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Zeng X, Liu C, Fan J, Zou J, Guo M, Sun G. RNF138 Downregulates Antiviral Innate Immunity by Inhibiting IRF3 Activation. Int J Mol Sci 2023; 24:16110. [PMID: 38003298 PMCID: PMC10671598 DOI: 10.3390/ijms242216110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
A viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induces type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-β induction. The overexpression of RNF138 inhibited the virus-induced activation of IRF3 and the transcription of the IFNB1 gene, whereas the knockout of RNF138 promoted the virus-induced activation of IRF3 and transcription of the IFNB1 gene. We further found that RNF138 promotes the ubiquitination of PTEN and subsequently inhibits PTEN interactions with IRF3, which is essential for the PTEN-mediated nuclear translocation of IRF3, thereby inhibiting IRF3 import into the nucleus. Our findings suggest that RNF138 negatively regulates virus-triggered signaling by inhibiting the interaction of PTEN with IRF3, and these data provide new insights into the molecular mechanisms of cellular antiviral responses.
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Affiliation(s)
- Xianhuang Zeng
- Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (X.Z.); (J.Z.)
| | - Chaozhi Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China;
| | - Jinhao Fan
- School of Ecology and Environment, Tibet University, Lhasa 850000, China;
| | - Jiabin Zou
- Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (X.Z.); (J.Z.)
| | - Mingxiong Guo
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China;
- School of Ecology and Environment, Tibet University, Lhasa 850000, China;
| | - Guihong Sun
- Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (X.Z.); (J.Z.)
- Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China
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2
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Salehi Z, Motlagh Ghoochani BFN, Hasani Nourian Y, Jamalkandi SA, Ghanei M. The controversial effect of smoking and nicotine in SARS-CoV-2 infection. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2023; 19:49. [PMID: 37264452 PMCID: PMC10234254 DOI: 10.1186/s13223-023-00797-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 04/18/2023] [Indexed: 06/03/2023]
Abstract
The effects of nicotine and cigarette smoke in many diseases, notably COVID-19 infection, are being debated more frequently. The current basic data for COVID-19 is increasing and indicating the higher risk of COVID-19 infections in smokers due to the overexpression of corresponding host receptors to viral entry. However, current multi-national epidemiological reports indicate a lower incidence of COVID-19 disease in smokers. Current data indicates that smokers are more susceptible to some diseases and more protective of some other. Interestingly, nicotine is also reported to play a dual role, being both inflammatory and anti-inflammatory. In the present study, we tried to investigate the effect of pure nicotine on various cells involved in COVID-19 infection. We followed an organ-based systematic approach to decipher the effect of nicotine in damaged organs corresponding to COVID-19 pathogenesis (12 related diseases). Considering that the effects of nicotine and cigarette smoke are different from each other, it is necessary to be careful in generalizing the effects of nicotine and cigarette to each other in the conducted researches. The generalization and the undifferentiation of nicotine from smoke is a significant bias. Moreover, different doses of nicotine stimulate different effects (dose-dependent response). In addition to further assessing the role of nicotine in COVID-19 infection and any other cases, a clever assessment of underlying diseases should also be considered to achieve a guideline for health providers and a personalized approach to treatment.
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Affiliation(s)
- Zahra Salehi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Yazdan Hasani Nourian
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sadegh Azimzadeh Jamalkandi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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3
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Cari L, Rosati L, Leoncini G, Lusenti E, Gentili M, Nocentini G, Riccardi C, Migliorati G, Ronchetti S. Association of GILZ with MUC2, TLR2, and TLR4 in Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:ijms24032235. [PMID: 36768553 PMCID: PMC9917296 DOI: 10.3390/ijms24032235] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
Ulcerative colitis (UC) and Crohn's Disease (CD) are chronic relapsing inflammatory diseases that are caused by genetic, environmental, and immune factors. Treatment strategies are currently based on symptomatic control by immunosuppression. The glucocorticoid-induced leucine zipper (GILZ), a mediator of several effects of glucocorticoids, was recently found to be secreted by goblet cells and play a role in inflammatory bowel disease (IBD). This study investigates which genes GILZ is associated with in its role in intestinal barrier functions. We examined datasets from the Gene Expression Omnibus (GEO) and ArrayExpress profiles of the gut of healthy subjects (HSs), as well as UC and CD patients. The human colonic epithelial HT29 cell line was used for in vitro validation experiments. GILZ was significantly correlated with MUC2, TLR2, and TLR4. In particular, an inverse correlation was found between the GILZ and MUC2 in HS and patients with IBD, mostly in those with an active disease. Further, direct pairwise correlations for GILZ/TLR2 and GILZ/TLR4 were found in HSs and UC patients, but not in CD patients. Overall, our results reveal the crosstalk at the transcription level between the GILZ, MUC2, and TLRs in the mucosal barrier through common pathways, and they open up new perspectives in terms of mucosal healing in IBD patients.
