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Cammisa I, Rigante D, Cipolla C. A Theoretical Link Between the GH/IGF-1 Axis and Cytokine Family in Children: Current Knowledge and Future Perspectives. CHILDREN (BASEL, SWITZERLAND) 2025; 12:495. [PMID: 40310145 PMCID: PMC12026182 DOI: 10.3390/children12040495] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND/OBJECTIVES Growth in childhood and adolescence is influenced by a complex interaction of genetic, environmental, and hormonal factors, with growth hormone (GH) and insulin-like growth factor 1 (IGF-1) playing crucial roles in linear growth and development. However, chronic inflammation, often detected in situations like inflammatory bowel disease and juvenile idiopathic arthritis, can significantly disrupt the GH/IGF-1 axis, causing a relevant growth impairment. METHODS We conducted a retrospective review focusing on the role of cytokines in the GH-IGF-1 axis and growth. RESULTS Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 have been shown to contribute to GH resistance through an array of mechanisms that involve the downregulation of GH receptors and alterations in IGF-1 metabolism. This disruption negatively impacts the growth plate, particularly by impairing chondrocyte proliferation and differentiation, which are essential for proper bone elongation. This review delves into the intricate relationship among growth, chronic inflammation, and GH-IGF-1 axis, emphasizing the contribution of inflammatory cytokines in modulating GH signaling. It also highlights how cytokines can interfere with the molecular pathways that regulate skeletal growth, ultimately leading to growth disturbances in children suffering from chronic inflammatory diseases. CONCLUSIONS The findings underscore the importance of controlling inflammation in affected individuals to mitigate its detrimental effects on growth and ensure that children may reach their growth full potential.
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Affiliation(s)
- Ignazio Cammisa
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
| | - Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
- Department of Life Sciences and Public Health, Università Cattolica Sacro Cuore, 20123 Rome, Italy
| | - Clelia Cipolla
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
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Golan-Gerstl R, Ben Ya’acov A, Musseri M, Goldenberg R, Chammah Y, Cherki T, Reif S, Bar Gil Shitrit A. Expression Profile of MicroRNAs in Breast Milk of Women With Inflammatory Bowel Disease: Correlation With Disease Activity and Medical Treatments. Inflamm Bowel Dis 2025; 31:912-922. [PMID: 39820274 PMCID: PMC11985391 DOI: 10.1093/ibd/izae290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND Although most inflammatory bowel disease (IBD) medications are considered safe during pregnancy, their impact on microRNAs (miRNAs) in breast milk is largely unknown. MiRNAs in milk, carried by milk-derived extracellular vesicles (MDEs), are transmitted to the newborn's gut to regulate genes. Aberrant miRNA expression profiles have been found in IBD within tissue, blood, and feces, but data on mother's milk are scarce. METHODS We collected breast milk samples from 32 mothers with Crohn's disease (CD), 14 mothers with ulcerative colitis (UC), and 44 healthy controls. We analyzed miRNA expression through qualitative real-time polymerase chain reaction and Affymetrix miRNA chips. Target genes of differentially expressed miRNAs were predicted using miRATBase. Statistical analyses were conducted using GraphPad Prism software with Mann-Whitney tests. RESULTS Milk-derived extracellular vesicles from mothers with IBD showed altered miRNA profiles compared to controls. Specifically, miR-21 and miR-320 were downregulated, while Let-7a was upregulated in IBD mothers. The expression patterns varied between CD and UC, with significantly lower MiR-21 in UC and higher Let-7a in CD. Additionally, anti-tumor necrosis factor treatment during pregnancy was associated with reduced miR-21 and miR-148a levels in MDEs. Pathway analysis revealed that these miRNAs are involved in immune regulation, particularly interleukin signaling pathways. CONCLUSIONS This study highlights that miRNAs in breast milk are differentially expressed in mothers with IBD, influenced by the disease and its treatments. These findings emphasize the impact of maternal health on milk composition and potential implications for infant immune development. Understanding these findings may guide personalized treatment strategies for mothers and promote breastfeeding among mothers with IBD.
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Affiliation(s)
- Regina Golan-Gerstl
- Department of Pediatrics, Hebrew University Hadassah Medical Center, Jerusalem, Israel
| | - Ami Ben Ya’acov
- Digestive Diseases Institute, Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Mirit Musseri
- Department of Pediatrics, Hebrew University Hadassah Medical Center, Jerusalem, Israel
| | - Rosi Goldenberg
- Digestive Diseases Institute, Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Yehudit Chammah
- Digestive Diseases Institute, Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Tal Cherki
- Digestive Diseases Institute, Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Shimon Reif
- Department of Pediatrics, Hebrew University Hadassah Medical Center, Jerusalem, Israel
| | - Ariella Bar Gil Shitrit
- Digestive Diseases Institute, Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem, Israel
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Moustafa HAM, Elsakka EGE, Abulsoud AI, Elshaer SS, Rashad AA, El-Dakroury WA, Sallam AAM, Rizk NI, Zaki MB, Gomaa RM, Elesawy AE, Mohammed OA, Abdel Mageed SS, Eleragi AMS, ElBoghdady JA, El-Fayoumi SH, Abdel-Reheim MA, Doghish AS. The miRNA Landscape in Crohn's disease: Implications for novel therapeutic approaches and interactions with Existing therapies. Exp Cell Res 2024; 442:114234. [PMID: 39233267 DOI: 10.1016/j.yexcr.2024.114234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/25/2024] [Accepted: 09/01/2024] [Indexed: 09/06/2024]
Abstract
MicroRNAs (miRNAs), which are non-coding RNAs consisting of 18-24 nucleotides, play a crucial role in the regulatory pathways of inflammatory diseases. Several recent investigations have examined the potential role of miRNAs in forming Crohn's disease (CD). It has been suggested that miRNAs serve as diagnostics for both fibrosis and inflammation in CD due to their involvement in the mechanisms of CD aggravation and fibrogenesis. More information on CD pathophysiology could be obtained by identifying the miRNAs concerned with CD and their target genes. These findings have prompted several in vitro and in vivo investigations into the putative function of miRNAs in CD treatment. Although there are still many unanswered questions, the growing body of evidence has brought miRNA-based therapy one step closer to clinical practice. This extensive narrative study offers a concise summary of the most current advancements in CD. We go over what is known about the diagnostic and therapeutic benefits of miRNA mimicry and inhibition so far, and we see what additional miRNA family targets could be useful for treating CD-related inflammation and fibrosis.
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Affiliation(s)
- Hebatallah Ahmed Mohamed Moustafa
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Ahmed A Rashad
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Al-Aliaa M Sallam
- epartment of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohamed Bakr Zaki
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Rania M Gomaa
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo (BUC), Badr City, Cairo P.O. Box 11829, Egypt
| | - Ahmed E Elesawy
- epartment of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Ali M S Eleragi
- Department of Microorganisms and Clinical Parasitology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Jasmine A ElBoghdady
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Shaimaa H El-Fayoumi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | | | - Ahmed S Doghish
- epartment of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
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Oliveira ECSD, Quaglio AEV, Grillo TG, Di Stasi LC, Sassaki LY. MicroRNAs in inflammatory bowel disease: What do we know and what can we expect? World J Gastroenterol 2024; 30:2184-2190. [PMID: 38690020 PMCID: PMC11056918 DOI: 10.3748/wjg.v30.i16.2184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/09/2024] [Accepted: 03/19/2024] [Indexed: 04/26/2024] Open
Abstract
MicroRNAs (miRNAs), small non-coding RNAs composed of 18-24 nucleotides, are potent regulators of gene expression, contributing to the regulation of more than 30% of protein-coding genes. Considering that miRNAs are regulators of inflammatory pathways and the differentiation of intestinal epithelial cells, there is an interest in exploring their importance in inflammatory bowel disease (IBD). IBD is a chronic and multifactorial disease of the gastrointestinal tract; the main forms are Crohn's disease and ulcerative colitis. Several studies have investigated the dysregulated expression of miRNAs in IBD, demonstrating their important roles as regulators and potential biomarkers of this disease. This editorial presents what is known and what is expected regarding miRNAs in IBD. Although the important regulatory roles of miRNAs in IBD are clearly established, biomarkers for IBD that can be applied in clinical practice are lacking, emphasizing the importance of further studies. Discoveries regarding the influence of miRNAs on the inflammatory process and the exploration of their role in gene regulation are expected to provide a basis for the use of miRNAs not only as potent biomarkers in IBD but also as therapeutic targets for the control of inflammatory processes in personalized medicine.
