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Hua S, Zhang Z, Zhang Z, Liu L, Yu S, Xiao Y, Liu Y, Wei S, Xu Y, Chen YG. Genetic disruption of the circadian gene Bmal1 in the intestinal epithelium reduces colonic inflammation. EMBO Rep 2025:10.1038/s44319-025-00464-y. [PMID: 40307620 DOI: 10.1038/s44319-025-00464-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 04/12/2025] [Accepted: 04/16/2025] [Indexed: 05/02/2025] Open
Abstract
Disruption of the circadian clock is associated with the development of inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. Here, we observe that mice in the early active phase (Zeitgeber time 12, ZT12) of the circadian clock are more tolerant to dextran sodium sulfate (DSS)-induced colitis, compared to those in the early resting phase (ZT0). The expression of the circadian gene Bmal1 peaks in the early resting phase and declines in the early active phase. Bmal1 knockout in the intestinal epithelium reduces DSS-induced inflammatory symptoms. Mechanistically, BMAL1 promotes apoptosis by binding to apoptosis-related genes, including Bax, p53, and Bak1, and promotes their expression. Intriguingly, we observe circadian apoptotic rhythms in the homeostatic intestinal epithelium, while Bmal1 deletion reduces cell apoptosis. Consistently, reducing Bmal1 expression by the REV-ERBα agonist SR9009 has the best therapeutic efficacy against DSS-induced colitis at ZT0. Collectively, our data demonstrate that the Bmal1-centered circadian clock is involved in intestinal injury repair.
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Affiliation(s)
- Shan Hua
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Ze Zhang
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Zhe Zhang
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Liansheng Liu
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Shicheng Yu
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Yanhui Xiao
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Yuan Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Siting Wei
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Ying Xu
- Cambridge-Su Genomic Resource Center, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Ye-Guang Chen
- Guangzhou National Laboratory, Guangzhou, 510005, China.
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
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2
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Li P, Wang Y, Hu H, Sun B. Role of PD-L1 in mediating the effect of lipid on ulcerative colitis: a mediation Mendelian randomization study. Front Genet 2025; 16:1390605. [PMID: 40034746 PMCID: PMC11872926 DOI: 10.3389/fgene.2025.1390605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 01/31/2025] [Indexed: 03/05/2025] Open
Abstract
Introduction Recent evidence suggests that lipids play a crucial role in intestinal metabolic balance and are closely linked to ulcerative colitis (UC). However, the mechanisms underlying their effects remain unclear. This study employed Mendelian randomization (MR) to investigate the relationships among lipids, inflammatory factors, and UC. Methods We analyzed data on 179 lipids from the GeneRISK cohort (7,174 individuals), 91 inflammation-related proteins from the EBI GWAS Catalog (14,824 participants), and UC GWAS summary statistics from the FinnGen Biobank (411,317 samples). Associations were assessed using inverse variance weighted (IVW) and Bayesian-weighted MR (BWMR) methods. A mediation analysis was conducted to explore the potential role of inflammatory factors in mediating lipid effects on UC. Results MR analysis revealed a significant negative association between sterol ester (27:1/20:4) levels and UC (SNPs = 31; IVW: OR = 0.900 [95% CI: 0.851-0.952], p < 0.001; BWMR: OR = 0.906 [95% CI: 0.849-0.967], p = 0.003). Furthermore, sterol ester (27:1/20:4) was negatively correlated with PD-L1 (SNPs = 30; IVW: OR = 0.961 [95% CI: 0.934-0.990], p = 0.008), and PD-L1 was found to be inversely associated with UC (SNPs = 24; IVW: OR = 0.850 [95% CI: 0.724-0.999], p = 0.048). Mediation analysis suggested that sterol esters (27:1/20:4) may indirectly increase UC risk by downregulating PD-L1 expression. However, the MR analysis results suggest that sterol esters (27:1/20:4) act as a protective factor against UC, which contradicts the mediation analysis. This discrepancy highlights the dual role of PD-L1 in UC pathogenesis. Discussion PD-L1 may serve as a key mediator in the regulation of UC pathogenesis by sterol esters, but the underlying complex mechanisms require further investigation.
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Affiliation(s)
- Peihong Li
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiwen Wang
- Department of Internal Medicine, Tianshan Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Hongyi Hu
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Boyun Sun
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Zhang P, Pei B, Yi C, Akanyibah FA, Mao F. The role of suppressor of cytokine signaling 3 in inflammatory bowel disease and its associated colorectal cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167578. [PMID: 39571630 DOI: 10.1016/j.bbadis.2024.167578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024]
Abstract
Inflammatory bowel disease (IBD) and colorectal cancer (CRC), as two of the major human intestinal diseases, provide challenges for the medical field. Suppressor of cytokine signaling 3 (SOCS3), a protein molecule that negatively regulates cytokine signaling through multiple pathways, is involved in the regulation of various inflammatory diseases and tumors. In IBD, SOCS3 acts on a variety of cells to repair mucosal damage and balance the immune response, including epithelial cells, macrophages, dendritic cells, neutrophils, and T cells. In CRC, SOCS3 is inextricably linked to tumor cell proliferation, invasion, metastasis, and drug resistance. Therefore, it is crucial to systematically investigate the pathogenic involvement of SOCS3 in IBD and CRC. This article reviews the mechanisms and pathways by which SOCS3 is involved in the inhibition of IBD and the mitigation of CRC, and details the therapeutic options for targeting SOCS3.
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Affiliation(s)
- Pengfei Zhang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Institute of Hematology, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian 223800, Jiangsu, PR China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang 212028, PR China
| | - Francis Atim Akanyibah
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China
| | - Fei Mao
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Institute of Hematology, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China.
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4
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Ullah H, Alioui Y, Ali M, Ali S, Farooqui NA, Siddiqui NZ, Alsholi DM, Ilyas M, Rahman MU, Xin Y, Wang L. Sea conch ( Rapana venosa) peptide hydrolysate regulates NF-κB pathway and restores intestinal immune homeostasis in DSS-induced colitis mice. Food Sci Nutr 2024; 12:10070-10086. [PMID: 39723032 PMCID: PMC11666983 DOI: 10.1002/fsn3.4410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 12/28/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. Sea conch peptide hydrolysate (CPH) was produced by enzymatic digestion of fresh conch meat with trypsin enzyme. To analyze the molecular composition, functional groups, and structural morphology of the hydrolysate, we employed liquid chromatography-mass spectrometry (LC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Results confirmed that crude protein could be effectively digested by enzymes to generate peptides. In this study, we evaluated the bioactivities of CPH on dextran sulfate solution (DSS)-induced colitis in mice. The findings demonstrated that CPH supplementation improved body weight, food and water intake, and colon length. The therapeutic efficacy and immunoregulatory effect of CPH were further determined. Our results exhibited that CPH treatment significantly ameliorated pathological symptoms by enhancing intestinal integrity, mucin production, and goblet cell count. Moreover, the immunoregulatory effect of CPH on mRNA expression levels of different pro- and anti-inflammatory cytokines was determined. Results exhibited a decrease in the expression of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines in the colon. Additionally, the CPH administration modulates the nuclear factor kappa B (NF-κB) pathway, preventing DNA damage and cell death. Assays for apoptosis and DNA damage revealed that CPH reduced oxidative DNA damage and apoptosis. These findings highlight the immunomodulatory and treatment amelioration effect of CPH in reducing the severity of colitis.
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Affiliation(s)
- Hidayat Ullah
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Yamina Alioui
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Muhsin Ali
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Sharafat Ali
- Department of Biochemistry and Molecular Biology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Nabeel Ahmed Farooqui
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Nimra Z. Siddiqui
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Duaa M. Alsholi
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Muhammad Ilyas
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Mujeeb U. Rahman
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Yi Xin
- Department of Biotechnology, College of Basic Medical ScienceDalian Medical UniversityDalianChina
| | - Liang Wang
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine CenterThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
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Gervason S, Meleine M, Lolignier S, Meynier M, Daugey V, Birer A, Aissouni Y, Berthon JY, Ardid D, Filaire E, Carvalho FA. Antihyperalgesic properties of gut microbiota: Parabacteroides distasonis as a new probiotic strategy to alleviate chronic abdominal pain. Pain 2024; 165:e39-e54. [PMID: 37756665 DOI: 10.1097/j.pain.0000000000003075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 08/08/2023] [Indexed: 09/29/2023]
Abstract
ABSTRACT The potential role of gut microbiota in pain modulation is arousing an emerging interest since recent years. This study investigated neuromodulatory properties of gut microbiota to identify next-generation probiotics to propose alternative therapies for visceral pain management. Neuromodulation ability of 10 bacterial strains isolated from a healthy donor was assessed both on ND7/23 immortalized cell line and primary neuronal cells from rat dorsal root ganglia. This screening highlighted the neuroinhibitory property of Parabacteroides distasonis (F1-2) strain, supported both by its intracellular content and membrane fraction, which was further investigated in visceral pain mouse models. Oral administration of F1-2 resulted in a significant decrease of colonic hypersensitivity (CHS) in dextran sulfate sodium (0.5%) model associated with low-grade inflammation and a significant decrease of CHS in Citrobacter rodentium postinfectious models. No effect of F1-2 oral administration on CHS was observed in a neonatal maternal separation stress model. Antihyperalgesic effect unlikely involved modulation of inflammatory processes or restoration of intestinal barrier. Exploration of direct dialogue mechanisms between this strain and nervous system, assessed by calcium imaging experiments, revealed that F1-2 interacts directly with nociceptors by reducing activation level on capsaicin, inflammatory soup, and bradykinin stimulations. Our study provides new insights about bacteria-host interaction and places P distasonis as a potential therapeutic strategy in the treatment of visceral pain observed in leaky gut-associated pathologies.
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Affiliation(s)
- Sandie Gervason
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Mathieu Meleine
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Stéphane Lolignier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Maëva Meynier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Valentine Daugey
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Aurélien Birer
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
- Centre National de Référence de la Résisitance aux Antibiotiques, Service de Bactériologie, Clermont-Ferrand, France
| | - Youssef Aissouni
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | | | - Denis Ardid
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Edith Filaire
- ECREIN Team, Human Nutrition Unit (UNH), UMR 1019 INRAE-UCA, University of Clermont-Auvergne, Clermont-Ferrand, France
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Huang D, Zou M, Xu C, Wang Y, Xu Z, Zhang W, Tang S, Weng Z. Colon-Targeted Oral Delivery of Hydroxyethyl Starch-Curcumin Microcapsules Loaded with Multiple Drugs Alleviates DSS-Induced Ulcerative Colitis in Mice. Macromol Biosci 2024; 24:e2300465. [PMID: 38111343 DOI: 10.1002/mabi.202300465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/05/2023] [Indexed: 12/20/2023]
Abstract
Combination therapy through colon-targeted oral delivery of multiple drugs presents a promising approach for effectively treating ulcerative colitis (UC). However, the codelivery of drugs with diverse physicochemical properties in a single formulation remains a formidable challenge. Here, microcapsules are designed based on hydroxyethyl starch-curcumin (HES─CUR) conjugates to enable the simultaneous delivery of hydrophobic dexamethasone acetate (DA) and hydrophilic cefazolin sodium (CS), yielding multiple drug-loaded microcapsules (CS/DA-loaded HES─CUR microcapsules, CDHC-MCs) tailored for colon-targeted therapy of UC. Thorough characterization confirms the successful synthesis and exceptional biocompatibility of CDHC-MCs. Biodistribution studies demonstrate that the microcapsules exhibit an impressive inflammatory targeting effect, accumulating preferentially in inflamed colons. In vivo experiments employing a dextran-sulfate-sodium-induced UC mouse model reveal that CDHC-MCs not only arrest UC progression but also facilitate the restoration of colon length and alleviate inflammation-related splenomegaly. These findings highlight the potential of colon-targeted delivery of multiple drugs within a single formulation as a promising strategy to enhance UC treatment, and the CDHC-MCs developed in this study hold great potential in developing novel oral formulations for advanced UC therapy.