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Affiliation(s)
- Luigi Cari
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Lucrezia Rosati
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Giuseppe Leoncini
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milano, Italy
| | - Eleonora Lusenti
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Marco Gentili
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Giuseppe Nocentini
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Carlo Riccardi
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Graziella Migliorati
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
| | - Simona Ronchetti
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
- Correspondence:
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4
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Chen RF, Chen PM, Pan CS, Huang CC, Chiang EPI. Association of metallothionein 2A rs10636 with low mean corpuscular volume (MCV), low mean corpuscular haemoglobin (MCH) in healthy Taiwanese. Sci Rep 2023; 13:1292. [PMID: 36690679 PMCID: PMC9869811 DOI: 10.1038/s41598-022-27304-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 12/29/2022] [Indexed: 01/25/2023] Open
Abstract
Human metallothionein-2A (MT2A) protein participates in metal homeostasis, detoxification, oxidative stress reduction, and immune defense. It decreases heavy metal ions and reactive oxygen species (ROS) during injury of cells and tissues. The single nucleotide polymorphisms at the MT2A gene have been associated in various human diseases including cancer. The current study aimed to elucidate associations between MT2A genotypes with the clinical, biochemical, and molecular characteristics that potentially related to lowered MT2A ex-pression. One hundred and forty-one healthy Taiwanese subjects were enrolled from Changhua Show-Chwan Memorial Hospital. Clinical, biochemical and molecular characteristics including the frequent minor allele SNPs, rs28366003 and rs10636, within the MT2A gene were determined. The genotype distribution of MT2A rs10636 fits the Hardy-Weinberg equilibrium. The significant associations with gradually decline of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were identified with MT2A rs10636 and rs28366003 using analysis of variance (ANOVA) with Tukey's analysis as a post hoc test. We further validated the correlations between the expressions of genes in erythropoiesis, cholesterol synthesis, platelet synthesis, insulin with MT2A using the web-based Gene Expression Profiling Interactive Analysis (GEPIA) databases. The results revealed that hypoxia-inducible factor 1α (HIF-1α), erythropoietin (EPO), lipoprotein lipase (LPL), and lecithin-cholesterol acyltransferase (LCAT) mRNA ex-pression are significantly correlated with MT2A mRNA expression. In conclusion, these results suggested that genetic variations of MT2A rs10636 and rs28366003 might be an important risk factor for erythropoiesis in the Taiwanese general population.
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Affiliation(s)
- Rong-Fu Chen
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan, Republic of China
| | - Po-Ming Chen
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China
- Research Assistant Center, Show-Chwan Memorial Hospital, Changhua, 500, Taiwan, Republic of China
| | - Chau-Shiung Pan
- Department of Neurology, Show-Chwan Memorial Hospital, Changhua, Taiwan, Republic of China
| | - Chieh-Cheng Huang
- Department of Life Science, National Chung Hsing University, Taichung, 40402, Taiwan, Republic of China
- Innovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University, Taichung, 402, Taiwan, Republic of China
| | - En-Pei Isabel Chiang
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China.
- Innovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University, Taichung, 402, Taiwan, Republic of China.
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5
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Lu Y, Huang R, Ying J, Li X, Jiao T, Guo L, Zhou H, Wang H, Tuersuntuoheti A, Liu J, Chen Q, Wang Y, Su L, Guo C, Xu F, Wang Z, Lu Y, Li K, Liang J, Huang Z, Chen X, Yao J, Hu H, Cheng X, Wan Y, Chen X, Zhang N, Miao S, Cai J, Wang L, Liu C, Song W, Zhao H. RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy. Signal Transduct Target Ther 2022; 7:185. [PMID: 35697692 PMCID: PMC9192753 DOI: 10.1038/s41392-022-00985-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 11/25/2022] Open
Abstract
Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138−/− mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.
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Affiliation(s)
- Yalan Lu
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.,Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, 100021, China
| | - Rong Huang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.,National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Jianming Ying
- Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xingchen Li
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Jiao
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Lei Guo
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Haitao Zhou
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Han Wang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Amannisa Tuersuntuoheti
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Jianmei Liu
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qichen Chen
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yanhong Wang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Luying Su
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Changyuan Guo
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fu Xu
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Ziyi Wang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Yan Lu
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Kai Li
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Junbo Liang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiao Chen
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jinjie Yao
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hanjie Hu
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaowen Cheng
- Department of Clinical Laboratory, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China
| | - Yufeng Wan
- Department of Clinical Laboratory, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China
| | - Xinyan Chen
- Department of Clinical Laboratory, the First Affiliated Hospital, Anhui Medical University, Hefei, 230022, China
| | - Ning Zhang
- Wellcome Centre for Anti-Infectives Research (WCAIR), Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Shiying Miao
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Linfang Wang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Changzheng Liu
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Wei Song
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Hong Zhao
- Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. .,Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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6
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Nicolaides S, Vasudevan A, Long T, van Langenberg D. The impact of tobacco smoking on treatment choice and efficacy in inflammatory bowel disease. Intest Res 2021; 19:158-170. [PMID: 33040518 PMCID: PMC8100381 DOI: 10.5217/ir.2020.00008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 12/18/2022] Open
Abstract
Smoking significantly increases the risk of developing and worsens Crohn's disease (CD), yet protects against the development and reduces the severity of ulcerative colitis. It is less clear whether smoking impacts the efficacy of therapeutics in inflammatory bowel disease (IBD). We review the literature regarding the relationship between smoking and the efficacy of medical and surgical therapy in IBD. Smoking is associated with alterations in thiopurine metabolism and may affect time to disease relapse. The outcomes of anti-tumor necrosis factor therapy in active smokers appear neutral with data lacking for newer biologics. Smoking increases the risk of postoperative recurrence in those requiring resection for CD, likely attributable to perturbations of the gut microbiota although further implications of these for disease onset/progression and treatment efficacy remain unclear. Multiple lifestyle and psychosocial confounders are likely under-recognized cofactors in the association between smoking and IBD. Despite the widely promulgated risks associated with cigarette smoking in CD, more incisive data are required to further elucidate the actual relationship between smoking and disease pathways, while accounting for the several negative cofactors prevalent in smokers which cast uncertainty on the magnitude of the direct effect of smoking on disease pathophysiology and the efficacy of therapy.