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Affiliation(s)
| | | | - Thais Gagno Grillo
- Department of Internal Medicine, Medical School, São Paulo State University (Unesp), Botucatu 18618-686, São Paulo, Brazil
| | - Luiz Claudio Di Stasi
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University (Unesp), Botucatu 18618-689, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, Medical School, São Paulo State University (Unesp), Botucatu 18618-686, São Paulo, Brazil
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Guglielmi G, Crucitta S, Bertani L, Ruglioni M, Baiano Svizzero G, Ceccarelli L, Del Re M, Danesi R, Costa F, Fogli S. Expression of Circulating let-7e and miR-126 May Predict Clinical Remission in Patients With Crohn's Disease Treated With Anti-TNF-α Biologics. Inflamm Bowel Dis 2024; 30:441-446. [PMID: 37696681 DOI: 10.1093/ibd/izad181] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND The identification of new biomarkers predictive of response to antitumor necrosis factor alpha (anti-TNF-α) monoclonal antibodies remains an unmet medical need in Crohn's disease (CD) because a high percentage of patients show no clinical improvement after treatment or can lose response over time. MicroRNAs (miRNAs) can regulate inflammatory and immunological responses and were found to play a role in CD. METHODS Baseline serum samples from 37 CD patients previously treated with infliximab or adalimumab, as per clinical practice, were obtained from the serum library at the Gastroenterology Unit of the University Hospital of Pisa, Italy. Patients were categorized as responders or nonresponders based on the following treatment outcomes: clinical remission at weeks 14 and 54 and endoscopic remission at week 54. The expression levels of a panel of selected miRNAs were analyzed by real-time polymerase chain reaction. Comparisons of miRNA expression between responders and nonresponders and statistical analyses were performed by MedCalc and GraphPad Prism software. Receiver operating characteristic curve analyses were calculated to evaluate the predictive performance of potential biomarkers. RESULTS Patients in clinical remission at week 14 had a lower let-7e expression, whereas those in clinical remission at week 54 had lower levels of circulating miR-126 than nonresponders. The receiver operating characteristic curve analysis identified optimal cutoff values with assay sensitivity and specificity of 92.9% and 61.1%, for let-7e, and 62.5% and 83.3%, for miR-126, respectively. CONCLUSION These results provide evidence that expression levels of circulating let-7e and miR-126 at baseline may predict clinical remission in CD patients treated with anti-TNF-α biologics.
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Affiliation(s)
- Giorgio Guglielmi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Stefania Crucitta
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Lorenzo Bertani
- IBD Unit, Department of General Surgery and Gastroenterology, University Hospital of Pisa, Pisa, Italy
| | - Martina Ruglioni
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giovanni Baiano Svizzero
- IBD Unit, Department of General Surgery and Gastroenterology, University Hospital of Pisa, Pisa, Italy
| | - Linda Ceccarelli
- IBD Unit, Department of General Surgery and Gastroenterology, University Hospital of Pisa, Pisa, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Costa
- IBD Unit, Department of General Surgery and Gastroenterology, University Hospital of Pisa, Pisa, Italy
| | - Stefano Fogli
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Casertano M, Trotta MC, Cenni S, Creoli M, Miele E, Martinelli M, Lepre CC, Russo M, Alfano R, D'Amico M, Strisciuglio C. Infliximab therapy decreases the expression of serum and faecal miR-126 and miR-20a in paediatric Crohn's disease: A pilot study. Acta Paediatr 2024; 113:590-597. [PMID: 38140840 DOI: 10.1111/apa.17072] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 11/17/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023]
Abstract
AIM We aimed to evaluate the serum and faecal expression of miR-126 and miR-20a in children with Crohn's disease (CD) during infliximab (IFX) therapy. METHODS In this prospective observational study, serum and faeces from CD patients were collected before IFX therapy (T0), after induction (T1) and after 6 months from IFX (T2). IFX levels were determined by Enzyme-linked immunosorbent assay at T1 and T2. miRNAs were profiled through Real-Time RT-PCR. The activity of disease was evaluated through the Paediatric Crohn's disease activity index (PCDAI), serum C-reactive protein (CRP) and faecal calprotectin. RESULTS Nine CD children were enrolled. Serum and faecal miR-126 and miR-20a levels were higher at T0 and showed a time-dependent decrease, being significantly down-regulated after IFX treatment at T2. Specifically, IFX levels recorded at T1 and T2 negatively correlated with the serum and faecal expression of miR-126 and miR-20a. Serum and faecal changes of miR-126 and miR20-a were positively associated with the decrease of the inflammatory marker CRP and PDCAI at all time points. CONCLUSION In children with CD, IFX therapy decreases the expression of serum and faecal miR-126 and miR-20a, suggesting an involvement of these two miRNAs in the action of the drug.
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Affiliation(s)
- Marianna Casertano
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Sabrina Cenni
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Mara Creoli
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Erasmo Miele
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Massimo Martinelli
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Caterina Claudia Lepre
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
- PhD Course in Translational Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marina Russo
- PhD Course of National Interest in Public Administration and Innovation for Disability and Social Inclusion, Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
- School of Pharmacology and Clinical Toxicology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Roberto Alfano
- Department of Advanced Medical and Surgical Sciences "DAMSS", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele D'Amico
- Therapeutic Monitoring Unit for Biological Drugs, UOC Clinic Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
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Shahraki K, Pak VI, Najafi A, Shahraki K, Boroumand PG, Sheervalilou R. Non-coding RNA-mediated epigenetic alterations in Grave's ophthalmopathy: A scoping systematic review. Noncoding RNA Res 2023; 8:426-450. [PMID: 37324526 PMCID: PMC10265490 DOI: 10.1016/j.ncrna.2023.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/25/2023] [Accepted: 04/27/2023] [Indexed: 06/17/2023] Open
Abstract
Background It is becoming more and more apparent that Grave's Ophthalmopathy (GO) pathogenesis may be aided by epigenetic processes such as DNA methylation modifications, histone tail covalent modifications, and non-coding RNA (ncRNA)-based epigenetic processes. In the present study, we aimed to focus more on the miRNAs rather than lncRNAs due to lack of investigations on these non-coding RNAs and their role in GO's pathogenesis. Methods A six-stage methodology framework and the PRISMA recommendation were used to conduct this scoping review. A comprehensive search was conducted across seven databases to discover relevant papers published until February 2022. The data extraction separately, and quantitative and qualitative analyses were conducted. Results A total of 20 articles were found to meet inclusion criteria. According to the results, ncRNA were involved in the regulation of inflammation (miR-146a, LPAL2/miR-1287-5p axis, LINC01820:13/hsa miR-27b-3p axis, and ENST00000499452/hsa-miR-27a-3p axis), regulation of T cell functions (miR-146a/miR-183/miR-96), regulation of glycosaminoglycan aggregation and fibrosis (miR-146a/miR-21), glucocorticoid sensitivity (miR-224-5p), lipid accumulation and adipogenesis (miR-27a/miR-27b/miR-130a), oxidative stress and angiogenesis (miR-199a), and orbital fibroblast proliferation (miR-21/miR-146a/miR-155). Eleven miRNAs (miR-146a/miR-224-5p/miR-Let7d-5p/miR-96-5p/miR-301a-3p/miR-21-5p) were also indicated to have the capacity to be used as biomarkers. Conclusions Regardless of the fact that there is significant documentation of ncRNA-mediated epigenetic dysfunction in GO, additional study is needed to thoroughly comprehend the epigenetic connections concerned in disease pathogenesis, paving the way for novel diagnostic and prognostic tools for epigenetic therapies among the patients.
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Affiliation(s)
- Kourosh Shahraki
- Ocular Tissue Engineering Research Center, Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Ophthalmology, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Vida Ilkhani Pak
- Ocular Tissue Engineering Research Center, Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amin Najafi
- Department of Ophthalmology, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Kianoush Shahraki
- Department of Ophthalmology, Zahedan University of Medical Sciences, Zahedan, Iran
- Cornea Department, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Paria Ghasemi Boroumand
- ENT, Head and Neck Research Center and Department, Iran University of Medical Science, Tehran, Iran
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Saccon TD, Dhahbi JM, Schneider A, Nunez Lopez YO, Qasem A, Cavalcante MB, Sing LK, Naser SA, Masternak MM. Plasma miRNA Profile of Crohn's Disease and Rheumatoid Arthritis Patients. BIOLOGY 2022; 11:508. [PMID: 35453708 PMCID: PMC9033111 DOI: 10.3390/biology11040508] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 06/14/2023]
Abstract
Crohn's disease (CD) and rheumatoid arthritis (RA) are immune mediated inflammatory diseases. Several studies indicate a role for microRNAs (miRNAs) in the pathogenesis of a variety of autoimmune diseases, including CD and RA. Our study's goal was to investigate circulating miRNAs in CD and RA patients to identify potential new biomarkers for early detection and personalized therapeutic approaches for autoimmune diseases. For this study, subjects with CD (n = 7), RA (n = 8) and healthy controls (n = 7) were recruited, and plasma was collected for miRNA sequencing. Comparison of the expression patterns of miRNAs between CD and healthy patients identified 99 differentially expressed miRNAs. Out of these miRNAs, 4 were down regulated, while 95 were up regulated. Comparison of miRNAs between RA and healthy patients identified 57 differentially expressed miRNAs. Out of those, 12 were down regulated, while 45 were up regulated. For all the miRNAs down regulated in CD and RA patients, 420 GO terms for biological processes were similarly regulated between both groups. Therefore, the identification of new plasma miRNAs allows the emergence of new biomarkers that can assist in the diagnosis and treatment of CD and RA.