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Affiliation(s)
- Da Huang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China
| | - Minglang Zou
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China
| | - Chenlan Xu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China
| | - Yongming Wang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China
| | - Zhenjin Xu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China
| | - Wancong Zhang
- Department of Plastic Surgery and Burn Center, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, 515051, China
- Plastic Surgery Institute of Shantou University Medical College, Shantou, Guangdong, 515051, China
- Shantou Plastic surgery Clinical Research Center, Shantou, Guangdong, 515051, China
| | - Shijie Tang
- Department of Plastic Surgery and Burn Center, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, 515051, China
- Plastic Surgery Institute of Shantou University Medical College, Shantou, Guangdong, 515051, China
- Shantou Plastic surgery Clinical Research Center, Shantou, Guangdong, 515051, China
| | - Zuquan Weng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China
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7
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Zhao Y, He R, Zang J, Yin W, Su R, Xiong W, Xu W, Zhang J, Liu Y, Ren T, Huang Y, Li Y. Pathologically catalyzed physical coating restores the intestinal barrier for inflammatory bowel disease therapy. J Nanobiotechnology 2023; 21:444. [PMID: 37996883 PMCID: PMC10668504 DOI: 10.1186/s12951-023-02227-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 11/19/2023] [Indexed: 11/25/2023] Open
Abstract
Intestinal epithelia impairment of inflammatory bowel disease (IBD) leads to the leakage of bacteria and antigens and the consequent persistent immune imbalance. Restoring the epithelial barrier is a promising therapeutic target but lacks effective and safe clinical interventions. By identifying the catalase (CAT) presence in the IBD pathological environment, we herein develop a CAT-catalyzed pathologically coating on the damaged epithelial barrier to inhibit intestinal leakage for IBD therapy. With the codelivery of CaO2 (a CAT substrate) and dopamine, the nanosystem can enable CAT-catalyzed oxygen (O2) production and in-situ polymerization of dopamine and then yield a thin and integrative polydopamine (PDA) coating on the intestinal barrier due to the highly adhesive property of PDA. In vivo study demonstrates that PDA coating provides not only a protective barrier by restricting intestinal leakage but also a favorable anti-inflammation effect. Beyond drug management, this work provides a physical repair strategy via catalyzed coating for IBD therapy.
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Affiliation(s)
- Yuge Zhao
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Ruiqing He
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jie Zang
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Weimin Yin
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Runping Su
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Wei Xiong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Weihua Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jiaxin Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yiqiong Liu
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Tianbin Ren
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yongzhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Yongyong Li
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), School of Medicine, Tongji University, Shanghai, 200092, China.
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8
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Ullah H, Deng T, Ali M, Farooqui NA, Alsholi DM, Siddiqui NZ, Rehman AU, Ali S, Ilyas M, Wang L, Xin Y. Sea Conch Peptides Hydrolysate Alleviates DSS-Induced Colitis in Mice through Immune Modulation and Gut Microbiota Restoration. Molecules 2023; 28:6849. [PMID: 37836692 PMCID: PMC10574497 DOI: 10.3390/molecules28196849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 10/15/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a persistent, lifelong inflammation of the digestive system. Dextran sulfate sodium is commonly used to induce colitis in experimental animal models, which causes epithelial damage, intestinal inflammation, mucin depletion, and dysbiosis of the gut microbiota. Various prebiotics, polysaccharides, and polypeptides are used for IBD treatment. In this study, we used a murine model utilizing BALB/c mice, with 10 mice per group, to investigate the treatment effect of sea conch peptide hydrolysate (CPH) on DSS-induced colitis mice. Colitis was induced through the administration of 2.5% DSS in drinking water over a seven-days period. Furthermore, on the eighth day of the experiment, sea conch peptide hydrolysate (CPH) at low (100 mg/kg), medium (200 mg/kg), and high (400 mg/kg) doses, which were continued for 14 days, were assessed for medicinal purposes in DSS-induced colitis mice. Our results showed that CPH treatment significantly alleviated the severity and symptoms of colitis. The epithelial integrity and histological damage were improved. Intestinal inflammation and inflammatory cell infiltration were improved. Furthermore, the expression of pro-inflammatory cytokines was reduced, and intestinal barrier integrity was restored by elevating the tight junction proteins. Moreover, 16s RNA sequencing revealed dysbiosis of the gut microbiota was observed upon DSS treatment, which was reinstated after CPH treatment. An increased level of Firmicutes and Lactobacillus was observed in the treatment groups. Finally, our results suggest that CPH would be recommended as a functional food source and also have the potential to be used as a medicinal product for different gastrointestinal disorders.
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Affiliation(s)
- Hidayat Ullah
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Ting Deng
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Muhsin Ali
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Nabeel Ahmed Farooqui
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Duaa M. Alsholi
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Nimra Zafar Siddiqui
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Ata Ur Rehman
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Sharafat Ali
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China;
| | - Muhammad Ilyas
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
| | - Liang Wang
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Yi Xin
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China; (H.U.); (T.D.); (M.A.); (N.A.F.); (D.M.A.); (N.Z.S.); (A.U.R.); (M.I.)
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9
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Yu T, Wu L, Zhang T, Hao H, Dong J, Xu Y, Yang H, Liu H, Xie L, Wang G, Liang Y. Insights into Q-markers and molecular mechanism of Sanguisorba saponins in treating ulcerative colitis based on lipid metabolism regulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154870. [PMID: 37207387 DOI: 10.1016/j.phymed.2023.154870] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/23/2023] [Accepted: 05/08/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND Sanguisorba saponin extract (SSE) is the main active part of Sanguisorba officinalis with various pharmacological activities such as anti-inflammatory, anti-bacterial and anti-oxidant. However, its therapeutic role and underlying mechanisms for ulcerative colitis (UC) still need to be elucidated. PURPOSE This study aims to explore the therapeutic effect, effectiveness-material basis-quality markers (Q-markers) and prospective mechanism of function of SSE on UC. METHODS Fresh 2.5% dextran sulfate sodium salt (DSS) solution was placed in drinking bottles for 7 days to induce a mouse model of UC. SSE and sulfasalazine (SASP) were supplemented to mice by gavage for consecutive 7 days to investigate the therapeutic role of SSE on UC. Mouse monocyte macrophages (RAW264.7) and human normal colonic epithelial (NCM460) cells were treated with LPS to induce inflammatory responses, followed by pharmacodynamic examination with different concentrations of SSE. Hematoxylin-eosin (HE) and Alcian blue staining were conducted to evaluate the pathological damage of mice colon. Lipidomic technology was conducted to explore the differential lipids closely related to the disease process of UC. Quantitative PCR analysis, immunohistochemistry and ELISA kit were used to measure the expression levels of the corresponding proteins and pro-inflammatory factors. RESULTS SSE treatment could effectively reduce the elevated expressions of pro-inflammatory factors in RAW264.7 and NCM460 cells due to LPS stimulation. Intragastric administration of SSE was found to significantly alleviate the symptoms of DSS-induced colon injury and low-polar saponins in SSE. Low polarity saponins, especially ZYS-II, were proved to be the main active substances of SSE in treating UC. In addition, SSE could significantly ameliorate the aberrant lipid metabolism in UC mice. The role of phosphatidylcholine (PC)34:1 in the UC pathogenesis has been fully verified in our previous studies. Herein, SSE-dosing effectively reversed the metabolic disorder of PCs in UC mice, and increased the PC34:1 level to normal via up-regulating the expression of phosphocholine cytidylyltransferase (PCYT1α). CONCLUSION Our data innovatively revealed that SSE could significantly alleviate the symptoms of UC by reversing the disorder of PC metabolism induced by DSS modeling. SSE was proved for the first time to be a promising and effective candidate for UC treatment.
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Affiliation(s)
- Tengjie Yu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Linlin Wu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Tingting Zhang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Hongyuan Hao
- Analytical Applications Center, Shimadzu (China) Co., Ltd., Yizou 180, Shanghai 200233, PR. China
| | - Jing Dong
- Analytical Applications Center, Shimadzu (China) Co., Ltd., Yizou 180, Shanghai 200233, PR. China
| | - Yexin Xu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Huizhu Yang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Huafang Liu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Lin Xie
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China
| | - Guangji Wang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China.
| | - Yan Liang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR. China.
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10
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Shibrya EE, Rashed RR, Abd El Fattah MA, El-Ghazaly MA, Kenawy SA. Apigenin and Exposure to Low Dose Gamma Radiation Ameliorate Acetic Acid-Induced Ulcerative Colitis in Rats. Dose Response 2023; 21:15593258231155787. [PMID: 36756150 PMCID: PMC9900677 DOI: 10.1177/15593258231155787] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease involving chronic and recurring colon inflammation. Current management protocols are limited by adverse effects or short-term symptomatic relief. We aimed to investigate the possible therapeutic prospect of low dose gamma (γ) irradiation or apigenin treatment in acetic acid-induced UC in rats. Induction of UC was carried out by installation of acetic acid intra-rectally. One hour post-induction, rats received a sole dose of γ-radiation (0.5 Gray) or were treated with apigenin (3 mg/kg/day, peroral) for 7 successive days. Antioxidant and anti-inflammatory effects of both agents were assessed via determination of colon malondialdehyde (MDA), reduced glutathione (GSH), total nitrate/nitrite (NOx), mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and interleukin-1beta (IL-1β) contents as well as myeloperoxidase (MPO) activity. Body weight (BW), colon weight/length (W/L) ratio, disease activity index (DAI), and histopathological changes were evaluated. Gamma irradiation and apigenin significantly ameliorated the acetic acid-induced biochemical and histopathological changes. Both therapeutic approaches significantly restored colon contents of the investigated biomarkers. They modulated BW, colon W/L ratio and DAI. This study proposes low dose γ-irradiation as a new therapeutic candidate for the management of UC. We also concluded that apigenin exhibited therapeutic benefits in UC management.
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Affiliation(s)
- Eman E. Shibrya
- Department of Drug Radiation
Research, National Centre for Radiation Research and Technology,
Egyptian
Atomic Energy Authority, Cairo,
Egypt
| | - Rasha R. Rashed
- Department of Drug Radiation
Research, National Centre for Radiation Research and Technology,
Egyptian
Atomic Energy Authority, Cairo,
Egypt
| | - Mai A. Abd El Fattah
- Department of Pharmacology and
Toxicology, Faculty of Pharmacy, Cairo
University, Cairo, Egypt
| | - Mona A. El-Ghazaly
- Department of Drug Radiation
Research, National Centre for Radiation Research and Technology,
Egyptian
Atomic Energy Authority, Cairo,
Egypt
| | - Sanaa A. Kenawy
- Department of Pharmacology and
Toxicology, Faculty of Pharmacy, Cairo
University, Cairo, Egypt,Sanaa A. Kenawy, Department of Pharmacology
and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Ainy street,
Cairo 12411, Egypt.
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11
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Li Z, Zhang S, Xu L, Fang X, Wan Y, Yu D, Guo Y. A tetrapeptide from maize combined with probiotics exerted strong anti-inflammatory effects and modulated gut microbiota in DSS-induced colitis mice. Food Funct 2022; 13:12602-12618. [PMID: 36373867 DOI: 10.1039/d2fo02678c] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent gastrointestinal inflammation caused by abnormal immune response, and patients usually have intestinal flora imbalance. At present, the pathogenesis of UC is not well understood, and it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Some food supplements such as specific peptides and probiotics have been investigated and shown the potential for the treatment of UC. The purpose of this study is to investigate the therapeutic effect and potential mechanism of tetrapeptide from maize (TPM) and probiotic treatment on dextran sulfate sodium (DSS)-induced UC in C57BL/6J mice. Our results indicated that the therapeutic effects of TPM and probiotics are positively associated with a reduction in pro-inflammatory cytokine levels and restoration of the gut microbiota. Treatment with TPM or probiotics effectively alleviated the adverse effects of UC, including weight loss, shortened colon length, and colon and kidney tissue damage in mice. Additionally, both TPM and probiotics significantly reduced pro-inflammatory cytokine levels and oxidative stress in UC mice, and the effect was more pronounced when both were used together. Moreover, co-treatment with TPM and probiotics increased the diversity of gut microbes in UC mice, reduced the ratio of Firmicutes to Bacteroidetes (F/B) and increased the abundance of bacterial species, including Muribaculaceae, Alistipes, Ligilactobacillus and Lactobacillus, and has been shown to be beneficial for a variety of pathological conditions.