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Affiliation(s)
- Steven Nicolaides
- Department of Gastroenterology, Eastern Health, Box Hill Hospital, Box Hill, Australia
| | - Abhinav Vasudevan
- Department of Gastroenterology, Eastern Health, Box Hill Hospital, Box Hill, Australia
| | - Tony Long
- Department of Gastroenterology, Eastern Health, Box Hill Hospital, Box Hill, Australia
| | - Daniel van Langenberg
- Department of Gastroenterology, Eastern Health, Box Hill Hospital, Box Hill, Australia
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7
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Santus P, Radovanovic D, Raiteri D, Pini S, Spagnolo G, Maconi G, Rizzi M. The effect of a multidisciplinary approach for smoking cessation in patients with Crohn's disease: Results from an observational cohort study. Tob Induc Dis 2020; 18:29. [PMID: 32336967 PMCID: PMC7177387 DOI: 10.18332/tid/119161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/09/2020] [Accepted: 03/17/2020] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION Cigarette smoking is the most important risk factor for Crohn’s disease (CD). The effectiveness of smoking cessation programs (SCPs) in patients with CD is still poorly understood. METHODS This was a retrospective, observational, single-centre, cohort study of 136 active smokers with mean age 55 years (SD=11), 58% males, including 27 (19.8%) patients with CD who entered the multidisciplinary SCP of the Luigi Sacco University Hospital of Milan from January 2017 through January 2019. A pulmonologist was responsible for the clinical and pharmacological management, while a psychiatrist and a psychologist conducted the counselling and assessed the motivation to quit, anxiety and depression using the Brief Psychiatric Rating Scale (BPRS) and the nicotine dependence with the Fagerström test. Patients were defined as quitters after 12 months. RESULTS Demographic and clinical characteristics, and Fagerström score, did not differ in patients with and without CD. At baseline, patients with CD had a higher BPRS (median: 27, IQR: 22–32; vs 25 and 22–28.5; p=0.03), and a lower motivation to quit score (median: 10, IQR: 9–13; vs 14 and 12–15; p<0.001). After 12 months, the quitting rate of smokers with CD was significantly lower (14.8% vs 36.7%; p<0.022) and the chance of quitting was negatively associated with the baseline BPRS (r=-0.256; p<0.003). Varenicline and nicotine replacement therapy tended to be less effective in patients with CD. CONCLUSIONS The lower efficacy of SCPs in patients with CD might be secondary to a higher prevalence of anxiety and depression. Psychological issue recognition and support should be enhanced to increase SCP effectiveness in CD.
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Affiliation(s)
- Pierachille Santus
- Division of Pulmonary Diseases, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan, Italy
| | - Dejan Radovanovic
- Division of Pulmonary Diseases, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan, Italy
| | - Davide Raiteri
- Division of Pulmonary Diseases, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan, Italy
| | - Stefano Pini
- Division of Pulmonary Diseases, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan, Italy
| | - Giuseppe Spagnolo
- Department of Medical and Surgical Physiopathology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Giovanni Maconi
- Division of Gastroenterology, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan, Italy
| | - Maurizio Rizzi
- Division of Pulmonary Diseases, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan, Italy
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8
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Kim W, Youn H, Lee S, Kim E, Kim D, Sub Lee J, Lee JM, Youn B. RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis. Exp Mol Med 2018; 50:e434. [PMID: 29371697 PMCID: PMC5799804 DOI: 10.1038/emm.2017.247] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 07/10/2017] [Accepted: 07/23/2017] [Indexed: 02/06/2023] Open
Abstract
An interaction between ribosomal protein S3 (rpS3) and nuclear factor kappa B or macrophage migration inhibitory factor in non-small-cell lung cancer is responsible for radioresistance. However, the role of rpS3 in glioblastoma (GBM) has not been investigated to date. Here we found that in irradiated GBM cells, rpS3 translocated into the nucleus and was subsequently ubiquitinated by ring finger protein 138 (RNF138). Ubiquitin-dependent degradation of rpS3 consequently led to radioresistance in GBM cells. To elucidate the apoptotic role of rpS3, we analyzed the interactome of rpS3 in ΔRNF138 GBM cells. Nuclear rpS3 interacted with DNA damage inducible transcript 3 (DDIT3), leading to DDIT3-induced apoptosis in irradiated ΔRNF138 GBM cells. These results were confirmed using in vivo orthotopic xenograft models and GBM patient tissues. This study aims to clarify the role of RNF138 in GBM cells and demonstrate that rpS3 may be a promising substrate of RNF138 for the induction of GBM radioresistance, indicating RNF138 as a potential target for GBM therapy.
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Affiliation(s)
- Wanyeon Kim
- Department of Biological Sciences, Pusan National University, Busan, Republic of Korea
| | - HyeSook Youn
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea
| | - Sungmin Lee
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
| | - EunGi Kim
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
| | - Daehoon Kim
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
| | - Jung Sub Lee
- Department of Orthopaedic Surgery, Medical Research Institute, Pusan National University School of Medicine, Busan, Republic of Korea
| | - Jae-Myung Lee
- Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, Republic of Korea
| | - BuHyun Youn
- Department of Biological Sciences, Pusan National University, Busan, Republic of Korea
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
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Sikkeland J, Sheng X, Jin Y, Saatcioglu F. STAMPing at the crossroads of normal physiology and disease states. Mol Cell Endocrinol 2016; 425:26-36. [PMID: 26911931 DOI: 10.1016/j.mce.2016.02.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/11/2016] [Accepted: 02/14/2016] [Indexed: 10/24/2022]
Abstract
The six transmembrane protein of prostate (STAMP) proteins, also known as six transmembrane epithelial antigen of prostate (STEAPs), comprises three members: STAMP1-3. Their expression is regulated by a variety of stimuli, including hormones and cytokines, in varied settings and tissues with important roles in secretion and cell differentiation. In addition, they are implicated in metabolic and inflammatory diseases and cancer. Here, we review the current knowledge on the role of STAMPs in both physiological and pathological states.
