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1
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Liu C, Liu J, Yang Y. Bulk and Single-Cell Transcriptomic Reveals Shared Key Genes and Patterns of Immune Dysregulation in Both Intestinal Inflammatory Disease and Sepsis. J Cell Mol Med 2025; 29:e70415. [PMID: 39993996 PMCID: PMC11850196 DOI: 10.1111/jcmm.70415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 02/26/2025] Open
Abstract
Inflammatory bowel disease (IBD) and Sepsis are both characterised by immune dysregulation. Notably, IBD is a factor in the increase in septic infections. However, these two conditions' shared molecular and pathophysiological mechanisms remain unclear. We used 'limma' and 'WGCNA' analyses to identify common DEGs between these two conditions. Single-cell RNA sequencing further assessed immune cell heterogeneity. We used machine learning algorithms to construct and identify diagnostic markers for Sepsis, which we then validated using receiver operating characteristic curve (ROC) analysis. A mouse model of IBD combined with Sepsis was constructed, and real-time PCR and western blot validated the expression of BCL2A1 and CEBPB. It was found that 58 shared DEGs identified in both IBD and Sepsis were highly enriched in immune and inflammation-related pathways. Single-cell analysis revealed that CD14+ monocytes (or IL1B+ macrophages) primarily express these hub genes. Both conditions significantly increased the proportion of this cell type compared to healthy controls. Finally, BCL2A1 and CEBPB were identified as potential biomarkers that have strong diagnostic potential. Furthermore, we confirmed that levels of BCL2A1 and CEBPB were elevated in mice with IBD complicated by Sepsis through real-time PCR and observed that IBD exacerbates the progression of Sepsis. We conclude that IL1B+ macrophages expressing high levels of these hub genes play a key role in the immune dysregulation associated with both IBD and Sepsis. The overlapping gene expression and pathway alterations in these cells indicate shared common molecular mechanisms, suggesting new strategies for targeted therapeutic interventions.
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Affiliation(s)
- Chao Liu
- Department of Infectious Diseases, The Second Affiliated HospitalZhejiang University School of MedicineZhejiangHangzhouChina
| | - Jinliang Liu
- Department of Infectious Diseases, The Second Affiliated HospitalZhejiang University School of MedicineZhejiangHangzhouChina
| | - Yitian Yang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityZhengzhouHenanChina
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2
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Ji S, Hu H, Zhu R, Guo D, Liu Y, Yang Y, Li T, Zou C, Jiang Y, Liu G. Integrative Multi-Omics Analysis Reveals Critical Molecular Networks Linking Intestinal-System Diseases to Colorectal Cancer Progression. Biomedicines 2024; 12:2656. [PMID: 39767563 PMCID: PMC11673540 DOI: 10.3390/biomedicines12122656] [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: 10/23/2024] [Revised: 11/14/2024] [Accepted: 11/16/2024] [Indexed: 01/06/2025] Open
Abstract
Background/Objectives: Colorectal cancer (CRC) frequently co-occurs with intestinal system diseases (ISDs), yet their molecular interplay remains poorly understood. We employed a comprehensive bioinformatics approach to elucidate shared genetic signatures and pathways between CRC and ISDs. Methods: We systematically analyzed 12 microarray and RNA-seq datasets encompassing 989 samples across seven ISDs and CRC. Differentially expressed genes (DEGs) were identified using Limma and DESeq2. Functional enrichment analysis was performed using clusterProfiler. Protein-protein interaction networks were constructed via STRING and visualized with Cytoscape to identify hub genes. Clinical significance of shared genes was further assessed through survival analysis and validated by immunohistochemistry staining of 30 paired CRC-normal tissue samples. Results: Integrating bioinformatics and machine learning approaches, we uncovered 160 shared DEGs (87 upregulated, 73 downregulated), which predominantly enriched cell metabolism, immune homeostasis, gut-brain communication, and inflammation pathways. Network analysis revealed nine key hub proteins linking CRC and ISDs, with seven upregulated (CD44, MYC, IL17A, CXCL1, FCGR3A, SPP1, and IL1A) and two downregulated (CXCL12 and CCL5). Survival analysis demonstrated the prognostic potential of these shared genes, while immunohistochemistry confirmed their differential expression in CRC tissues. Conclusions: Our findings unveil potential biomarkers and therapeutic targets, providing insights into ISD-influenced CRC progression and offering a robust foundation for improved diagnostic and treatment strategies in ISD-associated CRC.
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Affiliation(s)
- Shiliang Ji
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Haoran Hu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China;
| | - Ruifang Zhu
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Dongkai Guo
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Yujing Liu
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Yang Yang
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Tian Li
- School of Basic Medicine, Tianjin Medical University, Tianjin 300102, China;
| | - Chen Zou
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Yiguo Jiang
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
| | - Guilai Liu
- Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215163, China; (S.J.); (R.Z.); (D.G.); (Y.L.); (Y.Y.)
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Hong SM, Moon W. [Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-interleukins]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 84:65-81. [PMID: 39176462 DOI: 10.4166/kjg.2024.076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.
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Affiliation(s)
- Seung Min Hong
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
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4
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Liang J, Chen Y, Wang Z, Wang Y, Mu S, Zhang D, Wang Z, Zeng W. Exploring the association between rosacea and acne by integrated bioinformatics analysis. Sci Rep 2024; 14:3065. [PMID: 38321132 PMCID: PMC10847114 DOI: 10.1038/s41598-024-53453-x] [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: 07/04/2023] [Accepted: 01/31/2024] [Indexed: 02/08/2024] Open
Abstract
Clinically, rosacea occurs frequently in acne patients, which hints the existence of shared signals. However, the connection between the pathophysiology of rosacea and acne are not yet fully understood. This study aims to unveil molecular mechanism in the pathogenesis of rosacea and acne. We identified differentially expressed genes (DEGs) by limma and weighted gene co-expression network analysis and screened hub genes by constructing a protein-protein interaction network. The hub genes were verified in different datasets. Then, we performed a correlation analysis between the hub genes and the pathways. Finally, we predicted and verified transcription factors of hub genes, performed the immune cell infiltration analysis using CIBERSORT, and calculated the correlation between hub genes and immune cells. A total of 169 common DEGs were identified, which were mainly enriched in immune-related pathways. Finally, hub genes were identified as IL1B, PTPRC, CXCL8, MMP9, CCL4, CXCL10, CD163, CCR5, CXCR4, and TLR8. 9 transcription factors that regulated the expression of hub genes were identified. The infiltration of γδT cells was significantly increased in rosacea and acne lesions and positively linked with almost all hub genes. These identified hub genes and immune cells may play a crucial role in the development of rosacea and acne.
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Affiliation(s)
- Jingchen Liang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Chen
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zihao Wang
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yawen Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shengzhi Mu
- Department of Burn and Plastic Surgery, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Dewu Zhang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhao Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Weihui Zeng
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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5
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Rondeau LE, Da Luz BB, Santiago A, Bermudez-Brito M, Hann A, De Palma G, Jury J, Wang X, Verdu EF, Galipeau HJ, Rolland C, Deraison C, Ruf W, Bercik P, Vergnolle N, Caminero A. Proteolytic bacteria expansion during colitis amplifies inflammation through cleavage of the external domain of PAR2. Gut Microbes 2024; 16:2387857. [PMID: 39171684 PMCID: PMC11346554 DOI: 10.1080/19490976.2024.2387857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/03/2024] [Accepted: 07/23/2024] [Indexed: 08/23/2024] Open
Abstract
Imbalances in proteolytic activity have been linked to the development of inflammatory bowel diseases (IBD) and experimental colitis. Proteases in the intestine play important roles in maintaining homeostasis, but exposure of mucosal tissues to excess proteolytic activity can promote pathology through protease-activated receptors (PARs). Previous research implicates microbial proteases in IBD, but the underlying pathways and specific interactions between microbes and PARs remain unclear. In this study, we investigated the role of microbial proteolytic activation of the external domain of PAR2 in intestinal injury using mice expressing PAR2 with a mutated N-terminal external domain that is resistant to canonical activation by proteolytic cleavage. Our findings demonstrate the key role of proteolytic cleavage of the PAR2 external domain in promoting intestinal permeability and inflammation during colitis. In wild-type mice expressing protease-sensitive PAR2, excessive inflammation leads to the expansion of bacterial taxa that cleave the external domain of PAR2, exacerbating colitis severity. In contrast, mice expressing mutated protease-resistant PAR2 exhibit attenuated colitis severity and do not experience the same proteolytic bacterial expansion. Colonization of wild-type mice with proteolytic PAR2-activating Enterococcus and Staphylococcus worsens colitis severity. Our study identifies a previously unknown interaction between proteolytic bacterial communities, which are shaped by inflammation, and the external domain of PAR2 in colitis. The findings should encourage new therapeutic developments for IBD by targeting excessive PAR2 cleavage by bacterial proteases.
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Affiliation(s)
- Liam Emile Rondeau
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Bruna Barbosa Da Luz
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Alba Santiago
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Miriam Bermudez-Brito
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Amber Hann
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Giada De Palma
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jennifer Jury
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Xuanyu Wang
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Elena Francisca Verdu
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Heather Jean Galipeau
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Corinne Rolland
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Celine Deraison
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | | | - Alberto Caminero
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
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6
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Duan B, Hu Q, Ding F, Huang F, Wang W, Yin N, Liu Z, Zhang S, He D, Lu Q. The effect and mechanism of Huangqin-Baishao herb pair in the treatment of dextran sulfate sodium-induced ulcerative colitis. Heliyon 2023; 9:e23082. [PMID: 38144295 PMCID: PMC10746484 DOI: 10.1016/j.heliyon.2023.e23082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 10/03/2023] [Accepted: 11/27/2023] [Indexed: 12/26/2023] Open
Abstract
Background The haungqing (Scutellariae Radix) and baishao (Paeoniae Radix Alba) herb pair (HBHP) is a common prescribed herbal formula or is added to other traditional Chinese medicine (TCM) prescriptions to treat ulcerative colitis (UC). However, the underlying mechanism is unclear. Purpose Elucidate the efficacy and potential mechanism of HBHP against UC. Methods First, The UC model of mice induced by dextran sulfate sodium (DSS) was established. The mice were randomly divided into Control group, DSS group, SASP group (390 mg/kg), and HPHP group (1.95 g/kg), with 8 mice per group. Drugs were administrated via oral gavage for 7 days. Then, Disease activity index (DAI), length of the colon, histopathology, and changes in inflammatory cytokines in colonic tissues were analyzed to assess the effect of HBHP on UC. Besides, Network pharmacology was applied to identify the active compounds, core targets of HBHP in the treatment of UC, and the corresponding signaling pathways to explore the underlying mechanisms. Finally, Western blot (WB), immunohistochemistry (IHC) and molecular docking were performed to validate the results. Results HBHP significantly reduced DAI score and decreased colon length shortening in DSS-induced UC mice. The administration of HBHP was able to effectively alleviated mucosal ulceration and epithelial destruction. In addition, HBHP treatment obviously - reduced the expressions of TNF-α, IL-6, and IL-1β in colon tissues (p < 0.05 or p < 0.01). 35 bioactive compounds and 290 HBHP targets related to UC were obtained. Among them 3 key active compounds (baicalein, panicolin, and norwogonin) with higher degree values in the drug-compound-target network and 21 hub genes (STAT3, JAK2, SRC, AKT1, PIK3CA, and VEGFA, etc.) were identified. KEGG enrichment analysis suggested that HBHP's mechanisms mainly involve the JAK-STAT pathway. Abnormal activation of JAK/STAT signaling is believed to be involved in the pathogeneses of UC. Notably, WB and IHC showed that HBHP significantly down-regulated the protein expression levels of p-JAK2 (p < 0.05) and p-STAT3 (p < 0.05 or p < 0.01). JAK2 and STAT3 might be core targets for the action of HBHP; this possibility was also supported by molecular docking. Conclusions HBHP could alleviate DSS-induced UC, reduce tissue inflammation, and its mechanism might primarily be achieved by inhibiting JAK2/STAT3 signaling pathway. Meanwhile, our work revealed that network pharmacology combined with experimental verification is a cogent means of studying the mechanism of TCM.