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Affiliation(s)
- Tatiana D. Saccon
- Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas 96010-610, Brazil;
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (A.Q.); (M.B.C.); (S.A.N.)
| | - Joseph M. Dhahbi
- Department of Medical Education, School of Medicine, California University of Science & Medicine, San Bernardino, CA 92324, USA; (J.M.D.); (L.K.S.)
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas 96010-610, Brazil;
| | | | - Ahmad Qasem
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (A.Q.); (M.B.C.); (S.A.N.)
| | - Marcelo B. Cavalcante
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (A.Q.); (M.B.C.); (S.A.N.)
- Department of Obstetrics and Gynecology, Fortaleza University, Fortaleza 60811-905, Brazil
| | - Lauren K. Sing
- Department of Medical Education, School of Medicine, California University of Science & Medicine, San Bernardino, CA 92324, USA; (J.M.D.); (L.K.S.)
| | - Saleh A. Naser
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (A.Q.); (M.B.C.); (S.A.N.)
| | - Michal M. Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (A.Q.); (M.B.C.); (S.A.N.)
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland
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The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability. Cells 2021; 10:cells10123358. [PMID: 34943865 PMCID: PMC8699384 DOI: 10.3390/cells10123358] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/15/2022] Open
Abstract
Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability.
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Moret-Tatay I, Cerrillo E, Hervás D, Iborra M, Sáez-González E, Forment J, Tortosa L, Nos P, Gadea J, Beltrán B. Specific Plasma MicroRNA Signatures in Predicting and Confirming Crohn's Disease Recurrence: Role and Pathogenic Implications. Clin Transl Gastroenterol 2021; 12:e00416. [PMID: 34695034 PMCID: PMC8547914 DOI: 10.14309/ctg.0000000000000416] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 08/22/2021] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) are important epigenetic regulators in Crohn's disease (CD); however, their contribution to postoperative recurrence (POR) is still unknown. We aimed to characterize the potential role of miRNAs in predicting POR in patients with CD and to identify their pathogenic implications. METHODS Of 67 consecutively operated patients with CD, we included 44 with pure ileal CD. Peripheral blood samples were taken before surgery and during follow-up. The patients were classified according to the presence or absence of POR assessed by ileocolonoscopy or magnetic resonance imaging enterography. The miRNAs were profiled by reverse transcription polymerase chain reaction before surgery and during morphological POR or, for those who remained in remission, 1 year after surgery. R software and mirWalk were used. RESULTS Five human miRNAs (miR-191-5p, miR-15b-5p, miR-106b-5p, miR-451a, and miR-93-5p) were selected for discriminating between the 2 patient groups at presurgery (PS), with an area under the curve of 0.88 (95% confidence interval [0.79, 0.98]). Another 5 (miR-15b-5p, miR-451a, miR-93-5p, miR-423-5p, and miR-125b-5p) were selected for 1 year, with an area under the curve of 0.96 (95% confidence interval [0.91, 1.0]). We also created nomograms for POR risk estimation. CCND2 and BCL9L genes were related to PS miRNA profiles; SENP5 and AKT3 genes were related to PS and 1 year; and SUV39H1 and MAPK3K10 were related to 1 year. DISCUSSION Different plasma miRNA signatures identify patients at high POR risk, which could help optimize patient outcomes. We developed nomograms to facilitate the clinical use of these results. The identified miRNAs participate in apoptosis, autophagy, proinflammatory immunological T-cell clusters, and reactive oxygen species metabolism.
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Affiliation(s)
- Inés Moret-Tatay
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Biomedical Research Centre, Hepatic and Digestive Diseases Network [Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)], Madrid, Spain
| | - Elena Cerrillo
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - David Hervás
- Biostatistics Unit, Health Research IIS La Fe, Valencia, Spain
| | - Marisa Iborra
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Biomedical Research Centre, Hepatic and Digestive Diseases Network [Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)], Madrid, Spain
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Esteban Sáez-González
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Javier Forment
- The Institute for Plant Molecular and Cellular Biology (IBMCP), Polytechnic University of Valencia- Spanish Research Council (CSIC), Valencia, Spain
| | - Luis Tortosa
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Biomedical Research Centre, Hepatic and Digestive Diseases Network [Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)], Madrid, Spain
| | - Pilar Nos
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Biomedical Research Centre, Hepatic and Digestive Diseases Network [Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)], Madrid, Spain
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Jose Gadea
- The Institute for Plant Molecular and Cellular Biology (IBMCP), Polytechnic University of Valencia- Spanish Research Council (CSIC), Valencia, Spain
| | - Belén Beltrán
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- Biomedical Research Centre, Hepatic and Digestive Diseases Network [Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)], Madrid, Spain
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
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11
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Peng XX, Yu R, Wu X, Wu SY, Pi C, Chen ZH, Zhang XC, Gao CY, Shao YW, Liu L, Wu YL, Zhou Q. Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy in EGFR / ALK wild-type advanced non-small cell lung cancer. J Immunother Cancer 2021; 8:jitc-2019-000376. [PMID: 31959728 PMCID: PMC7057418 DOI: 10.1136/jitc-2019-000376] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2019] [Indexed: 12/13/2022] Open
Abstract
Background Immunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advanced EGFR/ALK negative NSCLC to immunotherapy. Methods From June 2017 to February 2019, 30 patients with advanced EGFR/ALK wild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis. Results In order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients. Conclusion Patients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.
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Affiliation(s)
- Xiao-Xiao Peng
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ruoying Yu
- Translational Medicine Research Institute, Geneseeq Technology Inc, Toronto, Ontario, Canada
| | - Xue Wu
- Translational Medicine Research Institute, Geneseeq Technology Inc, Toronto, Ontario, Canada
| | - Shu-Yu Wu
- Department of Research and Development, Nanjing Geneseeq Technology Inc, Nanjing, China
| | - Can Pi
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xu-Chao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Cun-Yi Gao
- Department of Research and Development, Nanjing Geneseeq Technology Inc, Nanjing, China
| | - Yang W Shao
- Department of Research and Development, Nanjing Geneseeq Technology Inc, Nanjing, China.,School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Li Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qing Zhou
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
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12
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Dragoni G, Innocenti T, Galli A. Biomarkers of Inflammation in Inflammatory Bowel Disease: How Long before Abandoning Single-Marker Approaches? Dig Dis 2020; 39:190-203. [PMID: 32942275 DOI: 10.1159/000511641] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 09/16/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronically relapsing disease with a continuous need for proactive monitoring to decide appropriate treatments and follow-up strategies. To date, gastrointestinal endoscopy with histologic examination of biopsies and contrast-enhanced imaging are mandatory techniques for the diagnosis and the activity assessment of IBD. SUMMARY In recent decades, many research efforts in the IBD field have been placed on finding non-invasive and reliable biomarkers of disease burden that can be easily tested in body fluids without impacting the quality of life of patients. Unfortunately, the ideal biomarker is yet to be discovered and recent studies have investigated the possibility to increase the accuracy of such measurements by combining different markers. In this review, we provide an update about the current knowledge on biomarkers of intestinal inflammation in IBD, focussing on disease diagnosis, correlation with endoscopic findings, and prediction of relapse. We also summarize composite scores of clinical and laboratory markers that have been recently proposed in various scenarios of disease activity. Key Messages: To date, only C-reactive protein and faecal calprotectin can be considered reliable markers of disease activity with demonstrated utility in IBD management. The combination of different parameters has recently shown higher accuracy and might substitute single-marker approaches in the future of research and clinical practice.
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Affiliation(s)
- Gabriele Dragoni
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy, .,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy, .,Department of Medical Biotechnologies, University of Siena, Siena, Italy,
| | - Tommaso Innocenti
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
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13
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Latini A, Borgiani P, Novelli G, Ciccacci C. miRNAs in drug response variability: potential utility as biomarkers for personalized medicine. Pharmacogenomics 2020; 20:1049-1059. [PMID: 31559917 DOI: 10.2217/pgs-2019-0089] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
MicroRNAs (miRNAs) are 18-22 nucleotide RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. Almost all physiological conditions are probably modulated by miRNAs, including pharmacological response. Indeed, acting on the regulation of numerous genes involved in the pharmacokinetics and pharmacodynamics of drugs, differences in the levels of circulating miRNAs or genetic variants in the sequences of the miRNA genes can contribute to interindividual variability in drug response, both in terms of toxicity and efficacy. For their stability in body fluids and the easy availability and accurate quantification, miRNAs could be ideal biomarkers of individual response to drugs. This review aims to give an overview on the available studies that have investigated the relationship between miRNAs and response to drugs in different classes of diseases and considered their possible clinical application as therapy response predictive biomarkers. A comprehensive search was conducted from the international web database PubMed. We included papers that investigated the relationship between miRNAs and response to drugs, published before January 2019.