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Affiliation(s)
| | - Xia Sheng
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Yang Jin
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Fahri Saatcioglu
- Department of Biosciences, University of Oslo, Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
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10
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Perricone C, Versini M, Ben-Ami D, Gertel S, Watad A, Segel MJ, Ceccarelli F, Conti F, Cantarini L, Bogdanos DP, Antonelli A, Amital H, Valesini G, Shoenfeld Y. Smoke and autoimmunity: The fire behind the disease. Autoimmun Rev 2016; 15:354-74. [DOI: 10.1016/j.autrev.2016.01.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Accepted: 12/31/2015] [Indexed: 12/14/2022]
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Underner M, Perriot J, Cosnes J, Beau P, Peiffer G, Meurice JC. [Smoking, smoking cessation and Crohn's disease]. Presse Med 2016; 45:390-402. [PMID: 27016849 DOI: 10.1016/j.lpm.2016.02.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 02/22/2016] [Indexed: 02/05/2023] Open
Abstract
CONTEXT Smoking whose prevalence is higher in patients with Crohn's disease (CD) worsens its evolution. Ulcerative colitis mostly affect non- or ex-smokers; smoking may improve the course of the disease. OBJECTIVES Systematic literature review of data on the relationship between smoking, smoking cessation and Crohn'disease. DOCUMENTARY SOURCES Medline, on the period 1980-2015 with the keywords "Crohn's disease" or "inflammatory bowel disease" and "smoking" or "smoking cessation"; limits "Title/Abstract"; the selected languages were English or French. STUDY SELECTION Among 1315 articles, 168 abstracts have given rise to a dual reading to select 69 studies (case-control, retrospective, reviews or meta-analysis). Data were extracted using a reading gate. RESULTS Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants. These deleterious effects are more common in women. Stopping smoking improves the course of the disease and represents an essential component of its management. LIMITS Heterogeneity of the studies collected according to the type, population characteristics, definition of smoking status and the validation of smoking cessation. CONCLUSION Smokers suffering from CD must routinely be made aware of the disadvantages of smoking, benefits of abstinence and helped to quit smoking.
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Affiliation(s)
- Michel Underner
- CHU La Milétrie, pavillon René-Beauchant, service de pneumologie, unité de tabacologie, BP 577, 86021 Poitiers cedex, France.
| | - Jean Perriot
- Dispensaire Émile-Roux, centre de tabacologie, 63100 Clermont-Ferrand, France
| | - Jacques Cosnes
- Hôpital Saint-Antoine, service d'hépatologie, gastro-entérologie et nutrition, 75012 Paris, France
| | - Philippe Beau
- CHU La Milétrie, service d'hépatologie, gastro-entérologie et nutrition, 86021 Poitiers, France
| | - Gérard Peiffer
- CHR Metz-Thionville, service de pneumologie, 57038 Metz, France
| | - Jean-Claude Meurice
- CHU La Milétrie, pavillon René-Beauchant, service de pneumologie, unité de tabacologie, BP 577, 86021 Poitiers cedex, France
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Differential Gene Expression in Colon Tissue Associated With Diet, Lifestyle, and Related Oxidative Stress. PLoS One 2015; 10:e0134406. [PMID: 26230583 PMCID: PMC4521956 DOI: 10.1371/journal.pone.0134406] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 07/08/2015] [Indexed: 12/21/2022] Open
Abstract
Several diet and lifestyle factors may impact health by influencing oxidative stress levels. We hypothesize that level of cigarette smoking, alcohol, anti-inflammatory drugs, and diet alter gene expression. We analyzed RNA-seq data from 144 colon cancer patients who had information on recent cigarette smoking, recent alcohol consumption, diet, and recent aspirin/non-steroidal anti-inflammatory use. Using a false discovery rate of 0.1, we evaluated gene differential expression between high and low levels of exposure using DESeq2. Ingenuity Pathway Analysis (IPA) was used to determine networks associated with de-regulated genes in our data. We identified 46 deregulated genes associated with recent cigarette use; these genes enriched causal networks regulated by TEK and MAP2K3. Different differentially expressed genes were associated with type of alcohol intake; five genes were associated with total alcohol, six were associated with beer intake, six were associated with wine intake, and four were associated with liquor consumption. Recent use of aspirin and/or ibuprofen was associated with differential expression of TMC06, ST8SIA4, and STEAP3 while a summary oxidative balance score (OBS) was associated with SYCP3, HDX, and NRG4 (all up-regulated with greater oxidative balance). Of the dietary antioxidants and carotenoids evaluated only intake of beta carotene (1 gene), Lutein/Zeaxanthine (5 genes), and Vitamin E (4 genes) were associated with differential gene expression. There were similarities in biological function of de-regulated genes associated with various dietary and lifestyle factors. Our data support the hypothesis that diet and lifestyle factors associated with oxidative stress can alter gene expression. However genes altered were unique to type of alcohol and type of antioxidant. Because of potential differences in associations observed between platforms these findings need replication in other populations.