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Affiliation(s)
- Bailu Duan
- Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Qiong Hu
- First People's Hospital of Jiangxia District, Wuhan City & Union Jiangnan Hospital, HUST, Wuhan, 430200, China
| | - Fengmin Ding
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Fang Huang
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Wei Wang
- Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
- Department of Orthopedics, Hubei Provincial Hospital of TCM Affiliated to Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Nina Yin
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Zhe Liu
- Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Song Zhang
- Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
| | - Dongchu He
- Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
| | - Qiping Lu
- Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
- Department of General Surgery, General Hospital of Central Theater Command of PLA, Wuhan, 430070, China
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7
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Yang Y, Xia L, Yang W, Wang Z, Meng W, Zhang M, Ma Q, Gou J, Wang J, Shu Y, Wu X. Transcriptome profiling of intact bowel wall reveals that PDE1A and SEMA3D are possible markers with roles in enteric smooth muscle apoptosis, proliferative disorders, and dysautonomia in Crohn's disease. Front Genet 2023; 14:1194882. [PMID: 37727374 PMCID: PMC10505932 DOI: 10.3389/fgene.2023.1194882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/16/2023] [Indexed: 09/21/2023] Open
Abstract
Background: Inflammatory bowel disease (IBD) is a complex and multifactorial inflammatory condition, comprising Crohn's disease (CD) and ulcerative colitis (UC). While numerous studies have explored the immune response in IBD through transcriptional profiling of the enteric mucosa, the subtle distinctions in the pathogenesis of Crohn's disease and ulcerative colitis remain insufficiently understood. Methods: The intact bowel wall specimens from IBD surgical patients were divided based on their inflammatory status into inflamed Crohn's disease (iCD), inflamed ulcerative colitis (iUC) and non-inflamed (niBD) groups for RNA sequencing. Differential mRNA GO (Gene Ontology), and KEGG (Kyoto Encyclopedia of Genes and Genomes), and GSEA (Gene Set Enrichment Analysis) bioinformatic analyses were performed with a focus on the enteric autonomic nervous system (ANS) and smooth muscle cell (SMC). The transcriptome results were validated by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Results: A total of 2099 differentially expressed genes were identified from the comparison between iCD and iUC. Regulation of SMC apoptosis and proliferation were significantly enriched in iCD, but not in iUC. The involved gene PDE1A in iCD was 4-fold and 1.5-fold upregulated at qPCR and IHC compared to that in iUC. Moreover, only iCD was significantly associated with the gene sets of ANS abnormality. The involved gene SEMA3D in iCD was upregulated 8- and 5-fold at qPCR and IHC levels compared to iUC. Conclusion: These findings suggest that PDE1A and SEMA3D may serve as potential markers implicated in enteric smooth muscle apoptosis, proliferative disorders, and dysautonomia specifically in Crohn's disease.
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Affiliation(s)
- Yun Yang
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Department of General Surgery, West China Chengdu Shangjin Nanfu Hospital, Sichuan University, Chengdu, China
| | - Lin Xia
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wenming Yang
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ziqiang Wang
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wenjian Meng
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mingming Zhang
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Department of General Surgery, West China Chengdu Shangjin Nanfu Hospital, Sichuan University, Chengdu, China
| | - Qin Ma
- Department of General Surgery, West China Chengdu Shangjin Nanfu Hospital, Sichuan University, Chengdu, China
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Junhe Gou
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Junjian Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Shu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoting Wu
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Colorectal and Pelvic Floor Center, West China Tianfu Hospital, Sichuan University, Chengdu, China
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8
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Althagafy HS, El-Aziz MA, Ibrahim IM, Abd-Alhameed EK, Hassanein EM. Pharmacological updates of nifuroxazide: Promising preclinical effects and the underlying molecular mechanisms. Eur J Pharmacol 2023; 951:175776. [PMID: 37192715 DOI: 10.1016/j.ejphar.2023.175776] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 05/04/2023] [Accepted: 05/08/2023] [Indexed: 05/18/2023]
Abstract
Nifuroxazide (NFX) is a safe nitrofuran antibacterial drug used clinically to treat acute diarrhea and infectious traveler diarrhea or colitis. Recent studies revealed that NFX displays multiple pharmacological effects, including anticancer, antioxidant, and anti-inflammatory effects. NFX has potential roles in inhibiting thyroid, breast, lung, bladder, liver, and colon cancers and osteosarcoma, melanoma, and others mediated by suppressing STAT3 as well as ALDH1, MMP2, MMP9, Bcl2 and upregulating Bax. Moreover, it has promising effects against sepsis-induced organ injury, hepatic disorders, diabetic nephropathy, ulcerative colitis, and immune disorders. These promising effects appear to be mediated by suppressing STAT3 as well as NF-κB, TLR4, and β-catenin expressions and effectively decreasing downstream cytokines TNF-α, IL-1β, and IL-6. Our review summarizes the available studies on the molecular biological mechanisms of NFX in cancer and other diseases and it is recommended to translate the studies in experimental animals and cultured cells and repurpose NFX in various diseases for scientific evidence based on human studies.
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Affiliation(s)
- Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | | | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Esraa K Abd-Alhameed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - EmadH M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.
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9
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Saadh MJ, Mikhailova MV, Rasoolzadegan S, Falaki M, Akhavanfar R, Gonzáles JLA, Rigi A, Kiasari BA. Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy. Eur J Med Res 2023; 28:47. [PMID: 36707899 PMCID: PMC9881387 DOI: 10.1186/s40001-023-01008-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 01/10/2023] [Indexed: 01/28/2023] Open
Abstract
Recently, mesenchymal stem/stromal cells (MSCs) therapy has become an emerging therapeutic modality for the treatment of inflammatory bowel disease (IBD), given their immunoregulatory and pro-survival attributes. MSCs alleviate dysregulated inflammatory responses through the secretion of a myriad of anti-inflammatory mediators, such as interleukin 10 (IL-10), transforming growth factor-β (TGFβ), prostaglandin E2 (PGE2), tumor necrosis factor-stimulated gene-6 (TSG-6), etc. Indeed, MSC treatment of IBD is largely carried out through local microcirculation construction, colonization and repair, and immunomodulation, thus alleviating diseases severity. The clinical therapeutic efficacy relies on to the marked secretion of various secretory molecules from viable MSCs via paracrine mechanisms that are required for gut immuno-microbiota regulation and the proliferation and differentiation of surrounding cells like intestinal epithelial cells (IECs) and intestinal stem cells (ISCs). For example, MSCs can induce IECs proliferation and upregulate the expression of tight junction (TJs)-associated protein, ensuring intestinal barrier integrity. Concerning the encouraging results derived from animal studies, various clinical trials are conducted or ongoing to address the safety and efficacy of MSCs administration in IBD patients. Although the safety and short-term efficacy of MSCs administration have been evinced, the long-term efficacy of MSCs transplantation has not yet been verified. Herein, we have emphasized the illumination of the therapeutic capacity of MSCs therapy, including naïve MSCs, preconditioned MSCs, and also MSCs-derived exosomes, to alleviate IBD severity in experimental models. Also, a brief overview of published clinical trials in IBD patients has been delivered.
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Affiliation(s)
- Mohamed J Saadh
- Department of Basic Sciences, Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Maria V Mikhailova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Soheil Rasoolzadegan
- Department of Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojgan Falaki
- Department of Internal Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roozbeh Akhavanfar
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Amir Rigi
- Department of Nursing, Young Researchers and Elite Club, Zahedan Branch, Azad University, Zahedan, Iran.
| | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran.
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10
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Huang J, Walters TD. Growth Impairment in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:151-172. [DOI: 10.1007/978-3-031-14744-9_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Zhang C, Ma Z, Nan X, Wang W, Zeng X, Chen J, Cai Z, Wang J. Comprehensive analysis to identify the influences of SARS-CoV-2 infections to inflammatory bowel disease. Front Immunol 2023; 14:1024041. [PMID: 36817436 PMCID: PMC9936160 DOI: 10.3389/fimmu.2023.1024041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Background Coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) are both caused by a disordered immune response and have direct and profound impacts on health care services. In this study, we implemented transcriptomic and single-cell analysis to detect common molecular and cellular intersections between COVID-19 and IBD that help understand the linkage of COVID-19 to the IBD patients. Methods Four RNA-sequencing datasets (GSE147507, GSE126124, GSE9686 and GSE36807) from Gene Expression Omnibus (GEO) database are extracted to detect mutual differentially expressed genes (DEGs) for IBD patients with the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to find shared pathways, candidate drugs, hub genes and regulatory networks. Two single-cell RNA sequencing (scRNA-eq) datasets (GSE150728, PRJCA003980) are used to analyze the immune characteristics of hub genes and the proportion of immune cell types, so as to find common immune responses between COVID-19 and IBD. Results A total of 121 common DEGs were identified among four RNA-seq datasets, and were all involved in the functional enrichment analysis related to inflammation and immune response. Transcription factors-DEGs interactions, miRNAs-DEGs coregulatory networks, and protein-drug interactions were identified based on these datasets. Protein-protein interactions (PPIs) was built and 59 hub genes were identified. Moreover, scRNA-seq of peripheral blood monocyte cells (PBMCs) from COVID-19 patients revealed a significant increase in the proportion of CD14+ monocytes, in which 38 of 59 hub genes were highly enriched. These genes, encoding inflammatory cytokines, were also highly expressed in inflammatory macrophages (IMacrophage) of intestinal tissues of IBD patients. Conclusions We conclude that COVID-19 may promote the progression of IBD through cytokine storms. The candidate drugs and DEGs-regulated networks may suggest effective therapeutic methods for both COVID-19 and IBD.
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Affiliation(s)
- Chengyan Zhang
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Zeyu Ma
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Nan
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenhui Wang
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianchang Zeng
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinming Chen
- Department of Anorectal, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhijian Cai
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.,Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianli Wang
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
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12
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Dovrolis N, Filidou E, Tarapatzi G, Kokkotis G, Spathakis M, Kandilogiannakis L, Drygiannakis I, Valatas V, Arvanitidis K, Karakasiliotis I, Vradelis S, Manolopoulos VG, Paspaliaris V, Bamias G, Kolios G. Co-expression of fibrotic genes in inflammatory bowel disease; A localized event? Front Immunol 2022; 13:1058237. [PMID: 36632136 PMCID: PMC9826764 DOI: 10.3389/fimmu.2022.1058237] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/08/2022] [Indexed: 12/27/2022] Open
Abstract
Introduction Extracellular matrix turnover, a ubiquitous dynamic biological process, can be diverted to fibrosis. The latter can affect the intestine as a serious complication of Inflammatory Bowel Diseases (IBD) and is resistant to current pharmacological interventions. It embosses the need for out-of-the-box approaches to identify and target molecular mechanisms of fibrosis. Methods and results In this study, a novel mRNA sequencing dataset of 22 pairs of intestinal biopsies from the terminal ileum (TI) and the sigmoid of 7 patients with Crohn's disease, 6 with ulcerative colitis and 9 control individuals (CI) served as a validation cohort of a core fibrotic transcriptomic signature (FIBSig), This signature, which was identified in publicly available data (839 samples from patients and healthy individuals) of 5 fibrotic disorders affecting different organs (GI tract, lung, skin, liver, kidney), encompasses 241 genes and the functional pathways which derive from their interactome. These genes were used in further bioinformatics co-expression analyses to elucidate the site-specific molecular background of intestinal fibrosis highlighting their involvement, particularly in the terminal ileum. We also confirmed different transcriptomic profiles of the sigmoid and terminal ileum in our validation cohort. Combining the results of these analyses we highlight 21 core hub genes within a larger single co-expression module, highly enriched in the terminal ileum of CD patients. Further pathway analysis revealed known and novel inflammation-regulated, fibrogenic pathways operating in the TI, such as IL-13 signaling and pyroptosis, respectively. Discussion These findings provide a rationale for the increased incidence of fibrosis at the terminal ileum of CD patients and highlight operating pathways in intestinal fibrosis for future evaluation with mechanistic and translational studies.