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Affiliation(s)
- Andrea Latini
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly.,IRCCS Neuromed, 86077, Pozzilli, IS, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly.,UniCamillus, Saint Camillus International University of Health Sciences, 00131, Rome, Italy
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14
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Verdier J, Breunig IR, Ohse MC, Roubrocks S, Kleinfeld S, Roy S, Streetz K, Trautwein C, Roderburg C, Sellge G. Faecal Micro-RNAs in Inflammatory Bowel Diseases. J Crohns Colitis 2020; 14:110-117. [PMID: 31209454 DOI: 10.1093/ecco-jcc/jjz120] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Faecal biomarkers are used as indicators of disease activity in inflammatory bowel diseases [IBD], which include Crohn's disease [CD] and ulcerative colitis [UC]. Micro-RNAs [miRNAs] are small non-coding RNAs detectable in extracellular fluids and can be used as clinical biomarkers. The aim of this study was to determine if faecal miRNA composition is altered in IBD. METHODS More than 800 different human faecal miRNAs were measured in stool samples from control individuals and patients with active CD by using NanoString technology. Selected miRNAs were quantified by qRT-PCR in faeces, serum and intestinal tissue of controls [n = 23] and patients with inactive or active CD [n = 22, n = 22] or UC [n = 11, n = 24] as well as patients with Clostridium difficile infection [CDI, n = 8]. RESULTS In total, 150 miRNAs were significantly detected in faeces from controls and patients, and multivariate analyses showed that CD patients with high disease activities had a distinct miRNA profile and that miR-223 and miR-1246 were distinct from other faecal miRNAs. In a larger cohort, active UC patients displayed significantly higher levels of miR-223 and miR-1246 than controls while patients with CDI had higher levels of faecal miR-1246 but not miR-223. No differences were noted in serum samples. CONCLUSIONS To our knowledge, this is the first comprehensive screen of faecal miRNAs performed in IBD. Further investigation will aim to confirm these findings in a larger cohort and to understand the biological function and cellular sources of faecal miRNAs.
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Affiliation(s)
- Julien Verdier
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.,INSERM, Sorbonne Universités, UPMC Univ Paris, AIM-Institute of Myology, Paris, France
| | | | - Margarete Clara Ohse
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Silvia Roubrocks
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sandra Kleinfeld
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sanchari Roy
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Konrad Streetz
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christoph Roderburg
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Gernot Sellge
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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15
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Zeng Z, Mukherjee A, Zhang H. From Genetics to Epigenetics, Roles of Epigenetics in Inflammatory Bowel Disease. Front Genet 2019; 10:1017. [PMID: 31737035 PMCID: PMC6834788 DOI: 10.3389/fgene.2019.01017] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 09/24/2019] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a destructive, recurrent, and heterogeneous disease. Its detailed pathogenesis is still unclear, although available evidence supports that IBD is caused by a complex interplay between genetic predispositions, environmental factors, and aberrant immune responses. Recent breakthroughs with regard to its genetics have offered valuable insights into the sophisticated genetic basis, but the identified genetic factors only explain a small part of overall disease variance. It is becoming increasingly apparent that epigenetic factors can mediate the interaction between genetics and environment, and play a fundamental role in the pathogenesis of IBD. This review outlines recent genetic and epigenetic discoveries in IBD, with a focus on the roles of epigenetics in disease susceptibility, activity, behavior and colorectal cancer (CRC), and their potential translational applications.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | | | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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16
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Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity. Int J Mol Sci 2019; 20:ijms20030676. [PMID: 30764482 PMCID: PMC6387440 DOI: 10.3390/ijms20030676] [Citation(s) in RCA: 242] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/23/2019] [Accepted: 01/31/2019] [Indexed: 12/24/2022] Open
Abstract
Systemic and local chronic inflammation might enhance the risk of pancreatic ductal adenocarcinoma (PDAC), and PDAC-associated inflammatory infiltrate in the tumor microenvironment concurs in enhancing tumor growth and metastasis. Inflammation is closely correlated with immunity, the same immune cell populations contributing to both inflammation and immune response. In the PDAC microenvironment, the inflammatory cell infiltrate is unbalanced towards an immunosuppressive phenotype, with a prevalence of myeloid derived suppressor cells (MDSC), M2 polarized macrophages, and Treg, over M1 macrophages, dendritic cells, and effector CD4⁺ and CD8⁺ T lymphocytes. The dynamic and continuously evolving cross-talk between inflammatory and cancer cells might be direct and contact-dependent, but it is mainly mediated by soluble and exosomes-carried cytokines. Among these, tumor necrosis factor alpha (TNFα) plays a relevant role in enhancing cancer risk, cancer growth, and cancer-associated cachexia. In this review, we describe the inflammatory cell types, the cytokines, and the mechanisms underlying PDAC risk, growth, and progression, with particular attention on TNFα, also in the light of the potential risks or benefits associated with anti-TNFα treatments.
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17
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Rojas-Feria M, Romero-García T, Fernández Caballero-Rico JÁ, Pastor Ramírez H, Avilés-Recio M, Castro-Fernandez M, Chueca Porcuna N, Romero-Gόmez M, García F, Grande L, Del Campo JA. Modulation of faecal metagenome in Crohn’s disease: Role of microRNAs as biomarkers. World J Gastroenterol 2018; 24:5223-5233. [PMID: 30581271 PMCID: PMC6295834 DOI: 10.3748/wjg.v24.i46.5223] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/13/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The gut microbiota plays a key role in the maintenance of intestinal homeostasis and the development and activation of the host immune system. It has been shown that commensal bacterial species can regulate the expression of host genes. 16S rRNA gene sequencing has shown that the microbiota in inflammatory bowel disease (IBD) is abnormal and characterized by reduced diversity. MicroRNAs (miRNAs) have been explored as biomarkers and therapeutic targets, since they are able to regulate specific genes associated with Crohn’s disease (CD). In this work, we aim to investigate the composition of gut microbiota of active treatment-naïve adult CD patients, with miRNA profile from gut microbiota.
AIM To investigate the composition of gut microbiota of active treatment-naïve adult CD patients, with miRNA profile from gut microbiota.
METHODS Patients attending the outpatient clinics at Valme University Hospital without relevant co-morbidities were matched according to age and gender. Faecal samples of new-onset CD patients, free of treatment, and healthy controls were collected. Faecal samples were homogenized, and DNA was amplified by PCR using primers directed to the 16S bacterial rRNA gene. Pyrosequencing was performed using GS-Junior platform. For sequence analysis, MG-RAST server with the database Ribosomal Project was used. MiRNA profile and their relative abundance were analyzed by quantitative PCR.
RESULTS Microbial community was characterized using 16S rRNA gene sequencing in 29 samples (n = 13 CD patients, and n = 16 healthy controls). The mean Shannon diversity was higher in the healthy control population compared to CD group (5.5 vs 3.7). A reduction in Firmicutes and an increase in Bacteroidetes were found. Clostridia class was also significantly reduced in CD. Principal components analysis showed a grouping pattern, identified in most of the subjects in both groups, showing a marked difference between control and CD groups. A functional metabolic study showed that a lower metabolism of carbohydrates (P = 0.000) was found in CD group, while the metabolism of lipids was increased. In CD patients, three miRNAs were induced in affected mucosa: mir-144 (6.2 ± 1.3 fold), mir-519 (21.8 ± 3.1) and mir-211 (2.3 ± 0.4).
CONCLUSION Changes in microbial function in active non-treated CD subjects and three miRNAs in affected vs non-affected mucosa have been found. miRNAs profile may serve as a biomarker.
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Affiliation(s)
- María Rojas-Feria
- Department of Digestive Diseases, Valme University Hospital, UGC Digestive Disease and CIBERehd, Servicio Andaluz de Salud, Seville E-41014, Spain
| | - Teresa Romero-García
- Department of Digestive Diseases, Valme University Hospital, UGC Digestive Disease and CIBERehd, Servicio Andaluz de Salud, Seville E-41014, Spain
| | - Jose Ángel Fernández Caballero-Rico
- Complejo Hospitalario Universitario de Granada, Microbiology, Granada E-18016, Spain
- Facultad de ciencias de la salud. Universidad Europea Miguel de Cervantes, Madrid E-28280, Spain
| | - Helena Pastor Ramírez
- Institute of Biomedicine of Seville, Digestive Diseases, Hospital Universitario Virgen del Rocío and CIBERehd, Seville E-41013, Spain
| | - Marta Avilés-Recio
- Department of Digestive Diseases, Valme University Hospital, UGC Digestive Disease and CIBERehd, Servicio Andaluz de Salud, Seville E-41014, Spain
| | - Manuel Castro-Fernandez
- Department of Digestive Diseases, Valme University Hospital, UGC Digestive Disease and CIBERehd, Servicio Andaluz de Salud, Seville E-41014, Spain
| | | | - Manuel Romero-Gόmez
- Institute of Biomedicine of Seville, Digestive Diseases, Hospital Universitario Virgen del Rocío and CIBERehd, Seville E-41013, Spain
| | - Federico García
- Complejo Hospitalario Universitario de Granada, Microbiology, Granada E-18016, Spain
| | - Lourdes Grande
- Department of Digestive Diseases, Valme University Hospital, UGC Digestive Disease and CIBERehd, Servicio Andaluz de Salud, Seville E-41014, Spain
| | - José A Del Campo
- Department of Digestive Diseases, Valme University Hospital, UGC Digestive Disease and CIBERehd, Servicio Andaluz de Salud, Seville E-41014, Spain
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18
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Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, Stocco G. Pharmacogenetics of treatments for inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2018; 14:1209-1223. [PMID: 30465611 DOI: 10.1080/17425255.2018.1551876] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.