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Affiliation(s)
- Zhiguo Li
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Shan Zhang
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Li Xu
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Xuexun Fang
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Youzhong Wan
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, China 130033, P. R. China
| | - Dahai Yu
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Yi Guo
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
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12
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Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
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13
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Yu T, Zhou Z, Liu S, Li C, Zhang ZW, Zhang Y, Jin W, Liu K, Mao S, Zhu L, Xie L, Wang G, Liang Y. The role of phosphatidylcholine 34:1 in the occurrence, development and treatment of ulcerative colitis. Acta Pharm Sin B 2022; 13:1231-1245. [PMID: 36970218 PMCID: PMC10031229 DOI: 10.1016/j.apsb.2022.09.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/16/2022] [Accepted: 08/23/2022] [Indexed: 11/29/2022] Open
Abstract
Lipid homeostasis is considered to be related to intestinal metabolic balance, while its role in the pathogenesis and treatment of ulcerative colitis (UC) remains largely unexplored. The present study aimed to identify the target lipids related to the occurrence, development and treatment of UC by comparing the lipidomics of UC patients, mice and colonic organoids with the corresponding healthy controls. Here, multi-dimensional lipidomics based on LC-QTOF/MS, LC-MS/MS and iMScope systems were constructed and used to decipher the alteration of lipidomic profiles. The results indicated that UC patients and mice were often accompanied by dysregulation of lipid homeostasis, in which triglycerides and phosphatidylcholines were significantly reduced. Notably, phosphatidylcholine 34:1 (PC34:1) was characterized by high abundance and closely correlation with UC disease. Our results also revealed that down-regulation of PC synthase PCYT1α and Pemt caused by UC modeling was the main factor leading to the reduction of PC34:1, and exogenous PC34:1 could greatly enhance the fumarate level via inhibiting the transformation of glutamate to N-acetylglutamate, thus exerting an anti-UC effect. Collectively, our study not only supplies common technologies and strategies for exploring lipid metabolism in mammals, but also provides opportunities for the discovery of therapeutic agents and biomarkers of UC.
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Affiliation(s)
- Tengjie Yu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zhihao Zhou
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Shijia Liu
- Affliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Changjian Li
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zhi-Wei Zhang
- College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, China
| | - Yong Zhang
- College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, China
| | - Wei Jin
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Keanqi Liu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Shuying Mao
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Zhu
- Affliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Lin Xie
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Guangji Wang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 25 83271060.
| | - Yan Liang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 25 83271060.
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14
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Zhu Y, Zhao Q, Huang Q, Li Y, Yu J, Zhang R, Liu J, Yan P, Xia J, Guo L, Liu G, Yang X, Zeng J. Nuciferine Regulates Immune Function and Gut Microbiota in DSS-Induced Ulcerative Colitis. Front Vet Sci 2022; 9:939377. [PMID: 35909691 PMCID: PMC9328756 DOI: 10.3389/fvets.2022.939377] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
Nuciferine, a major aporphine alkaloid obtained from the leaves of Nelumbo nucifera, exhibits anti-cancer and anti-inflammatory properties; however, its protective effects against inflammatory bowel diseases (IBD) has never been explored. In this study, an ulcerative colitis (UC) model was established in BALb/c mice by the continuous administration of 5% dextran sulfate sodium (DSS) in drinking water for 1 week. From day 8 to day 14, the DSS-treated mice were divided into a high-dose and a low-dose nuciferine treatment group and were intraperitoneally injected with the corresponding dose of the drug. Body weight loss, disease activity index (DAI), and colon length were measured. Histological changes were observed using hematoxylin and eosin staining. T lymphocyte proliferation was assessed by MTT assay. The ratio of CD3+, CD4+, CD8+, Th1, Th2, Th17, and Treg cells were estimated by flow cytometry. Finally, 16S rRNA sequencing was performed to compare the composition and relative abundance of the gut microbiota among the different treatment groups. The results showed that nuciferine treatment led to a significant improvement in symptoms, such as histological injury and colon shortening in mice with DSS-induced UC. Nuciferine treatment improved the Th1/Th2 and Treg/Th17 balance in the DSS-induced IBD model, as well as the composition of the intestinal microflora. At the phylum level, compared with the control group, the abundance of Firmicutes and Actinobacteriota was decreased in the model group, whereas that of Bacteroidetes increased. Meanwhile, at the genus level, compared with the control group, the numbers of the genera Lachnospiraceae_Clostridium, Bilophila and Halomonas reduced in the model group, while those of Bacteroides, Parabacteroides, and Paraprevotella increased. Notably, nuciferine administration reversed this DSS-induced gut dysbiosis. These results indicated that nuciferine modulates gut microbiota homeostasis and immune function in mice with DSS-induced UC.
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Affiliation(s)
- Yiling Zhu
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Qing Zhao
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Qi Huang
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Yana Li
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Jie Yu
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Rui Zhang
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Jiali Liu
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Pupu Yan
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Jinjin Xia
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Liwei Guo
- College of Animal Science, Yangtze University, Jingzhou, China
- *Correspondence: Liwei Guo
| | - Guoping Liu
- College of Animal Science, Yangtze University, Jingzhou, China
- Guoping Liu
| | - Xiaolin Yang
- College of Animal Science, Yangtze University, Jingzhou, China
| | - Jianguo Zeng
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, China
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15
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Chronic Experimental Model of TNBS-Induced Colitis to Study Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:ijms23094739. [PMID: 35563130 PMCID: PMC9105049 DOI: 10.3390/ijms23094739] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/21/2022] [Accepted: 04/24/2022] [Indexed: 01/14/2023] Open
Abstract
Background: Inflammatory bowel disease (IBD) is a world healthcare problem. In order to evaluate the effect of new pharmacological approaches for IBD, we aim to develop and validate chronic trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Methods: Experimental colitis was induced by the rectal administration of multiple doses of TNBS in female CD-1 mice. The protocol was performed with six experimental groups, depending on the TNBS administration frequency, and two control groups (sham and ethanol groups). Results: The survival rate was 73.3% in the first three weeks and, from week 4 until the end of the experimental protocol, the mice’s survival remained unaltered at 70.9%. Fecal hemoglobin presented a progressive increase until week 4 (5.8 ± 0.3 µmol Hg/g feces, p < 0.0001) compared with the ethanol group, with no statistical differences to week 6. The highest level of tumor necrosis factor-α was observed on week 3; however, after week 4, a slight decrease in tumor necrosis factor-α concentration was verified, and the level was maintained until week 6 (71.3 ± 3.3 pg/mL and 72.7 ± 3.6 pg/mL, respectively). Conclusions: These findings allowed the verification of a stable pattern of clinical and inflammation signs after week 4, suggesting that the chronic model of TNBS-induced colitis develops in 4 weeks.
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Chen Z, Hao W, Gao C, Zhou Y, Zhang C, Zhang J, Wang R, Wang Y, Wang S. A polyphenol-assisted IL-10 mRNA delivery system for ulcerative colitis. Acta Pharm Sin B 2022; 12:3367-3382. [PMID: 35967288 PMCID: PMC9366313 DOI: 10.1016/j.apsb.2022.03.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/23/2022] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
With the development of synthesis technology, modified messenger RNA (mRNA) has emerged as a novel category of therapeutic agents for a broad of diseases. However, effective intracellular delivery of mRNA remains challenging, especially for its sensitivity to enzymatic degradation. Here, we propose a polyphenol-assisted handy delivery strategy for efficient in vivo delivery of IL-10 mRNA. IL-10 mRNA binds to polyphenol ellagic acid through supramolecular binding to yield a negatively charged core, followed by complexing with linear polyetherimide and coating with bilirubin-modified hyaluronic acid to obtain a layer-by-layer nanostructure. The nanostructure specifically up-regulated the level of IL-10, effectively inhibited the expression of inflammatory factors, promoted mucosal repair, protected colonic epithelial cells against apoptosis, and exerted potent therapeutic efficacy in dextran sulfate sodium salt-induced acute and chronic murine models of colitis. The designed delivery system without systemic toxicity has the potential to facilitate the development of a promising platform for mRNA delivery in ulcerative colitis treatment.
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Affiliation(s)
- Zhejie Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macau 999078, China
| | - Wei Hao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macau 999078, China
| | - Caifang Gao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
| | - Yangyang Zhou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
| | - Chen Zhang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jinming Zhang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ruibing Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macau 999078, China
- Corresponding authors. Tel./fax: +853 88228559 (Shengpeng Wang), +853 88224691 (Yitao Wang).
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macau 999078, China
- Corresponding authors. Tel./fax: +853 88228559 (Shengpeng Wang), +853 88224691 (Yitao Wang).
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Roy S, Dhaneshwar S, Mahmood T. Exploring the Potential of IL-1β Inhibitor Diacerein and its Combination with 5-Aminosalicylic Acid for the Possible Ameliorating Effect in TNBS-induced Experimental Colitis in Wistar Rats. CURRENT DRUG THERAPY 2022. [DOI: 10.2174/1574885517666220328142715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin (IL), and oxidative stress are crucial players in the pathophysiology of inflammatory bowel disease (IBD) that contribute in perpetuating intestinal inflammation. Targeting them presents a novel approach in disease management. In the present study, the potential of an antiosteoarthritic IL-inhibitor drug, diacerein (DIA) was investigated in 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)- instigated ulcerative colitis (UC) in Wistar rats. A comparative study was also undertaken to investigate the potential of combination therapy of DIA with the standard drug 5-aminosalicylic acid (5-ASA) versus monotherapy.
Methods:
Colitis was developed by single intra-colonic administration of TNBS (100mg/kg); whereas drugs 5-ASA (25.5 mg/kg), DIA (100 mg/kg), and DIA+5-ASA (100+ 25.5 mg/kg) were administered orally for five days post-induction to various groups of rats. Parameters like disease activity score, colon/body weight ratio, colon length, diameter, gut pH were assessed, and histopathological analysis was carried out. Biochemical markers of colonic inflammation such as IL-1β, TNF-α, reduced glutathione (GSH), and malondialdehyde (MDA) were also estimated.
Results:
Combination of DIA and 5-ASA demonstrated the most significant reduction of the colon to body weight ratio and disease activity score. It prominently restored the colon length, diameter, and gut pH to normal. It attenuated the biochemical alterations induced by TNBS, indicating a highly significant defensive outcome against colonic inflammation. The histopathological report demonstrated the renovating effect of the combination of disrupted colonic histology with minimally distressing liver, stomach, or pancreas compared to individual drugs.
Conclusion:
The combination remarkably downregulated the level of inflammation by suppressing both provocative cytokines and reactive oxygen species production. It can be evaluated further in a clinical setup as a novel and promising drug therapy for UC.
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Affiliation(s)
- Supriya Roy
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Sector 125, Noida, 201313, India
| | - Suneela Dhaneshwar
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Sector 125, Noida, 201313, India
| | - Tarique Mahmood
- Faculty of Pharmacy, Integral University, Dasauli, Lucknow, India
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He BL, Xiong Y, Hu TG, Zong MH, Wu H. Bifidobacterium spp. as functional foods: A review of current status, challenges, and strategies. Crit Rev Food Sci Nutr 2022; 63:8048-8065. [PMID: 35319324 DOI: 10.1080/10408398.2022.2054934] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Members of Bifidobacterium are among the first microbes to colonize the human intestine naturally, their abundance and diversity in the colon are closely related to host health. Recently, the gut microbiota has been gradually proven to be crucial mediators of various metabolic processes between the external environment and the host. Therefore, the health-promoting benefits of Bifidobacterium spp. and their applications in food have gradually been widely concerned. The main purpose of this review is to comprehensively introduce general features, colonization methods, and safety of Bifidobacterium spp. in the human gut, highlighting its health benefits and industrial applications. On this basis, the existing limitations and scope for future research are also discussed. Bifidobacteria have beneficial effects on the host's digestive system, immune system, and nervous system. However, the first prerequisite for functioning is to have enough live bacteria before consumption and successfully colonize the colon after ingestion. At present, strain breeding, optimization (e.g., selecting acid and bile resistant strains, adaptive evolution, high cell density culture), and external protection technology (e.g., microencapsulation and protectants) are the main strategies to address these challenges in food application.
