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Ma X, Lin Y, Zhang L, Huang Z, Zhang Y, Fu X, Li P. The dual missions of FoxO3a in inflammatory diseases: Regulation of antioxidant enzymes and involvement in programmed cell death. Int Immunopharmacol 2025; 151:114369. [PMID: 40031428 DOI: 10.1016/j.intimp.2025.114369] [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: 01/20/2025] [Revised: 02/22/2025] [Accepted: 02/23/2025] [Indexed: 03/05/2025]
Abstract
The transcription factor FoxO3a plays a crucial role in the process of cells adapting to various stress conditions. Multiple post - translational modifications and epigenetic mechanisms work together to precisely regulate the activity of FoxO3a, influencing its subcellular localization, stability, interactions with other proteins, DNA - binding affinity, and transcriptional regulatory capacity. Under different chemical signal stimuli and subcellular environments, the activation of FoxO3a triggered by oxidative stress can initiate diverse transcriptional programs, which are essential for the body to resist oxidative damage. In the development and progression of inflammatory diseases, FoxO3a exerts an important function by regulating the expression levels of antioxidant enzymes and participating in key physiological processes such as programmed cell death. This article comprehensively reviews the structural characteristics, mechanism of action of FoxO3a, as well as its functions in regulating antioxidant enzymes and programmed cell death. The aim is to deeply explore the potential of FoxO3a as a potential therapeutic target for preventing and treating damages such as inflammatory diseases caused by cellular stress.
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Affiliation(s)
- Xiangli Ma
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Yujie Lin
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Ling Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Zhenzhen Huang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Yurong Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Xu Fu
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Peiwu Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China.
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Li W, Zeng Y, Zhong J, Hu Y, Xiong X, Zhou Y, Fu L. Probiotics Exert Gut Immunomodulatory Effects by Regulating the Expression of Host miRNAs. Probiotics Antimicrob Proteins 2025; 17:557-568. [PMID: 39754704 DOI: 10.1007/s12602-024-10443-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 01/06/2025]
Abstract
Probiotics exert a diverse range of immunomodulatory effects on the human gut immune system. These mechanisms encompass strengthening the intestinal mucosal barrier, inhibiting pathogen adhesion and colonization, stimulating immune modulation, and fostering the production of beneficial substances. As a result, probiotics hold significant potential in the prevention and treatment of various conditions, including inflammatory bowel disease and colorectal cancer. A pivotal mechanism by which probiotics achieve these effects is through modulating the expression of host miRNAs. miRNAs, non-coding RNA molecules, are vital regulators of fundamental biological processes like cell growth, differentiation, and apoptosis. By interacting with mRNAs, miRNAs can either promote their degradation or repress their translation, thereby regulating gene expression post-transcriptionally and modulating the immune system. This review provides a comprehensive overview of how probiotics modulate gut immune responses by altering miRNA expression levels, both upregulating and downregulating specific miRNAs. It further delves into how this modulation impacts the host's resistance to pathogens and susceptibility to diseases, offering a theoretical foundation and practical insights for the clinical utilization of probiotics in disease prevention and therapy.
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Affiliation(s)
- Wenjing Li
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Yongwei Zeng
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Jiayu Zhong
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Youyu Hu
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Xia Xiong
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yingshun Zhou
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
- Public Center of Experimental Technology of Pathogen Biology Technology Platform, Southwest Medical University, Luzhou, 646000, China.
| | - Li Fu
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
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Wu Q, Kan J, Fu C, Liu X, Cui Z, Wang S, Le Y, Li Z, Liu Q, Zhang Y, Du J. Insights into the unique roles of extracellular vesicles for gut health modulation: Mechanisms, challenges, and perspectives. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100301. [PMID: 39525958 PMCID: PMC11550031 DOI: 10.1016/j.crmicr.2024.100301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024] Open
Abstract
Extracellular vesicles (EVs), which play significant regulatory roles in maintaining homeostasis and influencing immune responses, significantly impact gut microbiota composition and function, affecting overall gut health. Despite considerable progress, there are still knowledge gaps regarding the mechanisms by which EVs, including plant-derived EVs (PDEVs), animal-derived EVs (ADEVs), and microbiota-derived EVs (MDEVs), modulate gut health. This review delves into the roles and mechanisms of EVs from diverse sources in regulating gut health, focusing on their contributions to maintaining epithelial barrier integrity, facilitating tissue healing, eliciting immune responses, controlling pathogens, and shaping microbiota. We emphasize open challenges and future perspectives for harnessing EVs in the modulation of gut health to gain a deeper understanding of their roles and impact. Importantly, a comprehensive research framework is presented to steer future investigations into the roles and implications of EVs on gut health, facilitating a more profound comprehension of this emerging field.
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Affiliation(s)
- Qiming Wu
- Nutrilite Health Institute, Shanghai 200031, China
| | - Juntao Kan
- Nutrilite Health Institute, Shanghai 200031, China
| | - Caili Fu
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Xin Liu
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Zhengying Cui
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Sixu Wang
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Yi Le
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Zhanming Li
- Department of Food Quality and Safety, Jiangsu University of Science and Technology, Zhenjiang 212100, China
| | - Qin Liu
- Centre for Chinese Medicine Drug Development Limited, Hong Kong Baptist University, 999077, Hong Kong Special Administrative Region of China
| | - Yuyu Zhang
- Key Laboratory of Geriatric Nutrition and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Jun Du
- Nutrilite Health Institute, Shanghai 200031, China
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Minea H, Singeap AM, Minea M, Juncu S, Muzica C, Sfarti CV, Girleanu I, Chiriac S, Miftode ID, Stanciu C, Trifan A. The Contribution of Genetic and Epigenetic Factors: An Emerging Concept in the Assessment and Prognosis of Inflammatory Bowel Diseases. Int J Mol Sci 2024; 25:8420. [PMID: 39125988 PMCID: PMC11313574 DOI: 10.3390/ijms25158420] [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: 07/03/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents heterogeneous and relapsing intestinal conditions with a severe impact on the quality of life of individuals and a continuously increasing prevalence. In recent years, the development of sequencing technology has provided new means of exploring the complex pathogenesis of IBD. An ideal solution is represented by the approach of precision medicine that investigates multiple cellular and molecular interactions, which are tools that perform a holistic, systematic, and impartial analysis of the genomic, transcriptomic, proteomic, metabolomic, and microbiomics sets. Hence, it has led to the orientation of current research towards the identification of new biomarkers that could be successfully used in the management of IBD patients. Multi-omics explores the dimension of variation in the characteristics of these diseases, offering the advantage of understanding the cellular and molecular mechanisms that affect intestinal homeostasis for a much better prediction of disease development and choice of treatment. This review focuses on the progress made in the field of prognostic and predictive biomarkers, highlighting the limitations, challenges, and also the opportunities associated with the application of genomics and epigenomics technologies in clinical practice.
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Affiliation(s)
- Horia Minea
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Manuela Minea
- Department of Microbiology, The National Institute of Public Health, 700464 Iasi, Romania;
| | - Simona Juncu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Cristina Muzica
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Catalin Victor Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Stefan Chiriac
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ioana Diandra Miftode
- Department of Radiology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Radiology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
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Khor YS, Wong PF. MicroRNAs-associated with FOXO3 in cellular senescence and other stress responses. Biogerontology 2024; 25:23-51. [PMID: 37646881 DOI: 10.1007/s10522-023-10059-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/01/2023] [Indexed: 09/01/2023]
Abstract
FOXO3 is a member of the FOXO transcription factor family and is known for regulating cellular survival in response to stress caused by various external and biological stimuli. FOXO3 decides cell fate by modulating cellular senescence, apoptosis and autophagy by transcriptional regulation of genes involved in DNA damage response and oxidative stress resistance. These cellular processes are tightly regulated physiologically, with FOXO3 acting as the hub that integrates signalling networks controlling them. The activity of FOXO3 is influenced by post-translational modifications, altering its subcellular localisation. In addition, FOXO3 can also be regulated directly or indirectly by microRNAs (miRNAs) or vice versa. This review discusses the involvement of various miRNAs in FOXO3-driven cellular responses such as senescence, apoptosis, autophagy, redox and inflammation defence. Given that these responses are linked and influence cell fate, a thorough understanding of the complex regulation by miRNAs would provide key information for developing therapeutic strategy and avoid unintended consequences caused by off-site targeting of FOXO3.
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Affiliation(s)
- Yi-Sheng Khor
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603, Wilayah Persekutuan Kuala Lumpur, Malaysia.