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Affiliation(s)
- Marianna Lucafò
- a Experimental and Clinical Pharmacology Unit , National Cancer Institute - Centro di Riferimento Oncologico , Aviano , Italy
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
| | - Raffaella Franca
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Davide Selvestrel
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Debora Curci
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Letizia Pugnetti
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Giuliana Decorti
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Gabriele Stocco
- e Department of Life Sciences , University of Trieste , Trieste , Italy
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19
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De Iudicibus S, Lucafò M, Vitulo N, Martelossi S, Zimbello R, De Pascale F, Forcato C, Naviglio S, Di Silvestre A, Gerdol M, Stocco G, Valle G, Ventura A, Bramuzzo M, Decorti G. High-Throughput Sequencing of microRNAs in Glucocorticoid Sensitive Paediatric Inflammatory Bowel Disease Patients. Int J Mol Sci 2018; 19:1399. [PMID: 29738455 PMCID: PMC5983624 DOI: 10.3390/ijms19051399] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 04/27/2018] [Accepted: 05/03/2018] [Indexed: 01/02/2023] Open
Abstract
The aim of this research was the identification of novel pharmacogenomic biomarkers for better understanding the complex gene regulation mechanisms underpinning glucocorticoid (GC) action in paediatric inflammatory bowel disease (IBD). This goal was achieved by evaluating high-throughput microRNA (miRNA) profiles during GC treatment, integrated with the assessment of expression changes in GC receptor (GR) heterocomplex genes. Furthermore, we tested the hypothesis that differentially expressed miRNAs could be directly regulated by GCs through investigating the presence of GC responsive elements (GREs) in their gene promoters. Ten IBD paediatric patients responding to GCs were enrolled. Peripheral blood was obtained at diagnosis (T0) and after four weeks of steroid treatment (T4). MicroRNA profiles were analyzed using next generation sequencing, and selected significantly differentially expressed miRNAs were validated by quantitative reverse transcription-polymerase chain reaction. In detail, 18 miRNAs were differentially expressed from T0 to T4, 16 of which were upregulated and 2 of which were downregulated. Out of these, three miRNAs (miR-144, miR-142, and miR-96) could putatively recognize the 3’UTR of the GR gene and three miRNAs (miR-363, miR-96, miR-142) contained GREs sequences, thereby potentially enabling direct regulation by the GR. In conclusion, we identified miRNAs differently expressed during GC treatment and miRNAs which could be directly regulated by GCs in blood cells of young IBD patients. These results could represent a first step towards their translation as pharmacogenomic biomarkers.
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Affiliation(s)
- Sara De Iudicibus
- Institute for Maternal and Child Health- IRCCS "Burlo Garofolo", 34127 Trieste, Italy.
| | - Marianna Lucafò
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Nicola Vitulo
- Department of Biotechnology, University of Verona, 37100 Verona, Italy.
| | - Stefano Martelossi
- Institute for Maternal and Child Health- IRCCS "Burlo Garofolo", 34127 Trieste, Italy.
| | - Rosanna Zimbello
- CRIBI Biotechnology Centre, University of Padua, 35100 Padua, Italy.
| | - Fabio De Pascale
- CRIBI Biotechnology Centre, University of Padua, 35100 Padua, Italy.
| | - Claudio Forcato
- CRIBI Biotechnology Centre, University of Padua, 35100 Padua, Italy.
| | - Samuele Naviglio
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Alessia Di Silvestre
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Marco Gerdol
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Giorgio Valle
- CRIBI Biotechnology Centre, University of Padua, 35100 Padua, Italy.
| | - Alessandro Ventura
- Institute for Maternal and Child Health- IRCCS "Burlo Garofolo", 34127 Trieste, Italy.
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health- IRCCS "Burlo Garofolo", 34127 Trieste, Italy.
| | - Giuliana Decorti
- Institute for Maternal and Child Health- IRCCS "Burlo Garofolo", 34127 Trieste, Italy.
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
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20
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Cirillo F, Lazzeroni P, Catellani C, Sartori C, Amarri S, Street ME. MicroRNAs link chronic inflammation in childhood to growth impairment and insulin-resistance. Cytokine Growth Factor Rev 2018; 39:1-18. [DOI: 10.1016/j.cytogfr.2017.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 12/21/2017] [Indexed: 02/07/2023]
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21
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Netz U, Carter J, Eichenberger MR, Feagins K, Galbraith NJ, Dryden GW, Pan J, Rai SN, Galandiuk S. Plasma microRNA Profile Differentiates Crohn's Colitis From Ulcerative Colitis. Inflamm Bowel Dis 2018; 24:159-165. [PMID: 29272478 PMCID: PMC5858028 DOI: 10.1093/ibd/izx009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. METHODS Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. RESULTS Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). CONCLUSIONS We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions.
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Affiliation(s)
- Uri Netz
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky,Department of Surgery A, Soroka University Medical Center, Beer Sheva,
Israel,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva,
Israel
| | - Jane Carter
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - M Robert Eichenberger
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Kayla Feagins
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Norman J Galbraith
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Gerald W Dryden
- Department of Medicine, Division of Gastroenterology, Hepatology, and
Nutrition University of Louisville School of Medicine Louisville, Kentucky
| | - Jianmin Pan
- Department of Bioinformatics and Biostatistics, University of Louisville
School of Public Health and Information Sciences, Louisville, Kentucky
| | - Shesh N Rai
- Department of Bioinformatics and Biostatistics, University of Louisville
School of Public Health and Information Sciences, Louisville, Kentucky
| | - Susan Galandiuk
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky,Address correspondence to: Susan Galandiuk, MD, FACG, AGAF, The Hiram C.
Polk Jr, MD Department of Surgery, 550 South Jackson Street, Louisville, KY 40202 (e-mail:
)
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22
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Papaconstantinou I, Kapizioni C, Legaki E, Xourgia E, Karamanolis G, Gklavas A, Gazouli M. Association of miR-146 rs2910164, miR-196a rs11614913, miR-221 rs113054794 and miR-224 rs188519172 polymorphisms with anti-TNF treatment response in a Greek population with Crohn's disease. World J Gastrointest Pharmacol Ther 2017; 8:193-200. [PMID: 29152405 PMCID: PMC5680166 DOI: 10.4292/wjgpt.v8.i4.193] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/21/2017] [Accepted: 09/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the correlation between rs2910164, rs11 614913, rs113054794, and rs188519172 polymorphisms and response to anti-TNF treatment in patients with Crohn's disease (CD). METHODS One hundred seven patients with CD based on standard clinical, endoscopic, radiological, and pathological criteria were included in the study. They all received infliximab or adalimumab intravenously or subcutaneously at standard induction doses as per international guidelines. Clinical and biochemical response was assessed using the Harvey-Bradshaw index and CRP levels respectively. Endoscopic response was evaluated by ileocolonoscopy at week 12-20 of therapy. The changes in endoscopic appearance compared to baseline were classified into four categories, and patients were classified as responders and non-responders. Whole peripheral blood was extracted and genotyping was performed by PCR. RESULTS One hundred and seven patients were included in the study. Seventy two (67.3%) patients were classified as complete responders, 22 (20.5%) as partial while 13 (12.1%) were primary non-responders. No correlation was detected between response to anti-TNF agents and patients' characteristics such as gender, age and disease duration while clinical and biochemical indexes used were associated with endoscopic response. Concerning prevalence of rs2910164, rs11614913, and rs188519172 polymorphisms of miR-146, miR-196a and miR-224 respectively no statistically important difference was found between complete, partial, and non-responders to anti-TNF treatment. Actually CC genotype of rs2910164 was not detected in any patient. Regarding rs113054794 of miR-221, normal CC genotype was the only one detected in all studied patients, suggesting this polymorphism is highly rare in the studied population. CONCLUSION No correlation is detected between studied polymorphisms and patients' response to anti-TNF treatment. Polymorphism rs113054794 is not detected in our population.