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Affiliation(s)
- Bao-Lin He
- School of Food Science and Engineering, South China University of Technology/Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Guangzhou, China
| | - Yong Xiong
- School of Food Science and Engineering, South China University of Technology/Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Guangzhou, China
| | - Teng-Gen Hu
- Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Guangzhou, China
| | - Min-Hua Zong
- School of Food Science and Engineering, South China University of Technology/Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Guangzhou, China
| | - Hong Wu
- School of Food Science and Engineering, South China University of Technology/Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, Guangzhou, China
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Yao H, Yan J, Yin L, Chen W. Picroside II alleviates DSS-induced ulcerative colitis by suppressing the production of NLRP3 inflammasomes through NF-κB signaling pathway. Immunopharmacol Immunotoxicol 2022; 44:437-446. [PMID: 35293848 DOI: 10.1080/08923973.2022.2054425] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT Ulcerative colitis (UC) is a common acute or chronic intestinal disease with the imbalance of inflammation. Picroside II (P-II) exerts the protective role in various inflammation-related diseases. However, the effect of P-II on UC is still unclear. OBJECTIVE To explore the effect of P-II on UC and its potential mechanism. MATERIALS AND METHODS Human monocytic leukemia cell line THP-1 were treated with phorbol ester (PMA) to differentiate into macrophage. The differentiated THP-1 cells were hatched with LPS combined with ATP or Nigericin to activate the NLRP3 inflammasome in vitro. The UC model was constructed by injection of DSS into mice. RESULTS The maximum non-toxic concentration of P-II on THP-1 cells was 60 μM. LPS combined with ATP or Nigericin stimulated the production of IL-1β, which was antagonized by P-II treatment. Meanwhile, P-II administration interfered the aggregation of ASC and the assembly of NLRP3 inflammasomes. Also, P-II treatment reduced the LPS and ATP-induced elevation of the relative protein expression of NLRP3, pro-caspase-1, IL-1β and p-p65/p65, and the concentration of TNF-α and IL-6. Besides, the NF-κB specific inhibitor BAY-117082 notably repressed the LPS together with ATP-enhanced the relative protein expression of NLRP3, caspase-1 and IL-1β. Moreover, in vivo results showed that P-II relieved the DDS-induced UC, as evidenced by the improvement of mice weight, DAI and pathological scores. In addition, P-II treatment notably decreased DDS-promoted expression of NLRP3 inflammasomes and inflammatory factors in vivo. CONCLUSION P-II alleviated DSS-induced UC by repressing the production of NLRP3 inflammasomes via NF-κB signaling pathway.
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Affiliation(s)
- Huixiang Yao
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P R China
| | - Jun Yan
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P R China
| | - Li Yin
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P R China
| | - Wei Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P R China
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Correia B, Fernandes J, Botica MJ, Ferreira C, Quintas A. Novel Psychoactive Substances: The Razor's Edge between Therapeutical Potential and Psychoactive Recreational Misuse. MEDICINES (BASEL, SWITZERLAND) 2022; 9:medicines9030019. [PMID: 35323718 PMCID: PMC8950629 DOI: 10.3390/medicines9030019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Novel psychoactive substances (NPS) are compounds of natural and synthetic origin, similar to traditional drugs of abuse. NPS are involved in a contemporary trend whose origin lies in a thinner balance between legitimate therapeutic drug research and legislative control. The contemporary NPS trend resulted from the replacement of MDMA by synthetic cathinones in 'ecstasy' during the 2000s. The most common NPS are synthetic cannabinoids and synthetic cathinones. Interestingly, during the last 50 years, these two classes of NPS have been the object of scientific research for a set of health conditions. METHODS Searches were conducted in the online database PubMed using boolean equations. RESULTS Synthetic cannabinoids displayed protective and therapeutic effects for inflammatory, neurodegenerative and oncologic pathologies, activating the immune system and reducing inflammation. Synthetic cathinones act similarly to amphetamine-type stimulants and can be used for depression and chronic fatigue. CONCLUSIONS Despite the scientific advances in this field of research, pharmacological application of NPS is being jeopardized by fatalities associated with their recreational use. This review addresses the scientific achievements of these two classes of NPS and the toxicological data, ending with a reflection on Illicit and NPS control frames.
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Affiliation(s)
- Beatriz Correia
- Laboratório de Ciências Forenses e Psicológicas Egas Moniz, Campus Universitário—Quinta da Granja, Monte de Caparica, 2825-084 Caparica, Portugal; (B.C.); (J.F.); (C.F.)
| | - Joana Fernandes
- Laboratório de Ciências Forenses e Psicológicas Egas Moniz, Campus Universitário—Quinta da Granja, Monte de Caparica, 2825-084 Caparica, Portugal; (B.C.); (J.F.); (C.F.)
| | - Maria João Botica
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPO), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
| | - Carla Ferreira
- Laboratório de Ciências Forenses e Psicológicas Egas Moniz, Campus Universitário—Quinta da Granja, Monte de Caparica, 2825-084 Caparica, Portugal; (B.C.); (J.F.); (C.F.)
- Molecular Pathology and Forensic Biochemistry Laboratory, Centro de Investigação Interdisciplinar Egas Moniz, 2825-084 Caparica, Portugal
- Faculty of Medicine of Porto University, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal
| | - Alexandre Quintas
- Laboratório de Ciências Forenses e Psicológicas Egas Moniz, Campus Universitário—Quinta da Granja, Monte de Caparica, 2825-084 Caparica, Portugal; (B.C.); (J.F.); (C.F.)
- Molecular Pathology and Forensic Biochemistry Laboratory, Centro de Investigação Interdisciplinar Egas Moniz, 2825-084 Caparica, Portugal
- Correspondence:
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21
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Yener S, Akbulut KG, Karakuş R, Erdoğan D, Acartürk F. Development of melatonin loaded pectin nanoparticles for the treatment of inflammatory bowel disease: In vitro and in vivo studies. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2021.102861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Alenazi N, Alsaeed H, Alsulami A, Alanzi T. A Review of Hyperbaric Oxygen Therapy for Inflammatory Bowel Disease. Int J Gen Med 2021; 14:7099-7105. [PMID: 34729019 PMCID: PMC8554584 DOI: 10.2147/ijgm.s336678] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/04/2021] [Indexed: 11/23/2022] Open
Abstract
IBD (inflammatory bowel disease) characterized by chronic inflammation of the gastrointestinal (GI) tract is one of the chronic diseases the prevalence of which has been increasing globally. In the past few decades, significant improvements were made in the treatments relating to IBD which have reduced the hospitalization and mortality rates; however, there is still room for improvement with other alternative therapies. HBOT (hyperbaric oxygen treatment) is one of the effective therapies used in treating various conditions including wounds, decompression sickness, stroke, etc. Several studies have reported the role of HBOT as an adjunctive treatment to IBD, while adopting conventional treatment procedures. There is an increasing trend of research in this particular area. Studies have shown that HBOT reflects its therapeutic effect by controlling inflammation, reducing oxidation stress, improving the process of cleaning damaged cells and recruiting the cells involved in repair; thereby improving the immunity response system. In this context, the purpose of this review is to summarize past clinical and experimental studies and to understand the role of hyperbaric treatment for IBD. The findings from the review have suggested that hyperbaric therapy can be an effective adjunctive approach for IBD, based on which some ideas for future clinical and research work are provided.
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Affiliation(s)
- Naif Alenazi
- Diving and Hyperbaric Medicine Department, Diving Unit, Medical Services, Dammam, Saudi Arabia
| | - Hesham Alsaeed
- Diving and Hyperbaric Medicine Department, Diving Unit, Medical Services, Dammam, Saudi Arabia
| | - Adel Alsulami
- Diving and Hyperbaric Medicine Department, Diving Unit, Medical Services, Dammam, Saudi Arabia
| | - Turki Alanzi
- Department of Health Information Management and Technology, College of Public Health, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Inflammation- and Gut-Homing Macrophages, Engineered to De Novo Overexpress Active Vitamin D, Promoted the Regenerative Function of Intestinal Stem Cells. Int J Mol Sci 2021; 22:ijms22179516. [PMID: 34502422 PMCID: PMC8430522 DOI: 10.3390/ijms22179516] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/24/2021] [Accepted: 08/28/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.
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Garcia-Romero R, Martinez de Zabarte Fernandez JM, Pujol-Muncunill G, Donat-Aliaga E, Segarra-Cantón O, Irastorza-Terradillos I, Medina-Benitez E, Ruiz-Hernández CJ, Carrillo-Palau M, Ros-Arnal I, Rodriguez-Martínez A, Escartin-Madurga L, Gutiérrez-Junquera C, Vicente-Santamaría S, Velasco Rodriguez-Belvis M, Fernández-Fernández S, Alberto-Alonso JR, Montraveta M, Torres-Peral R, Navalon-Rubio M, Navas-López VM, Martin de Carpi J. Safety and effectiveness of vedolizumab in paediatric patients with inflammatory bowel disease: an observational multicentre Spanish study. Eur J Pediatr 2021; 180:3029-3038. [PMID: 33880650 DOI: 10.1007/s00431-021-04063-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 02/27/2021] [Accepted: 04/04/2021] [Indexed: 12/23/2022]
Abstract
Vedolizumab is a humanised monoclonal antibody that binds to integrin α4β7 expressed in T-cells, inhibiting its binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is specifically expressed in the small intestine and colon, playing a fundamental role in T-cell migration to the gastrointestinal tract. Vedolizumab has been shown to be effective in treating adults with inflammatory bowel disease; however, efficacy data for paediatric use are scarce. The objective of the present study was to assess the effectiveness and safety of vedolizumab for inducing and maintaining clinical remission in children with inflammatory bowel disease. We conducted a retrospective multicentre study of patients younger than 18 years with inflammatory bowel disease refractory to anti-tumour necrosis factor alpha (anti-TNF-α) drugs, who underwent treatment with vedolizumab. Clinical remission was defined as a score < 10 points in the activity indices. We included 42 patients, 22 of whom were male (52.3%), with a median age of 13.1 years (IQR 10.2-14.2) at the start of treatment. Of the 42 patients, 14 (33.3%) had Crohn's disease (CD) and 28 (66.7%) had ulcerative colitis (UC). At the start of treatment with vedolizumab, the Paediatric Crohn's Disease Activity Index was 36 (IQR 24-40) and the Paediatric Ulcerative Colitis Activity Index was 47 (IQR 25-65). All of them had received prior treatment with anti-TNF and 3 patients ustekinumab. At week 14, 69% of the patients responded to the treatment (57.1% of those with CD and 75% of those with UC; p=0.238), and 52.4% achieved remission (35.7% with CD and 60.7% with UC; p=0.126). At 30 weeks, the response rate was 66.7% (46.2% and 78.3% for CD and UC, respectively; p=0.049), and 52.8% achieved remission (30.8% and 65.2% for CD and UC, respectively; p=0.047). Among the patients with remission at week 14, 80% of the patients with CD and 84.5% of those with UC maintained the remission at 52 weeks. Adverse effects were uncommon and mild. Three patients (7.1%) presented headaches, 1 presented alopecia, 1 presented anaemia and 1 presented dermatitis.Conclusion: The results show that treatment with vedolizumab is a safe and effective option for achieving clinical remission in paediatric patients with inflammatory bowel disease with primary failure or loss of response to other treatments, especially in UC. What is Known: • Vedolizumab is effective in inducing and maintaining remission in adult patients with inflammatory bowel disease. • Most studies and clinical trials have been performed on adult populations, and there is currently no indication for paediatric populations. What is New: • Children with inflammatory bowel disease refractory to anti-TNF presented higher clinical remission rates than those published for adults. • There are few publications of this magnitude on paediatric populations treated with vedolizumab and with long-term follow-up (52 weeks).