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Zhang J, Guo Z, Wang Z, Zhu W, Li Q. Fecal miR-223 is a noninvasive biomarker for estimating Crohn's disease activity. Immun Inflamm Dis 2023; 11:e1131. [PMID: 38156390 PMCID: PMC10753866 DOI: 10.1002/iid3.1131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/30/2023] Open
Abstract
INTRODUCTION MicroRNA-223 (miR-223) has emerged as a promising noninvasive biomarker for Crohn's disease (CD). However, it is unclear which tissue derived miRNA-223 can more accurately estimate CD disease activity. MATERIALS AND METHODS To collect serum, terminal ileal mucosa biopsy and fecal samples from CD patients and healthy controls. The CD Activity Index (CDAI) score, Montreal classification, maintenance medicines, peripheral blood inflammatory markers, fecal calprotectin (FC) and the Simple Endoscopic Score for CD (SES-CD) were recorded. To compare the expression of miR-223 in the serum, intestinal tissue, and feces. RESULTS MiR-223 expression levels in the serum, intestinal tissue and feces of CD patients were significantly higher than those of controls. The level of miR-223 in the serum, intestinal tissue and feces increased significantly in active CD patients compared with that in inactive CD patients. The levels of serum, intestinal tissue and fecal miR-223 were correlated with the CDAI. Serum miR-223 was also correlated with C-reactive protein (CRP) and IL-6, tissue miR-223 correlated with IL-6 and FC, and fecal miR-223 correlated with FC. In terms of the association with FC, fecal miR-223 had a higher Spearman r value than tissue miR-223. The area under the curve (AUC) values of serum, tissue and fecal miR-223 to diagnose CD were similar to those of CRP and FC (AUC > 0.8). The AUC values of tissue and fecal miR-223 to evaluate CD disease activity were 0.832 and 0.818, respectively, and were higher than serum miR-223, CRP and FC. Fecal miR-223 had a higher specificity of 92.3%. CONCLUSIONS Fecal miR-223 might be a novel, noninvasive biomarker for estimating the disease activity of CD patients.
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Affiliation(s)
- Juanjuan Zhang
- Research Institute of General SurgeryJinling HospitalNanjingChina
| | - Zhen Guo
- Research Institute of General SurgeryJinling HospitalNanjingChina
| | - Zhiming Wang
- Research Institute of General SurgeryJinling HospitalNanjingChina
| | - Weiming Zhu
- Research Institute of General SurgeryJinling HospitalNanjingChina
| | - Qiurong Li
- Research Institute of General SurgeryJinling HospitalNanjingChina
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Macias-Ceja DC, Barrachina MD, Ortiz-Masià D. Autophagy in intestinal fibrosis: relevance in inflammatory bowel disease. Front Pharmacol 2023; 14:1170436. [PMID: 37397491 PMCID: PMC10307973 DOI: 10.3389/fphar.2023.1170436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/06/2023] [Indexed: 07/04/2023] Open
Abstract
Chronic inflammation is often associated with fibrotic disorders in which an excessive deposition of extracellular matrix is a hallmark. Long-term fibrosis starts with tissue hypofunction and finally ends in organ failure. Intestinal fibrosis is not an exception, and it is a frequent complication of inflammatory bowel disease (IBD). Several studies have confirmed the link between deregulated autophagy and fibrosis and the presence of common prognostic markers; indeed, both up- and downregulation of autophagy are presumed to be implicated in the progression of fibrosis. A better knowledge of the role of autophagy in fibrosis may lead to it becoming a potential target of antifibrotic therapy. In this review we explore novel advances in the field that highlight the relevance of autophagy in fibrosis, and give special focus to fibrosis in IBD patients.
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Affiliation(s)
- Dulce C. Macias-Ceja
- Departamento de Farmacología and CIBER, Facultad de Medicina y Odontología, Universitat de Valencia, Valencia, Spain
| | - María D. Barrachina
- Departamento de Farmacología and CIBER, Facultad de Medicina y Odontología, Universitat de Valencia, Valencia, Spain
| | - Dolores Ortiz-Masià
- Departamento de Farmacología and CIBER, Facultad de Medicina y Odontología, Universitat de Valencia, Valencia, Spain
- Departamento de Medicina, Facultad de Medicina y Odontología, Universitat de Valencia, Valencia, Spain
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Alfaifi J, Germain A, Heba AC, Arnone D, Gailly L, Ndiaye NC, Viennois E, Caron B, Peyrin-Biroulet L, Dreumont N. Deep Dive Into MicroRNAs in Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:986-999. [PMID: 36545755 DOI: 10.1093/ibd/izac250] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Indexed: 06/02/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is thought to develop in genetically predisposed individuals as a consequence of complex interactions between dysregulated inflammatory stimuli, immunological responses, and environmental factors. The pathogenesis of IBD has yet to be fully understood. The global increase in the incidence of IBD suggests a gap in the current understanding of the disease. The development of a new diagnostic tool for inflammatory bowel disease that is both less invasive and more cost-effective would allow for better management of this condition. MicroRNAs (miRNAs) are a class of noncoding RNAs with important roles as posttranscriptional regulators of gene expression, which has led to new insights into understanding IBD. Using techniques such as microarrays and real-time polymerase chain reactions, researchers have investigated the patterns in which patients with Crohn's disease and ulcerative colitis show alterations in the expression of miRNA in tissue, blood, and feces. These miRNAs are found to be differentially expressed in IBD and implicated in its pathogenesis through alterations in autophagy, intestinal barrier, and immune homeostasis. In this review, we discuss the miRNA expression profiles associated with IBD in tissue, peripheral blood, and feces and provide an overview of the miRNA mechanisms involved in IBD.
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Affiliation(s)
- Jaber Alfaifi
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Adeline Germain
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Anne-Charlotte Heba
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Djésia Arnone
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Laura Gailly
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Ndeye Coumba Ndiaye
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Emilie Viennois
- INSERM U1149, Center of Research on Inflammation, Université de Paris, Paris, France
| | - Bénédicte Caron
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Laurent Peyrin-Biroulet
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Natacha Dreumont
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
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Ghafouri-Fard S, Safarzadeh A, Akhavan-Bahabadi M, Hussen BM, Taheri M, Dilmaghani NA. Expression pattern of non-coding RNAs in non-functioning pituitary adenoma. Front Oncol 2022; 12:978016. [PMID: 36119500 PMCID: PMC9478794 DOI: 10.3389/fonc.2022.978016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Non-functioning pituitary adenoma (NFPA) is a benign tumor arising from the adenohypophyseal cells. They can be associated with symptoms arising from mass effect. Although these tumors are regarded to be benign tumors, they are associated with increased comorbidity and mortality. Several studies have indicated abnormal expression of genes in these tumors. In the current study, we have used existing methods to identify differentially expressed genes (DEGs) including DE long non-coding RNAs (DElncRNAs) and DE microRNAs (DEmiRNAs) in NFPAs compared with normal samples. Then, we have assessed the relation between these genes and important signaling pathways. Our analyses led to identification of 3131 DEGs, including 189 downregulated DEGs (such as RPS4Y1 and DDX3Y) and 2898 upregulated DEGs (such as ASB3 and DRD4), and 44 DElncRNAs, including 8 downregulated DElncRNAs (such as NUTM2B-AS1 and MALAT1) and 36 upregulated DElncRNAs (such as BCAR4 and SRD5A3-AS1). GnRH signaling pathway, Tight junction, Gap junction, Melanogenesis, DNA replication, Nucleotide excision repair, Mismatch repair and N-Glycan biosynthesis have been among dysregulated pathways in NFPAs. Taken together, our study has revealed differential expression of several genes and signaling pathways in this type of tumors.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Safarzadeh
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- *Correspondence: Mohammad Taheri, ; Nader Akbari Dilmaghani,
| | - Nader Akbari Dilmaghani
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Mohammad Taheri, ; Nader Akbari Dilmaghani,
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Zhang YQ, Chen RL, Shang LQ, Yang SM. Nicotine-induced miR-21-3p promotes chemoresistance in lung cancer by negatively regulating FOXO3a. Oncol Lett 2022; 24:260. [PMID: 35765274 PMCID: PMC9219026 DOI: 10.3892/ol.2022.13380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 10/01/2021] [Indexed: 01/18/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide and cigarette smoking is reported to contribute to the lung cancer-related mortality. The present study aimed to investigate the molecular mechanism underlying nicotine-induced chemoresistance in lung cancer. The expression of microRNA (miR)-21-3p and its predicted target FOXO3a in lung cancer cells was detected via reverse transcription-quantitative PCR, in the presence or absence of nicotine. The regulatory effect of miR-21-3p and FOXO3a on lung cancer cell proliferation and apoptosis induced by docetaxel or cisplatin treatment was evaluated by performing Cell Counting Kit-8 and Annexin V/PI staining assays, respectively. The interaction between miR-21-3p and FOXO3a was analyzed by performing luciferase reporter assays and western blotting. FOXO3a overexpression rescue experiments were conducted in vitro and in vivo using a xenograft mouse model to assess the function of miR-21-3p/FOXO3a in lung cancer. Nicotine induced miR-21-3p expression in lung cancer cells in a dose-dependent manner. miR-21-3p downregulated FOXO3a expression by directly binding to the 3′-untranslated region of FOXO3a. Moreover, miR-21-3p knockdown sensitized lung cancer cells to docetaxel or cisplatin treatment. Mechanistically, FOXO3a was predicted as a direct target of miR-21-3p. FOXO3a overexpression promoted the chemosensitivity of lung cancer cells to docetaxel or cisplatin treatment. Furthermore, FOXO3a overexpression antagonized the regulatory function of miR-21-3p on docetaxel- or cisplatin-treated lung cancer cells. In the docetaxel- or cisplatin-treated lung cancer xenograft mouse model, miR-21-3p promoted chemoresistance via negatively regulating FOXO3a. Therefore, the present study demonstrated that nicotine-induced miR-21-3p promoted chemoresistance to docetaxel or cisplatin treatment via negatively regulating FOXO3a, which may serve as a novel therapeutic strategy for the treatment of patients with chemoresistant lung cancer.