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Affiliation(s)
- Ioannis Papaconstantinou
- 2nd Department of Surgery, Aretaieio Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Christina Kapizioni
- Gastroenterology Department, Tzaneion General Hospital, 18536 Piraeus, Greece
| | - Evangelia Legaki
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Elena Xourgia
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - George Karamanolis
- Gastroenterology Unit, 2nd Department of Surgery, Aretaieio Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Antonios Gklavas
- 2nd Department of Surgery, Aretaieio Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Cirillo F, Lazzeroni P, Sartori C, Street ME. Inflammatory Diseases and Growth: Effects on the GH-IGF Axis and on Growth Plate. Int J Mol Sci 2017; 18:E1878. [PMID: 28858208 PMCID: PMC5618527 DOI: 10.3390/ijms18091878] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 08/23/2017] [Accepted: 08/29/2017] [Indexed: 02/08/2023] Open
Abstract
This review briefly describes the most common chronic inflammatory diseases in childhood, such as cystic fibrosis (CF), inflammatory bowel diseases (IBDs), juvenile idiopathic arthritis (JIA), and intrauterine growth restriction (IUGR) that can be considered, as such, for the changes reported in the placenta and cord blood of these subjects. Changes in growth hormone (GH) secretion, GH resistance, and changes in the insulin-like growth factor (IGF) system are described mainly in relationship with the increase in nuclear factor-κB (NF-κB) and pro-inflammatory cytokines. Changes in the growth plate are also reported as well as a potential role for microRNAs (miRNAs) and thus epigenetic changes in chronic inflammation. Many mechanisms leading to growth failure are currently known; however, it is clear that further research in the field is still warranted.
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Affiliation(s)
- Francesca Cirillo
- Division of Paediatric Endocrinology and Diabetology, Department of Obstetrics, Gynaecology and Paediatrics, Azienda AUSL-IRCCS, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy.
| | - Pietro Lazzeroni
- Division of Paediatric Endocrinology and Diabetology, Department of Obstetrics, Gynaecology and Paediatrics, Azienda AUSL-IRCCS, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy.
| | - Chiara Sartori
- Division of Paediatric Endocrinology and Diabetology, Department of Obstetrics, Gynaecology and Paediatrics, Azienda AUSL-IRCCS, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy.
| | - Maria Elisabeth Street
- Division of Paediatric Endocrinology and Diabetology, Department of Obstetrics, Gynaecology and Paediatrics, Azienda AUSL-IRCCS, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy.
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24
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Cao B, Zhou X, Ma J, Zhou W, Yang W, Fan D, Hong L. Role of MiRNAs in Inflammatory Bowel Disease. Dig Dis Sci 2017; 62:1426-1438. [PMID: 28391412 DOI: 10.1007/s10620-017-4567-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 04/01/2017] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBD), mainly including Crohn's disease and ulcerative colitis, are characterized by chronic inflammation of the gastrointestinal tract. Despite improvements in detection, drug treatment and surgery, the pathogenesis of IBD has not been clarified. A number of miRNAs have been found to be involved in the initiation, development and progression of IBD, and they may have the potential to be used as biomarkers and therapeutic targets. Here, we have summarized the recent advances about the roles of miRNAs in IBD and analyzed the contribution of miRNAs to general diagnosis, differential diagnosis and activity judgment of IBD. Furthermore, we have also elaborated the promising role of miRNAs in IBD-related cancer prevention and prognosis prediction.
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Affiliation(s)
- Bo Cao
- The First Brigade of Student, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Xin Zhou
- The First Brigade of Student, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Jiaojiao Ma
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Wei Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Wanli Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Liu Hong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
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25
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Béres NJ, Kiss Z, Sztupinszki Z, Lendvai G, Arató A, Sziksz E, Vannay Á, Szabó AJ, Müller KE, Cseh Á, Boros K, Veres G. Altered mucosal expression of microRNAs in pediatric patients with inflammatory bowel disease. Dig Liver Dis 2017; 49:378-387. [PMID: 28077249 DOI: 10.1016/j.dld.2016.12.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 12/15/2016] [Accepted: 12/18/2016] [Indexed: 12/11/2022]
Abstract
INTRODUCTION MicroRNAs (miRs) came recently into focus as promising novel research targets offering new insights into the pathogenesis of inflammatory bowel diseases (IBD). AIMS The aim of our study was to identify a pediatric IBD (pIBD) characteristic miR profile serving as potential Crohn's disease (CD) and ulcerative colitis (UC) specific diagnostic pattern and to further analyze the related target genes. METHODS Small RNA sequencing was performed on inflamed and intact colonic biopsies of CD, and control patients. Selected miRs were further investigated by RT-PCR, complemented with an UC group, in order to address the differential diagnostic potential of miRs in the two IBD subtypes. To analyze network connection of differentially expressed miRs and their target genes MiRTarBase database and previous transcriptome sequencing data from pediatric patient groups were used. RESULTS Sequencing analysis identified 170 miRs with altered expression. RT-PCR analysis revealed altered expression of miR-31, -125a, -142-3p, and -146a discriminating between the inflamed mucosa of CD and UC. In the intact mucosa of CD patients the expression of miR-18a, -20a, -21, -31, -99a, -99b, -100, -125a, -126, -142-5p, -146a, -185, -204, -221, and -223 was elevated compared to the controls. The expression of miR-20a, -204 and -221 was elevated exclusively in the intact region of CD patients compared to the controls. Enrichment analysis identified main IBD-related functional groups. CONCLUSIONS We demonstrated a characteristic colonic miR pattern in pIBD that could facilitate deeper understanding of the pathomechanism of IBD and may serve as a diagnostic tool.
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Affiliation(s)
- Nóra Judit Béres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Zoltán Kiss
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | | | - Gábor Lendvai
- MTA-SE Tumor Progression Research Group, Budapest, Hungary
| | - András Arató
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Erna Sziksz
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | - Ádám Vannay
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | - Attila J Szabó
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | | | - Áron Cseh
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Kriszta Boros
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Gábor Veres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
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26
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Cuppen BVJ, Rossato M, Fritsch-Stork RDE, Concepcion AN, Schenk Y, Bijlsma JWJ, Radstake TRDJ, Lafeber FPJG. Can baseline serum microRNAs predict response to TNF-alpha inhibitors in rheumatoid arthritis? Arthritis Res Ther 2016; 18:189. [PMID: 27558398 PMCID: PMC4997731 DOI: 10.1186/s13075-016-1085-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 08/01/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND In rheumatoid arthritis, prediction of response to TNF-alpha inhibitor (TNFi) treatment would be of clinical value. This study aims to discover miRNAs that predict response and aims to replicate results of two previous studies addressing this topic. METHODS From the observational BiOCURA cohort, 40 adalimumab- (ADA) and 40 etanercept- (ETN) treated patients were selected to enter the discovery cohort and baseline serum profiling on 758 miRNAs was performed. The added value of univariately selected miRNAs (p < 0.05) over clinical parameters in prediction of response was determined by means of the area under the receiver operating characteristic curve (AUC-ROC). Validation was performed by TaqMan single qPCR assays in 40 new patients. RESULTS Expression of miR-99a and miR-143 predicted response to ADA, and miR-23a and miR-197 predicted response to ETN. The addition of miRNAs increased the AUC-ROC of a model containing only clinical parameters for ADA (0.75 to 0.97) and ETN (0.68 to 0.78). In validation, none of the selected miRNAs significantly predicted response. miR-23a was the only overlapping miRNA compared to the two previous studies, however inversely related with response in one of these studies. The reasons for the inability to replicate previously proposed miRNAs predicting response to TNFi and replicate those from the discovery cohort were investigated and discussed. CONCLUSIONS To date, no miRNA consistently predicting response to TNFi therapy in RA has been identified. Future studies on this topic should meet a minimum of standards in design that are addressed in this study, in order to increase the reproducibility.
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Affiliation(s)
- Bart V J Cuppen
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
| | - Marzia Rossato
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.,Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Ruth D E Fritsch-Stork
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.,1st Medical Department & Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Hanusch Hospital, Heinrich-Collin-Straße 30, 1140, Vienna, Austria.,Sigmund Freud University, Freudplatz 1, 1020, Vienna, Austria
| | - Arno N Concepcion
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Yolande Schenk
- Rheumatology, Diakonessen Hospital, Bosboomstraat 1, 3582 KE, Utrecht, The Netherlands
| | - Johannes W J Bijlsma
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Timothy R D J Radstake
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.,Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Floris P J G Lafeber
- Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
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Guo Z, Gong J, Li Y, Gu L, Cao L, Wang Z, Zhu W, Li J. Mucosal MicroRNAs Expression Profiles before and after Exclusive Enteral Nutrition Therapy in Adult Patients with Crohn's Disease. Nutrients 2016; 8:519. [PMID: 27556489 PMCID: PMC4997431 DOI: 10.3390/nu8080519] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 08/07/2016] [Accepted: 08/15/2016] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) have been shown to be important for the pathogenesis of Crohn's disease (CD). Exclusive enteral nutrition (EEN) is an effective therapy for inducing remission in CD. We aimed to investigate the alteration of miRNAs expression profile in the terminal ileal mucosa of CD patients before and after EEN. Twenty-five patients and ten healthy individuals were included. MiRNAs expression profile was firstly assessed using microarray technology and then validation was performed by qRT-PCR. The correlations between miRNAs and CD activity index (CDAI) score and serum C-reactive protein (CRP) level were also evaluated. Microarray analysis showed that mucosal miRNAs expression profile after EEN therapy was significantly changed compared with inflamed mucosa before treatment, and was most similar to the healthy one among all CD groups. Altered expressions of hsa-miR-192-5p, hsa-miR-423-3p, hsa-miR-99a-5p, hsa-miR-124-3p, hsa-miR-301a-5p, hsa-miR-495-5p, and hsa-let-7b-5p were confirmed by qRT-PCR. hsa-let-7b-5p was significantly correlated with serum CRP levels before and after EEN treatment (r = -0.518, p = 0.008, and r = -0.569, p = 0.003). Our study showed EEN induction therapy was associated with a trend for normalizing of the mucosal miRNAs expression profile, and expression of mucosal hsa-let-7b-5p was correlated with serum CRP level in patients with CD.