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Affiliation(s)
- Ruth Garcia-Romero
- Paediatric Gastroenterology, Hepatology and Nutrition, Paediatric University Hospital Miguel Servet, Zaragoza, Spain.
| | | | - Gemma Pujol-Muncunill
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Ester Donat-Aliaga
- Paediatric Gastroenterology, Hepatology and Nutrition, Polytechnic University Hospital La Fe, Valencia, Spain
| | - Oscar Segarra-Cantón
- Paediatric Gastroenterology, Hepatology and Nutrition, Mother-Child University Hospital, Vall Hebrón, Barcelona, Spain
| | | | - Enrique Medina-Benitez
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, University Hospital 12 de Octubre, Madrid, Spain
| | - Carlos José Ruiz-Hernández
- Paediatric Gastroenterology and Nutrition, Department of Paediatrics, Hospital Parc Taulí, Sabadell, Spain
| | - Marta Carrillo-Palau
- Department of Gastroenterology, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
| | - Ignacio Ros-Arnal
- Paediatric Gastroenterology, Hepatology and Nutrition, Paediatric University Hospital Miguel Servet, Zaragoza, Spain
| | | | - Laura Escartin-Madurga
- Paediatric Gastroenterology, Hepatology and Nutrition, University Clinic Hospital Lozano Blesa, Zaragoza, Spain
| | - Carolina Gutiérrez-Junquera
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Saioa Vicente-Santamaría
- Paediatric Gastroenterology, Hepatology and Nutrition, University Hospital Ramon y Cajal, Madrid, Spain
| | | | - Sonia Fernández-Fernández
- Paediatric Gastroenterology, Hepatology and Nutrition, University Hospital Severo Ochoa, Leganés, Madrid, Spain
| | - José Ramón Alberto-Alonso
- Paediatric Gastroenterology, Hepatology and Nutrition, University Hospital Ntra. Sra. de Candelaria, Tenerife, Spain
| | - Montserrat Montraveta
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Ricardo Torres-Peral
- Paediatric Gastroenterology and Nutrition Unit, Department of Paediatrics, University Hospital Complex, Salamanca, Spain
| | - María Navalon-Rubio
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Víctor Manuel Navas-López
- Paediatric Gastroenterology and Nutrition Section, Regional University Hospital of Malaga, Málaga, Spain
| | - Javier Martin de Carpi
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain
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Chen J, Li L, Liu J, Yuan S, Liao W, Slominski AT, Li W, Żmijewski MA, Chen J. Discovery of novel 3-hydroxyandrosta-5,7-Diene-17-Carboxylic acid derivatives as anti-inflammatory bowel diseases (IBD) agents. Eur J Med Chem 2021; 220:113468. [PMID: 33933753 DOI: 10.1016/j.ejmech.2021.113468] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/29/2021] [Accepted: 04/09/2021] [Indexed: 01/08/2023]
Abstract
A series of steroidal compounds based on 3-hydroxyandrosta-5,7-diene-17-carboxylic acid core structure were designed, synthesized and bio-evaluated for their anti-inflammatory potency. Among them, compound 5c, 6f, and 6q effectively inhibited the production of nitric oxide (NO) in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. They inhibited the expression of inducible NO synthase (iNOS) and prostaglandin synthase-2 (COX-2) at mRNA level. Compound 6q displayed inhibitory effects on both iNOS and COX-2 expression in a concentration-dependent manner. Furthermore, 6q was found to effectively decrease the mRNA and protein levels of interleukin 6 (IL-6). Mechanically, 6q could potently downregulate NF-κB signaling via suppression of the Akt/PI3K pathway. Moreover, 6q demonstrated high in vivo anti-inflammatory activities in a mouse colitis model induced by dextran sulfate sodium (DSS). Taken together, these data indicate that 6q represents a novel and promising anti-inflammatory bowel diseases (IBD) agent worthy of further investigation.
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Affiliation(s)
- Jingxuan Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China
| | - Ling Li
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China
| | - Jin Liu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China
| | - Sijie Yuan
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Wenzhen Liao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Andrzej T Slominski
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Wei Li
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Michał A Żmijewski
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Jianjun Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
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Prevalence of inflammatory bowel disease in the Australian general practice population: A cross-sectional study. PLoS One 2021; 16:e0252458. [PMID: 34043730 PMCID: PMC8158877 DOI: 10.1371/journal.pone.0252458] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 05/14/2021] [Indexed: 12/31/2022] Open
Abstract
The burden of inflammatory bowel disease (IBD) in Australia is increasing but national data about the current prevalence are limited. We aimed to estimate the prevalence of IBD (including Crohn’s disease, ulcerative colitis and unspecified IBD) as well as Crohn’s disease and ulcerative colitis separately in a general practice population in Australia. We also assessed risk factors associated with Crohn’s disease and ulcerative colitis. We conducted a cross-sectional study using data from MedicineInsight, a national database of general practice electronic health records, from 1 July 2017 to 30 June 2019. The prevalence of IBD was calculated and stratified by sociodemographic characteristics. Logistic regression analysis was conducted to assess risk factors associated with Crohn’s disease and ulcerative colitis. The study comprised 2,428,461 regular patients from 481 practices. The estimated crude prevalence of IBD was 653 per 100,000 patients; Crohn’s disease was 306 per 100,000 and ulcerative colitis was 334 per 100,000. Males were independently associated with a lower risk of Crohn’s disease (OR: 0.86; 95% CI: 0.81, 0.90) but a greater risk of ulcerative colitis (OR: 1.12; 95% CI: 1.06, 1.17) than females. Compared to non-smokers, patients who were current smokers were associated with a greater risk of Crohn’s disease (OR: 1.13; 95% CI: 1.04, 1.23) but a lower risk of ulcerative colitis (OR: 0.52; 95% CI: 0.47, 0.57). Other factors positively associated with both Crohn’s disease and ulcerative colitis were age (≥ 25 years), non-Indigenous status and socioeconomic advantage. Our findings provide a current estimate of the prevalence of IBD, Crohn’s disease and ulcerative colitis in a large national general practice population in Australia and an assessment of the factors associated with Crohn’s disease and ulcerative colitis. These data can assist in estimating the health burden and costs, and planning for health services.
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Asperuloside suppressing oxidative stress and inflammation in DSS-induced chronic colitis and RAW 264.7 macrophages via Nrf2/HO-1 and NF-κB pathways. Chem Biol Interact 2021; 344:109512. [PMID: 33974900 DOI: 10.1016/j.cbi.2021.109512] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/18/2021] [Accepted: 05/05/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs), which mainly include Crohn's disease (CD) and ulcerative colitis (UC), are chronic idiopathic inflammatory disease of the gastrointestinal tract for which effective pharmacological treatments are lacking or options are very limited. PURPOSE Here, we aim to investigate the therapeutic effects of an iridoid glycoside, asperuloside (ASP) on mice experimental chronic colitis induced by dextran sulfate sodium (DSS) and further explore underlying mechanisms in vitro and in vivo. METHODS LPS-treated RAW 264.7 cells showed inflammation and were assessed for various physiological, morphological and biochemical parameters in the absence or presence of ASP. Chronic colitis was induced by 2% DSS in mice, which were used as an animal model to explore the pharmacodynamics of ASP. We detected p65 and Nrf2 pathway proteins via Western blot and RT-PCR analysis, assessed the cytokines TNF-α and IL-6 via ELISA, tested p65 and Nrf2 nuclear translocation via fluorescence. In addition, the docking affinity of ASP and p65 or Nrf2 proteins in the MOE 2015 software. RESULTS We found that ASP attenuated weight loss, disease activity index (DAI) and colonic pathological damage in colitis mice and restored the expressions of inflammatory cytokines in the colon. In addition, ASP restored antioxidant capacity in DSS-induced chronic colitis mice and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Furthermore, ASP suppressed oxidative stress through increasing Nrf2, HO-1 and NQO-1 proteins expressions, and down-regulated nuclear levels of p65 to inhibit DSS-induced colonic oxidative stress and inflammation. Validation of the molecular docking results also indicated that ASP interacts with Nrf2 or p65 proteins. In summary, ASP improved DSS-induced chronic colitis by alleviating inflammation and oxidative stress, activating Nrf2/HO-1 signaling and limiting NF-κB signaling pathway, which may be an effective candidate for the treatment of IBD.
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Jin QW, Wang XD. Progress in research of vedolizumab in treatment of inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2021; 29:248-255. [DOI: 10.11569/wcjd.v29.i5.248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease is a kind of chronic inflammatory disease of the gastrointestinal tract with unclear etiology. At present, its main therapeutic drugs include aminosalicylates, glucocorticoids, immunosuppressive agents, and biological agents. With the deepening study of the disease and the progress of science and technology, there have been more and more studies on the targets for biological agents, including tumor necrosis factor-α, Janus kinase, interleukin, intestinal integrin, etc. As a humanized integrin antagonist, vedolizumab can selectively inhibit the interaction between integrin α4β7 and mucosal addressin cell adhesion molecule-1, and block the migration of lymphocytes to the intestinal tract to alleviate the intestinal inflammation, so as to achieve the therapeutic effect. This article reviews the mechanism, clinical efficacy, and application of vedolizumab in the treatment of inflammatory bowel disease.
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Affiliation(s)
- Qi-Wen Jin
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Xiao-Di Wang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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Lang-Schwarz C, Agaimy A, Atreya R, Becker C, Danese S, Fléjou JF, Gaßler N, Grabsch HI, Hartmann A, Kamarádová K, Kühl AA, Lauwers GY, Lugli A, Nagtegaal I, Neurath MF, Oberhuber G, Peyrin-Biroulet L, Rath T, Riddell R, Rubio CA, Sheahan K, Tilg H, Villanacci V, Westerhoff M, Vieth M. Maximizing the diagnostic information from biopsies in chronic inflammatory bowel diseases: recommendations from the Erlangen International Consensus Conference on Inflammatory Bowel Diseases and presentation of the IBD-DCA score as a proposal for a new index for histologic activity assessment in ulcerative colitis and Crohn's disease. Virchows Arch 2021; 478:581-594. [PMID: 33373023 PMCID: PMC7973393 DOI: 10.1007/s00428-020-02982-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/13/2020] [Accepted: 12/01/2020] [Indexed: 12/13/2022]
Grants
- TRR241 projects INF, A03, C02, C03, C04 Deutsche Forschungsgemeinschaft
- TRR241 projects INF, A03, C02, C03 and C04 Deutsche Forschungsgemeinschaft
- TRR241 projects INF, A03,C02, C03 and C04 Deutsche Forschungsgemeinschaft
- Heisenberg Professorship Deutsche Forschungsgemeinschaft
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Affiliation(s)
- Corinna Lang-Schwarz
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445, Bayreuth, Germany
| | - Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander University, Erlangen, Germany
| | - Raja Atreya
- Medical Clinic 1, Department of Medicine & Deutsches Zentrum Immuntherapie DZI, University Hospital, Friedrich-Alexander University, Erlangen, Germany
- The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Christoph Becker
- Medical Clinic 1, Department of Medicine & Deutsches Zentrum Immuntherapie DZI, University Hospital, Friedrich-Alexander University, Erlangen, Germany
- The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Silvio Danese
- Department of Gastroenterology, IBD Centre, Humanitas Research Hospital, Via A. Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Jean-François Fléjou
- Pathology Department, Saint-Antoine Hospital, APHP, Sorbonne University, Paris, France
| | - Nikolaus Gaßler
- Institute for Legal Medicine, Section Pathology, University Hospital, Jena, Germany
| | - Heike I Grabsch
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander University, Erlangen, Germany
| | - Kateřina Kamarádová
- The Fingerland Department of Pathology, Faculty of Medicine and University Hospital, Charles University, Hradec Králové, Czech Republic
| | - Anja A Kühl
- The Transregio 241 IBDome Consortium, Erlangen, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, iPATH.Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany
| | | | | | - Iris Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Markus F Neurath
- Medical Clinic 1, Department of Medicine & Deutsches Zentrum Immuntherapie DZI, University Hospital, Friedrich-Alexander University, Erlangen, Germany
- The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Georg Oberhuber
- INNPATH, Institute of Pathology, Tirol Kliniken, Innsbruck, Austria & Patho im Zentrum, St. Pölten, Austria
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandoeuvre, France & Inserm U1256, Lorraine University, Vandoeuvre, France
| | - Timo Rath
- Medical Clinic 1, Department of Medicine & Deutsches Zentrum Immuntherapie DZI, University Hospital, Friedrich-Alexander University, Erlangen, Germany
| | - Robert Riddell
- Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Carlos A Rubio
- Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Kieran Sheahan
- Department of Pathology & Centre for Colorectal Disease, St Vincent's University Hospital & University College, Dublin, Ireland
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | | | - Maria Westerhoff
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445, Bayreuth, Germany.