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Affiliation(s)
- Yong-Qing Zhang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Rui-Lin Chen
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Li-Qun Shang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Shu-Mei Yang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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Morus macroura Miq. Fruit extract protects against acetic acid-induced ulcerative colitis in rats: Novel mechanistic insights on its impact on miRNA-223 and on the TNFα/NFκB/NLRP3 inflammatory axis. Food Chem Toxicol 2022; 165:113146. [PMID: 35595039 DOI: 10.1016/j.fct.2022.113146] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/06/2022] [Accepted: 05/13/2022] [Indexed: 11/23/2022]
Abstract
Nod-like receptor pyrin domain-1 containing 3 (NLRP3) inflammasome/tumor necrosis factor alpha (TNFα)/nuclear factor kappa B (NFκB) inflammatory pathway is known to be involved in the pathogenesis of ulcerative colitis (UC). Inversely, miRNA-223 can exert counter-regulatory effect on NLRP3 expression. The mulberry tree (Morus macroura) fruit is attaining increased importance for its antioxidant and anti-inflammatory activity in addition to its high safety profile. Accordingly, we attempted to explore the possible protective effect of mulberry fruit extract (MFE) in acetic acid (AA)-induced UC rat model. Phytochemical constituents of MFE were characterized using high performance liquid chromatography coupled to mass spectrometry (HPLC-MS). In the in vivo study, three doses of MFE were orally given for seven days before intra-rectal induction of UC by AA on day eight. Screening study revealed that MFE (300 mg/kg) significantly reduced macroscopic and microscopic UC scores. Biochemically, MFE ameliorated oxidative stress, levels of TNFR1, NLRP3, p-NFκB p65, TNFα, IL-1β, and IL-18, caspase-1 activity, but enhanced miRNA-223 expression. In conclusion, our study provided a novel protective impact for MFE against UC, in which miRNA-223 and TNFα/NFκB/NLRP3 pathway are involved. These results provide a promising step that might encourage further investigations of MFE as a protective agent in UC patients.
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12
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Sudhakar P, Alsoud D, Wellens J, Verstockt S, Arnauts K, Verstockt B, Vermeire S. Tailoring Multi-omics to Inflammatory Bowel Diseases: All for One and One for All. J Crohns Colitis 2022; 16:1306-1320. [PMID: 35150242 PMCID: PMC9426669 DOI: 10.1093/ecco-jcc/jjac027] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/02/2022] [Accepted: 02/10/2022] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease [IBD] has a multifactorial origin and originates from a complex interplay of environmental factors with the innate immune system at the intestinal epithelial interface in a genetically susceptible individual. All these factors make its aetiology intricate and largely unknown. Multi-omic datasets obtained from IBD patients are required to gain further insights into IBD biology. We here review the landscape of multi-omic data availability in IBD and identify barriers and gaps for future research. We also outline the various technical and non-technical factors that influence the utility and interpretability of multi-omic datasets and thereby the study design of any research project generating such datasets. Coordinated generation of multi-omic datasets and their systemic integration with clinical phenotypes and environmental exposures will not only enhance understanding of the fundamental mechanisms of IBD but also improve therapeutic strategies. Finally, we provide recommendations to enable and facilitate generation of multi-omic datasets.
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Affiliation(s)
- Padhmanand Sudhakar
- Corresponding author: Padhmanand Sudhakar, Translational Research in Gastrointestinal Disorders [TARGID], ON I, Herestraat 49, box 701, 3000 Leuven, Belgium. Tel.: 0032 [0]16 19 49 40;
| | - Dahham Alsoud
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Judith Wellens
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Sare Verstockt
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Kaline Arnauts
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Bram Verstockt
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Severine Vermeire
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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13
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Xu S, Zhang X, Ma Y, Xu S, Pan F. The Expression Level of FOXO3a in Patients With Autoimmune Diseases: A Meta-analysis. J Clin Rheumatol 2022; 28:e228-e233. [PMID: 33938500 DOI: 10.1097/rhu.0000000000001675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
METHODS PubMed, Web of Science, and China National Knowledge Infrastructure were used to retrieve relevant articles. The pooled standard mean difference with 95% confidence interval was calculated. RESULTS Totally, 10 studies from 7 publications were included. The levels of FOXO3a were significantly decreased in patients with autoimmune diseases compared with healthy controls (standard mean difference, -1.045; 95% confidence interval, -1.892 to -0.197). When stratified by disease, FOXO3a levels were significantly decreased in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), but were significantly increased in systemic lupus erythematosus. FOXO3a levels of specific tissues or cells in patients with autoimmune diseases were significantly decreased, but no significant difference was observed in the subgroup of peripheral blood mononuclear cells. In the subgroup analysis combining disease and sample, significant differences of FOXO3a were observed in non-PMBCs of RA and IBD patients. CONCLUSIONS Our study indicated that FOXO3a were significantly decreased in patients with autoimmune diseases. FOXO3a levels was a potential therapeutic target of autoimmune diseases.
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Affiliation(s)
| | - Xiaoyi Zhang
- Department of Health Toxicology, School of Public Health, Anhui Medical University
| | | | - Shengqian Xu
- Department of Rheumatism and Immunity, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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14
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Jia Z, Tu K, Xu Q, Gao W, Liu C, Fang B, Zhang M. A novel disease-associated nucleic acid sensing platform based on split DNA-scaffolded sliver nanocluster. Anal Chim Acta 2021; 1175:338734. [PMID: 34330446 DOI: 10.1016/j.aca.2021.338734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/01/2021] [Accepted: 06/01/2021] [Indexed: 12/18/2022]
Abstract
Disease-associated nucleic acids, such as DNAs and miRNAs, are important biomarkers for the diagnosis, prognosis and treatment guidance of human diseases. Therefore, the accurate and sensitive detection of nucleic acid is of great significance for the early diagnosis of diseases. DNA-scaffolded silver nanocluster (DNA-Ag NC) is a new type of probe with good photostability and low toxicity that has been widely used in biomedical analysis. In this work, a new universal sensing platform based on target triggered labeling luminescent DNA-Ag NC for disease-related nucleic acids detection was constructed. The assembled split DNA fragment pair (C4AC4T and C3GT4) could be used as a template to develop a bright green fluorescent Ag NC. According to this phenomenon, we devised two probe sequences DNA 1 and DNA 2, which could hybridize to the same one target and contained a different split fragment of Ag NC' scaffold. The target compelled the split fragments close to each other through base pairing with DNA 1 and DNA 2, thus quantification of the target could be achieved through measuring green fluorescence of Ag NC that produced by assembled scaffold in ternary hybrid products. We applied this platform successfully for miR-362, a potential biomarker of inflammatory bowel diseases (IBD), or HIV-related DNA (hDNA) detection, achieving the detection limits of 6.5 nM and 1.7 nM, respectively. Both of the assays showed excellent reproducibility, selectivity and potential applications in human serum samples. In summary, an economic and convenient universal platform was developed for disease-associated nucleic acid detection.
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Affiliation(s)
- Zhenzhen Jia
- School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, 710061, China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Wenhui Gao
- School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, 710061, China
| | - Cui Liu
- School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, 710061, China
| | - Biyun Fang
- School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, 710061, China.
| | - Mingzhen Zhang
- School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, 710061, China.