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Affiliation(s)
- Nikolas Dovrolis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Laboratory of Biology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece,*Correspondence: George Kolios, ; Nikolas Dovrolis,
| | - Eirini Filidou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Gesthimani Tarapatzi
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Georgios Kokkotis
- Gastrointestinal (GI) Unit, 3 Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Michail Spathakis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Leonidas Kandilogiannakis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Ioannis Drygiannakis
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, Heraklion, Greece
| | - Vassilis Valatas
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, Heraklion, Greece
| | - Konstantinos Arvanitidis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | - Ioannis Karakasiliotis
- Laboratory of Biology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Stergios Vradelis
- Second Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece
| | | | - Giorgos Bamias
- Gastrointestinal (GI) Unit, 3 Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Kolios
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece,Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece,*Correspondence: George Kolios, ; Nikolas Dovrolis,
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13
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Deng J, Zhao N, Lv LP, Ma P, Zhang YY, Xu JB, Zhou XP, Chen ZA, Zhang YY. Integrated analysis of multiple microarray studies to establish differential diagnostic models of Crohn's disease and ulcerative colitis based on a metalloproteinase-associated module. Front Immunol 2022; 13:1022850. [PMID: 36479126 PMCID: PMC9720321 DOI: 10.3389/fimmu.2022.1022850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/25/2022] [Indexed: 11/22/2022] Open
Abstract
Background The ulcerative colitis (UC) and Crohn's disease (CD) subtypes of inflammatory bowel disease (IBD) are autoimmune diseases influenced by multiple complex factors. The clinical treatment strategies for UC and CD often differ, indicating the importance of improving their discrimination. Methods Two methods, robust rank aggregation (RRA) analysis and merging and intersection, were applied to integrate data from multiple IBD cohorts, and the identified differentially expressed genes (DEGs) were used to establish a protein-protein interaction (PPI) network. Molecular complex detection (MCODE) was used to identify important gene sets. Two differential diagnostic models to distinguish CD and UC were established via a least absolute shrinkage and selection operator (LASSO) logistic regression, and model evaluation was performed in both the training and testing groups, including receiver operating characteristic (ROC) curves, calibration plots and decision curve analysis (DCA). The potential value of MMP-associated genes was further verified using different IBD cohorts and clinical samples. Results Four datasets (GSE75214, GSE10616, GSE36807, and GSE9686) were included in the analysis. Both data integration methods indicated that the activation of the MMP-associated module was significantly elevated in UC. Two LASSO models based on continuous variable (Model_1) and binary variable (Model_2) MMP-associated genes were established to discriminate CD and UC. The results showed that Model_1 exhibited good discrimination in the training and testing groups. The calibration analysis and DCA showed that Model_1 exhibited good performance in the training group but failed in the testing group. Model_2 exhibited good discrimination, calibration and DCA results in the training and testing groups and exhibited greater diagnostic value. The effects of Model_1 and Model_2 were further verified in a new IBD cohort of GSE179285. The MMP genes exhibited high value as biomarkers for the discrimination of IBD patients using published cohort and immunohistochemistry (IHC) staining data. The MMP-associated gene levels were statistically significantly positively correlated with the levels of the differentially expressed cell types, indicating their potential value in differential diagnosis. The single-cell analysis confirmed that the expression of ANXA1 in UC was higher than that in CD. Conclusion MMP-associated modules are the main differential gene sets between CD and UC. The established Model_2 overcomes batch differences and has good clinical applicability. Subsequent in-depth research investigating how MMPs are involved in the development of different IBD subtypes is necessary.
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Affiliation(s)
- Jiang Deng
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Ning Zhao
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Li-ping Lv
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Ping Ma
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Yang-yang Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Jin-bo Xu
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Xi-peng Zhou
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Zi-an Chen
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, Hebei, China,*Correspondence: Zi-an Chen, ; Yan-yu Zhang,
| | - Yan-yu Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China,*Correspondence: Zi-an Chen, ; Yan-yu Zhang,
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14
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Bouwman W, Verhaegh W, van de Stolpe A. Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity. Front Pharmacol 2022; 13:1008976. [PMID: 37090899 PMCID: PMC10115426 DOI: 10.3389/fphar.2022.1008976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/22/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Ulcerative colitis (UC) and Crohn’s disease (CD) are two subtypes of chronic inflammatory bowel disease (IBD). Differential diagnosis remains a challenge. Anti-TNFα treatment is an important treatment for IBD, yet resistance frequently occurs and cannot be predicted. Consequently, many patients receive ineffective therapy with potentially adverse effects. Novel assays are needed to improve diagnosis, and predict and monitor response to anti-TNF-α compounds.Design: Signal transduction pathway (STP) technology was used to quantify activity of STPs (androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, Hedgehog, Wnt, NFκB, JAK-STAT1/2, and JAK-STAT3 pathways) in colon mucosa samples of CD and UC patients, based on transcriptome analysis. Previously described STP assay technology is based on computational inference of STP activity from mRNA levels of target genes of the STP transcription factor.Results: Results show that NFκB, JAK-STAT3, Wnt, MAPK, and androgen receptor pathways were abnormally active in CD and UC. Colon and ileum-localized CD differed with respect to STP activity, the JAK-STAT1/2 pathway being abnormally active in ileal CD. High activity of NFκB, JAK-STAT3, and TGFβ pathways was associated with resistance to anti-TNFα treatment in UC and colon-located CD, but not in ileal CD. Abnormal STP activity decreased with successful treatment.Conclusion: We believe that measuring mucosal STP activity provides clinically relevant information to improve differential diagnosis of IBD and prediction of resistance to anti-TNFα treatment in patients with colon-localized IBD, and provides new targets for treatment and overcoming anti-TNFα resistance.
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15
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Thanki KK, Johnson P, Higgins EJ, Maskey M, Phillips C, Dash S, Almenas FA, Govar AA, Tian B, Villéger R, Beswick E, Wang R, Szabo C, Chao C, Pinchuk IV, Hellmich MR, Módis K. Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis. Redox Biol 2022; 55:102417. [PMID: 35933902 PMCID: PMC9357841 DOI: 10.1016/j.redox.2022.102417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/27/2022] [Accepted: 07/17/2022] [Indexed: 11/24/2022] Open
Abstract
Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.
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Affiliation(s)
- Ketan K Thanki
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Paul Johnson
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Edward J Higgins
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Manjit Maskey
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Ches'Nique Phillips
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Swetaleena Dash
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | | | | | - Bing Tian
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Romain Villéger
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Ellen Beswick
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
| | - Rui Wang
- Department of Biology, York University, Toronto, ON, Canada.
| | - Csaba Szabo
- Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
| | - Celia Chao
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Irina V Pinchuk
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Mark R Hellmich
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Katalin Módis
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
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16
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Takada I, Hidano S, Takahashi S, Yanaka K, Ogawa H, Tsuchiya M, Yokoyama A, Sato S, Ochi H, Nakagawa T, Kobayashi T, Nakagawa S, Makishima M. Transcriptional coregulator Ess2 controls survival of post-thymic CD4 + T cells through the Myc and IL-7 signaling pathways. J Biol Chem 2022; 298:102342. [PMID: 35933014 PMCID: PMC9436822 DOI: 10.1016/j.jbc.2022.102342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 07/18/2022] [Accepted: 07/26/2022] [Indexed: 11/21/2022] Open
Abstract
Ess2, also known as Dgcr14, is a transcriptional co-regulator of CD4+ T cells. Ess2 is located in a chromosomal region, the loss of which has been associated with 22q11.2 deletion syndrome (22q11DS), which causes heart defects, skeletal abnormalities, and immunodeficiency. However, the specific association of Ess2 with 22q11DS remains unclear. To elucidate the role of Ess2 in T-cell development, we generated Ess2 floxed (Ess2fl/fl) and CD4+ T cell-specific Ess2 KO (Ess2ΔCD4/ΔCD4) mice using the Cre/loxP system. Interestingly, Ess2ΔCD4/ΔCD4 mice exhibited reduced naïve T-cell numbers in the spleen, while the number of thymocytes (CD4-CD8-, CD4+CD8+, CD4+CD8-, and CD4-CD8+) in the thymus remained unchanged. Furthermore, Ess2ΔCD4/ΔCD4 mice had decreased NKT cells and increased γδT cells in the thymus and spleen. A genome-wide expression analysis using RNA-seq revealed that Ess2 deletion alters the expression of many genes in CD4 single-positive thymocytes, including genes related to the immune system and Myc target genes. In addition, Ess2 enhanced the transcriptional activity of c-Myc. Some genes identified as Ess2 targets in mice show expressional correlation with ESS2 in human immune cells. Moreover, Ess2ΔCD4/ΔCD4 naïve CD4+ T cells did not maintain survival in response to IL-7. Our results suggest that Ess2 plays a critical role in post-thymic T-cell survival through the Myc and IL-7 signaling pathways.
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Affiliation(s)
- Ichiro Takada
- Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University, Itabashi-ku, Tokyo, Japan.
| | - Shinya Hidano
- Department of Infectious Diseases Control, Faculty of Medicine, Oita University, Oita, Japan
| | - Sayuri Takahashi
- Department of Urology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kaori Yanaka
- RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama, Japan
| | - Hidesato Ogawa
- Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
| | - Megumi Tsuchiya
- Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
| | - Atsushi Yokoyama
- Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Shingo Sato
- Center for Innovative Cancer Treatment, Tokyo Medical and Dental University Medical Hospital, Tokyo, Japan
| | - Hiroki Ochi
- Department of Rehabilitation for Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Tokorozawa, Saitama, Japan
| | - Tohru Nakagawa
- Department of Urology, Teikyo University, Itabashi-ku, Tokyo, Japan
| | - Takashi Kobayashi
- Department of Infectious Diseases Control, Faculty of Medicine, Oita University, Oita, Japan
| | - Shinichi Nakagawa
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Makoto Makishima
- Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University, Itabashi-ku, Tokyo, Japan.
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17
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Qin W, Luo H, Yang L, Hu D, Jiang SP, Peng DY, Hu JM, Liu SJ. Rubia cordifolia L. ameliorates DSS-induced ulcerative colitis in mice through dual inhibition of NLRP3 inflammasome and IL-6/JAK2/STAT3 pathways. Heliyon 2022; 8:e10314. [PMID: 36082330 PMCID: PMC9445285 DOI: 10.1016/j.heliyon.2022.e10314] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 06/01/2022] [Accepted: 08/11/2022] [Indexed: 10/25/2022] Open
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18
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Brown RE, Jacobse J, Anant SA, Blunt KM, Chen B, Vega PN, Jones CT, Pilat JM, Revetta F, Gorby AH, Stengel KR, Choksi YA, Palin K, Piazuelo MB, Washington MK, Lau KS, Goettel JA, Hiebert SW, Short SP, Williams CS. MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors. JCI Insight 2022; 7:e153045. [PMID: 35503250 PMCID: PMC9220854 DOI: 10.1172/jci.insight.153045] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/13/2022] [Indexed: 12/04/2022] Open
Abstract
Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium-induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16-/- colon in the azoxymethane/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
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Affiliation(s)
- Rachel E. Brown
- Program in Cancer Biology and
- Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Justin Jacobse
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
- Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Koral M. Blunt
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Bob Chen
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Paige N. Vega
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology and
| | - Chase T. Jones
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Frank Revetta
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Aidan H. Gorby
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kristy R. Stengel
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Yash A. Choksi
- Program in Cancer Biology and
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kimmo Palin
- Department of Medical and Clinical Genetics
- Applied Tumor Genomics Research Program, Research Programs Unit, and
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
| | - M. Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mary Kay Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Ken S. Lau
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology and
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jeremy A. Goettel
- Program in Cancer Biology and
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Scott W. Hiebert
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sarah P. Short
- Program in Cancer Biology and
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Christopher S. Williams
- Program in Cancer Biology and
- Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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19
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Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10 -/- model of colitis. Cell Death Differ 2022; 29:585-599. [PMID: 34588632 PMCID: PMC8901686 DOI: 10.1038/s41418-021-00876-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 02/08/2023] Open
Abstract
Mutations in susceptibility alleles correlate with gut-inflammatory diseases, such as Crohn's disease; however, this does not often impact the disease progression indicating the existence of compensatory genes. We show that a reduction in Foxo3a expression in IL-10-deficient mice results in a spontaneous and aggressive Crohn's- like disease with 100% penetrance, which is rescued by deletion of myeloid cells, T cells and inhibition of mTORC1. In Foxo3a-/- IL-10-/- mice, there is poor cell death of myeloid cells in the gut, leading to increased accumulation of myeloid and T cells in the gut. Myeloid cells express high levels of inflammatory cytokines, and regulatory T cells are dysfunctional despite increased abundance. Foxo3a signaling represses the transcription of glutaminase (GLS/GLS2) to prevent over-consumption of glutamine by activated T cells and its conversion to glutamate that contributes to the TCA cycle and mTORC1 activation. Finally, we show that Foxo3a restricts the abundance of colitogenic microbiota in IL-10-deficient mice. Thus, by suppressing glutaminolysis in activated T cells Foxo3a mediates a critical checkpoint that prevents the development of fulminant gut inflammatory disease.