- Institute of Pathology, Friedrich-Alexander University, Erlangen, Germany.
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30
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Chen X, Berin MC, Gillespie VL, Sampson HA, Dunkin D. Treatment of Intestinal Inflammation With Epicutaneous Immunotherapy Requires TGF-β and IL-10 but Not Foxp3 + Tregs. Front Immunol 2021; 12:637630. [PMID: 33717186 PMCID: PMC7952322 DOI: 10.3389/fimmu.2021.637630] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/28/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET). Methods: RAG1-/- mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10-/-, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation. Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10-/- or CD4-dnTGFBRII mice. Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.
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Affiliation(s)
- Xin Chen
- Division of Pediatric Gastroenterology and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - M Cecilia Berin
- Division of Pediatric Allergy and Immunology, Precision Immunology Institute and Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Virginia L Gillespie
- Center for Comparative Medicine and Surgery, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Hugh A Sampson
- Division of Pediatric Allergy and Immunology, Precision Immunology Institute and Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States.,DBV Technologies, LLC, Montrouge, France
| | - David Dunkin
- Division of Pediatric Gastroenterology and the Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York City, NY, United States
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31
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Hua YL, Jia YQ, Zhang XS, Yuan ZW, Ji P, Hu JJ, Wei YM. Baitouweng Tang ameliorates DSS-induced ulcerative colitis through the regulation of the gut microbiota and bile acids via pathways involving FXR and TGR5. Biomed Pharmacother 2021; 137:111320. [PMID: 33578232 DOI: 10.1016/j.biopha.2021.111320] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/16/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
In China, Baitouweng Tang (BTWT) is a commonly prescribed remedy for the treatment of ulcerative colitis (UC). Herein, the present study aims to assess the anti-colitis activity of BTWT and its underlying mechanisms in UC BALB/c mice. Induction of UC in BALB/c mice was carried out by adding 3.5% DSS in the drinking water of underlined mice. After UC induction, the mice were administrated with BTWT for 7 days. Clinical symptoms were assessed, followed by analyzing the bile acids (BAs) in serum, liver, colon, bile, and feces of UC mice through UPLC-MS/MS. The modified 16S rDNA high-throughput sequencing was carried out to examine the gut microbiota of feces. BTWT significantly improved the clinical symptoms such as and histological injury and colon shortening in UC induced mice. Furthermore, BTWT remarkably ameliorated colonic inflammatory response. After BTWT treatment, the increased concentrations of UDCA, HDCA, αMCA, βMCA, CA, and GLCA in UC were decreased, and the levels of some BAs, especially CA, αMCA, and βMCA were normalized. Moreover, the relative species abundance and gut microbiota diversity in the BTWT-exposed groups were found to be considerably elevated than those in the DSS-treated group. BTWT increased the relative abundance of Firmicutes, Proteobacteria, Actinobacteria, Tenericutes, and TM7, which were statistically lower in the fecal microbiota of UC mice. The relative abundance of Bacteroidetes was found to be elevated in the DSS group and normalized after BTWT treatment. BTWT increased the expression of FXR and TGR5 in the liver. BTWT administration improved DSS-induced mice signs by increasing the TGR5 and FXR expression levels. This result was achieved by the regulation of the BAs and gut microbiota.
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Affiliation(s)
- Yong-Li Hua
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
| | - Ya-Qian Jia
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
| | - Xiao-Song Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
| | - Zi-Wen Yuan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
| | - Peng Ji
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
| | - Jun-Jie Hu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
| | - Yan-Ming Wei
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu Province, 730070, People's Republic of China.
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32
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Huang Y, Zhang Y, Wan T, Mei Y, Wang Z, Xue J, Luo Y, Li M, Fang S, Pan H, Wang Q, Fang J. Systems pharmacology approach uncovers Ligustilide attenuates experimental colitis in mice by inhibiting PPARγ-mediated inflammation pathways. Cell Biol Toxicol 2021; 37:113-128. [PMID: 33130971 DOI: 10.1007/s10565-020-09563-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 10/19/2020] [Indexed: 10/23/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology-driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components of Angelica acutiloba and Cnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1β, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow-derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.Graphical abstract This study suggested novel computational and experimental pharmacology approaches to identify potential IBD therapeutic agents by exploiting polypharmacology of natural products. We demonstrated that LIG could attenuate inflammation in IBD by inhibiting NF-κB and AP-1 pathways via PPARγ activation to reduce the expression of pro-inflammatory cytokines in macrophages. These findings offer comprehensive pre-clinical evidence that LIG may serve as a promising candidate for IBD therapy in the future. Graphical headlights: 1. Systems pharmacology uncovered Ligustilide attenuates experimental colitis in mice. 2. Network-based analysis predicted the mechanism of Ligustilide against IBD, which was validated by inhibiting PPARγ-mediated inflammation pathways. 3. Ligustilide activated PPARγ to inhibit NF-κB and AP-1 activation thus eventually alleviated DSS-induced colitis.4. Ligustilide has promising activities and may serve as a candidate for the treatment of IBD.
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Affiliation(s)
- Yujie Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China.
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, Guangdong, China.
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
| | - Yifan Zhang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Ting Wan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Yu Mei
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Zihao Wang
- Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Jincheng Xue
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Yi Luo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Min Li
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Shuhuan Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Huafeng Pan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China.
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China.
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
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33
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Grüner N, Mattner J. Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver-Gut Axis. Int J Mol Sci 2021; 22:1397. [PMID: 33573273 PMCID: PMC7866539 DOI: 10.3390/ijms22031397] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 12/12/2022] Open
Abstract
After their synthesis from cholesterol in hepatic tissues, bile acids (BAs) are secreted into the intestinal lumen. Most BAs are subsequently re-absorbed in the terminal ileum and are transported back for recycling to the liver. Some of them, however, reach the colon and change their physicochemical properties upon modification by gut bacteria, and vice versa, BAs also shape the composition and function of the intestinal microbiota. This mutual interplay of both BAs and gut microbiota regulates many physiological processes, including the lipid, carbohydrate and energy metabolism of the host. Emerging evidence also implies an important role of this enterohepatic BA circuit in shaping mucosal colonization resistance as well as local and distant immune responses, tissue physiology and carcinogenesis. Subsequently, disrupted interactions of gut bacteria and BAs are associated with many disorders as diverse as Clostridioides difficile or Salmonella Typhimurium infection, inflammatory bowel disease, type 1 diabetes, asthma, metabolic syndrome, obesity, Parkinson's disease, schizophrenia and epilepsy. As we cannot address all of these interesting underlying pathophysiologic mechanisms here, we summarize the current knowledge about the physiologic and pathogenic interplay of local site microbiota and the enterohepatic BA metabolism using a few selected examples of liver and gut diseases.
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Affiliation(s)
- Niklas Grüner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany;
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany
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34
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Sens J, Hoffmann D, Lange L, Vollmer Barbosa P, Morgan M, Falk CS, Schambach A. Knockout-Induced Pluripotent Stem Cells for Disease and Therapy Modeling of IL-10-Associated Primary Immunodeficiencies. Hum Gene Ther 2021; 32:77-95. [PMID: 33023317 DOI: 10.1089/hum.2020.235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Samples from patients with rare diseases, such as primary immunodeficiencies, are often limited, which hampers careful analysis of the pathomechanisms involved in immune cell dysregulation. To overcome this issue, induced pluripotent stem cells (iPSCs) represent an almost inexhaustible cell source and thus provide an excellent opportunity to generate disease models for rare diseases and to validate new therapeutic approaches. To obtain a better understanding of primary immunodeficiencies associated with the interleukin (IL)-10 signaling pathway, for example, very-early-onset inflammatory bowel disease (VEO-IBD), we generated genetic knockouts (KOs) of IL-10RA (IL-10 receptor α-chain) and IL-10RB (IL-10 receptor β-chain) as well as the downstream targets of the IL-10-receptor (IL-10R) signal transducers and activators of transcription (STAT)1 and STAT3 via an sgRNA (single-guide RNA)-CRISPR-Cas9-expressing lentiviral system. IL-10 signaling-associated KO models and a VEO-IBD patient-derived iPSC clone were differentiated into macrophages for disease models. IL-10R- or STAT3-deficient disease models showed no IL-10-induced BCL3 or SOCS3 expression, whereas lipopolysaccharide (LPS) stimulation induced IL-10R independently of BCL3 and SOCS3 expression. Cytokine secretion profiles from iPSC-derived macrophage disease models showed that IL-10 was involved in many inflammatory cytokine secretions, which indicated formation of both anti- and proinflammatory macrophage phenotypes. Macrophage-secreted cytokines were separated into IL-10R- and STAT3-dependent (IL-6, TNF-α), or into IL-10R-, STAT1-, and STAT3-dependent cytokines (CCL2, CXCL10). Importantly, lentiviral correction restored IL-10-mediated regulation of LPS-induced cytokine secretion in corrected IL-10RB, STAT1, and VEO-IBD patient-derived disease models. Furthermore, treatment of IL-10RB-deficient macrophages with anti-inflammatory small molecules (SB202190, filgotinib) reduced proinflammatory cytokine secretion patterns. Taken together, the described iPSC KO models gave new insights into the pathomechanisms of immune cell dysregulation and served as model systems to test potential therapeutic approaches, including lentiviral gene therapy and targeted small-molecule treatment.
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Affiliation(s)
- Johanna Sens
- Institute of Experimental Hematology.,REBIRTH-Research Center for Translational Regenerative Medicine
| | - Dirk Hoffmann
- Institute of Experimental Hematology.,REBIRTH-Research Center for Translational Regenerative Medicine
| | - Lucas Lange
- Institute of Experimental Hematology.,REBIRTH-Research Center for Translational Regenerative Medicine
| | - Philippe Vollmer Barbosa
- Institute of Experimental Hematology.,REBIRTH-Research Center for Translational Regenerative Medicine.,Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Michael Morgan
- Institute of Experimental Hematology.,REBIRTH-Research Center for Translational Regenerative Medicine
| | - Christine S Falk
- Institute of Transplant Immunology; Hannover Medical School, Hannover, Germany
| | - Axel Schambach
- Institute of Experimental Hematology.,REBIRTH-Research Center for Translational Regenerative Medicine.,Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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35
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Venkateswaran N, Weismiller S, Clarke K. Indeterminate Colitis - Update on Treatment Options. J Inflamm Res 2021; 14:6383-6395. [PMID: 34876831 PMCID: PMC8643196 DOI: 10.2147/jir.s268262] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 11/17/2021] [Indexed: 12/30/2022] Open
Abstract
Indeterminate colitis (IC) is described in approximately 5-15% of patients with inflammatory bowel disease (IBD). It usually reflects a difficulty or lack of clarity in distinguishing between ulcerative colitis (UC) and Crohn's disease (CD) on biopsy or colectomy specimens. The diagnostic difficulty may explain the variability in the reported prevalence and incidence of IC. Clinically, most IC patients tend to evolve over time to a definite diagnosis of either UC or CD. IC has also been interchangeably described as inflammatory bowel disease unclassified (IBDU). This review offers an overview of the available limited literature on the conventional medical and surgical treatments for IC. In contrast to the numerous studies on the medical management of UC and CD, there are very few data from dedicated controlled trials on the treatment of IC. The natural evolution of IC more closely mimics UC. Regarding medical options for treatment, most patients diagnosed with IC are treated similarly to UC, and treatment choices are based on disease severity. Others are managed similarly to CD if there are features suggestive of CD, including fissures, skin tags, or rectal sparing. In medically refractory IC, surgical treatment options are limited and include total proctocolectomy (TPC) and ileal pouch-anal anastomosis (IPAA), with its associated risk factors and complications. Post-surgical complications and pouch failure rates were historically thought to be more common in IC patients, but recent meta-analyses reveal similar rates between UC and IC patients. Future therapies in IBD are focused on known mechanisms in the disease pathways of UC and CD. Owing to the lack of IC-specific studies, clinicians have traditionally and historically extrapolated the data to IC patients based on their symptomatology, clinical course, and endoscopic findings.