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15
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Xu S, Pan Z, Huang L, Chen Y, Xie H, Wang F, Zhou T, Yu L, Kong J, Xu S, Pan F. Association of FOXO3a gene polymorphisms and ankylosing spondylitis susceptibility in Eastern Chinese Han population. Gene 2021; 800:145832. [PMID: 34274476 DOI: 10.1016/j.gene.2021.145832] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/26/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To investigate the association of FOXO3a polymorphisms and ankylosing spondylitis (AS) susceptibility in Eastern Chinese Han population. METHODS FOXO3a polymorphisms rs12206094, rs12212067, rs2253310, rs3800232, and rs4946933 were genotyped in 650 AS patients and 646 controls by the improved Multiple Ligase Detection Reaction. RESULTS The distribution of genotype in rs12212067 polymorphism was significantly different between AS patients and controls (P = 0.020), especially in male population (P = 0.009). There was significant difference of the genotype frequency distribution at rs3800232 between patients and controls in male population. The results of binary regression analysis showed that the rs12212067 GG genotype and rs3800232 TT genotype were obviously correlated with elevated AS risk, and the associations were still significant after being adjusted by age and gender (all P < 0.05). Interestingly, rs12212067 and rs3800232 genotypes were associated with disease activity of patients. Additionally, haplotype block rs12212067G- rs3800232T (OR = 1.403, 95%CI = 1.011-1.949) was further shown to confer promoting effect on developing AS. CONCLUSION Among Eastern Chinese Han population, FOXO3a polymorphism rs12212067 and rs3800232 may contribute to increased risk of developing AS, but well-designed multicenter studies are needed to further confirm these preliminary findings in the future.
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Affiliation(s)
- Shanshan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Zhipeng Pan
- Department of Medical Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Li Huang
- Anhui Medical College, 387 Wuhu Road, Hefei, Anhui 230032, China
| | - Yuting Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Huimin Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Feier Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Tingting Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Lingxiang Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Jiangpiang Kong
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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16
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Jiao P, Wang XP, Luoreng ZM, Yang J, Jia L, Ma Y, Wei DW. miR-223: An Effective Regulator of Immune Cell Differentiation and Inflammation. Int J Biol Sci 2021; 17:2308-2322. [PMID: 34239357 PMCID: PMC8241730 DOI: 10.7150/ijbs.59876] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/21/2021] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) play a critical role in regulating various biological processes, such as cell differentiation and immune modulation by binding to their target genes. miR-223 is a miRNA with important functions and has been widely investigated in recent years. Under certain physiological conditions, miR-223 is regulated by different transcription factors, including sirtuin1 (Sirt1), PU.1 and Mef2c, and its biological functions are mediated through changes in its cellular or tissue expression. This review paper summarizes miR-223 biosynthesis and its regulatory role in the differentiation of granulocytes, dendritic cells (DCs) and lymphocytes, macrophage polarization, and endothelial and epithelial inflammation. In addition, it describes the molecular mechanisms of miR-223 in regulating lung inflammation, rheumatoid arthritis, enteritis, neuroinflammation and mastitis to provide insights into the existing molecular regulatory networks and therapies for inflammatory diseases in humans and animals.
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Affiliation(s)
- Peng Jiao
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Xing-Ping Wang
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Zhuo-Ma Luoreng
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Jian Yang
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Li Jia
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Yun Ma
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Da-Wei Wei
- School of Agriculture, Ningxia University, Yinchuan 750021, China
- Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
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17
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Wu YZ, Chan KYY, Leung KT, Lam HS, Tam YH, Lee KH, Li K, Ng PC. The miR-223/nuclear factor I-A axis regulates inflammation and cellular functions in intestinal tissues with necrotizing enterocolitis. FEBS Open Bio 2021; 11:1907-1920. [PMID: 33932136 PMCID: PMC8255851 DOI: 10.1002/2211-5463.13164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/05/2021] [Accepted: 04/12/2021] [Indexed: 01/01/2023] Open
Abstract
We previously demonstrated that microRNA(miR)‐223 is overexpressed in intestinal tissue of infants with necrotizing enterocolitis (NEC). The objective of the current study was to identify the target gene of miR‐223 and to investigate the role of the miR‐223/nuclear factor I‐A (NFIA) axis in cellular functions that underpin the pathophysiology of NEC. The target gene of miR‐223 was identified by in silico target prediction bioinformatics, luciferase assay, and western blotting. We investigated downstream signals of miR‐223 and cellular functions by overexpressing the miRNA in Caco‐2 and FHs74 cells stimulated with lipopolysaccharide or lipoteichoic acid (LTA). NFIA was identified as a target gene of miR‐223. Overexpression of miR‐223 significantly induced MYOM1 and inhibited NFIA and RGN in Caco‐2 cells, while costimulation with LTA decreased expression of GNA11, MYLK, and PRKCZ. Expression levels of GNA11, MYLK, IL‐6, and IL‐8 were increased, and levels of NFIA and RGN were decreased in FHs74 cells. These potential downstream genes were significantly correlated with levels of miR‐223 or NFIA in primary NEC tissues. Overexpression of miR‐223 significantly increased apoptosis of Caco‐2 and FHs74 cells, while proliferation of FHs74 was inhibited. These results suggest that upon binding with NFIA, miR‐223 regulates functional effectors in pathways of apoptosis, cell proliferation, G protein signaling, inflammation, and smooth muscle contraction. The miR‐223/NFIA axis may play an important role in the pathophysiology of NEC by enhancing inflammation and tissue damage.
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Affiliation(s)
- Yu Zheng Wu
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Kathy Yuen Yee Chan
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Kam Tong Leung
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Hugh Simon Lam
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Yuk Him Tam
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Kim Hung Lee
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Karen Li
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Pak Cheung Ng
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
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18
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Jung H, Kim JS, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Smith L, Koyanagi A, Jacob L, Li H, Hong SH, Yon DK, Lee SW, Kim MS, Wasuwanich P, Karnsakul W, Shin JI, Kronbichler A. Roles of microRNAs in inflammatory bowel disease. Int J Biol Sci 2021; 17:2112-2123. [PMID: 34131410 PMCID: PMC8193269 DOI: 10.7150/ijbs.59904] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/08/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.
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Affiliation(s)
- HyunTaek Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Seok Kim
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kalthoum Tizaoui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, CB1 1PT, UK
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Louis Jacob
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Sung Hwi Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Keon Yon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Data Science, Sejong University College of Software Convergence, Seoul, Republic of Korea
| | - Min Seo Kim
- Korea University, College of Medicine, Seoul, Republic of Korea
| | - Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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Zhang J, Wang C, Guo Z, Da B, Zhu W, Li Q. miR-223 improves intestinal inflammation through inhibiting the IL-6/STAT3 signaling pathway in dextran sodium sulfate-induced experimental colitis. Immun Inflamm Dis 2021; 9:319-327. [PMID: 33332758 PMCID: PMC7860526 DOI: 10.1002/iid3.395] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/13/2020] [Accepted: 12/02/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION The pathogenesis of inflammatory bowel disease (IBD) has not yet been clarified and is closely related to several pro-inflammatory factors. MicroRNA-233 (miR-223) might be involved in the development of IBD; however, the mechanism underlying its pathogenesis is unclear. In this study, we attempted to determine the role of miR-223 in dextran sodium sulfate (DSS)-induced colitis and explore the involvement of the IL-6/STAT3 pathway in the development of intestinal mucosal inflammation. MATERIALS AND METHODS Except control (WT) group, male C57BL/6 mice were provided DSS, then treated for with miR-223 agomir or antagomir including DSS group, DSS + miR-223 agomir (DSS + A) group, and DSS + miR-223 antagomir (DSS + AN) group. The colitis symptoms were observed, the disease activity index (DAI) score were recorded daily, and colonic inflammation was evaluated by histopathological scoring. The expression of myeloperoxidase (MPO), cytokines and IL-6/STAT3 pathway-related proteins were measured. RESULTS miR-223 expression in the terminal ileum and colon was increased in the DSS group compared with the WT group. Colitis symptoms were significantly alleviated in the DSS + A group and exacerbated in the DSS + AN group after administration of the miR-223 agomir and antagomir, respectively. MPO, tumor necrosis factor-α, IL-6, and IL-17 were decreased and IL-10 was increased in the DSS + A group, but these changes were reversed in the DSS + AN group. Gp130, p-STAT3, Bcl-2, and Bcl-xl in the colon declined in the DSS + A group, but these levels increased in the DSS + AN group. CONCLUSIONS The upregulation of miR-223 by agomir administration alleviated colonic inflammation in a DSS-induced colitis model, which was likely mediated by inhibiting the production of pro-inflammatory cytokines via the IL-6/STAT3 signaling pathway. These findings provide evidence that miR-223 might have potential therapeutic implications in IBD.