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20
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Wong WY, Chan BD, Leung TW, Chen M, Tai WCS. Beneficial and anti-inflammatory effects of formulated prebiotics, probiotics, and synbiotics in normal and acute colitis mice. J Funct Foods 2022. [DOI: 10.1016/j.jff.2021.104871] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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21
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Cao Y, Dai Y, Zhang L, Wang D, Yu Q, Hu W, Wang X, Yu P, Ping Y, Sun T, Sang Y, Liu Z, Chen Y, Tao Z. Serum oncostatin M is a potential biomarker of disease activity and infliximab response in inflammatory bowel disease measured by chemiluminescence immunoassay. Clin Biochem 2021; 100:35-41. [PMID: 34843732 DOI: 10.1016/j.clinbiochem.2021.11.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/17/2021] [Accepted: 11/20/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND Although endoscopy is the gold standard to assess disease activity and infliximab efficacy in inflammatory bowel disease (IBD), the invasive, costly, and time-consuming procedure limits its routine applications. We aimed to investigate the clinical value of serum oncostatin M (OSM) as a surrogate biomarker. METHODS Fifty healthy controls, 34 non-IBD patients, and 189 IBD patients who were pre-infliximab treatment (n = 122) or in infliximab maintenance (n = 67) were enrolled. A chemiluminescence immunoassay (CLIA) was constructed to quantify serum OSM concentrations. Receiver operator characteristic (ROC) curve analysis was used to evaluate the performance of blood biomarkers for IBD management. RESULTS The methodology of CLIA exhibited great analytical performance with a wide linear range of 31.25-25000 pg/mL, a low detection limit of 23.2 pg/mL, acceptable precision, and applicable accuracy. Patients with IBD (121.5 [43.3-249.4] pg/mL, p < 0.001) and non-IBD (72.4 [51.4-129.6] pg/mL, p = 0.005) had higher serum OSM levels than healthy controls (35.8 [23.2-56.4] pg/mL). In the analysis of clinical and endoscopic activity, serum OSM levels were elevated in moderate and severe patients compared to those in remission. IBD patients without mucosal healing had higher serum OSM levels than those with mucosal healing (AUC = 0.843). Besides, serum OSM levels were increased in clinical non-responders (287.3 [127.9-438] pg/mL) compared to responders (24.1 [23.2-53.4] pg/mL, p < 0.001), and showed great recognition ability with an AUC of 0.898. CONCLUSIONS The newly developed methodology of CLIA had great potential for use in the clinic. Elevated serum OSM expression was a promising biomarker of severe disease and infliximab non-response in IBD patients.
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Affiliation(s)
- Ying Cao
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Yibei Dai
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Lingyu Zhang
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Danhua Wang
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Qiao Yu
- Center for Inflammatory Bowel Diseases, Department of Gastroenterology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Wen Hu
- National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine First Affiliated Hospital, Zhejiang Province, China
| | - Xuchu Wang
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Pan Yu
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Ying Ping
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Tao Sun
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Yiwen Sang
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China
| | - Zhenping Liu
- Department of Laboratory Medicine, the First People's Hospital of Yuhang District, Hangzhou 311100, Zhejiang Province, China
| | - Yan Chen
- Center for Inflammatory Bowel Diseases, Department of Gastroenterology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China.
| | - Zhihua Tao
- Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, Zhejiang Province, China.
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22
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Bai L, Scott MKD, Steinberg E, Kalesinskas L, Habtezion A, Shah NH, Khatri P. Computational drug repositioning of atorvastatin for ulcerative colitis. J Am Med Inform Assoc 2021; 28:2325-2335. [PMID: 34529084 PMCID: PMC8510297 DOI: 10.1093/jamia/ocab165] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/22/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Ulcerative colitis (UC) is a chronic inflammatory disorder with limited effective therapeutic options for long-term treatment and disease maintenance. We hypothesized that a multi-cohort analysis of independent cohorts representing real-world heterogeneity of UC would identify a robust transcriptomic signature to improve identification of FDA-approved drugs that can be repurposed to treat patients with UC. MATERIALS AND METHODS We performed a multi-cohort analysis of 272 colon biopsy transcriptome samples across 11 publicly available datasets to identify a robust UC disease gene signature. We compared the gene signature to in vitro transcriptomic profiles induced by 781 FDA-approved drugs to identify potential drug targets. We used a retrospective cohort study design modeled after a target trial to evaluate the protective effect of predicted drugs on colectomy risk in patients with UC from the Stanford Research Repository (STARR) database and Optum Clinformatics DataMart. RESULTS Atorvastatin treatment had the highest inverse-correlation with the UC gene signature among non-oncolytic FDA-approved therapies. In both STARR (n = 827) and Optum (n = 7821), atorvastatin intake was significantly associated with a decreased risk of colectomy, a marker of treatment-refractory disease, compared to patients prescribed a comparator drug (STARR: HR = 0.47, P = .03; Optum: HR = 0.66, P = .03), irrespective of age and length of atorvastatin treatment. DISCUSSION & CONCLUSION These findings suggest that atorvastatin may serve as a novel therapeutic option for ameliorating disease in patients with UC. Importantly, we provide a systematic framework for integrating publicly available heterogeneous molecular data with clinical data at a large scale to repurpose existing FDA-approved drugs for a wide range of human diseases.
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Affiliation(s)
- Lawrence Bai
- Immunology Program, Stanford University School of Medicine, Stanford, California, USA.,Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.,Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA
| | - Madeleine K D Scott
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.,Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA.,Biophysics Program, Stanford University School of Medicine, Stanford, California, USA
| | - Ethan Steinberg
- Computer Science Program, Department of Computer Science, Stanford University, Stanford, California, USA
| | - Laurynas Kalesinskas
- Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, California, USA
| | - Aida Habtezion
- Immunology Program, Stanford University School of Medicine, Stanford, California, USA.,Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Nigam H Shah
- Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA
| | - Purvesh Khatri
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.,Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA
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23
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Wang L, Chen Y, Zhou W, Miao X, Zhou H. Utilization of physiologically-based pharmacokinetic model to assess disease-mediated therapeutic protein-disease-drug interaction in immune-mediated inflammatory diseases. Clin Transl Sci 2021; 15:464-476. [PMID: 34581012 PMCID: PMC8841519 DOI: 10.1111/cts.13164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/30/2021] [Accepted: 09/06/2021] [Indexed: 11/30/2022] Open
Abstract
It is known that interleukin-6 (IL-6) can significantly modulate some key drug-metabolizing enzymes, such as phase I cytochrome P450s (CYPs). In this study, a physiologically-based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP-DIs) in patients with immune-mediated inflammatory diseases (IMIDs) with elevated systemic IL-6 levels when treated by anti-IL-6 therapies. Literature data of IL-6 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations. The modulation effects of systemic IL-6 level and local IL-6 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL-6 signaling pathway by an anti-IL-6 treatment, the area under plasma concentration versus time curves (AUCs) of S-warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn's disease and ulcerative colitis treated with an anti-IL-6 therapy, the lowering of the elevated IL-6 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP-DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP-DI in patients with elevated IL-6 levels when an anti-IL-6 therapeutic is used with concomitant small-molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period.
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Affiliation(s)
- Lujing Wang
- Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.,Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA
| | - Yang Chen
- Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - Wangda Zhou
- Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - Xin Miao
- Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - Honghui Zhou
- Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
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24
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Yun SW, Kim JK, Han MJ, Kim DH. Lacticaseibacillus paracasei NK112 mitigates Escherichia coli-induced depression and cognitive impairment in mice by regulating IL-6 expression and gut microbiota. Benef Microbes 2021; 12:541-551. [PMID: 34511050 DOI: 10.3920/bm2020.0109] [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: 12/14/2022]
Abstract
The gut microbiota communicates with the brain through microbiota-gut-brain (MGB) and hypothalamus-pituitary-adrenal (HPA) axes and other pathways. Excessive expression of interleukin (IL)-6 is closely associated with the occurrence of the psychiatric disorders depression and dementia. Therefore, to understand whether IL-6 expression-suppressing probiotics could alleviate psychiatric disorders, we isolated IL-6 expression-inhibiting Lacticaseibacillus paracasei (formerly Lactobacillus paracasei) NK112 from the human faecal bacteria strain collection (Neurobiota Research Center, Seoul, Korea) and examined its therapeutic effect for the depression and cognitive impairment in mice. C57 BL/6J mice with depression and cognitive impairment were prepared by exposure to Escherichia coli K1. Oral gavage of NK112 significantly alleviated K1-induced anxious, depressive, and memory-impaired behaviours in the elevated plus maze, tail-suspension and Y-maze tasks, IL-1β, IL-6, and tumour necrosis factor (TNF)-α expression, and nuclear factor kappa beta (NF-κB) activation in the hippocampus, while K1-suppressed brain-derived neurotrophic factor (BDNF) expression increased. Treatment with NK112 also improved K1-induced myeloperoxidase activity, IL-6 and TNF-α expression, and NF-κB activation in the colon and reduced K1-induced Proteobacteria population in the gut microbiota. Heat-killed NK112 and its lysate supernatant, and precipitate fractions also improved anxiety/depression, cognitive impairment, and colitis in mice. In conclusion, NK112, even if heat-killed or lysed, alleviated K1 stress-induced colitis, anxiety/depression, and cognitive impairment by suppressing IL-6, TNF-α, and BDNF expression through the regulation of gut microbiota and NF-κB activation.
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Affiliation(s)
- S-W Yun
- Department of Food and Nutrition, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - J-K Kim
- Neurobiota Research Center, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - M J Han
- Department of Food and Nutrition, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - D-H Kim
- Neurobiota Research Center, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
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25
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Yang S, He X, Zhao J, Wang D, Guo S, Gao T, Wang G, Jin C, Yan Z, Wang N, Wang Y, Zhao Y, Xing J, Huang Q. Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer. Cancer Commun (Lond) 2021; 41:695-714. [PMID: 34160895 PMCID: PMC8360642 DOI: 10.1002/cac2.12184] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/22/2021] [Accepted: 06/14/2021] [Indexed: 01/01/2023] Open
Abstract
Background Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC). Methods TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)‐specific TFAM‐knockout mice (TFAM△IEC) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis. Results The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin‐6 in a signal transducer and activator of transcription 3 (STAT3)/miR‐23b‐dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis‐associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β‐catenin induced the upregulation of TFAM through c‐Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity. Conclusions TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.
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Affiliation(s)
- Shirong Yang
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China.,Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Jing Zhao
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Dalin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Shanshan Guo
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Tian Gao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Gang Wang
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Chao Jin
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Zeyu Yan
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Yongxing Wang
- Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Yilin Zhao
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
| | - Qichao Huang
- State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, P. R. China
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26
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Manz A, Allenspach K, Kummer S, Richter B, Walter I, Macho-Maschler S, Tichy A, Burgener IA, Luckschander-Zeller N. Upregulation of signal transducer and activator of transcription 3 in dogs with chronic inflammatory enteropathies. J Vet Intern Med 2021; 35:1288-1296. [PMID: 33955083 PMCID: PMC8163116 DOI: 10.1111/jvim.16141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/11/2021] [Accepted: 04/16/2021] [Indexed: 12/13/2022] Open
Abstract
Background In inflammatory bowel disease (IBD) in humans, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is upregulated in mucosal epithelial cells and correlates with clinical severity. Hypothesis/Objective To investigate the expression pattern of pSTAT3 in the mucosa of dogs with chronic inflammatory enteropathy (CIE) and explore correlations between its expression and clinical and histopathological severity scoring. Animals Twenty‐eight canine CIE patients grouped into food‐responsive enteropathy (FRE; 9), steroid‐responsive enteropathy (SRE; 10), and protein‐losing enteropathy (PLE; 9). Ten healthy beagle dogs served as controls (CO). Methods Retrospective case control study. Immunohistochemistry was used to detect pSTAT3 in canine duodenal mucosa samples. Results Compared to CO, SRE (P < .001) and PLE (P < .001) dogs had significantly higher pSTAT3 expression in the villus epithelium. The SRE group had a significantly higher expression in the villus lamina propria (VLP) compared to controls (P = .009). In the crypt epithelium (CE), all CIE dogs had significantly higher pSTAT3 expression (FRE, P = .002; SRE, P = .003; PLE, P < .001) compared to CO. In the lamina propria crypt region (CLP), dogs with FRE (P = .04) and SRE (P = .03) had significantly upregulated pSTAT3 compared to controls. A positive correlation was found between canine chronic enteropathy clinical activity index (CCECAI) scoring and pSTAT3 expression for both epithelial (rho = .541; P < .001) and crypt regions (rho = .32; P = .02). Conclusions and Clinical Importance pSTAT3 is upregulated in CIE in dogs, correlates with clinical severity, and may be helpful as a clinical marker in dogs with CIE.