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Mirza AH, Berthelsen CH, Seemann SE, Pan X, Frederiksen KS, Vilien M, Gorodkin J, Pociot F. Transcriptomic landscape of lncRNAs in inflammatory bowel disease. Genome Med 2015; 7:39. [PMID: 25991924 PMCID: PMC4437449 DOI: 10.1186/s13073-015-0162-2] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 04/09/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn's disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. METHODS In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in 96 colon pinch biopsies (inflamed and non-inflamed) extracted from multiple colonic locations from 45 patients (CD = 13, UC = 20, controls = 12) using an expression microarray platform. RESULTS In our study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In cases of inflamed CD and UC, we identified 438 and 745 differentially expressed lncRNAs, respectively, while in cases of the non-inflamed CD and UC, we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (P-value <0.001, Pearson's Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed their involvement in the immune response, pro-inflammatory cytokine activity and MHC protein complex. CONCLUSIONS The lncRNA expression profiling in both inflamed and non-inflamed CD and UC successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggest their potential as biomarkers in IBD.
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Affiliation(s)
- Aashiq H Mirza
- Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, 1870 Denmark ; Department of Pediatrics E, Copenhagen Diabetes Research Center (CPH-DIRECT), Herlev University Hospital, Herlev, 2730 Denmark ; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200 Denmark
| | - Claus Hb Berthelsen
- Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, 1870 Denmark ; Department of Obesity Biology, Novo Nordisk, Måløv, 2760 Denmark
| | - Stefan E Seemann
- Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, 1870 Denmark ; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200 Denmark
| | - Xiaoyong Pan
- Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, 1870 Denmark ; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200 Denmark ; The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, 2200 Denmark
| | | | - Mogens Vilien
- Department of Surgery, North Zealand Hospital, Hillerød, 3400 Denmark
| | - Jan Gorodkin
- Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, 1870 Denmark ; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200 Denmark
| | - Flemming Pociot
- Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, 1870 Denmark ; Department of Pediatrics E, Copenhagen Diabetes Research Center (CPH-DIRECT), Herlev University Hospital, Herlev, 2730 Denmark ; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200 Denmark
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14
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Krauss E, Agaimy A, Gottfried A, Maiss J, Weidinger T, Albrecht H, Hartmann A, Hohenberger W, Neurath MF, Kessler H, Mudter J. Long term follow up of through-the-scope balloon dilation as compared to strictureplasty and bowel resection of intestinal strictures in crohn's disease. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:7419-7431. [PMID: 25550777 PMCID: PMC4270558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 11/10/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND & AIMS Ileo-colonic strictures are common complication of Crohn's disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital. METHODS In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations. RESULTS 53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon. CONCLUSIONS Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment.
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Affiliation(s)
- Ekaterina Krauss
- Department of Medicine 1, University of Erlangen-NurembergUlmenweg 18, D-91054 Erlangen, Germany
| | - Abbas Agaimy
- Institute of Pathology, University of Erlangen-NurembergKrankenhausstr 8-10, 91054 Erlangen, Germany
| | - Angelina Gottfried
- Department of Medicine 1, University of Erlangen-NurembergUlmenweg 18, D-91054 Erlangen, Germany
| | - Juergen Maiss
- Gastroenterology Associates Dr. Kerzel/Prof MaissMozartstr. 1, 91301 Forchheim
| | - Thomas Weidinger
- Department of Abdominal Surgery, University of Erlangen-NurembergKrankenhausstr 12, D-91054 Erlangen, Germany
| | - Heinz Albrecht
- Department of Medicine 1, University of Erlangen-NurembergUlmenweg 18, D-91054 Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University of Erlangen-NurembergKrankenhausstr 8-10, 91054 Erlangen, Germany
| | - Werner Hohenberger
- Department of Abdominal Surgery, University of Erlangen-NurembergKrankenhausstr 12, D-91054 Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-NurembergUlmenweg 18, D-91054 Erlangen, Germany
| | - Hermann Kessler
- Department of Abdominal Surgery, University of Erlangen-NurembergKrankenhausstr 12, D-91054 Erlangen, Germany
| | - Jonas Mudter
- Sana Kliniken GmbH Eastern HolsteinEutin 23701, Germany
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Abstract
Smoking is the second leading cause of preventable death in the United States. Cohort epidemiological studies have demonstrated that women are more vulnerable to cigarette-smoking induced diseases than their male counterparts, however, the molecular basis of these differences has remained unknown. In this study, we explored if there were differences in the gene expression patterns between male and female smokers, and how these patterns might reflect different sex-specific responses to the stress of smoking. Using whole genome microarray gene expression profiling, we found that a substantial number of oxidant related genes were expressed in both male and female smokers, however, smoking-responsive genes did indeed differ greatly between male and female smokers. Gene set enrichment analysis (GSEA) against reference oncogenic signature gene sets identified a large number of oncogenic pathway gene-sets that were significantly altered in female smokers compared to male smokers. In addition, functional annotation with Ingenuity Pathway Analysis (IPA) identified smoking-correlated genes associated with biological functions in male and female smokers that are directly relevant to well-known smoking related pathologies. However, these relevant biological functions were strikingly overrepresented in female smokers compared to male smokers. IPA network analysis with the functional categories of immune and inflammatory response gene products suggested potential interactions between smoking response and female hormones. Our results demonstrate a striking dichotomy between male and female gene expression responses to smoking. This is the first genome-wide expression study to compare the sex-specific impacts of smoking at a molecular level and suggests a novel potential connection between sex hormone signaling and smoking-induced diseases in female smokers.