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Affiliation(s)
- Juanjuan Zhang
- Research Institute of General Surgery, Jinling HospitalNanjing Medical UniversityNanjingJiangsuChina
| | - Chenyang Wang
- Research Institute of General SurgeryJinling HospitalNanjingJiangsuChina
| | - Zhen Guo
- Research Institute of General SurgeryJinling HospitalNanjingJiangsuChina
| | - Binlin Da
- Research Institute of General SurgeryJinling HospitalNanjingJiangsuChina
| | - Weiming Zhu
- Research Institute of General Surgery, Jinling HospitalNanjing Medical UniversityNanjingJiangsuChina
| | - Qiurong Li
- Research Institute of General Surgery, Jinling HospitalNanjing Medical UniversityNanjingJiangsuChina
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20
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Diaz-Garrido N, Cordero C, Olivo-Martinez Y, Badia J, Baldomà L. Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease. Int J Mol Sci 2021; 22:ijms22042213. [PMID: 33672304 PMCID: PMC7927122 DOI: 10.3390/ijms22042213] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.
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Affiliation(s)
- Natalia Diaz-Garrido
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Cecilia Cordero
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Yenifer Olivo-Martinez
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Josefa Badia
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Laura Baldomà
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
- Correspondence: ; Tel.: +34-93-403-44-96
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21
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Zhao H, Jiang S. MiR-204-5p Performs a Protective Effect on Cerulein-Induced Rat Pancreatic Acinar Cell AR42J Cell Damage by Targeting Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Gamma and Regulating PI3K/Hippo Pathways. Pancreas 2021; 50:243-250. [PMID: 33565802 DOI: 10.1097/mpa.0000000000001748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE This research plans to address the function of miR-204-5p/tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) in cerulein-induced acute pancreatitis (AP). METHODS Rat pancreatic acinar cell AR42J was stimulated by 100 nmol/L of cerulein to mimic the situation in AP. Gene Expression Omnibus database was used to select differentially expressed genes. StarBase database and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were used to select the target genes of miR-204-5p, which were further affirmed by dual luciferase assay. The biological behaviors of AR42J cells were measured by cell proliferation and flow cytometry assays. Quantitative real-time polymerase chain reaction and western blot assays were executed to assess YWHAG expression. The secretion of C-C Motif Chemokine Ligand 2/Timp metallopeptidase inhibitor 1 in AR42J cells was evaluated by enzyme-linked immunosorbent assay. The protein expression of YAP1/p-YAP1/PI3K/p-PI3K was measured by western blot. RESULTS miR-204-5p expression was profoundly reduced in cerulein-induced AP model. YWHAG was upregulated in cerulein-induced AP model and related to C-C Motif Chemokine Ligand 2/Timp1. In addition to the negative association between miR-204-5p and YWHAG, the alleviation impact of miR-204-5p mimic on cerulein-induced AR42J cell damage was blocked by YWHAG overexpression and PI3K/Hippo signaling pathways activation. CONCLUSIONS These observations indicated that the alleviation impact of miR-204-5p on cerulein-induced AR42J cell damage was mediated via YWHAG and PI3K/Hippo signaling pathways.
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Affiliation(s)
- Hongbo Zhao
- From the Department of Gastroenterology, Central Hospital of Shanxian, Heze
| | - Shaolian Jiang
- Department of Gastroenterology, The Second People's Hospital of Jingmen, Jingmen, China
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22
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MicroRNA Biomarkers in IBD-Differential Diagnosis and Prediction of Colitis-Associated Cancer. Int J Mol Sci 2020; 21:ijms21217893. [PMID: 33114313 PMCID: PMC7660644 DOI: 10.3390/ijms21217893] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). These are chronic autoimmune diseases of unknown etiology affecting the gastrointestinal tract. The IBD population includes a heterogeneous group of patients with varying disease courses requiring personalized treatment protocols. The complexity of the disease often delays the diagnosis and the initiation of appropriate treatments. In a subset of patients, IBD leads to colitis-associated cancer (CAC). MicroRNAs are single-stranded regulatory noncoding RNAs of 18 to 22 nucleotides with putative roles in the pathogenesis of IBD and colorectal cancer. They have been explored as biomarkers and therapeutic targets. Both tissue-derived and circulating microRNAs have emerged as promising biomarkers in the differential diagnosis and in the prognosis of disease severity of IBD as well as predictive biomarkers in drug resistance. In addition, knowledge of the cellular localization of differentially expressed microRNAs is a prerequisite for deciphering the biological role of these important epigenetic regulators and the cellular localization may even contribute to an alternative repertoire of biomarkers. In this review, we discuss findings based on RT-qPCR, microarray profiling, next generation sequencing and in situ hybridization of microRNA biomarkers identified in the circulation and in tissue biopsies.
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23
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Wang F, Yao S, Xia H. SIRT1 is a key regulatory target for the treatment of the endoplasmic reticulum stress-related organ damage. Biomed Pharmacother 2020; 130:110601. [PMID: 32784049 DOI: 10.1016/j.biopha.2020.110601] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/28/2020] [Accepted: 08/02/2020] [Indexed: 02/08/2023] Open
Abstract
Endoplasmic reticulum (ER) stress is an evolutionarily conserved adaptive response that contributes to deal with the misfolded or unfolded protein in the lumen of the ER and restore the ER homeostasis. However, excessive and prolonged ER stress can trigger the cell-death signaling pathway which causes cell death, usually in the form of apoptosis. It is generally accepted that inappropriate cellular apoptosis and a series of the subsequent inflammatory response and oxidative stress can cause disturbance of normal physiological functions and organ damage. A lot of evidence shows that the excessive activation of the ER stress contributes to the pathogenesis of many kinds of diseases and inhibiting the inappropriate stress is of great significance for maintaining the normal physiological function. In recent years, Sirtuin1 (SIRT1) has become a research hotspot on ER stress. As a master regulator of ER stress, increasing evidence suggests that SIRT1 plays a positive role in a variety of ER stress-induced organ damage via multiple mechanisms, including inhibiting cellular apoptosis and promoting autophagy. Furthermore, a lot of factors have shown effective regulation of SIRT1, which indicates the feasibility of treating SIRT1 as a target for the treatment of ER stress-related diseases. We summarize and reveal the molecular mechanisms underlying the protective effect of SIRT1 in multiple ER stress-mediated organ damage in this review. We also summed up the possible adjustment mechanism of SIRT1, which provides a theoretical basis for the treatment of ER stress-related diseases.
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Affiliation(s)
- Fuquan Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430022, China
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430022, China.
| | - Haifa Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430022, China.
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24
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Nair VD, Ge Y, Li S, Pincas H, Jain N, Seenarine N, Amper MAS, Goodpaster BH, Walsh MJ, Coen PM, Sealfon SC. Sedentary and Trained Older Men Have Distinct Circulating Exosomal microRNA Profiles at Baseline and in Response to Acute Exercise. Front Physiol 2020; 11:605. [PMID: 32587527 PMCID: PMC7298138 DOI: 10.3389/fphys.2020.00605] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/14/2020] [Indexed: 12/20/2022] Open
Abstract
Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men (n = 5) and age-matched sedentary males (n = 5) at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost). Following the isolation and enrichment of exosomes from plasma, exosome-enriched preparations were characterized and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed by comparing the baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost). Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. While further validation is needed, including measurements of IGF-1/IGF-1 signaling in blood or skeletal muscle, our results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.
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Affiliation(s)
- Venugopalan D. Nair
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Yongchao Ge
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Side Li
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Hanna Pincas
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Nimisha Jain
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Nitish Seenarine
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Mary Anne S. Amper
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Bret H. Goodpaster
- Translational Research Institute, AdventHealth, Orlando, FL, United States
| | - Martin J. Walsh
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Paul M. Coen
- Translational Research Institute, AdventHealth, Orlando, FL, United States
| | - Stuart C. Sealfon
- Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Chen L, Chen J, Xie G, Zhu L. MiR-222 inhibition alleviates Staphylococcal Enterotoxin B-induced inflammatory acute lung injury by targeting Foxo3. J Biosci 2020. [DOI: 10.1007/s12038-020-00037-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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26
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Ng PC, Chan KYY, Lam HS, Wong RPO, Ma TPY, Sit T, Leung KT, Chan LCN, Pang YLI, Cheung HM, Chu WCW, Li K. A Prospective Cohort Study of Fecal miR-223 and miR-451a as Noninvasive and Specific Biomarkers for Diagnosis of Necrotizing Enterocolitis in Preterm Infants. Neonatology 2020; 117:555-561. [PMID: 33238267 DOI: 10.1159/000511655] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/16/2020] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The objective of this study is to evaluate the usefulness of fecal microRNA (miR)-223 and miR-451a, as novel noninvasive biomarkers for early diagnosis of necrotizing enterocolitis (NEC) in preterm infants. METHODS Among the top-listed target miRNAs in our previous differential microarray analysis, miR-223 and miR-451a were quantified in a pilot validation case-controlled study (NEC vs. non-NEC/nonsepsis infants; n = 6 in each group). A definitive prospective cohort study (n = 218) further assessed their clinical usefulness as noninvasive and specific diagnostic biomarkers. Fecal calprotectin was quantified in parallel for comparison. RESULTS Of 43 proven NEC cases in the cohort study, 24 (55.8%) had fecal samples recovered within the first 3 days of clinical presentation. Fecal miRNA-223 (10.5 fold), miR-451a (4.5 fold), and calprotectin (2.1 fold) concentrations were significant higher in NEC compared with the non-NEC group (p < 0.009). Accepting a minimum sensitivity of 0.75, the positive predictive values (PPVs) ranged between 0.19 and 0.20. Combining fecal biomarkers and CRP (Day 1) could marginally increase the PPVs (0.31-0.34) but adversely lowered the sensitivity (0.54-0.63). CONCLUSIONS Although fecal miRNA biomarkers and calprotectin concentrations were significantly higher in the NEC group, the considerable overlapping of concentrations between groups and low recovery of stool specimens within 72 h of clinical presentation rendered fecal noninvasive tests of limited clinical value in guiding diagnosis of NEC during the acute phase. A further study is underway to evaluate their roles in surveillance for predicting high-risk premature infants developing NEC.