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Affiliation(s)
- Anita Manz
- Internal Medicine, Clinic for Small Animals, Department for Companion Animals and Horses, University of Veterinary Medicine, Vienna, Austria
| | - Karin Allenspach
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA
| | - Stefan Kummer
- Department for Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Barbara Richter
- Institute of Pathology, University of Veterinary Medicine, Vienna, Austria
| | - Ingrid Walter
- VetCore Facility for Research, University of Veterinary Medicine, Vienna, Austria
| | - Sabine Macho-Maschler
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.,Department of Biomedical Sciences, Unit of Physiology, Pathophysiology and Experimental Endocrinology, University of Veterinary Medicine, Vienna, Austria
| | - Alexander Tichy
- Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Iwan A Burgener
- Internal Medicine, Clinic for Small Animals, Department for Companion Animals and Horses, University of Veterinary Medicine, Vienna, Austria
| | - Nicole Luckschander-Zeller
- Internal Medicine, Clinic for Small Animals, Department for Companion Animals and Horses, University of Veterinary Medicine, Vienna, Austria
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27
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Ali FEM, M Elfiky M, Fadda WA, Ali HS, Mahmoud AR, Mohammedsaleh ZM, Abd-Elhamid TH. Regulation of IL-6/STAT-3/Wnt axis by nifuroxazide dampens colon ulcer in acetic acid-induced ulcerative colitis model: Novel mechanistic insight. Life Sci 2021; 276:119433. [PMID: 33794250 DOI: 10.1016/j.lfs.2021.119433] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/12/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
AIM Ulcerative colitis (UC) is a common intestinal problem characterized by the diffusion of colon inflammation and immunity dysregulation. Nifuroxazide, a potent STAT-3 inhibitor, exhibits diverse pharmacological properties. The present study aimed to elucidate a novel anti-colitis mechanism of nifuroxazide against the acetic acid-induced UC model. METHODS Rats were grouped into control (received vehicle), UC (2 ml of 5% acetic acid by intrarectal infusion), UC plus sulfasalazine (100 mg/kg/day, P.O.), UC plus nifuroxazide (25 mg/kg/day, P.O.), and UC plus nifuroxazide (50 mg/kg/day, P.O.) and lasted for 6 days. RESULTS The present study revealed that nifuroxazide significantly reduced UC measures, hematological changes, and histological alteration. In addition, treatment with nifuroxazide significantly down-regulated serum CRP as well as the colonic expressions of MPO, IL-6, TNF-α, TLR-4, NF-κB-p65, JAK1, STAT-3, DKK1 in a dose-dependent manner. Besides, our results showed that the colonic Wnt expression was up-regulated with nifuroxazide treatment. In a dose-dependent manner, nifuroxazide markedly alleviated acetic acid-induced cellular infiltration and improved ulcer healing by increasing intestinal epithelial cell regeneration. SIGNIFICANCE Our results collectively indicate that nifuroxazide is an effective anti-colitis agent through regulation of colon inflammation and proliferation via modulation IL-6/STAT-3/Wnt signaling pathway.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
| | - Mohamed M Elfiky
- Human Anatomy and Embryology Department, Faculty of Medicine, Menoufia University, Shebin ElKoum-Menoufia, Egypt
| | - Walaa A Fadda
- Human Anatomy and Embryology Department, Faculty of Medicine, Menoufia University, Shebin ElKoum-Menoufia, Egypt; Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Howaida S Ali
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt; Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Amany Refaat Mahmoud
- Department of Human Anatomy and Embryology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Zuhair M Mohammedsaleh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Tarek Hamdy Abd-Elhamid
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
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Zhu L, Zhu C, Cao S, Zhang Q. Helicobacter hepaticus Induce Colitis in Male IL-10 -/- Mice Dependent by Cytolethal Distending Toxin B and via the Activation of Jak/Stat Signaling Pathway. Front Cell Infect Microbiol 2021; 11:616218. [PMID: 33777833 PMCID: PMC7994616 DOI: 10.3389/fcimb.2021.616218] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 02/09/2021] [Indexed: 01/08/2023] Open
Abstract
It has been well documented that cytolethal distending toxin (CDT) from Helicobacter hepaticus (H. hepaticus), Campylobacter jejuni (C. jejuni) and other Gram-negative intestinal pathogens is linked to the inflammatory bowel disease (IBD). However, the mechanisms underlying the progression of H. hepaticus induced colitis remains unclear. In this study, male B6.129P2-IL10tm1Cgn/J mice were infected by H. hepaticus and ΔCdtB H. hepaticus for 6, 12, 18, and 24 weeks. Histopathology, H. hepaticus colonization levels, expression of inflammatory cytokines, signaling pathways, and content of NO in proximal colon were examined. We found that Cytolethal distending toxin subunit B (CdtB) deletion had no influence on colonization ability of H. hepaticus in colon of B6.129P2-IL10tm1cgn/J mice, and there was no significant difference in abundance of colonic H. hepaticus over infection duration. H. hepaticus aggravated rectocele and proximal colonic inflammation, especially at 24 WPI, while ΔCdtB H. hepaticus could not cause significant symptom. Furthermore, mRNA levels of Il-6, Tnf-α, Il-1β, and iNOS significantly increased in the proximal colon of H. hepaticus-infected mice compared to ΔCdtB H. hepaticus infected group from 12 WPI to 24 WPI. In addition, the elevated content of NO and activated Stat3 and Jak2 in colon were observed in H. hepaticus infected mice. These data demonstrated that CdtB promote colitis development in male B6.129P2-IL10tm1Cgn/J mice by induction of inflammatory response and activation of Jak-Stat signaling pathway.
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Affiliation(s)
- Liqi Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Chen Zhu
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Shuyang Cao
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Quan Zhang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
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29
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Cui Y, Han C, Li S, Geng Y, Wei Y, Shi W, Bao Y. High-throughput sequencing-based analysis of the intestinal microbiota of broiler chickens fed with compound small peptides of Chinese medicine. Poult Sci 2021; 100:100897. [PMID: 33518313 PMCID: PMC7936118 DOI: 10.1016/j.psj.2020.11.066] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
The objective of this study was to determine the effects of compound small peptides of Chinese medicine (CSPCM) on the intestinal microbiota of broilers. A total of thirty-six 1-day-old Arbor Acres broilers were assigned to 6 dietary treatments that include 250, 500, and 750 g/T of CSPCM in feed, 100 g/T of Bacillus subtilis and Clostridium butyricum in feed, and 100 g/T of 50,000 IU xylanase in feed. Each treatment had 2 replicates with 2 cages (3 birds per cage). The jejunal digesta samples were collected from chickens at 42 d. Operational taxonomic unit analysis showed that adding CSPCM at a concentration of 750 g/T of feed can increase the number of operational taxonomic unit samples than other groups. Compared with the control group, adding 250 g/T of CSPCM of feed can improve content of Lactobacillus, Cupriavidus, Ochrobactrum, Candidatus_Arthromitus, Acinetobacter, and Sphingomonas. Adding 500 g/T of CSPCM in feed resulted in varying degrees of improvement in Candidatus_Arthromitus, Acinetobacter, and Sphingomonas. Adding 750 g/T of CSPCM in feed can increase the content of Lactobacillus and Candidatus_Arthromitus. In PICRUSt function prediction analysis, CSPCM acts on the body by creating an environment suitable for the growth of beneficial bacteria. Adding 250 g/T of CSPCM in feed can improve amino acid metabolism, endocrine system function, membrane transport, and cell mobility function. Adding 500 g/T of CSPCM in feed can improve replication and repair and membrane transport function. Adding 750 g/T of CSPCM in feed can increase carbohydrate metabolism, replication and repair, and membrane transport function. Adding B. subtilis and C. butyricum in feed increased replication and repair and membrane transport function. Adding xylanase in feed increased membrane transport function. In conclusion, this study demonstrated that dietary supplementation of CSPCM to broiler diets increased beneficial flora content, metabolism of carbohydrates, amino acid metabolism, the deposition of proteins, renewal of bacteria, and maintenance of vigorous vitality. Among the 3 additive quantities of 250 g/t, 500 g/t, and 750 g/t of CSPCM in feed, 250 g/t of CSPCM improved parameters that are necessary for improved growth and production.
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Affiliation(s)
- YuQing Cui
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Chao Han
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - ShuYing Li
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - YuMeng Geng
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - YuanYuan Wei
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - WanYu Shi
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China; Hebei Provincial Engineering Center for Chinese Veterinary Herbal Medicine, Baoding, China.
| | - YongZhan Bao
- Institute of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China; Hebei Provincial Engineering Center for Chinese Veterinary Herbal Medicine, Baoding, China
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30
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Modeling drug response using network-based personalized treatment prediction (NetPTP) with applications to inflammatory bowel disease. PLoS Comput Biol 2021; 17:e1008631. [PMID: 33544718 PMCID: PMC7891788 DOI: 10.1371/journal.pcbi.1008631] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 02/18/2021] [Accepted: 12/14/2020] [Indexed: 12/15/2022] Open
Abstract
For many prevalent complex diseases, treatment regimens are frequently ineffective. For example, despite multiple available immunomodulators and immunosuppressants, inflammatory bowel disease (IBD) remains difficult to treat. Heterogeneity in the disease across patients makes it challenging to select the optimal treatment regimens, and some patients do not respond to any of the existing treatment choices. Drug repurposing strategies for IBD have had limited clinical success and have not typically offered individualized patient-level treatment recommendations. In this work, we present NetPTP, a Network-based Personalized Treatment Prediction framework which models measured drug effects from gene expression data and applies them to patient samples to generate personalized ranked treatment lists. To accomplish this, we combine publicly available network, drug target, and drug effect data to generate treatment rankings using patient data. These ranked lists can then be used to prioritize existing treatments and discover new therapies for individual patients. We demonstrate how NetPTP captures and models drug effects, and we apply our framework to individual IBD samples to provide novel insights into IBD treatment. Offering personalized treatment results is an important tenant of precision medicine, particularly in complex diseases which have high variability in disease manifestation and treatment response. We have developed a novel framework, NetPTP (Network-based Personalized Treatment Prediction), for making personalized drug ranking lists for patient samples. Our method uses networks to model drug effects from gene expression data and applies these captured effects to individual samples to produce tailored drug treatment rankings. We applied NetPTP to inflammatory bowel disease, yielding insights into the treatment of this particular disease. Our method is modular and generalizable, and thus can be applied to other diseases that could benefit from a personalized treatment approach.
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31
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Sarangdhar M, Yacyshyn MB, Gruenzel AR, Engevik MA, Harris NL, Aronow BJ, Yacyshyn BR. Therapeutic Opportunities for Intestinal Angioectasia- Targeting PPARγ and Oxidative Stress. Clin Transl Sci 2020; 14:518-528. [PMID: 33048460 PMCID: PMC7993272 DOI: 10.1111/cts.12899] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 08/30/2020] [Indexed: 01/22/2023] Open
Abstract
Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.
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Affiliation(s)
- Mayur Sarangdhar
- Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Mary B Yacyshyn
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Andrew R Gruenzel
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Department of Anesthesiology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Melinda A Engevik
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA.,Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
| | - Nathaniel L Harris
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Bruce J Aronow
- Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Bruce R Yacyshyn
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA.,Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA
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32
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Oral delivery of folate-targeted resveratrol-loaded nanoparticles for inflammatory bowel disease therapy in rats. Life Sci 2020; 262:118555. [PMID: 33035579 DOI: 10.1016/j.lfs.2020.118555] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 01/05/2023]
Abstract
AIMS In the current study, resveratrol-loaded PLGA nanoparticles targeted with folate were developed in order to protect resveratrol from fast degradation, modify its pharmacokinetics and increase its intestinal permeation. Then, the therapeutic efficacy of the prepared system was evaluated in suppression of colon inflammation on TNBS-induced colitis model. MAIN METHODS In this regard, resveratrol was encapsulated in PLGA and FA-conjugated PLGA in order to prepare non-targeted (PLGA-RSV) and targeted (PLGA-FA-RSV) platforms, respectively. KEY FINDINGS Obtained results demonstrated that the prepared formulations encapsulated the resveratrol with high encapsulation efficiency of 90.7% ± 5.1% for PLGA-RSV and 59.1% ± 3.3% for PLGA-FA-RSV. In vitro release experiment showed that the prepared formulations were capable of retaining good amount of resveratrol under the simulated gastric condition (HCl 0.1 N, pH 1.2), while significant amount of resveratrol was released under simulated intestinal condition (PBS, pH 7.4). The trans-well permeability rates through Caco-2 monolayer during 180 min, was determined to be 4.5%, 61% and 99% for resveratrol, PLGA-RSV and PLGA-FA-RSV respectively. The pathological analysis of the rat intestinal sections (hematoxylin & eosin staining) at 7th day post-TNBS colonic inflammation induction illustrated that the oral administrations of FA-PLGA-RSV and PLGA-RSV were able to significantly inhibit the inflammation and reduce neutrophil and lymphocytes accumulation. It is worth noting that the folate-targeted system demonstrated highest efficacy in suppressing colon inflammation. SIGNIFICANCE It could be concluded that the encapsulation of resveratrol into biodegradable folate-targeted PLGA nanoparticles could introduce a potent platform in suppressing colonic inflammation thus offering a great capability for clinical translation.