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Affiliation(s)
- Sunirmal Paul
- Center for Radiological Research, Columbia University Medical Center, New York, NY ; Department of Radiology, New Jersey Medical School, Cancer Center RUTGERS, Newark, NJ
| | - Sally A Amundson
- Center for Radiological Research, Columbia University Medical Center, New York, NY
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16
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Cigarette smoking and inflammation revisited. Respir Physiol Neurobiol 2013; 187:5-10. [PMID: 23376061 DOI: 10.1016/j.resp.2013.01.013] [Citation(s) in RCA: 150] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 01/23/2013] [Accepted: 01/23/2013] [Indexed: 12/14/2022]
Abstract
Despite the significant health risks resulting from tobacco use, the prevalence of smokers worldwide remains high. Cigarette smoking is one of the major sources of toxic chemical exposure to humans and is the greatest cause of preventable illnesses and premature death. The adverse consequences of smoking in various pathologies are mediated by its effects on the immune-inflammatory system. In this review, we aim to explore the effects of cigarette smoking on the inflammatory response and molecular mechanisms with emphasis on the nuclear factor kappa B (NF-kB) pathway. The effects of smoking on various inflammatory pathologies will be discussed, focusing on oral diseases, airway inflammation, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD).
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17
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Deuring JJ, de Haar C, Kuipers EJ, Peppelenbosch MP, van der Woude CJ. The cell biology of the intestinal epithelium and its relation to inflammatory bowel disease. Int J Biochem Cell Biol 2013; 45:798-806. [PMID: 23291352 DOI: 10.1016/j.biocel.2012.12.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 12/18/2012] [Accepted: 12/24/2012] [Indexed: 12/14/2022]
Abstract
The epithelial layer of our intestines must meet two opposing requirements. On one hand it must allow for efficient uptake of nutrients and fluids, on the other hand it is a vital defence barrier between the milieu interior and the milieu exterior. In contrast to the lung that by virtue of cilia movement is kept virtually sterile, the gut epithelium is confronted by a stupendous microbiological load and a substantial xenobiotic challenge. The efficiency by which our intestinal epithelium manages to deal with the challenge of efficient nutrient absorption while simultaneously fulfilling its barrier function is testimony to what the forces of evolution can accomplish. Importantly, our understanding as to how our gut epithelial compartment manages this balancing act is now rapidly emerging, answering one of the oldest questions in cell biology. Importantly, when aberrations in this balance occur, for instance as a consequence genetic polymorphisms, increased propensity to develop chronic inflammation and inflammatory bowel disease is the result. Thus the knowledge on intestinal cell biology and biochemistry is not only of academic interest but may also aid design of novel avenues for the rational treatment of mucosal disease.
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Affiliation(s)
- J Jasper Deuring
- Erasmus MC - University Medical Centre Rotterdam, Department Gastroenterology and Hepatology, The Netherlands
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18
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Silva J, Garcia V, Rodriguez M, Compte M, Cisneros E, Veguillas P, Garcia JM, Dominguez G, Campos-Martin Y, Cuevas J, Peña C, Herrera M, Diaz R, Mohammed N, Bonilla F. Analysis of exosome release and its prognostic value in human colorectal cancer. Genes Chromosomes Cancer 2012; 51:409-18. [PMID: 22420032 DOI: 10.1002/gcc.21926] [Citation(s) in RCA: 231] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
A significant proportion of extracellular nucleic acids in plasma circulate highly protected in tumor-specific exosomes, but it is unclear how the release of exosomes is modulated in carcinogenesis. We quantified by cytometry exosomes in plasma of 91 colorectal cancer patients to evaluate their potential as a tumor indicator and their repercussions on diagnosis and prognosis. We examined the involvement of TSAP6, a TP53-regulated gene involved in the regulation of vesicular secretion, in levels of circulating exosomes in plasma of colorectal patients and in HCT116 TP53-(wild-type and null) human colorectal cancer cell lines. The fraction of exosomes in cancer patients was statistically higher than in healthy controls (mean rank ¼ 53.93 vs. 24.35). High levels of exosomes in plasma of patients correlated with high levels of carcino-embryonic antigen (P ¼ 0.029) and with poorly differentiated tumors (P ¼ 0.039) and tended to have shorter overall survival than patients with low levels (P ¼ 0.056). Release of exosomes did not correlate with TSAP6 expression; and regulation of TSAP6 by TP53 was not shown either in tumor samples or in HCT116 cell lines. Although it was not suggested that the TP53/TSAP6 pathway regulates the release of exosomes into the plasma of colorectal cancer patients, the level of circulating exosomes may be used as a tumor indicator, because it correlates with poor prognosis parameters and shorter survival.