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Affiliation(s)
- Niranjani Venkateswaran
- Division of General Internal Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Scott Weismiller
- Division of General Internal Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Kofi Clarke
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
- Correspondence: Kofi Clarke Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USATel +1 717-531-8741Fax +1 717-531-6770 Email
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36
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Jacob EM, Borah A, Pillai SC, Kumar DS. Inflammatory Bowel Disease: The Emergence of New Trends in Lifestyle and Nanomedicine as the Modern Tool for Pharmacotherapy. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2460. [PMID: 33316984 PMCID: PMC7764399 DOI: 10.3390/nano10122460] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/08/2023]
Abstract
The human intestine, which harbors trillions of symbiotic microorganisms, may enter into dysbiosis when exposed to a genetic defect or environmental stress. The naissance of chronic inflammation due to the battle of the immune system with the trespassing gut bacteria leads to the rise of inflammatory bowel disease (IBD). Though the genes behind the scenes and their link to the disease are still unclear, the onset of IBD occurs in young adults and has expanded from the Western world into the newly industrialized countries. Conventional drug deliveries depend on a daily heavy dosage of immune suppressants or anti-inflammatory drugs targeted for the treatment of two types of IBD, ulcerative colitis (UC) and Crohn's disease (CD), which are often associated with systemic side effects and adverse toxicities. Advances in oral delivery through nanotechnology seek remedies to overcome the drawbacks of these conventional drug delivery systems through improved drug encapsulation and targeted delivery. In this review, we discuss the association of genetic factors, the immune system, the gut microbiome, and environmental factors like diet in the pathogenesis of IBD. We also review the various physiological concerns required for oral delivery to the gastrointestinal tract (GIT) and new strategies in nanotechnology-derived, colon-targeting drug delivery systems.
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Affiliation(s)
| | | | | | - D. Sakthi Kumar
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama 350-8585, Japan; (E.M.J.); (A.B.); (S.C.P.)
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37
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Lahue KG, Lara MK, Linton AA, Lavoie B, Fang Q, McGill MM, Crothers JW, Teuscher C, Mawe GM, Tyler AL, Mahoney JM, Krementsov DN. Identification of novel loci controlling inflammatory bowel disease susceptibility utilizing the genetic diversity of wild-derived mice. Genes Immun 2020; 21:311-325. [PMID: 32848229 PMCID: PMC7657953 DOI: 10.1038/s41435-020-00110-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity, we utilized a panel of chromosome (Chr) substitution strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background, as well as their parental B6 and PWD strains. Two models of IBD were used, TNBS- and DSS-induced colitis. Compared with B6 mice, PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we identified several PWD-derived loci that exhibited profound effects on IBD susceptibility. The most pronounced of these were loci on Chr1 and Chr2, which yielded high susceptibility in both IBD models, each acting at distinct phases of the disease. Leveraging transcriptomic data from B6 and PWD immune cells, together with a machine learning approach incorporating human IBD genetic associations, we identified lead candidate genes, including Itga4, Pip4k2a, Lcn10, Lgmn, and Gpr65.
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Affiliation(s)
- Karolyn G Lahue
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Montana K Lara
- Department of Neurological Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Alisha A Linton
- Department of Neurological Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Brigitte Lavoie
- Department of Neurological Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Qian Fang
- Department of Medicine, University of Vermont, Burlington, VT, 05405, USA
| | - Mahalia M McGill
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Jessica W Crothers
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, 05405, USA
| | - Cory Teuscher
- Department of Medicine, University of Vermont, Burlington, VT, 05405, USA
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, 05405, USA
| | - Gary M Mawe
- Department of Neurological Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Anna L Tyler
- The Jackson Laboratory, 600 Main St., Bar Harbor, ME, 04609, USA
| | - J Matthew Mahoney
- Department of Neurological Sciences, University of Vermont, Burlington, VT, 05405, USA
- Department of Computer Science University of Vermont, Burlington, VT, 05405, USA
| | - Dimitry N Krementsov
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05405, USA.
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Zhao Y, Yang Y, Zhang J, Wang R, Cheng B, Kalambhe D, Wang Y, Gu Z, Chen D, Wang B, Huang Y. Lactoferrin-mediated macrophage targeting delivery and patchouli alcohol-based therapeutic strategy for inflammatory bowel diseases. Acta Pharm Sin B 2020; 10:1966-1976. [PMID: 33163347 PMCID: PMC7606100 DOI: 10.1016/j.apsb.2020.07.019] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/24/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are the incurable chronic recurrent gastrointestinal disorders and currently lack in safe and effective drugs. In this study, patchouli alcohol, a main active compound of traditional Chinese herb patchouli, was developed into biomimetic liposomes for macrophage-targeting delivery for IBD treatment. The developed lactoferrin-modified liposomes (LF-lipo) can specifically bind to LRP-1 expressed on the activated colonic macrophages and achieve cell-targeting anti-inflammatory therapy. LF-lipo reduced the levels of inflammatory cytokines and ROS and suppressed the MAPK/NF-κB pathway. LF-lipo also suppressed the formation of NLRP3 inflammasome and the consequent IL-1β activation. LF-lipo showed improved therapeutic efficacy in a DSS-induced colitis murine model, evidenced by the reduced disease activity index, the improved colon functions, and the downregulated inflammatory cytokines in the colon. LF-lipo provided an effective and safe macrophage-targeting delivery and therapeutic strategy for addressing the unmet medical need in IBD management.
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Chen JF, Luo DD, Lin YS, Liu YH, Wu JZ, Yi XQ, Wu Y, Zhang Q, Gao CJ, Cai J, Su ZR. Aqueous extract of Bruguiera gymnorrhiza leaves protects against dextran sulfate sodium induced ulcerative colitis in mice via suppressing NF-κB activation and modulating intestinal microbiota. JOURNAL OF ETHNOPHARMACOLOGY 2020; 251:112554. [PMID: 31923541 DOI: 10.1016/j.jep.2020.112554] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/31/2019] [Accepted: 01/06/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is tightly associated with inflammation response and oxidative stress. As a folk medicine applied in treatment of diarrhea, Bruguiera gymnorrhiza also possesses anti-inflammatory and anti-oxidative activities, which indicated that B. gymnorrhiza may exert anti-colitis effect. AIM OF THE STUDY To investigate effect and mechanism of B. gymnorrhiza on experimental UC. MATERIALS AND METHODS Aqueous extract of B. gymnorrhiza leaves (ABL) was used for investigation in the present study. Murine UC was established through access to 3% dextran sulfate sodium (DSS) for 7 days. Meanwhile, mice accepted treatment with ABL (25, 50, 100 mg/kg) or sulfasalazine (200 mg/kg) once daily. On the last day, disease activity index (DAI) including body weight loss, fecal character and degree of bloody diarrhea was evaluated, colon segments were obtained for length measurement and further analysis and feces were collected for intestinal microbiota analysis. RESULTS ABL ameliorated DAI scores, colon length shortening and histopathological damage in DSS-induced colitis mice obviously. SOD activity, levels of MDA and GSH altered by colitis were restored remarkably after ABL treatment. ABL inhibited increases in levels of colonic COX-2, iNOS, TNF-α, IL-6, IL-1β, IL-4, IL-10 and IL-11 in colitis mice. Moreover, ABL prominently suppressed NF-κB p65 and IκB phosphorylation and down-regulated mRNA levels of COX-2, iNOS, TNF-α, IL-6 and IL-1β elevated by colitis. As shown in microbiota analysis, ABL modulated composition of intestinal microbiota of colitis mice. CONCLUSION ABL exhibited protective effect against DSS-induced ulcerative colitis through suppressing NF-κB activation and modulating intestinal microbiota.
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Affiliation(s)
- Jin-Fen Chen
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.
| | - Dan-Dan Luo
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.
| | - Yin-Si Lin
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.
| | - Yu-Hong Liu
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.
| | - Jia-Zhen Wu
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.
| | - Xiao-Qing Yi
- Guangdong Academy of Forestry, Guangzhou, 510520, People's Republic of China.
| | - Yan Wu
- Guangdong Academy of Forestry, Guangzhou, 510520, People's Republic of China.
| | - Qian Zhang
- Guangdong Academy of Forestry, Guangzhou, 510520, People's Republic of China; Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization, Guangzhou, 510520, People's Republic of China.
| | - Chang-Jun Gao
- Guangdong Academy of Forestry, Guangzhou, 510520, People's Republic of China; Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization, Guangzhou, 510520, People's Republic of China.
| | - Jian Cai
- Guangdong Academy of Forestry, Guangzhou, 510520, People's Republic of China; Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization, Guangzhou, 510520, People's Republic of China.
| | - Zi-Ren Su
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China; Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Medicine, Dongguan, 523808, People's Republic of China.
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40
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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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Abstract
In recent years, the therapeutic goals in ulcerative colitis (UC) have become increasingly stringent. Histological features seem to be a reliable predictor of disease outcomes after therapy, and histological remission (HR) is the new frontier in the treatment of UC. Here, we first provide a historical perspective before reviewing indexes in the era of biologics; histology as a treatment goal in UC trials; the poor correlation between symptoms, endoscopy, and histology; and the impact of histology on disease outcomes. HR seems to be a promising end point for the treatment of UC because it is typically associated with better outcomes. Two new validated indexes are available to assess histology more accurately in trials, and they may also be applicable to clinical practice. Additional interventional trials are now necessary to establish definitions of HR and its potential for disease modification.
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42
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Chu H, Tao X, Sun Z, Hao W, Wei X. Galactooligosaccharides protects against DSS-induced murine colitis through regulating intestinal flora and inhibiting NF-κB pathway. Life Sci 2020; 242:117220. [DOI: 10.1016/j.lfs.2019.117220] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/12/2019] [Accepted: 12/22/2019] [Indexed: 02/08/2023]
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43
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Mei Y, Wang Z, Zhang Y, Wan T, Xue J, He W, Luo Y, Xu Y, Bai X, Wang Q, Huang Y. FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Ameliorates DSS-Induced Colitis Against Oxidative Stress by Activating Nrf2/HO-1 Pathway. Front Immunol 2020; 10:2969. [PMID: 31969881 PMCID: PMC6960141 DOI: 10.3389/fimmu.2019.02969] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/03/2019] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder of gastro-intestinal tract, lacking effective drug targets and medications. Caffeic acid phenethyl ester (CAPE), a phenolic constituent derived from propolis, has been reported to be a potential therapeutic agent for IBD with low water solubility and poor bioavailability. In this study, we synthesized a new CAPE derivative (FA-97) and aimed to investigate the effect of FA-97 on DSS-induced colitis. Here, we found that FA-97 attenuated body weight loss, colon length shortening and colonic pathological damage in colitis mice, as well as inhibited inflammatory cell infiltration and expression of pro-inflammatory cytokines in colons. In addition, FA-97 reduced ROS production and MDA generation, while total antioxidant capacity both in DSS-induced colitis mice and LPS-stimulated primary BMDMs and RAW 264.7 cells were enhanced. Mechanically, FA-97 activated Nrf2 followed by increased HO-1 and NQO-1 and down-regulated nuclear levels of p65 and c-Jun, to suppress DSS-induced colonic oxidative stress. Moreover, FA-97 decreased pro-inflammatory cytokine expression and increased the antioxidant defenses in RAW 264.7 via Nrf2 activation. In general, this study reveals that FA-97 activates Nrf2/HO-1 pathway to eventually alleviate DSS-induced colitis against oxidative stress, which has potential activity and may serve as a candidate for IBD therapy.