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33
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Andrighetti T, Bohar B, Lemke N, Sudhakar P, Korcsmaros T. MicrobioLink: An Integrated Computational Pipeline to Infer Functional Effects of Microbiome-Host Interactions. Cells 2020; 9:cells9051278. [PMID: 32455748 PMCID: PMC7291277 DOI: 10.3390/cells9051278] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 02/07/2023] Open
Abstract
Microbiome–host interactions play significant roles in health and in various diseases including autoimmune disorders. Uncovering these inter-kingdom cross-talks propels our understanding of disease pathogenesis and provides useful leads on potential therapeutic targets. Despite the biological significance of microbe–host interactions, there is a big gap in understanding the downstream effects of these interactions on host processes. Computational methods are expected to fill this gap by generating, integrating, and prioritizing predictions—as experimental detection remains challenging due to feasibility issues. Here, we present MicrobioLink, a computational pipeline to integrate predicted interactions between microbial and host proteins together with host molecular networks. Using the concept of network diffusion, MicrobioLink can analyse how microbial proteins in a certain context are influencing cellular processes by modulating gene or protein expression. We demonstrated the applicability of the pipeline using a case study. We used gut metaproteomic data from Crohn’s disease patients and healthy controls to uncover the mechanisms by which the microbial proteins can modulate host genes which belong to biological processes implicated in disease pathogenesis. MicrobioLink, which is agnostic of the microbial protein sources (bacterial, viral, etc.), is freely available on GitHub.
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Affiliation(s)
- Tahila Andrighetti
- Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK; (T.A.); (B.B.)
- Institute of Biosciences, São Paulo University (UNESP), Botucatu 18618-689, SP, Brazil;
| | - Balazs Bohar
- Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK; (T.A.); (B.B.)
- Department of Genetics, Eötvös Loránd University, Budapest 1117, Hungary
| | - Ney Lemke
- Institute of Biosciences, São Paulo University (UNESP), Botucatu 18618-689, SP, Brazil;
| | - Padhmanand Sudhakar
- Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK; (T.A.); (B.B.)
- Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven BE-3000, Leuven, Belgium
- Correspondence: (T.K.); (P.S.)
| | - Tamas Korcsmaros
- Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK; (T.A.); (B.B.)
- Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
- Correspondence: (T.K.); (P.S.)
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34
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Muller M, Hansmannel F, Arnone D, Choukour M, Ndiaye NC, Kokten T, Houlgatte R, Peyrin-Biroulet L. Genomic and molecular alterations in human inflammatory bowel disease-associated colorectal cancer. United European Gastroenterol J 2020; 8:675-684. [PMID: 32268844 DOI: 10.1177/2050640620919254] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Patients with inflammatory bowel disease are at increased risk of colorectal cancer, which has worse prognosis than sporadic colorectal cancer. Until recently, understanding of pathogenesis in inflammatory bowel disease-associated colorectal cancer was restricted to the demonstration of chromosomic/microsatellite instabilities and aneuploidy. The advance of high-throughput sequencing technologies has highlighted the complexity of the pathobiology and revealed recurrently mutated genes involved in the RTK/RAS, PI3K, WNT, and TGFβ pathways, leading to potentially new targetable mutations. Moreover, alterations of mitochondrial DNA and the dysregulation of non-coding sequences have also been described, as well as several epigenetic modifications. Although recent studies have brought new insights into pathobiology and raised the prospect of innovative therapeutic approaches, the understanding of colorectal carcinogenesis in inflammatory bowel disease and how it differs from sporadic colorectal cancer remains not fully elucidated. Further studies are required to better understand the pathogenesis and molecular alterations leading to human inflammatory bowel disease-associated colorectal cancer.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France
| | - Franck Hansmannel
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Djesia Arnone
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Myriam Choukour
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France
| | - Ndeye Coumba Ndiaye
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Tunay Kokten
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Rémi Houlgatte
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France.,Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
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35
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Li X, Li M, Zheng R, Chen X, Xiang J, Wu FX, Wang J. Evaluation of Pathway Activation for a Single Sample Toward Inflammatory Bowel Disease Classification. Front Genet 2020; 10:1401. [PMID: 32117426 PMCID: PMC7013001 DOI: 10.3389/fgene.2019.01401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/23/2019] [Indexed: 12/25/2022] Open
Abstract
Since similar complex diseases are much alike in clinical symptoms, patients are easily misdiagnosed and mistreated. It is crucial to accurately predict the disease status and identify markers with high sensitivity and specificity for classifying similar complex diseases. Many approaches incorporating network information have been put forward to predict outcomes, but they are not robust because of their low reproducibility. Several pathway-based methods are robust and functionally interpretable. However, few methods characterize the disease-specific states of single samples from the perspective of pathways. In this study, we propose a novel framework, Pathway Activation for Single Sample (PASS), which utilizes the pathway information in a single sample way to better recognize the differences between two similar complex diseases. PASS can mainly be divided into two parts: for each pathway, the extent of perturbation of edges and the statistic difference of genes caused by a single disease sample are quantified; then, a novel method, named as an AUCpath, is applied to evaluate the pathway activation for single samples from the perspective of genes and their interactions. We have applied PASS to two main types of inflammatory bowel disease (IBD) and widely verified the characteristics of PASS. For a new patient, PASS features can be used as the indicators or potential pathway biomarkers to precisely diagnose complex diseases, discover significant features with interpretability and explore changes in the biological mechanisms of diseases.
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Affiliation(s)
- Xingyi Li
- School of Computer Science and Engineering, Central South University, Changsha, China
| | - Min Li
- School of Computer Science and Engineering, Central South University, Changsha, China
| | - Ruiqing Zheng
- School of Computer Science and Engineering, Central South University, Changsha, China
| | - Xiang Chen
- School of Computer Science and Engineering, Central South University, Changsha, China
| | - Ju Xiang
- School of Computer Science and Engineering, Central South University, Changsha, China.,Neuroscience Research Center & Department of Basic Medical Sciences, Changsha Medical University, Changsha, China
| | - Fang-Xiang Wu
- Department of Mechanical Engineering and Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, SK, Canada
| | - Jianxin Wang
- School of Computer Science and Engineering, Central South University, Changsha, China
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36
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Li X, Lee EJ, Gawel DR, Lilja S, Schäfer S, Zhang H, Benson M. Meta-Analysis of Expression Profiling Data Indicates Need for Combinatorial Biomarkers in Pediatric Ulcerative Colitis. J Immunol Res 2020; 2020:8279619. [PMID: 32411805 PMCID: PMC7204128 DOI: 10.1155/2020/8279619] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/02/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Unbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative colitis (UC). However, clinical translation has been proven difficult. Here, we hypothesized that one reason could be differences between inflammatory responses in an inflamed gut and in peripheral blood cells. METHODS We performed meta-analysis of gene expression microarray data from intestinal biopsies and whole blood cells (WBC) from pediatric patients with UC and healthy controls in order to identify overlapping pathways, predicted upstream regulators, and potential biomarkers. RESULTS Analyses of profiling datasets from colonic biopsies showed good agreement between different studies regarding pathways and predicted upstream regulators. The most activated predicted upstream regulators included TNF, which is known to have a key pathogenic and therapeutic role in pediatric UC. Despite this, the expression levels of TNF were increased in neither colonic biopsies nor WBC. A potential explanation was increased expression of TNFR2, one of the membrane-bound receptors of TNF in the inflamed colon. Further analyses showed a similar pattern of complex relations between the expression levels of the regulators and their receptors. We also found limited overlap between pathways and predicted upstream regulators in colonic biopsies and WBC. An extended search including all differentially expressed genes that overlapped between colonic biopsies and WBC only resulted in identification of three potential biomarkers involved in the regulation of intestinal inflammation. However, two had been previously proposed in adult inflammatory bowel diseases (IBD), namely, MMP9 and PROK2. CONCLUSIONS Our findings indicate that biomarker identification in pediatric UC is complicated by the involvement of multiple pathways, each of which includes many different types of genes in the blood or inflamed intestine. Therefore, further studies for identification of combinatorial biomarkers are warranted. Our study may provide candidate biomarkers for such studies.
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Affiliation(s)
- Xinxiu Li
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Eun Jung Lee
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Danuta R. Gawel
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Sandra Lilja
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Samuel Schäfer
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Huan Zhang
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children's Hospital, Linköping University Hospital, Sweden
| | - Mikael Benson
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children's Hospital, Linköping University Hospital, Sweden
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37
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Jin H, Guo J, Liu J, Lyu B, Foreman RD, Shi Z, Yin J, Chen JDZ. Autonomically mediated anti-inflammatory effects of electrical stimulation at acupoints in a rodent model of colonic inflammation. Neurogastroenterol Motil 2019; 31:e13615. [PMID: 31117153 DOI: 10.1111/nmo.13615] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/27/2019] [Accepted: 04/16/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Acupuncture has been widely accepted for treatments of many diseases. This study was performed to determine effects and mechanisms of electroacupuncture (EA) by chronically implanted electrodes at acupoint ST36 on colonic inflammation induced by TNBS in rats. METHODS After intrarectal administration of TNBS, the rats were treated with sham-EA, EA1/EA2 (two sets of parameters) for 3 weeks. Disease activity index (DAI), macroscopic and microscopic lesions, plasma levels of TNF-α, IL-1β and IL-6 were observed as evaluation of inflammatory responses. The autonomic function was assessed by analysis of the heart rate variability. RESULTS (a) Vagal activity was significantly increased with both acute and chronic EA1/EA2; (b) DAI was significantly decreased with both chronic EA1 and EA2, and EA2 was more potent than EA1 (P < 0.05); (c) The macroscopic score was 6.4 ± 0.6 with sham-EA and reduced to 4.9 ± 0.1 with EA1 (P < 0.05) and 4.0 ± 0.2 with EA2 (all P < 0.05). The histological score was 4.05 ± 0.58 with sham-EA and remained unchanged (3.71 ± 0.28) with EA1 (P > 0.05) but reduced to 3.0 ± 0.3 with EA2 (P < 0.01); (d) The plasma levels of TNF-α, IL-1β and IL-6 were significantly decreased with EA2. CONCLUSIONS Electrical stimulation at ST36 improves colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines via the autonomic mechanism.
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Affiliation(s)
- Haifeng Jin
- Veterans Affairs Medical Center, Veterans Research and Education Foundation, Oklahoma City, Oklahoma.,The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, China.,University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.,Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Jie Guo
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland.,The First Hospital of Wuhan, Wuhan, China
| | - Jiemin Liu
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.,Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland.,Guizhou Provincial People's Hospital, Guizhou, Guiyang, China
| | - Bin Lyu
- The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, China
| | - Robert D Foreman
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Zhaohong Shi
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland.,The First Hospital of Wuhan, Wuhan, China
| | - Jieyun Yin
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Jiande D Z Chen
- Veterans Affairs Medical Center, Veterans Research and Education Foundation, Oklahoma City, Oklahoma.,Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
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38
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Dovrolis N, Filidou E, Kolios G. Systems biology in inflammatory bowel diseases: on the way to precision medicine. Ann Gastroenterol 2019; 32:233-246. [PMID: 31040620 PMCID: PMC6479645 DOI: 10.20524/aog.2019.0373] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 02/25/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic and recurrent inflammatory disorders of the gastrointestinal tract. The elucidation of their etiopathology requires complex and multiple approaches. Systems biology has come to fulfill this need in approaching the pathogenetic mechanisms of IBD and its etiopathology, in a comprehensive way, by combining data from different scientific sources. In combination with bioinformatics and network medicine, it uses principles from computer science, mathematics, physics, chemistry, biology, medicine and computational tools to achieve its purposes. Systems biology utilizes scientific sources that provide data from omics studies (e.g., genomics, transcriptomics, etc.) and clinical observations, whose combined analysis leads to network formation and ultimately to a more integrative image of disease etiopathogenesis. In this review, we analyze the current literature on the methods and the tools utilized by systems biology in order to cover an innovative and exciting field: IBD-omics.
