Jun Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Dongxu Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Di Pan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China
| | - Changqing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China.
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Yang W, Sun Z, Yang B, Wang Q. Nrf2-Knockout Protects from Intestinal Injuries in C57BL/6J Mice Following Abdominal Irradiation with γ Rays. Int J Mol Sci 2017; 18:ijms18081656. [PMID: 28758961 PMCID: PMC5578046 DOI: 10.3390/ijms18081656] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 07/23/2017] [Accepted: 07/27/2017] [Indexed: 12/15/2022] Open
Abstract
Radiation-induced intestinal injuries (RIII) commonly occur in patients who suffer from pelvic or abdominal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant, and the radioprotective role of Nrf2 is found in bone marrow, lung, and intestine, etc. Here, we investigated the effect of Nrf2 knockout on radiation-induced intestinal injuries using Nrf2 knockout (Nrf2-/-) mice and wild-type (Nrf2+/+) C57BL/6J mice following 13 Gy abdominal irradiation (ABI). It was found that Nrf2 knockout promoted the survival of irradiated mice, protected the crypt-villus structure of the small intestine, and elevated peripheral blood lymphocyte count and thymus coefficients. The DNA damage of peripheral blood lymphocytes and the apoptosis of intestinal epithelial cells (IECs) of irradiated Nrf2-/- mice were decreased. Furthermore, compared with that of Nrf2+/+ mice, Nrf2 knockout increased the number of Lgr5⁺ intestinal stem cells (ISCs) and their daughter cells including Ki67⁺ transient amplifying cells, Villin⁺ enterocytes, and lysozyme⁺ Paneth cells. Nuclear factor-κB (NF-κB) was accumulated in the crypt base nuclei of the small intestine, and the mRNA expression of NF-κB target genes Bcl-2, uPA, and Xiap of the small intestine from irradiated Nrf2-/- mice were increased. Collectively, Nrf2 knockout has the protective effect on small intestine damage following abdominal irradiation by prompting the proliferation and differentiation of Lgr5⁺ intestinal stem cells and activation of NF-κB.
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Affiliation(s)
- Wenyan Yang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
| | - Zhijuan Sun
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
| | - Bing Yang
- Department of Cellular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
| | - Qin Wang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
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Zheng L, Zhang YL, Dai YC, Chen X, Chen DL, Dai YT, Tang ZP. Jianpi Qingchang decoction alleviates ulcerative colitis by inhibiting nuclear factor-κB activation. World J Gastroenterol 2017; 23:1180-1188. [PMID: 28275298 PMCID: PMC5323443 DOI: 10.3748/wjg.v23.i7.1180] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/13/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the therapeutic effect of Jianpi Qingchang decoction (JPQCD) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. METHODS C57BL/c mice were injected intragastrically with 5% DSS instead of drinking water for 7 d, and their body weight, diarrhea severity and fecal bleeding were monitored, while the mice in the control group were treated with standard drinking water, without DSS. After 7 d, the DSS drinking water was changed to normal water and the DSS group continued with DSS water. The control and DSS groups were given normal saline by intragastric injection. The 5-aminosalicylic acid (5-ASA) group was treated orally with 5-ASA at a dose of 100 mg/kg daily. The JPQCD group was treated orally with JPQCD at a dose of 17.1 g/kg daily. On day 14, the colon length was measured, the colorectal histopathological damage score was assessed, and protein levels of interleukin (IL)-1β, IL-8 and tumor necrosis factor-alpha (TNF-α) in colon supernatants were measured by enzyme-linked immunosorbent assay. mRNA expression of IL-1β, IL-8, TNF-α and nuclear factor-kappa B (NF-κB) was detected by real-time quantitative polymerase chain reaction. Western blotting was used to detect the protein expression of NF-κB and inhibitor of kappa B. RESULTS Acute inflammation occurred in the mice administered DSS, including the symptoms of losing body weight, loose feces/watery diarrhea and presence of fecal blood; all these symptoms worsened at 7 d. The colons of mice treated with DSS were assessed by histological examination, and the results confirmed that acute inflammation had occurred, as evidenced by loss of colonic mucosa and chronic inflammatory cell infiltration, and these features extended into the deeper layer of the colon walls. The expression levels of IL-1β, IL-8 and TNF-α in the DSS group were higher than those in the control group (P < 0.05), and the expression levels of IL-1β, IL-8 and TNF-α in the JPQCD and 5-ASA groups were lower than those in the DSS group after treating with JPQCD and 5-ASA. Comparing with the DSS group, the mRNA level of IL-1β, IL-8, TNF-α and NF-κB was significantly reduced by 5-ASA and JPQCD. The difference between JPQCD and 5-ASA groups was not statistically significant (P > 0.05). Comparing with the DSS group, due to using JPQCD and 5-ASA, significant suppression of activation in DSS-induced NF-κB and increased phosphorylation of IκB in mice with experimental colitis occurred (P < 0.05). The difference between the JPQCD group and the 5-ASA group was not statistically significant (P > 0.05). CONCLUSION Activation of the NF-κB signaling pathway is inhibited by JPQCD, which shows the potential mechanism by which JPQCD treats UC.
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Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation. Biochem Pharmacol 2016; 112:37-49. [DOI: 10.1016/j.bcp.2016.05.002] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/04/2016] [Indexed: 02/07/2023]
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Antioxidant therapy for treatment of inflammatory bowel disease: Does it work? Redox Biol 2015; 6:617-639. [PMID: 26520808 PMCID: PMC4637335 DOI: 10.1016/j.redox.2015.10.006] [Citation(s) in RCA: 266] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/18/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.
Major biomarkers used for evaluation of antioxidant therapy were MPO, TBARS/MDA and glutathione levels. Challenges were identified for the yet poor use of antioxidant therapy in IBD. This review stimulates the investigation of alternative and efficacious antioxidant therapies.
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Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:605208. [PMID: 26075036 PMCID: PMC4436474 DOI: 10.1155/2015/605208] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/23/2015] [Indexed: 12/20/2022]
Abstract
The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P < 0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3Y705 pathways.
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