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Affiliation(s)
- Pak Cheung Ng
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China,
| | - Kathy Yuen Yee Chan
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Hugh Simon Lam
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Raymond Pui On Wong
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Terence Ping Yuen Ma
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Tony Sit
- Department of Statistics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Kam Tong Leung
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Lawrence Chi Ngong Chan
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Yennie Lap Ian Pang
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Hon Ming Cheung
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Winnie Chiu Wing Chu
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Karen Li
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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27
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Ding S, Liu G, Jiang H, Fang J. MicroRNA Determines the Fate of Intestinal Epithelial Cell Differentiation and Regulates Intestinal Diseases. Curr Protein Pept Sci 2019; 20:666-673. [PMID: 30678626 DOI: 10.2174/1389203720666190125110626] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 12/30/2018] [Accepted: 01/10/2019] [Indexed: 12/19/2022]
Abstract
The rapid self-renewal of intestinal epithelial cells enhances intestinal function, promotes the nutritional needs of animals and strengthens intestinal barrier function to resist the invasion of foreign pathogens. MicroRNAs (miRNAs) are a class of short-chain, non-coding RNAs that regulate stem cell proliferation and differentiation by down-regulating hundreds of conserved target genes after transcription via seed pairing to the 3' untranslated regions. Numerous studies have shown that miRNAs can improve intestinal function by participating in the proliferation and differentiation of different cell populations in the intestine. In addition, miRNAs also contribute to disease regulation and therefore not only play a vital role in the gastrointestinal disease management but also act as blood or tissue biomarkers of disease. As changes to the levels of miRNAs can change cell fates, miRNA-mediated gene regulation can be used to update therapeutic strategies and approaches to disease treatment.
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Affiliation(s)
- Sujuan Ding
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China.,Hunan Province Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, Hunan, China.,Academician Workstation of Hunan Baodong Farming Co., Ltd., Hunan 422001, China
| | - Gang Liu
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China.,Hunan Province Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, Hunan, China
| | - Hongmei Jiang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
| | - Jun Fang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
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28
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Chen G, Feng Y, Li X, Jiang Z, Bei B, Zhang L, Han Y, Li Y, Li N. Post-transcriptional Gene Regulation in Colitis Associated Cancer. Front Genet 2019; 10:585. [PMID: 31275360 PMCID: PMC6593052 DOI: 10.3389/fgene.2019.00585] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 06/04/2019] [Indexed: 01/07/2023] Open
Abstract
Colitis-associated cancer (CAC) has been linked to microRNA (miRNA) aberrant expression elicited by inflammation. In this study, we used the AOM/DSS-induced CAC mice model to explore the ectopic expression of miRNAs in the precancerous stage of CAC. As a result, we found that miR-31-5p, miR-223-3p, and let-7f-5p were dysregulated during the development of intestinal dysplasia. Subsequently, we first identified the role of these three miRNAs in CAC. Adenomatous polyposis coli (APC) was revealed as a new target of miR-223-3p, and solute carrier family 9- subfamily A-member 9 (SLC9A9) and APC membrane recruitment protein 3 (AMER3) were suggested as two new targets for let-7f-5p. For miR-31-5p, we proved that it can target LATS2 mRNA so as to modulate Hippo pathway in Caco2 cells. Second, to examine if targeting these three miRNAs would lead to CAC prevention, pedunculoside, a natural triterpene glycoside capable of rescuing the down-regulation of LATS2 and APC caused by either miR-31-5p or miR-223-3p overexpression, respectively, was used in the in vivo AOM/DSS-induced CAC model. The results showed that pedunculoside (25 mg/kg) substantially mitigated the damage to mice intestine caused by DSS/AOM. These results suggested that miRNAs-elicited post-transcriptional regulation is involved in the pathogenesis of CAC, and CAC can be prevented through targeting key miRNAs that are ectopically expressed in CAC.
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Affiliation(s)
- Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.,Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Xuezheng Li
- Department of Pharmacy, Yanbian University Hospital, Yanji, China
| | - Zhe Jiang
- Department of Pharmacy, Yanbian University Hospital, Yanji, China
| | - Bei Bei
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Lin Zhang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Yueqing Han
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Yanwu Li
- Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.,Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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29
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Feng Y, Zhang Y, Zhou D, Chen G, Li N. MicroRNAs, intestinal inflammatory and tumor. Bioorg Med Chem Lett 2019; 29:2051-2058. [PMID: 31213403 DOI: 10.1016/j.bmcl.2019.06.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) is the third most malignant tumor. Inflammatory bowel disease (IBD) can increase the risk of colorectal cancer. And colitis-associated cancer (CAC) is a CRC subtype, representing the inflammation-related colorectal cancer. For the past decades, we have known that ectopic microRNA (miRNA) expression was involved in the pathogenesis of IBD and CRC, playing a pivotal role in the progression of inflammation to colorectal cancer. Thus, this review provides the recent advances in altered human tissue-specific miRNAs that contribute to IBD, CRC and CAC pathogenesis, diagnosis and treatment. Meanwhile, the potential utilization of miRNAs as novel therapeutic targets for the prevention of CRC was also discussed.
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Affiliation(s)
- Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China
| | - Yuan Zhang
- Tianjin Vocational College of Bioengineering, Tianjin 300462, China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China.
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China.
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30
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Fogel O, Bugge Tinggaard A, Fagny M, Sigrist N, Roche E, Leclere L, Deleuze JF, Batteux F, Dougados M, Miceli-Richard C, Tost J. Deregulation of microRNA expression in monocytes and CD4 + T lymphocytes from patients with axial spondyloarthritis. Arthritis Res Ther 2019; 21:51. [PMID: 30755244 PMCID: PMC6373047 DOI: 10.1186/s13075-019-1829-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 01/18/2019] [Indexed: 02/07/2023] Open
Abstract
Background MicroRNAs (MiRs) play an important role in the pathogenesis of chronic inflammatory diseases. This study is the first to investigate miR expression profiles in purified CD4+ T lymphocytes and CD14+ monocytes from patients with axial spondyloarthritis (axSpA) using a high-throughput qPCR approach. Methods A total of 81 axSpA patients fulfilling the 2009 ASAS classification criteria, and 55 controls were recruited from October 2014 to July 2017. CD14+ monocytes and CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells. MiR expression was investigated by qPCR using the Exiqon Human MiRnome panel I analyzing 372 miRNAs. Differentially expressed miRNAs identified in the discovery cohort were validated in the replication cohort. Results We found a major difference in miR expression patterns between T lymphocytes and monocytes regardless of the patient or control status. Comparing disease-specific differentially expressed miRs, 13 miRs were found consistently deregulated in CD14+ cells in both cohorts with miR-361-3p, miR-223-3p, miR-484, and miR-16-5p being the most differentially expressed. In CD4+ T cells, 11 miRs were differentially expressed between patients and controls with miR-16-1-3p, miR-28-5p, miR-199a-5p, and miR-126-3p were the most strongly upregulated miRs among patients. These miRs are involved in disease relevant pathways such as inflammation, intestinal permeability or bone formation. Mir-146a-5p levels correlated inversely with the degree of inflammation in axSpA patients. Conclusions We demonstrate a consistent deregulation of miRs in both monocytes and CD4+ T cells from axSpA patients, which could contribute to the pathophysiology of the disease with potential interest from a therapeutic perspective. Electronic supplementary material The online version of this article (10.1186/s13075-019-1829-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Olivier Fogel
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France.,Department of Rheumatology - Hôpital Cochin. Assistance Publique - Hôpitaux de Paris, Paris Descartes University, Paris, France
| | - Andreas Bugge Tinggaard
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Maud Fagny
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France
| | - Nelly Sigrist
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France
| | - Elodie Roche
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France
| | - Laurence Leclere
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France
| | - Jean-François Deleuze
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France
| | | | - Maxime Dougados
- Department of Rheumatology - Hôpital Cochin. Assistance Publique - Hôpitaux de Paris, Paris Descartes University, Paris, France.,Unité Mixte AP-HP/ Institut Pasteur, Institut Pasteur, Immunoregulation Unit, Paris, France.,INSERM (U1153) : Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, Paris, France
| | - Corinne Miceli-Richard
- Department of Rheumatology - Hôpital Cochin. Assistance Publique - Hôpitaux de Paris, Paris Descartes University, Paris, France.,Unité Mixte AP-HP/ Institut Pasteur, Institut Pasteur, Immunoregulation Unit, Paris, France
| | - Jörg Tost
- Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, 2 rue Gaston Crémieux, Evry, France.