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Affiliation(s)
- Nikolas Dovrolis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Eirini Filidou
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- Correspondence to: Prof. George Kolios, MD PhD, Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Dragana, Alexandroupolis, 68100, Greece, e-mail:
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Haberman Y, Karns R, Dexheimer PJ, Schirmer M, Somekh J, Jurickova I, Braun T, Novak E, Bauman L, Collins MH, Mo A, Rosen MJ, Bonkowski E, Gotman N, Marquis A, Nistel M, Rufo PA, Baker SS, Sauer CG, Markowitz J, Pfefferkorn MD, Rosh JR, Boyle BM, Mack DR, Baldassano RN, Shah S, Leleiko NS, Heyman MB, Grifiths AM, Patel AS, Noe JD, Aronow BJ, Kugathasan S, Walters TD, Gibson G, Thomas SD, Mollen K, Shen-Orr S, Huttenhower C, Xavier RJ, Hyams JS, Denson LA. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun 2019; 10:38. [PMID: 30604764 PMCID: PMC6318335 DOI: 10.1038/s41467-018-07841-3] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/28/2018] [Indexed: 02/07/2023] Open
Abstract
Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.
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Affiliation(s)
- Yael Haberman
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
- Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, 5265601, Israel
| | - Rebekah Karns
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Phillip J Dexheimer
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Melanie Schirmer
- Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA
| | - Judith Somekh
- Faculty of Medicine, Technion, Haifa, 3109601, Israel
- Department of Information Systems, University of Haifa, Haifa, 3498838, Israel
| | - Ingrid Jurickova
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Tzipi Braun
- Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, 5265601, Israel
| | - Elizabeth Novak
- Children's Hospital of Pittsburgh, Pittsburgh, 15224, PA, USA
| | - Laura Bauman
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
- Department of Pediatrics, University of California at San Diego, La Jolla, 92162, CA, USA
| | - Margaret H Collins
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Angela Mo
- Georgia Institute of Technology, Atlanta, 30332, GA, USA
| | - Michael J Rosen
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Erin Bonkowski
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Nathan Gotman
- Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA
| | - Alison Marquis
- Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA
| | - Mason Nistel
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Paul A Rufo
- Harvard-Children's Hospital Boston, Boston, 02115, MA, USA
| | - Susan S Baker
- Women & Children's Hospital of Buffalo WCHOB, Buffalo, 14222, NY, USA
| | | | - James Markowitz
- Cohen Children's Medical Center of New York, 11040, New Hyde Park, NY, USA
| | | | - Joel R Rosh
- Goryeb Children's Hospital-Atlantic Health, Morristown, 07960, NJ, USA
| | | | - David R Mack
- Children's Hospital of East Ontario, Ottawa, Ontario, K1P 1J1, Canada
| | | | - Sapana Shah
- Children's Hospital of Pittsburgh of UPMC, Pittsburgh, 15224, PA, USA
| | | | - Melvin B Heyman
- University of California at San Francisco, San Francisco, 94143, CA, USA
| | | | | | - Joshua D Noe
- Medical College of Wisconsin, Milwaukee, 53226, WI, USA
| | - Bruce J Aronow
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | | | | | - Greg Gibson
- Georgia Institute of Technology, Atlanta, 30332, GA, USA
| | - Sonia Davis Thomas
- Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA
- RTI International, Research Triangle Park, 27709, NC, USA
| | - Kevin Mollen
- Children's Hospital of Pittsburgh, Pittsburgh, 15224, PA, USA
| | - Shai Shen-Orr
- Faculty of Medicine, Technion, Haifa, 3109601, Israel
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA
- Harvard School of Public Health, Boston, 02115, MA, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA
- Massachusetts General Hospital, Harvard Medical School, Boston, 02114, MA, USA
| | - Jeffrey S Hyams
- Connecticut Children's Medical Center, Hartford, 06106, CT, USA
| | - Lee A Denson
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA.
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Transcriptome meta-analysis identifies immune signature comprising of RNA binding proteins in ulcerative colitis patients. Cell Immunol 2018; 334:42-48. [PMID: 30327138 DOI: 10.1016/j.cellimm.2018.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 09/01/2018] [Accepted: 09/16/2018] [Indexed: 12/14/2022]
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Disdier C, Chen X, Kim JE, Threlkeld SW, Stonestreet BS. Anti-Cytokine Therapy to Attenuate Ischemic-Reperfusion Associated Brain Injury in the Perinatal Period. Brain Sci 2018; 8:E101. [PMID: 29875342 PMCID: PMC6025309 DOI: 10.3390/brainsci8060101] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 05/31/2018] [Accepted: 06/05/2018] [Indexed: 12/26/2022] Open
Abstract
Perinatal brain injury is a major cause of morbidity and long-standing disability in newborns. Hypothermia is the only therapy approved to attenuate brain injury in the newborn. However, this treatment is unfortunately only partially neuroprotective and can only be used to treat hypoxic-ischemic encephalopathy in full term infants. Therefore, there is an urgent need for adjunctive therapeutic strategies. Post-ischemic neuro-inflammation is a crucial contributor to the evolution of brain injury in neonates and constitutes a promising therapeutic target. Recently, we demonstrated encouraging neuroprotective capacities of anti-cytokine monoclonal antibodies (mAbs) in an ischemic-reperfusion (I/R) model of brain injury in the ovine fetus. The purpose of this review is to summarize the current knowledge regarding the inflammatory response in the perinatal sheep brain after I/R injury and to review our recent findings regarding the beneficial effects of treatment with anti-cytokine mAbs.
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Affiliation(s)
- Clémence Disdier
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
| | - Xiaodi Chen
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
| | - Jeong-Eun Kim
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
| | | | - Barbara S Stonestreet
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
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Xie D, Zhang Y, Qu H. Crucial genes of inflammatory bowel diseases explored by gene expression profiling analysis. Scand J Gastroenterol 2018; 53:685-691. [PMID: 29909694 DOI: 10.1080/00365521.2018.1461923] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES This study aimed to uncover new potential genes associated with the inflammatory bowel diseases (IBDs). MATERIALS AND METHODS The datasets GSE36807 and GSE9686 were obtained from Gene Expression Omnibus (GEO). Totally, 24 Crohn's disease (CD) samples, 20 ulcerative colitis (UC) samples and 15 healthy controls in the two datasets were used for our analysis. The differentially expressed genes (DEGs) were identified by limma package. Then, co-expression network was constructed by weighted gene correlation network analysis (WGCNA) package, and co-expression network modules were obtained via clustering method. The top 100 genes with the highest connectivity degrees were selected to construct a new co-expression network (CEN). Besides, pathway enrichment analysis for the genes in identified modules was conducted with the clusterProfiler package in R. RESULTS Totally, 302 and 2276 DEGs were respectively identified in CD and UC samples, and 291 ones were both differentially expressed in the two subtypes. Five modules were identified from the CEN. In the new CEN consisted of the top 100 genes with the highest connectivity degrees, the up-regulated DEGs all belonged to module 5, and the down-regulated ones all belonged to module 1. Furthermore, pathway enrichment analysis showed that some DEGs were related to primary immunodeficiency (e.g., CD4, CD3D and CD40LG), complement and coagulation cascades (e.g., C2, C1QB and C7) and nitrogen metabolism (e.g., CA1, CA12 and CA2). CONCLUSION The DEGs correlated with primary immunodeficiency, complement and coagulation cascades and nitrogen metabolism might be important for the development of IBD.
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Affiliation(s)
- Dehong Xie
- a Department of General Surgery , Beijing Chao-Yang Hospital, Capital University of Medical Sciences , Beijing , China
| | - Yudong Zhang
- a Department of General Surgery , Beijing Chao-Yang Hospital, Capital University of Medical Sciences , Beijing , China
| | - Hao Qu
- a Department of General Surgery , Beijing Chao-Yang Hospital, Capital University of Medical Sciences , Beijing , China
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Battu S, Afroz S, Giddaluru J, Naz S, Huang W, Khumukcham SS, Khan RA, Bhat SY, Qureshi IA, Manavathi B, Khan AA, August A, Hasnain SE, Khan N. Amino acid starvation sensing dampens IL-1β production by activating riboclustering and autophagy. PLoS Biol 2018; 16:e2005317. [PMID: 29621237 PMCID: PMC5903674 DOI: 10.1371/journal.pbio.2005317] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/17/2018] [Accepted: 03/05/2018] [Indexed: 11/22/2022] Open
Abstract
Activation of the amino acid starvation response (AAR) increases lifespan and acute stress resistance as well as regulates inflammation. However, the underlying mechanisms remain unclear. Here, we show that activation of AAR pharmacologically by Halofuginone (HF) significantly inhibits production of the proinflammatory cytokine interleukin 1β (IL-1β) and provides protection from intestinal inflammation in mice. HF inhibits IL-1β through general control nonderepressible 2 kinase (GCN2)–dependent activation of the cytoprotective integrated stress response (ISR) pathway, resulting in rerouting of IL-1β mRNA from translationally active polysomes to inactive ribocluster complexes—such as stress granules (SGs)—via recruitment of RNA-binding proteins (RBPs) T cell–restricted intracellular antigen-1(TIA-1)/TIA-1–related (TIAR), which are further cleared through induction of autophagy. GCN2 ablation resulted in reduced autophagy and SG formation, which is inversely correlated with IL-1β production. Furthermore, HF diminishes inflammasome activation through suppression of reactive oxygen species (ROS) production. Our study unveils a novel mechanism by which IL-1β is regulated by AAR and further suggests that administration of HF might offer an effective therapeutic intervention against inflammatory diseases. Reduced intake of food (also known as dietary restriction) without malnutrition has been shown to benefit health in humans and animals, including an increase in life expectancy, metabolic fitness, and resistance to acute stress. Recent studies have attributed the benefits associated with dietary restriction to the reduced intake of amino acids. However, the underlying mechanisms through which amino acid restriction regulates various homeostatic processes are poorly defined. Here, we show that activation of amino acid starvation response (AAR) by the small molecule Halofuginone (HF) results in a significant inhibition of production of interleukin 1β (IL-1β), a proinflammatory mediator. We find that AAR provides protection from intestinal inflammation–associated pathology in a mouse model of colitis through a novel mechanism involving the formation of riboclusters (groups of RNA-binding proteins (RBPs) and stalled mRNA complexes) and autophagy. We further show that HF-mediated inhibition in IL-1β production is dependent on general control nonderepressible 2 kinase (GCN2), an amino acid deprivation sensor. This study provides the mechanisms regulating AAR-induced benefits in the context of inflammation and further suggests that the administration of HF might offer an effective therapeutic intervention against inflammatory diseases in mammals.
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Affiliation(s)
- Srikanth Battu
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Sumbul Afroz
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Jeevan Giddaluru
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Saima Naz
- Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Weishan Huang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | | | - Rafiq Ahmad Khan
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Saleem Yousuf Bhat
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Insaf Ahmed Qureshi
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Bramanandam Manavathi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Aleem Ahmed Khan
- Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Avery August
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Seyed Ehtesham Hasnain
- JH-Institute of Molecular Medicine, Jamia Hamdard University, Hamdard Nagar, New Delhi, India
- Molecular Infection and Functional Biology Laboratory, Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India
- Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India
| | - Nooruddin Khan
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
- * E-mail:
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Savić Mlakar A, Hojsak I, Jergović M, Čimić S, Bendelja K. Pediatric Crohn disease is characterized by Th1 in the terminal ileum and Th1/Th17 immune response in the colon. Eur J Pediatr 2018; 177:611-616. [PMID: 29397417 DOI: 10.1007/s00431-017-3076-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 12/15/2017] [Accepted: 12/18/2017] [Indexed: 12/27/2022]
Abstract
UNLABELLED The aim of this study was to assess the expression of inflammatory mediators in the affected terminal ileum and colon in pediatric Crohn disease (CD) patients with different stages of disease. Additionally, we assessed the role of efflux transporters in disease pathogenesis and their correlation with immune response. The study included 26 CD patients (10 newly diagnosed (CD-new), 8 CD-treated, and 8 CD-remission) and 15 control subjects. The terminal ileum IFN-γ, IL-6, and IL-1β were elevated in CD-new, while in the colon, the IFN-γ, IL-17A, and IL-6 were elevated in both CD-new and CD-treated subgroups. SOCS3 expression was elevated in both subgroups with active inflammation at both ileum and colon, while SOCS1 was elevated only in CD-new ileum and CD-treated colon. MDR1 expression in ileum was reduced in both subgroups with active inflammation, while BCRP was reduced only in CD-new subgroup. CONCLUSION New onset pediatric CD is characterized by Th1 response in ileum and mixed Th1/Th17 response in the colon, with elevated expressions of innate IL-6 and IL-1β. SOCS1/SOCS3 expressions seem to be insufficient for the regulation of the immune response. The reduction in MDR1 expression points to its role in the disease pathogenesis. What is Known: • CD is characterized by an aberrant immune response What is New: • The immune response in new onset pediatric CD differs between terminal ileum and colon • MDR1 expression is downregulated at both terminal ileum and colon irrespective of the disease activity.