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Affiliation(s)
- J Silva
- Departmentof MedicalOncology, University Hospital Puerta de Hierro, Majadahonda, Madrid, Spain
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Aldhous MC, Soo K, Stark LA, Ulanicka AA, Easterbrook JE, Dunlop MG, Satsangi J. Cigarette smoke extract (CSE) delays NOD2 expression and affects NOD2/RIPK2 interactions in intestinal epithelial cells. PLoS One 2011; 6:e24715. [PMID: 21931826 PMCID: PMC3171477 DOI: 10.1371/journal.pone.0024715] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Accepted: 08/19/2011] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Genetic and environmental factors influence susceptibility to Crohn's disease (CD): NOD2 is the strongest individual genetic determinant and smoking the best-characterised environmental factor. Carriage of NOD2 mutations predispose to small-intestinal, stricturing CD, a phenotype also associated with smoking. We hypothesised that cigarette smoke extract (CSE) altered NOD2 expression and function in intestinal epithelial cells. METHODS AND FINDINGS Intestinal epithelial cell-lines (SW480, HT29, HCT116) were stimulated with CSE and nicotine (to mimic smoking) ±TNFα (to mimic inflammation). NOD2 expression was measured by qRT-PCR and western blotting; NOD2-RIPK2 interactions by co-immunoprecipitation (CoIP); nuclear NFκB-p65 by ELISA; NFκB activity by luciferase reporter assays and chemokines (CCL20, IL8) in culture supernatants by ELISA. In SW480 and HT29 cells the TNFα-induced NOD2 expression at 4 hours was reduced by CSE (p = 0.0226), a response that was dose-dependent (p = 0.003) and time-dependent (p = 0.0004). Similar effects of CSE on NOD2 expression were seen in cultured ileal biopsies from healthy individuals. In SW480 cells CSE reduced TNFα-induced NFκB-p65 translocation at 15 minutes post-stimulation, upstream of NOD2. Levels of the NOD2-RIPK2 complex were no different at 8 hours post-stimulation with combinations of CSE, nicotine and TNFα, but at 18 hours it was increased in cells stimulated with TNFα+CSE but decreased with TNFα alone (p = 0.0330); CSE reduced TNFα-induced NFκB activity (p = 0.0014) at the same time-point. At 24 hours, basal CCL20 and IL8 (p<0.001 for both) and TNFα-induced CCL20 (p = 0.0330) production were decreased by CSE. CSE also reduced NOD2 expression, CCL20 and IL8 production seen with MDP-stimulation of SW480 cells pre-treated with combinations of TNFα and CSE. CONCLUSIONS CSE delayed TNFα-induced NOD2 mRNA expression and was associated with abnormal NOD2/RIPK2 interaction, reduced NFκB activity and decreased chemokine production. These effects may be involved in the pathogenesis of small-intestinal CD and may have wider implications for the effects of smoking in NOD2-mediated responses.
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Affiliation(s)
- Marian C Aldhous
- Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
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Nos P, Domènech E. Management of Crohn's disease in smokers: is an alternative approach necessary? World J Gastroenterol 2011; 17:3567-74. [PMID: 21987601 PMCID: PMC3180011 DOI: 10.3748/wjg.v17.i31.3567] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 09/01/2010] [Accepted: 09/08/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease is a chronic condition with a pathogenic background that involves both genetic and environmental factors. Although important progress has been made regarding the former in the last decade, scarce knowledge is available for the latter. In this sense, smoking remains the most important environmental factor in IBD. Active smoking increases the risk of developing Crohn's disease (CD). Moreover, CD patients who start or continue smoking after disease diagnosis are at risk for poorer outcomes such as higher therapeutic requirements and disease-related complications, as compared to those patients who quit smoking or who never smoked. However, the harmful effect of active smoking is not uniform in all patients or in all clinical scenarios. Interventions designed to facilitate smoking cessation may impact the course of the disease. In this article, the available evidence of the deleterious effects of smoking on CD is reviewed in detail, and alternative therapeutic approaches to CD in smokers are proposed.
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21
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Verschuere S, Bracke KR, Demoor T, Plantinga M, Verbrugghe P, Ferdinande L, Lambrecht BN, Brusselle GGG, Cuvelier CA. Cigarette smoking alters epithelial apoptosis and immune composition in murine GALT. J Transl Med 2011; 91:1056-67. [PMID: 21537330 DOI: 10.1038/labinvest.2011.74] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Smokers have a twofold increased risk to develop Crohn's disease (CD). However, little is known about the mechanisms through which smoking affects CD pathogenesis. Especially Crohn's ileitis is negatively influenced by smoking. Interestingly, the ileum and, more in particular, the Peyer's patches in the terminal ileum are also the sites where the first CD lesions are found. Several chemokines are implicated in the pathogenesis, among which is the CCL20-CCR6 pathway. Here, we studied the gut-associated lymphoid tissue in C57BL/6 wild-type mice and in CCR6-deficient mice after exposure to air or cigarette smoke for 24 weeks. Apoptotic index of the follicle-associated epithelium overlying the Peyer's patches was evaluated. We found that chronic smoke exposure induced apoptosis in the follicle-associated epithelium. Furthermore, immune cell numbers and differentiation along with chemokine expression were determined in Peyer's patches. Important changes in immune cell composition were observed: total dendritic cells, CD4+ T cells (including regulatory T cells) and CD8+ T cells increased significantly after smoke exposure. The CD11b+ dendritic cell subset almost doubled. Interestingly, these changes were accompanied by an upregulated mRNA expression of the chemokines CCL9 and CCL20. However, no differences in the increase of dendritic cells were observed between wild-type and CCR6-deficient mice. Our results show that cigarette smoke exposure increases apoptosis in the follicle-associated epithelium and is associated with immune cell accumulation in Peyer's patches.
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Greenstein RJ, Su L, Brown ST. Growth of M. avium subspecies paratuberculosis in culture is enhanced by nicotinic acid, nicotinamide, and α and β nicotinamide adenine dinucleotide. Dig Dis Sci 2011; 56:368-75. [PMID: 20585983 DOI: 10.1007/s10620-010-1301-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 06/03/2010] [Indexed: 01/15/2023]
Abstract
BACKGROUND Without known mechanisms of action, Crohn's disease is exacerbated, and ulcerative colitis is improved, by the use of tobacco. Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. We hypothesized that tobacco components might alter the growth kinetics of MAP, explaining these divergent clinical observations. METHODS The effect of nicotine, nicotinic acid, nicotinamide and α and β nicotinamide adenine dinucleotide (α and β NAD) were studied on eight strains of three mycobacterial species (MAP, M. avium and M. tb. complex). Data are obtained as "cumulative growth index," (cGI) and presented as "percent increase in cumulative GI" (% + ΔcGI). RESULTS Nicotinic acid enhances the two human MAP isolates (Dominic; 225% + ΔcGI and UCF-4; 92% + ΔcGI) and M. avium (ATCC 25291; 175% + ΔcGI). Nicotinamide (at 6.4 µg/ml) enhances the human MAP isolates (Dominic; 156% + ΔcGI and UCF-4; 79% + ΔcGI) and M. avium (ATCC 25291; 144% + ΔcGI.) Both α and β NAD enhance Dominic; (135 and 150 % + ΔcGI) and UCF-4; (81 and 79% + ΔcGI). At the doses tested, nicotine has no effect on any strain studied. CONCLUSIONS We show enhancement of MAP growth by nicotinic acid, one of ≥4,000 tobacco-related molecules, its amide, nicotinamide and α and β NAD. Pure nicotine has no enhancing effect at the doses studies.