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Liu Q, Shan P, Li H. Gambogic acid prevents angiotensin II‑induced abdominal aortic aneurysm through inflammatory and oxidative stress dependent targeting the PI3K/Akt/mTOR and NF‑κB signaling pathways. Mol Med Rep 2018; 19:1396-1402. [PMID: 30535428 DOI: 10.3892/mmr.2018.9720] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 09/12/2017] [Indexed: 12/21/2022] Open
Abstract
Gamboge is the dry resin secreted by Garcinia hanbaryi Hook.f, with the function of promoting blood circulation and anti‑cancer effects, detoxification, hemostasis and killing insects. It is also used for the treatment of cancer, brain edema and other diseases. Gambogic acid is the main effective constituent of Gamboge. The present study tested the hypothesis that the effect of Gambogic acid prevents angiotensin II‑induced abdominal aortic aneurysm (AAA), and explored its underlying mechanism. It was demonstrated that gambogic acid significantly inhibited AAA incidence rate, and reduced edge leading aortic diameter and aortic wall thickness in AAA mice. Gambogic acid treatment markedly decreased the levels of proinflammatory cytokines and oxidative stress factors, and transforming growth factor‑β (TGF‑β) and matrix metalloproteinase (MMP)‑2 and MMP‑9 protein expression in AAA mice. Furthermore, Gambogic acid decreased expression of phosphatidylinositol 3‑kinase (PI3K), and phosphorylation of protein kinase B (Akt), mechanistic target of rapamycin (mTOR) and p70‑S6 kinase 1. It also suppressed nuclear factor (NF)‑κB protein expression in AAA mice. The findings of the present study indicated that Gambogic acid prevents angiotensin II‑induced AAA through inflammatory and oxidative stress‑dependent targeting of the PI3K/Akt/mTOR and NF‑κB signaling pathways.
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Affiliation(s)
- Qiang Liu
- Department of Vascular Surgery, The First Hospital of Qiqihar City, Qiqihar, Heilongjiang 161021, P.R. China
| | - Peng Shan
- Department of Vascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150036, P.R. China
| | - Haibin Li
- Department of Vascular Surgery, The First Hospital of Qiqihar City, Qiqihar, Heilongjiang 161021, P.R. China
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Bao L, Chau C, Bao J, Tsoukas MM, Chan LS. IL-4 dysregulates microRNAs involved in inflammation, angiogenesis and apoptosis in epidermal keratinocytes. Microbiol Immunol 2018; 62:732-736. [DOI: 10.1111/1348-0421.12650] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/28/2018] [Accepted: 09/16/2018] [Indexed: 01/29/2023]
Affiliation(s)
- Lei Bao
- Department of Dermatology; University of Illinois; 808 S Wood St. Chicago, Illinois 60612 USA
| | - Cecilia Chau
- Research Resources Center; University of Illinois; 832 South Wolcott Avenue Chicago, Illinois 60612 USA
| | - Jeremy Bao
- Department of Dermatology; University of Illinois; 808 S Wood St. Chicago, Illinois 60612 USA
| | - Maria M. Tsoukas
- Department of Dermatology; University of Illinois; 808 S Wood St. Chicago, Illinois 60612 USA
| | - Lawrence S. Chan
- Department of Dermatology; University of Illinois; 808 S Wood St. Chicago, Illinois 60612 USA
- Medical Service; Jesse Brown Veterans Affairs Hospital; 820 S. Damen Avenue Chicago, Illinois 60612 USA
- Medical Service; Captain James A. Lovell Federal Health Care Center; 3001 Green Bay Road North Chicago, Illinois 60064 USA
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Diao X, Zhou J, Wang S, Ma X. Upregulation of miR-132 contributes to the pathophysiology of COPD via targeting SOCS5. Exp Mol Pathol 2018; 105:285-292. [PMID: 30292646 DOI: 10.1016/j.yexmp.2018.10.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 09/19/2018] [Accepted: 10/03/2018] [Indexed: 12/20/2022]
Abstract
The role of microRNAs has been recently identified in chronic obstructive pulmonary disease (COPD). This study aimed to examine the role of miR-132 in the pathophysiology of COPD and to explore the underlying molecular mechanisms of miR-132 in COPD. MiR-132 and suppressor of cytokine signaling 5 (SOCS5) mRNA expression were detected by qRT-PCR. The number of CD4+ and CD8+ T cells was analyzed by flow cytometry. SOCS5 and epidermal growth factor receptor (EGFR) protein levels were determined by western blot. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) concentrations were measured by ELISA. MiR-132 expression was up-regulated in the serum from COPD patients and smokers compared with nonsmoker controls. The number of CD8+ T cells was significantly increased in the serum from COPD patients and smokers. MiR-132 expression was negatively correlated with FEV1/FVC%, and positively correlated with CD8+ T cells (%). MiR-132 overexpression repressed SOCS5 expression via directly targeting SOCS5 3'UTR in human monocyte-like cells (THP-1), which was confirmed by luciferase reporter assay. MiR-132 overexpression increased EGFR protein levels and the concentrations of inflammatory cytokines (IL-1β and TNF-α) in THP-1 cells, and these effects were attenuated by enforced expression of SOCS5. Further, cigarette smoke extract (CSE) treatment up-regulated miR-132 expression, down-regulated SOCS5 expression, and increased inflammatory cytokines levels, which was attenuated by miR-132 knockdown in THP-1 cells. Consistent findings were also found in the human bronchial epithelial cells (BEAS-2B). Collectively, our data implicated that miR-132 may promote inflammation in THP-1 and BEAS-2B cells at least via targeting SOCS5 in COPD.
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Affiliation(s)
- Xin Diao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an City, Shaanxi Province, China.
| | - Jing Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an City, Shaanxi Province, China
| | - Shengyu Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an City, Shaanxi Province, China
| | - Xuan Ma
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an City, Shaanxi Province, China
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Dong P, Zhang X, Zhao J, Li D, Li L, Yang B. Anti-microRNA-132 causes sevoflurane‑induced neuronal apoptosis via the PI3K/AKT/FOXO3a pathway. Int J Mol Med 2018; 42:3238-3246. [PMID: 30272258 PMCID: PMC6202078 DOI: 10.3892/ijmm.2018.3895] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 07/10/2018] [Indexed: 01/06/2023] Open
Abstract
In the present study, the mechanisms underlying the protective effects of microRNA‑132 (miRNA‑132) on sevoflurane‑induced neuronal apoptosis were investigated. Reverse transcription‑quantitative polymerase chain reaction and gene microarray hybridization were used to analyze alterations in microRNA levels. Cell viability, apoptosis and caspase‑3/9 activity were measured using MTT, flow cytometry and caspase‑3/9 activity kits. Immunofluorescence staining and western blot analysis were used to measure protein expression of phosphoinositide 3‑kinase (PI3K) and phosphorylated (p‑)AKT, forkhead box O3a (FOXO3a). In sevoflurane‑induced rats, the expression of miRNA‑132 was downregulated, compared with that in negative control rats. The downregulation of miRNA‑132 increased neuronal apoptosis and the upregulation of miRNA‑132 inhibited neuronal apoptosis in the sevoflurane‑induced in vitro model. The downregulation of miRNA‑132 suppressed the protein expression of PI3K and p‑AKT, and suppressed the protein expression of FOXO3a in the sevoflurane‑induced in vitro model. The PI3K inhibitor increased the effects of anti‑miRNA‑132 on neuronal apoptosis through the AKT/FOXO3a pathway in the sevoflurane‑induced in vitro model. The promotion of FOXO3a inhibited the effects of anti‑miRNA‑132 on neuronal apoptosis through the AKT/FOXO3a pathway in the sevoflurane‑induced in vitro model. These data suggested that miRNA‑132 caused sevoflurane‑induced neuronal apoptosis via suppression of the PI3K/AKT/FOXO3a pathway.