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Affiliation(s)
- Ana Savić Mlakar
- Center for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, 10000, Zagreb, Croatia.
| | - Iva Hojsak
- Referral Center for Pediatric Gastroenterology and Nutrition, Children's Hospital Zagreb, University of Zagreb, School of Medicine, Klaićeva 16, Zagreb, Croatia
| | - Mladen Jergović
- Center for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, 10000, Zagreb, Croatia
| | - Samir Čimić
- School of Dental Medicine, University of Zagreb, Ivana Gundulića 5, Zagreb, Croatia
| | - Krešo Bendelja
- Center for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Rockefellerova 10, 10000, Zagreb, Croatia
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Han L, Maciejewski M, Brockel C, Gordon W, Snapper SB, Korzenik JR, Afzelius L, Altman RB. A probabilistic pathway score (PROPS) for classification with applications to inflammatory bowel disease. Bioinformatics 2018; 34:985-993. [PMID: 29048458 PMCID: PMC5860179 DOI: 10.1093/bioinformatics/btx651] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/25/2017] [Accepted: 10/17/2017] [Indexed: 12/15/2022] Open
Abstract
Summary Gene-based supervised machine learning classification models have been widely used to differentiate disease states, predict disease progression and determine effective treatment options. However, many of these classifiers are sensitive to noise and frequently do not replicate in external validation sets. For complex, heterogeneous diseases, these classifiers are further limited by being unable to capture varying combinations of genes that lead to the same phenotype. Pathway-based classification can overcome these challenges by using robust, aggregate features to represent biological mechanisms. In this work, we developed a novel pathway-based approach, PRObabilistic Pathway Score, which uses genes to calculate individualized pathway scores for classification. Unlike previous individualized pathway-based classification methods that use gene sets, we incorporate gene interactions using probabilistic graphical models to more accurately represent the underlying biology and achieve better performance. We apply our method to differentiate two similar complex diseases, ulcerative colitis (UC) and Crohn's disease (CD), which are the two main types of inflammatory bowel disease (IBD). Using five IBD datasets, we compare our method against four gene-based and four alternative pathway-based classifiers in distinguishing CD from UC. We demonstrate superior classification performance and provide biological insight into the top pathways separating CD from UC. Availability and Implementation PROPS is available as a R package, which can be downloaded at http://simtk.org/home/props or on Bioconductor. Contact rbaltman@stanford.edu. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Lichy Han
- Biomedical Informatics Training Program, Stanford University, Stanford, CA, USA
| | | | | | - William Gordon
- Inflammation & Immunology, Pfizer Inc., Cambridge, MA, USA
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Joshua R Korzenik
- Department of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Russ B Altman
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Bioengineering, Stanford University, Stanford, CA, USA
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Li F, Li XM, Sheng D, Chen SR, Nie X, Liu Z, Wang D, Zhao Q, Wang Y, Wang Y, Zhou GC. Discovery and preliminary SAR of 14-aryloxy-andrographolide derivatives as antibacterial agents with immunosuppressant activity. RSC Adv 2018; 8:9440-9456. [PMID: 35541862 PMCID: PMC9078697 DOI: 10.1039/c8ra01063c] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 02/19/2018] [Indexed: 01/01/2023] Open
Abstract
Antibacterials (which restore gut flora balance) and immunosuppressants (which correct immune defects) are two important and effective therapeutic agents for the treatment of inflammatory bowel disease (IBD) in clinical use today. Since the structural skeleton of andrographolide, isolated from Andrographis paniculata, has become known as a natural antibiotic with anti-inflammation and heat-clearing and detoxifying properties, 14-aryloxy andrographolide derivatives have been designed, synthesized, and tested for their antibacterial effects on E. coli, S. aureus, and E. faecalis, which are related to IBD. It has been discovered in this study that the andrographolide skeleton is more selective against E. faecalis, the 14-aryloxy group with basicity is important for antibacterial functions, and the 14-(8'-quinolinyloxy) group is a good pharmacophore with antibacterial activity. In addition, we found that 7b1 and 8b1 are good and selective inhibitors of E. faecalis; two 14β-(8'-quinolinyloxy) andrographolide derivatives, 6b17 and 9b, exhibit good activity against E. coli, S. aureus, and E. faecalis. Likewise and importantly, further exploration of immunosuppressant activity for IBD shows that compound 7b1 is a selective inhibitor of the TNF-α/NF-κB signaling pathway, whereas 8b1 is selectively active against the TLR4/NF-κB signaling pathway; moreover, the compounds 6b17 and 9b are active in inhibiting the IL-6/STAT3, TLR4/NF-κB, and TNF-α/NF-κB signaling pathways. Based on these results, we have further focused on the development of dual function inhibitors of IBD as antibacterial and immunosuppressant agents by structural modification of andrographolide.
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Affiliation(s)
- Feng Li
- School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China +86-25-58139415
| | - Xiao-Min Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau Avenida da Universidade, Taipa Macao SAR PR China
| | - Dekuan Sheng
- School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China +86-25-58139415
| | - Shao-Ru Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau Avenida da Universidade, Taipa Macao SAR PR China
| | - Xin Nie
- School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China +86-25-58139415
| | - Zhuyun Liu
- School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China +86-25-58139415
| | - Decai Wang
- School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China +86-25-58139415
| | - Qi Zhao
- Faculty of Health Sciences, University of Macau Avenida da Universidade, Taipa Macao SAR PR China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau Avenida da Universidade, Taipa Macao SAR PR China
| | - Ying Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau Avenida da Universidade, Taipa Macao SAR PR China
| | - Guo-Chun Zhou
- School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China +86-25-58139415
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Han L, Maciejewski M, Brockel C, Afzelius L, Altman RB. Mendelian Disease Associations Reveal Novel Insights into Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:471-481. [PMID: 29462399 PMCID: PMC6037048 DOI: 10.1093/ibd/izx087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Indexed: 12/14/2022]
Abstract
Background Monogenic diseases have been shown to contribute to complex disease risk and may hold new insights into the underlying biological mechanism of Inflammatory Bowel Disease (IBD). Methods We analyzed Mendelian disease associations with IBD using over 55 million patients from the Optum's deidentified electronic health records dataset database. Using the significant Mendelian diseases, we performed pathway enrichment analysis and constructed a model using gene expression datasets to differentiate Crohn's disease (CD), ulcerative colitis (UC), and healthy patient samples. Results We found 50 Mendelian diseases were significantly associated with IBD, with 40 being significantly associated with both CD and UC. Our results for CD replicated those from previous studies. Pathways that were enriched consisted of mainly immune and metabolic processes with a focus on tolerance and oxidative stress. Our 3-way classifier for UC, CD, and healthy samples yielded an accuracy of 72%. Conclusions Mendelian diseases that are significantly associated with IBD may reveal novel insights into the genetic architecture of IBD.
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Affiliation(s)
- Lichy Han
- Biomedical Informatics Training Program, Stanford University, Stanford, CA
| | | | | | | | - Russ B Altman
- Biomedical Informatics Training Program, Stanford University, Stanford, CA
- Department of Genetics, Stanford University, Stanford, CA
- Department of Bioengineering, Stanford University, Stanford, CA
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Zaidi D, Wine E. Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κβ) in Inflammatory Bowel Diseases. Front Pediatr 2018; 6:317. [PMID: 30425977 PMCID: PMC6218406 DOI: 10.3389/fped.2018.00317] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/05/2018] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD), encompassing both Crohn Disease (CD) and ulcerative colitis (UC) are globally prevalent diseases, impacting children of all ages. The hallmark of IBD is a perturbed immune system that leads to continuous inflammation in the gut and challenges optimal treatment. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ), a nuclear transcription factor, plays a major role in gut homeostasis and contributes significantly toward a balanced, homeostatic immune system. Dysregulation in the NF-κβ pathway and factors that regulate it lead to a state of uncontrolled inflammation and altered immunity, as typically observed in IBD. Levels of proinflammatory cytokines that are regulated through NF-κβ are increased in both CD and UC. Genes known to activate NF-κβ, such as, Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Interleukin 23 (IL-23), are associated with IBD. Factors involved in inhibition of NF-κβ, such as A20 and TOLLIP, are also affected in IBD, resulting in failed inflammation suppression/regulation. NOD-2 and A20 have specifically been found to be strongly associated with pediatric IBD. Gut commensals are known to exert anti-inflammatory activities toward NF-κβ and can have a potential role in attenuating inflammation that likely occurs due to microbial dysbiosis in IBD. Failure to terminate/downregulate NF-κβ signaling results in chronic inflammation in IBD. Well-regulated control of inflammation in children with IBD can help better control the disease and suppress immune responses. Better understanding of factors that control NF-κβ can potentially lead toward discovering targeted therapeutic interventions for IBD. Suppression of NF-κβ can be achieved through many modalities including anti-sense oligonucleotides (ASOs), siRNA (small interfering RNA), factors regulating NF-κβ, and microbes. This review focuses on the role of NF-κβ, especially in pediatric IBD, and potential therapeutic venues for attenuating NF-κβ-induced inflammation.
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Affiliation(s)
- Deenaz Zaidi
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.,Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, Canada
| | - Eytan Wine
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.,Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, Canada.,Department of Physiology, University of Alberta, Edmonton, AB, Canada
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Chen Y, Zhou W, Roh T, Estes MK, Kaplan DL. In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS One 2017; 12:e0187880. [PMID: 29186150 PMCID: PMC5706668 DOI: 10.1371/journal.pone.0187880] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/28/2017] [Indexed: 12/30/2022] Open
Abstract
There is a need for functional in vitro 3D human intestine systems that can bridge the gap between conventional cell culture studies and human trials. The successful engineering in vitro of human intestinal tissues relies on the use of the appropriate cell sources, biomimetic scaffolds, and 3D culture conditions to support vital organ functions. We previously established a compartmentalized scaffold consisting of a hollow space within a porous bulk matrix, in which a functional and physiologically relevant intestinal epithelium system was generated using intestinal cell lines. In this study, we adopt the 3D scaffold system for the cultivation of stem cell-derived human small intestinal enteriods (HIEs) to engineer an in vitro 3D model of a nonstransformed human small intestinal epithelium. Characterization of tissue properties revealed a mature HIE-derived epithelium displaying four major terminally differentiated epithelial cell types (enterocytes, Goblet cells, Paneth cells, enteroendocrine cells), with tight junction formation, microvilli polarization, digestive enzyme secretion, and low oxygen tension in the lumen. Moreover, the tissue model demonstrates significant antibacterial responses to E. coli infection, as evidenced by the significant upregulation of genes involved in the innate immune response. Importantly, many of these genes are activated in human patients with inflammatory bowel disease (IBD), implicating the potential application of the 3D stem-cell derived epithelium for the in vitro study of host-microbe-pathogen interplay and IBD pathogenesis.
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Affiliation(s)
- Ying Chen
- Department of Biomedical Engineering, Tufts University, Medford, MA, United States of America
| | - Wenda Zhou
- Department of Biomedical Engineering, Tufts University, Medford, MA, United States of America
| | - Terrence Roh
- Department of Biomedical Engineering, Tufts University, Medford, MA, United States of America
| | - Mary K. Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States of America
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - David L. Kaplan
- Department of Biomedical Engineering, Tufts University, Medford, MA, United States of America
- * E-mail:
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Association of Inflammatory Bowel Disease with Arthritis: Evidence from In Silico Gene Expression Patterns and Network Topological Analysis. Interdiscip Sci 2017; 11:387-396. [DOI: 10.1007/s12539-017-0272-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/02/2017] [Accepted: 11/06/2017] [Indexed: 12/11/2022]
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