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Affiliation(s)
- Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Lili Gu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Lei Cao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Zhiming Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
| | - Jieshou Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, China.
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28
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Pellino G, Pallante P, Selvaggi F. Novel biomarkers of fibrosis in Crohn’s disease. World J Gastrointest Pathophysiol 2016; 7:266-275. [PMID: 27574564 PMCID: PMC4981766 DOI: 10.4291/wjgp.v7.i3.266] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 06/27/2016] [Accepted: 07/22/2016] [Indexed: 02/06/2023] Open
Abstract
Fibrosis represents a major challenge in Crohn’s disease (CD), and many CD patients will develop fibrotic strictures requiring treatment throughout their lifetime. There is no drug that can reverse intestinal fibrosis, and so endoscopic balloon dilatation and surgery are the only effective treatments. Since patients may need repeated treatments, it is important to obtain the diagnosis at an early stage before strictures become symptomatic with extensive fibrosis. Several markers of fibrosis have been proposed, but most need further validation. Biomarkers can be measured either in biological samples obtained from the serum or bowel of CD patients, or using imaging tools and tests. The ideal tool should be easily obtained, cost-effective, and reliable. Even more challenging is fibrosis occurring in ulcerative colitis. Despite the important burden of intestinal fibrosis, including its detrimental effect on outcomes and quality of life in CD patients, it has received less attention than fibrosis occurring in other organs. A common mechanism that acts via a specific signaling pathway could underlie both intestinal fibrosis and cancer. A comprehensive overview of recently introduced biomarkers of fibrosis in CD is presented, along with a discussion of the controversial areas remaining in this field.
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Abstract
There is currently no single test available to confidently diagnose cases of inflammatory bowel disease (IBD). Physicians rely on a number of diagnostic tools, including clinical evaluation, serum testing, and imaging, which are used on conjunction with endoscopic evaluation. It is often difficult to determine whether patients with abdominal pain and change in bowel habit have functional bowel symptoms or whether they have a true diagnosis of IBD. Even once a diagnosis of IBD has been made, a significant proportion of patients are labeled with the term "indeterminate colitis" where histological sampling cannot confidently subclassify patients as either Crohn's or ulcerative colitis. Colonoscopy is an inconvenient and uncomfortable test for most patients. In addition, it is not without serious risks of perforation, as well as risks which can be associated with sedation and analgesia given during the procedure. The use of biomarkers to aid in the diagnosis, subclassification, and monitoring of IBD is an ever expanding area. In this review, we have concentrated on noninvasive biomarkers of IBD, because these are more acceptable to patients and easier to perform in everyday clinical practice. We will first touch on those biomarkers currently well established and in wide clinical use, such as C-reactive protein, erythrocyte sedimentation rate. Faecal calprotectin and their use in the diagnosis of IBD. Following on, we will review more novel biomarkers and their use in subclassification and monitoring of IBD, including a variety of antibodies, genetics, and microRNAs, as well as touching on metabolomics.
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Abstract
PURPOSE OF REVIEW MicroRNAs (miRNAs), small noncoding RNA molecules of approximately 22 nucleotides, have emerged as critical mediators of gene expression. As the dysregulation of gene expression can have far reaching impact on health and disease, miRNAs are being examined as potent new mediators of disease as either biomarkers or potential therapeutic targets. The purpose of this review is to evaluate the contribution of miRNAs to inflammatory bowel disease (IBD) pathophysiology. RECENT FINDINGS Recent studies have evaluated the expression of miRNAs in tissue and body fluid specimens from patients with the main subtypes of IBD - Crohn's disease and ulcerative colitis. Unique miRNA expression patterns that may distinguish IBD subtypes have been uncovered. SUMMARY Significant progress has been made in illuminating the complex interactive networks of miRNAs and gene targets in IBD. The potential use of miRNAs as disease biomarkers or therapeutics shows promise. However, there are still significant hurdles to overcome before miRNA-based therapeutics and diagnostics will be of clinical utility.
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Béres NJ, Szabó D, Kocsis D, Szűcs D, Kiss Z, Müller KE, Lendvai G, Kiss A, Arató A, Sziksz E, Vannay Á, Szabó AJ, Veres G. Role of Altered Expression of miR-146a, miR-155, and miR-122 in Pediatric Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:327-35. [PMID: 26752469 DOI: 10.1097/mib.0000000000000687] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Evidence suggests the central role of tumor necrosis factor (TNF)-α in the pathomechanism of inflammatory bowel disease (IBD); however, its effect on epigenetic factors, including small non-coding microRNAs (miRs), is less known. Our present aim was the comparative investigation of the expression of TNF-α and immune response-related miRs in children with Crohn's disease (CD) and ulcerative colitis (UC). METHODS Fresh-frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) biopsies were used to analyze the expression of miR-146a, -155, -122, and TNF-α by real-time reverse transcription polymerase chain reaction in macroscopically inflamed (CD: 12 FFPE and 24 FF; UC: 10 FF) and intact (CD: 12 FFPE; 14 FF) colonic biopsies of children with IBD and controls (16 FFPE; 23 FF). The expression of miR-146a, -155, and -122 was also determined in TNF-α-treated HT-29 colonic epithelial cells. RESULTS Increased expression of TNF-α was observed in the colonic mucosa of children with CD and UC in comparison with controls. Expression of miR-146a and -155 was higher in the inflamed mucosa of children with CD and UC than in the intact mucosa. Expression of miR-122 elevated in the macroscopically intact colonic regions of CD compared with controls and patients with UC. In HT-29 cells, TNF-α treatment increased the expression of miR-146a and -155, but not that of miR-122. CONCLUSIONS Our results showed altered expression of miR-146a, -155, and -122 in the colonic mucosa of children with IBD and in TNF-α-treated colonic epithelial cells. Our data suggest the TNF-α-related involvement of these miRs in the pathogenesis of IBD.
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Affiliation(s)
- Nóra J Béres
- *1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; †2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary; ‡Department of Pediatrics and Pediatric Health Care Center, University of Szeged, Szeged, Hungary; §2nd Department of Pathology, Semmelweis University, Budapest, Hungary; ‖MTA-SE, Tumor Progression Research Group, Budapest, Hungary; and ¶MTA-SE, Pediatrics and Nephrology Research Group, Budapest, Hungary
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Possible Biomarkers in Blood for Crohn's Disease: Oxidative Stress and MicroRNAs-Current Evidences and Further Aspects to Unravel. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:2325162. [PMID: 26823944 PMCID: PMC4707323 DOI: 10.1155/2016/2325162] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/29/2015] [Accepted: 10/05/2015] [Indexed: 12/14/2022]
Abstract
Crohn's disease (CD) is an inflammatory disorder characterised by a transmural inflammation of the intestinal wall. Although the physiopathology of the disease is not yet fully understood, it is clear that the immune response plays an important role in it. This hyperreactive immune system is accompanied by the presence of unregulated reactive oxygen species (ROS). These elements are modulated in normal conditions by different elements, including enzymes that function as antioxidant defences preventing the harmful effects of ROS. However, in CD there is an imbalance between ROS production and these antioxidant elements, resulting in oxidative stress (OxS) phenomena. In fact, now OxS is being considered more a potential etiological factor for Crohn's disease rather than a concomitant effect in the disease. The persistence of the OxS can also be influencing the evolution of the disease. Furthermore, the epigenetic mechanisms, above all microRNAs, are being considered key elements in the pathogenesis of CD. These elements and the presence of OxS have also been linked to several diseases. We, therefore, describe in this review the most significant findings related to oxidative stress and microRNAs profiles in the peripheral blood of CD patients.
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Koturbash I, Tolleson WH, Guo L, Yu D, Chen S, Hong H, Mattes W, Ning B. microRNAs as pharmacogenomic biomarkers for drug efficacy and drug safety assessment. Biomark Med 2015; 9:1153-76. [PMID: 26501795 PMCID: PMC5712454 DOI: 10.2217/bmm.15.89] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Much evidence has documented that microRNAs (miRNAs) play an important role in the modulation of interindividual variability in the production of drug metabolizing enzymes and transporters (DMETs) and nuclear receptors (NRs) through multidirectional interactions involving environmental stimuli/stressors, the expression of miRNA molecules and genetic polymorphisms. MiRNA expression has been reported to be affected by drugs and miRNAs themselves may affect drug metabolism and toxicity. In cancer research, miRNA biomarkers have been identified to mediate intrinsic and acquired resistance to cancer therapies. In drug safety assessment, miRNAs have been found associated with cardiotoxicity, hepatotoxicity and nephrotoxicity. This review article summarizes published studies to show that miRNAs can serve as early biomarkers for the evaluation of drug efficacy and drug safety.