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Whitwell SCL, Mathew CG, Lewis CM, Forbes A, Watts S, Sanderson J, Hollands GJ, Prevost AT, Armstrong D, Kinmonth AL, Sutton S, Marteau TM. Trial Protocol: Communicating DNA-based risk assessments for Crohn's disease: a randomised controlled trial assessing impact upon stopping smoking. BMC Public Health 2011; 11:44. [PMID: 21247480 PMCID: PMC3036624 DOI: 10.1186/1471-2458-11-44] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Accepted: 01/19/2011] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Estimates of the risk of developing Crohn's disease (CD) can be made using DNA testing for mutations in the NOD2 (CARD15) gene, family history, and smoking status. Smoking doubles the risk of CD, a risk that is reduced by stopping. CD therefore serves as a timely and novel paradigm within which to assess the utility of predictive genetic testing to motivate behaviour change to reduce the risk of disease. The aim of the study is to describe the impact upon stopping smoking of communicating a risk of developing CD that incorporates DNA analysis. We will test the following main hypothesis:Smokers who are first degree relatives (FDRs) of CD probands are more likely to make smoking cessation attempts following communication of risk estimates of developing CD that incorporate DNA analysis, compared with an equivalent communication that does not incorporate DNA analysis. METHODS/DESIGN A parallel groups randomised controlled trial in which smokers who are FDRs of probands with CD are randomly allocated in families to undergo one of two types of assessment of risk for developing CD based on either: i. DNA analysis, family history of CD and smoking status, or ii. Family history of CD and smoking status. The primary outcome is stopping smoking for 24 hours or longer in the six months following provision of risk information. The secondary outcomes are seven-day smoking abstinence at one week and six month follow-ups. Randomisation of 470 smoking FDRs of CD probands, with 400 followed up (85%), provides 80% power to detect a difference in the primary outcome of 14% between randomised arms, at the 5% significance level. DISCUSSION This trial provides one of the strongest tests to date of the impact of communicating DNA-based risk assessment on risk-reducing behaviour change. Specific issues regarding the choice of trial design are discussed.
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Affiliation(s)
- Sophia CL Whitwell
- Health Psychology Section, Department of Psychology, King's College London, 5th Floor Bermondsey Wing, Guy's Campus, London SE1 9RT, UK
| | - Christopher G Mathew
- Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
| | - Cathryn M Lewis
- Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
| | - Alastair Forbes
- Department of Gastroenterology and Clinical Nutrition, University College Hospital, 235 Euston Road, London NW1 2BU, UK
| | - Sally Watts
- Clinical Genetics, 7th Floor New Guy's House, Guy's Hospital, London SE1 9RT, UK
| | | | - Gareth J Hollands
- Health Psychology Section, Department of Psychology, King's College London, 5th Floor Bermondsey Wing, Guy's Campus, London SE1 9RT, UK
| | - A Toby Prevost
- King's College London, Department of Primary Care and Public Health Sciences, 5th Floor Capital House, 42 Weston Street, London SE1 3QD, UK
| | - David Armstrong
- King's College London, Department of Primary Care and Public Health Sciences, 5th Floor Capital House, 42 Weston Street, London SE1 3QD, UK
| | - Ann Louise Kinmonth
- University of Cambridge Department of Public Health and Primary Care, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK
| | - Stephen Sutton
- University of Cambridge Department of Public Health and Primary Care, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK
| | - Theresa M Marteau
- Health Psychology Section, Department of Psychology, King's College London, 5th Floor Bermondsey Wing, Guy's Campus, London SE1 9RT, UK
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Aldhous MC, Satsangi J. The impact of smoking in Crohn's disease: no smoke without fire. Frontline Gastroenterol 2010; 1:156-164. [PMID: 28839569 PMCID: PMC5517176 DOI: 10.1136/fg.2010.001487] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/15/2010] [Indexed: 02/04/2023] Open
Abstract
Smoking habit is the most widely accepted environmental factor affecting the incidence and disease progression in the inflammatory bowel diseases. The contrasting effects in Crohn's disease (CD) and ulcerative colitis are unexplained. The purpose of this review is to summarise the existing data on the effects of smoking in CD on disease history, recurrence after surgery, effects on drug responses and to review available evidence that carriage of some of the known susceptibility genes may be disproportionate in smokers with CD. The review also highlights potential mechanisms involved and factors that might affect patients' smoking habits. The clinical and scientific implications of the data are discussed.
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Affiliation(s)
- Marian C Aldhous
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
| | - J Satsangi
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
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25
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Abstract
The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools.
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Affiliation(s)
- Bu'Hussain Hayee
- Department of Molecular Medicine, University College London, London, WC1E 6JJ, UK.
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