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Affiliation(s)
- Yu Mei
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zihao Wang
- Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Institute of Brain and Gut Axis (IBAG), Hong Kong Baptist University, Kowloon Tong, China.,Department of Chemistry, Southern University of Science and Technology, Shenzhen, China
| | - Yifan Zhang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Wan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jincheng Xue
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei He
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Luo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yijun Xu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue Bai
- Southwestern Medical University Affiliated Chinese Medicine Hospital, Quzhou, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yujie Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
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44
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Attenuation of DSS induced colitis by Dictyophora indusiata polysaccharide (DIP) via modulation of gut microbiota and inflammatory related signaling pathways. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103641] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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45
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A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. J Immunol Res 2019; 2019:7247238. [PMID: 31886308 PMCID: PMC6914932 DOI: 10.1155/2019/7247238] [Citation(s) in RCA: 607] [Impact Index Per Article: 101.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/15/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The pathogenesis of IBD is complex. Recent studies have greatly improved our knowledge of the pathophysiology of IBD, leading to great advances in the treatment as well as diagnosis of IBD. In this review, we have systemically reviewed the pathogenesis of IBD and highlighted recent advances in host genetic factors, gut microbiota, and environmental factors and, especially, in abnormal innate and adaptive immune responses and their interactions, which may hold the keys to identify novel predictive or prognostic biomarkers and develop new therapies.
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46
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Mortensen JH, Lindholm M, Langholm LL, Kjeldsen J, Bay-Jensen AC, Karsdal MA, Manon-Jensen T. The intestinal tissue homeostasis - the role of extracellular matrix remodeling in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2019; 13:977-993. [PMID: 31587588 DOI: 10.1080/17474124.2019.1673729] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Extracellular matrix (ECM) remodeling of the intestinal tissue is important in inflammatory bowel disease (IBD) due to the extensive mucosal remodeling. There are still gaps in our knowledge as to how ECM remodeling is related to intestinal epithelium homeostasis and healing of the intestinal mucosa.Areas covered: The aim of this review is to highlight the importance of the ECM in relation to the pathogenesis of IBD, while addressing basement membrane and interstitial matrix remodeling, and the processes of wound healing of the intestinal tissue in IBD.Expert opinion: In IBD, basement membrane remodeling may reflect the integrity of the intestinal epithelial-cell homeostasis. The interstitial matrix remodeling is associated with deep inflammation such as the transmural inflammation as seen in fistulas and intestinal fibrosis leading to fibrostenotic strictures, in patients with CD. The interplay between wound healing processes and ECM remodeling also affects the tissue homeostasis in IBD. The interstitial matrix, produced by fibroblasts, holds a very different biology as compared to the epithelial basement membrane in IBD. In combination with integration of wound healing, quantifying the interplay between damage and repair to these sub compartments may provide essential information in IBD patient profiling, mucosal healing and disease management.
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Affiliation(s)
- J H Mortensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - M Lindholm
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.,Department of Medical Gastroenterology, Odense University hospital, Odense, Denmark
| | - L L Langholm
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - J Kjeldsen
- Department of Medical Gastroenterology, Odense University hospital, Odense, Denmark
| | - A C Bay-Jensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - M A Karsdal
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - T Manon-Jensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
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47
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Silva I, Pinto R, Mateus V. Preclinical Study in Vivo for New Pharmacological Approaches in Inflammatory Bowel Disease: A Systematic Review of Chronic Model of TNBS-Induced Colitis. J Clin Med 2019; 8:jcm8101574. [PMID: 31581545 PMCID: PMC6832474 DOI: 10.3390/jcm8101574] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/19/2019] [Accepted: 09/25/2019] [Indexed: 12/14/2022] Open
Abstract
The preclinical studies in vivo provide means of characterizing physiologic interactions when our understanding of such processes is insufficient to allow replacement with in vitro systems and play a pivotal role in the development of a novel therapeutic drug cure. Chemically induced colitis models are relatively easy and rapid to develop. The 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis model is one of the main models in the experimental studies of inflammatory bowel disease (IBD) since inflammation induced by TNBS mimics several features of Crohn’s disease. This review aims to summarize the existing literature and discuss different protocols for the induction of chronic model of TNBS-induced colitis. We searched MEDLINE via Pubmed platform for studies published through December 2018, using MeSH terms (Crohn Disease.kw) OR (Inflammatory Bowel Diseases.kw) OR (Colitis, Ulcerative.kw) AND (trinitrobenzenesulfonic acid.kw) AND (disease models, animal.kw) AND (mice.all). The inclusion criteria were original articles, preclinical studies in vivo using mice, chronic model of colitis, and TNBS as the inducer of colitis and articles published in English. Chronic TNBS-induced colitis is made with multiple TNBS intrarectal administrations in an average dose of 1.2 mg using a volume lower than 150 μL in 50% ethanol. The strains mostly used are Balb/c and C57BL/6 with 5–6 weeks. To characterize the preclinical model the parameters more used include body weight, stool consistency and morbidity, inflammatory biomarkers like interferon (IFN)-γ, myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10, presence of ulcers, thickness or hyperemia in the colon, and histological evaluation of the inflammation. Experimental chronic colitis is induced by multiple rectal instillations of TNBS increasing doses in ethanol using Balb/c and C57BL/6 mice.
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Affiliation(s)
- Inês Silva
- H&TRC–Health and Technology Research Center, ESTeSL–Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal;
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1990-096 Lisboa, Portugal;
| | - Rui Pinto
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1990-096 Lisboa, Portugal;
- JCS, Dr. Joaquim Chaves, Laboratório de Análises Clínicas, Miraflores, 1495-069 Algés, Portugal
| | - Vanessa Mateus
- H&TRC–Health and Technology Research Center, ESTeSL–Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal;
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1990-096 Lisboa, Portugal;
- Correspondence: ; Tel.: +351-218-980-400; Fax: +351-218-980-460
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48
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He R, Li Y, Han C, Lin R, Qian W, Hou X. L-Fucose ameliorates DSS-induced acute colitis via inhibiting macrophage M1 polarization and inhibiting NLRP3 inflammasome and NF-kB activation. Int Immunopharmacol 2019; 73:379-388. [PMID: 31132733 DOI: 10.1016/j.intimp.2019.05.013] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/08/2019] [Accepted: 05/08/2019] [Indexed: 12/12/2022]
Abstract
Previous studies reported that L-fucose had anti-inflammatory effects in respiratory and cutaneous system. However, the effect of L-fucose on colitis and the underlying mechanism is poorly understood. We studied the anti-inflammatory effects of L-fucose on Dextran sulfate sodium (DSS)-induced acute colitis in vivo and on LPS/ATP-induced bone marrow derived macrophages (BMDMs) damage in vitro. Our results show that L-fucose significantly alleviated weight loss and disease activity index (DAI) scores in colitis and reduced the infiltration of macrophages and neutrophils. In addition, L-fucose can inhibit macrophage M1 polarization, inactivate the NLRP3 inflammasome and reduce the release of TNFα, IL1β, IL6 pro-inflammatory cytokines. In vitro studies showed that L-fucose ameliorated cell damage resulting from the administration of LPS with ATP in BMDMs, inhibited NLRP3 inflammasome activation and reduced the release of corresponding pro-inflammatory cytokines. Finally, L-fucose can inhibit the expression of p-NF-kB in vivo and in vitro. Overall, our results show that L-fucose can attenuate colitis by inhibiting macrophage M1 polarization, inhibiting NLRP3 inflammasome and NF-kB activation, and down-regulation of pro-inflammatory cytokines.
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Affiliation(s)
- Ruohang He
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ying Li
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chaoqun Han
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rong Lin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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49
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Direito R, Rocha J, Lima A, Gonçalves MM, Duarte MP, Mateus V, Sousa C, Fernandes A, Pinto R, Boavida Ferreira R, Sepodes B, Figueira ME. Reduction of Inflammation and Colon Injury by a Spearmint Phenolic Extract in Experimental Bowel Disease in Mice. MEDICINES (BASEL, SWITZERLAND) 2019; 6:E65. [PMID: 31174376 PMCID: PMC6630206 DOI: 10.3390/medicines6020065] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 05/30/2019] [Accepted: 06/03/2019] [Indexed: 02/07/2023]
Abstract
Background: Inflammatory Bowel Diseases (IBD) encompasses both Crohn's Disease and Ulcerative Colitis, known to be connected to an enlarged risk for developing colorectal cancer (CRC). Spearmint (Mentha spicata L.) is a Mediterranean plant used as an aromatic agent, and studies have mainly focused on the essential oil suggesting an anti-inflammatory activity. This work aimed to perform a preliminary screening of the in vivo anti-inflammatory effects of a spearmint phenolic extract in an acute inflammation model, in a chronic inflammation model of colitis, and also study the effects in vitro on a colon cancer model. Methods: Spearmint extract was administered to rats of a paw oedema model (induced by carrageenan) and to mice from a TNBS-induced colitis model in parallel with studies using HT-29 CRC cells. Results: Administration of the extract led to reduced paw inflammation, reduction of colon injury and inflammation, with attenuation of histological markers, and reduction of iNOS expression. It repressed the in vitro movement of HT-29 cells in a wound healing assay. Conclusions: These findings suggest that spearmint extract exhibits acute and chronic anti-inflammatory activity and is able to inhibit migration of cancer cells, suggesting a potential role in the supplementary therapy of IBD patients.
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Affiliation(s)
- Rosa Direito
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
| | - João Rocha
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
| | - Ana Lima
- Disease & Stress Biology Group, LEAF, Instituto Superior de Agronomia, Universidade de Lisboa, 1349-017 Lisbon, Portugal.
| | - Maria Margarida Gonçalves
- Unidade de Biotecnologia Ambiental, Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Monte da Caparica, Portugal.
| | - Maria Paula Duarte
- Unidade de Biotecnologia Ambiental (UBiA), Grupo de Disciplinas da Ecologia da Hidrosfera, Faculdade de Ciências e Tecnologia, FCT, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
| | - Vanessa Mateus
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal.
| | - Catarina Sousa
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
| | - Adelaide Fernandes
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
| | - Rui Pinto
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
- Joaquim Chaves Saúde, Dr Joaquim Chaves Lab Analises Clínicas, 1495-068 Miraflores-Algés, Portugal.
| | - Ricardo Boavida Ferreira
- Disease & Stress Biology Group, LEAF, Instituto Superior de Agronomia, Universidade de Lisboa, 1349-017 Lisbon, Portugal.
| | - Bruno Sepodes
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
| | - Maria-Eduardo Figueira
- Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
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50
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REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis. Nat Commun 2018; 9:4246. [PMID: 30315268 PMCID: PMC6185905 DOI: 10.1038/s41467-018-06568-5] [Citation(s) in RCA: 226] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 09/12/2018] [Indexed: 12/11/2022] Open
Abstract
The roles of Rev-erbα and circadian clock in colonic inflammation remain unclarified. Here we show colon clock genes (including Rev-erbα) are dysregulated in mice with DSS-induced colitis. In turn, disruption of the circadian clock exacerbates experimental colitis. Rev-erbα-deficient mice are more sensitive to DSS-induced colitis, supporting a critical role of Rev-erbα in disease development. Further, Rev-erbα ablation causes activation of Nlrp3 inflammasome in mice. Cell-based experiments reveal Rev-erbα inactivates Nlrp3 inflammasome mainly at the priming stage. Rev-erbα directly represses Nlrp3 transcription through specific binding to the promoter region. Additionally, Rev-erbα represses p65 transcription and indirectly repressed Nlrp3 via the NF-κB pathway. Interestingly, Rev-erbα activation in wild-type mice by SR9009 attenuates DSS-induced colitis, whereas the protective effects are lost in Nlrp3−/− and Rev-erbα−/− mice. Taken together, Rev-erbα regulates experimental colitis through its repressive action on the NF-κB/Nlrp3 axis. Targeting Rev-erbα may represent a promising approach for prevention and management of colitis. REV-ERBα is a nuclear receptor that links the circadian pathways with those of metabolism. Here the authors show REV-ERBα is also involved with linking the circadian system with the inflammatory pathways of an experimental model of colitis through regulation of the NF-κB/NLRP3 axis.
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