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Affiliation(s)
- Igor Koturbash
- Department of Environmental & Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - William H Tolleson
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
| | - Lei Guo
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
| | - Dianke Yu
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
| | - Si Chen
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
| | - Huixiao Hong
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
| | - William Mattes
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
| | - Baitang Ning
- National Center for Toxicological Research, US Food & Drug Administration, Jefferson, AR 72079, USA
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Jensen MD, Andersen RF, Christensen H, Nathan T, Kjeldsen J, Madsen JS. Circulating microRNAs as biomarkers of adult Crohn's disease. Eur J Gastroenterol Hepatol 2015; 27:1038-44. [PMID: 26230660 DOI: 10.1097/meg.0000000000000430] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Previous studies have found a differential expression of microRNAs (miRNAs) in the blood of patients with Crohn's disease (CD) compared with healthy controls. The aim of this study was to identify circulating miRNAs expressed in CD and assess their performance as biomarkers in patients with clinically suspected or known CD. METHODS The study consisted of two parts: (a) miRNA profiling: The miRNA expression pattern was examined in six patients with CD and six controls using OpenArray miRNA profiling, and the best miRNAs were selected according to their P-value. (b) Validation cohort: In a well-characterized cohort of 102 patients with suspected or known CD, miRNAs identified by miRNA profiling or selected from previously published studies (hsa-miR-16, hsa-miR-21, hsa-miR-106a, and hsa-miR-140-3p) were measured in plasma using reverse transcription PCR. RESULTS miRNA profiling: hsa-miR-369-3p, hsa-miR-376a, hsa-miR-376, hsa-miR-411#, hsa-miR-411, and mmu-miR-379 were downregulated in CD patients compared with the controls; hsa-miR-200c, hsa-miR-181-2#, and hsa-miR-125a-5p were upregulated (P<0.05). Validation cohort: Only hsa-miR-16 was significantly downregulated in patients with CD compared with patients without CD (fold change 0.83, P=0.02). Receiver operating characteristic analyses showed an area under the curve of 0.65. miRNAs could not discriminate inflammatory from stricturing CD or small bowel CD from CD involving the colon. CONCLUSION In a clinically relevant cohort of patients, miRNAs in plasma identified in the present and previous studies were inadequate biomarkers for the diagnosis of CD.
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Affiliation(s)
- Michael D Jensen
- aDepartment of Internal Medicine, Section of Gastroenterology bDepartment of Clinical Biochemistry, Lillebaelt Hospital, Vejle cDepartment of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
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Abstract
BACKGROUND Development of fibrosis and subsequent stricture formation in Crohn's disease (CD) increases morbidity and rates of surgery and reduces patients' quality of life. There are currently no biomarkers of intestinal fibrosis that might allow earlier identification and better management of patients at increased risk of stricture formation. METHODS MicroRNA profiling of serum from CD patients was used to identify microRNAs associated with stricture formation. Differential expression of miR-19a-3p and miR-19b-3p was validated by quantitative PCR in independent CD cohort of stricturing and nonstricturing patients (n = 46 and n = 62, respectively). Levels of miR-19a-3p and miR-19b-3p were also quantified in baseline serum samples, and expression compared between CD patients who subsequently developed stricture and those who did not (n = 11 and n = 44, respectively). RESULTS Serum levels of miR-19a-3p and miR-19b-3p in the array were lower in CD patients with a stricturing phenotype than in control CD patients (P = 0.007 and 0.008, respectively). The reduction in miR-19a-3p and 19b-3p was verified in a second cohort (P = 0.002). The association of miR-19-3p with stricturing CD was independent of potential confounding clinical variables, including disease duration, disease activity, site, gender, and age. Serum analyses in patients with 4 years of follow-up support the hypothesis that reduced miR-19a-3p and miR-19b-3p predate stricture development with a trend toward significance (P = 0.077 and P = 0.060, respectively). CONCLUSIONS These data identify miR-19-3p as a potential circulating marker of stricturing CD. Our data show that microRNAs have utility as noninvasive biomarkers of stricturing CD. Further longitudinal studies are required to determine the prognostic value of miR-19-3p at diagnosis.
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MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms. Br J Cancer 2015; 112:1480-90. [PMID: 25919696 PMCID: PMC4453675 DOI: 10.1038/bjc.2015.125] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/18/2015] [Accepted: 03/12/2015] [Indexed: 02/07/2023] Open
Abstract
Background: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. Methods: We used TaqMan low-density array (TLDA) qRT–PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. Results: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial–mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. Conclusions: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.
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Shen L, Huang F, Ye L, Zhu W, Zhang X, Wang S, Wang W, Ning G. Circulating microRNA predicts insensitivity to glucocorticoid therapy in Graves' ophthalmopathy. Endocrine 2015; 49:445-56. [PMID: 25588771 DOI: 10.1007/s12020-014-0487-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 11/18/2014] [Indexed: 12/21/2022]
Abstract
Glucocorticoid (GC) insensitivity occurs commonly in Graves' ophthalmopathy (GO), and GC therapy is associated with major adverse effects. A reliable and easily accessible biomarker is required to predict the outcome of GC therapy. This study aimed to evaluate the performance of circulating microRNA (miRNA) to predict GC insensitivity in GO patients. A total of 35 consecutive patients were included in this study. A cumulative dose of 4.5 g of methylprednisolone (MP) was administered intravenously for 12 weeks. Pretreatment serum miRNAs from the best- (N = 5) and worst- (N = 4) responding patients were profiled using miScript PCR arrays and validated by quantitative PCR in all patients. We calculated the predictive value of pretreatment assays of serum miRNAs with regard to GC insensitivity. We further investigated the roles of target miRNAs in modulating NF-κB activity and restoring transrepression of an NF-κB reporter by dexamethasone. Nine miRNAs displayed significant differences between responsive and resistant patients by miScript PCR arrays. Validation of the top two miRNAs in all 35 patients confirmed a significantly lower serum level of miR-224-5p (p = 0.0048) in resistant patients. A multivariate logistic regression model identified a composite biomarker combining baseline serum miR-224-5p and TRAb was independently associated with GC response (OR: 2.565, 95 % CI 1.011-6.505, p = 0.047). Receiver operating characteristic (ROC) curves analysis revealed the composite marker combining miR-224-5p and TRAb led to a 91.67 % positive prediction value (PPV) and a 69.56 % negative prediction value (NPV) with regard to GC resistance. Overexpression of miR-224-5p restored transrepression of the NF-κB reporter by dexamethasone under induced resistance, which may be via targeting GSK-3β to increase GR protein level. Our study demonstrated baseline serum miR-224-5p was associated with GC sensitivity in GO and in vitro overexpression of miR-224-5p restored GC sensitivity in a resistant cell model. A parameter combined serum miR-224-5p and TRAb could effectively predict GC sensitivity in GO patients.
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Affiliation(s)
- Liyun Shen
- Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China
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Jiang W, Li X. Molecular Analysis of Inflammatory Bowel Disease: Clinically Useful Tools for Diagnosis, Response Prediction, and Monitoring of Targeted Therapy. Mol Diagn Ther 2015; 19:141-58. [DOI: 10.1007/s40291-015-0142-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Intestinal fibrosis in Crohn's disease: role of microRNAs as fibrogenic modulators, serum biomarkers, and therapeutic targets. Inflamm Bowel Dis 2015; 21:1141-50. [PMID: 25636122 DOI: 10.1097/mib.0000000000000298] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammation often precedes fibrosis and stricture formation in patients with Crohn's disease. Established medical therapies reduce inflammation, but there are currently no specific therapies to prevent fibrosis or treat established fibrosis. Our understanding of the pathogenic processes underpinning fibrogenesis is limited compared with our knowledge of the events initiating and propagating inflammation. There are several biomarkers for intestinal inflammation, but there are none that reflect the development of fibrosis. MicroRNAs (miRNAs) are regulators of cellular activities including inflammation and fibrosis and may serve as biomarkers of disease processes. Differential serum and mucosal miRNA expression profiles have been identified between patients with inflammatory bowel disease with active and inactive inflammatory disease. In contrast, studies in patients with fibrotic phenotypes are comparatively few, although specific miRNAs have defined roles in the development of fibrosis in other organ systems. Here, we discuss the most recent research on miRNA and fibrogenesis with a particular emphasis on Crohn's disease. We also anticipate the potential of miRNAs in fulfilling current unmet translational needs in this patient group by focusing on the role of miRNAs as modulators of fibrogenesis and on their potential value as serum biomarkers and therapeutic targets in the management of fibrosis.
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