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Affiliation(s)
- Ping Dong
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiyan Zhang
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jian Zhao
- Department of Anesthesiology, The People's Hospital of Chiping, Chiping, Shandong 252100, P.R. China
| | - Dongliang Li
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Liang Li
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Bo Yang
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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Iwamoto N, Fukui S, Takatani A, Shimizu T, Umeda M, Nishino A, Igawa T, Koga T, Kawashiri SY, Ichinose K, Tmai M, Nakamura H, Origuchi T, Chiba K, Osaki M, Jüngel A, Gay S, Kawakami A. Osteogenic differentiation of fibroblast-like synovial cells in rheumatoid arthritis is induced by microRNA-218 through a ROBO/Slit pathway. Arthritis Res Ther 2018; 20:189. [PMID: 30157923 PMCID: PMC6116572 DOI: 10.1186/s13075-018-1703-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 08/16/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Fibroblast-like synovial cells (FLS) have multilineage differentiation potential including osteoblasts. We aimed to investigate the role of microRNAs during the osteogenic differentiation of rheumatoid arthritis (RA)-FLS. METHODS RA-FLS were differentiated in osteogenic medium for 21 days. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) staining and Alizarin Red staining. MicroRNA (miRNA) array analysis was performed to investigate the differentially expressed miRNAs during osteogenic differentiation. Expression of miR-218-5p (miR-218) during the osteogenic differentiation was determined by quantitative real-time PCR. Transfections with an miR-218 precursor and inhibitor were used to confirm the targets of miR-218 and to analyze the ability of miR-218 to induce osteogenic differentiation. Secreted Dickkopf-1 (DKK1) from FLS transfected with miR-218 precursor/inhibitor or roundabout 1 (ROBO1) knockdown FLS established using ROBO1-small interfering RNA (siRNA) were measured by ELISA. RESULTS The miRNA array revealed that 12 miRNAs were upregulated and 24 miRNAs were downregulated after osteogenic differentiation. We observed that the level of miR-218 rose in the early phase of osteogenic differentiation and then decreased. Pro-inflammatory cytokines modified the expression of miR-218. The induction of miR-218 in RA-FLS decreased ROBO1 expression, and promoted osteogenic differentiation. Both the overexpression of miR-218 and the knockdown of ROBO1 in RA-FLS decreased DKK1 secretion. CONCLUSION We identified miR-218 as a crucial inducer of the osteogenic differentiation of RA-FLS. MiR-218 modulates the osteogenic differentiation of RA-FLS through the ROBO1/DKK-1 axis. The induction of the osteogenic differentiation of proliferating RA-FLS through the provision of miR-218 into RA-FLS or by boosting the cellular reservoir of miR-218 might thus become a therapeutic strategy for RA.
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Affiliation(s)
- Naoki Iwamoto
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Shoichi Fukui
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Ayuko Takatani
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Toshimasa Shimizu
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Masataka Umeda
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
- Medical Education Development Center, Nagasaki University School Hospital, Nagasaki, Japan
| | - Ayako Nishino
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
- Center for Comprehensive Community Care Education, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takashi Igawa
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Tomohiro Koga
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
- Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shin-ya Kawashiri
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
- Departments of Community Medicine, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kunihiro Ichinose
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Mami Tmai
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Hideki Nakamura
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
| | - Tomoki Origuchi
- Department of Physical Therapy, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ko Chiba
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Makoto Osaki
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Astrid Jüngel
- Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Schlieren, Zurich, Switzerland
| | - Steffen Gay
- Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Schlieren, Zurich, Switzerland
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan
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Chan SN, Low END, Raja Ali RA, Mokhtar NM. Delineating inflammatory bowel disease through transcriptomic studies: current review of progress and evidence. Intest Res 2018; 16:374-383. [PMID: 30090036 PMCID: PMC6077315 DOI: 10.5217/ir.2018.16.3.374] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/23/2018] [Accepted: 01/29/2018] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD), which comprises of Crohn's disease and ulcerative colitis, is an idiopathic relapsing and remitting disease in which the interplay of different environment, microbial, immunological and genetic factors that attribute to the progression of the disease. Numerous studies have been conducted in multiple aspects including clinical, endoscopy and histopathology for the diagnostics and treatment of IBD. However, the molecular mechanism underlying the aetiology and pathogenesis of IBD is still poorly understood. This review tries to critically assess the scientific evidence at the transcriptomic level as it would help in the discovery of RNA molecules in tissues or serum between the healthy and diseased or different IBD subtypes. These molecular signatures could potentially serve as a reliable diagnostic or prognostic biomarker. Researchers have also embarked on the study of transcriptome to be utilized in targeted therapy. We focus on the evaluation and discussion related to the publications reporting the different approaches and techniques used in investigating the transcriptomic changes in IBD with the intention to offer new perspectives to the landscape of the disease.
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Affiliation(s)
- Seow-Neng Chan
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Eden Ngah Den Low
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, Yu W, Wang Y, Li P, Wang J. Critical role of FOXO3a in carcinogenesis. Mol Cancer 2018; 17:104. [PMID: 30045773 PMCID: PMC6060507 DOI: 10.1186/s12943-018-0856-3] [Citation(s) in RCA: 339] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 07/12/2018] [Indexed: 12/13/2022] Open
Abstract
FOXO3a is a member of the FOXO subfamily of forkhead transcription factors that mediate a variety of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage and tumorigenesis. It also responds to several cellular stresses such as UV irradiation and oxidative stress. The function of FOXO3a is regulated by a complex network of processes, including post-transcriptional suppression by microRNAs (miRNAs), post-translational modifications (PTMs) and protein-protein interactions. FOXO3a is widely implicated in a variety of diseases, particularly in malignancy of breast, liver, colon, prostate, bladder, and nasopharyngeal cancers. Emerging evidences indicate that FOXO3a acts as a tumor suppressor in cancer. FOXO3a is frequently inactivated in cancer cell lines by mutation of the FOXO3a gene or cytoplasmic sequestration of FOXO3a protein. And its inactivation is associated with the initiation and progression of cancer. In experimental studies, overexpression of FOXO3a inhibits the proliferation, tumorigenic potential, and invasiveness of cancer cells, while silencing of FOXO3a results in marked attenuation in protection against tumorigenesis. The role of FOXO3a in both normal physiology as well as in cancer development have presented a great challenge to formulating an effective therapeutic strategy for cancer. In this review, we summarize the recent findings and overview of the current understanding of the influence of FOXO3a in cancer development and progression.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Xiang Ao
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Wei Ding
- Department of comprehensive internal medicine, Affiliated Hospital, Qingdao University, Qingdao, 266003 China
| | - Murugavel Ponnusamy
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Wei Wu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Xiaodan Hao
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Wanpeng Yu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Yifei Wang
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Peifeng Li
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
| | - Jianxun Wang
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, 266021 China
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Wu X, Yang J, Yu L, Long D. Plasma miRNA-223 correlates with risk, inflammatory markers as well as prognosis in sepsis patients. Medicine (Baltimore) 2018; 97:e11352. [PMID: 29979415 PMCID: PMC6076081 DOI: 10.1097/md.0000000000011352] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The purpose was to evaluate the role of plasma microRNA-223 (miRNA-223) in risk and prognosis in sepsis patients, and its correlation with inflammatory markers.In this study, 187 sepsis patients from July 2015 to December 2016 were consecutively enrolled. Blood samples from septic patients and healthy controls (HCs) were collected, and plasma was separated for miRNA-223 expression detected by quantitative real-time PCR (qPCR). Enzyme-linked immune sorbent assay (ELISA) was performed to detect inflammatory markers.The results were as follows: miRNA-223 was highly expressed in sepsis patients compared to HCs (P < .001). Receiver operating characteristic (ROC) curve revealed miRNA-223 disclosed a good diagnostic value of sepsis with area under curve (AUC) of 0.754, 95% CI: 0.706-0.803. Sensitivity and specificity were 56.6% and 86.6% at the best cut-off point, respectively. Multivariate logistic analysis indicated that miRNA-223 could predict sepsis risk independently. Spearman's correlation disclosed that miRNA-223 relatively expression positively correlated with APCHE II score (r = 0.459, P < 0.001), CRP (r = 0.326, P < 0.001), TNFα (r = 0.325, P < 0.001), IL-1β (r = 0.165, P = 0.024), IL-6 (r = 0.229, P = 0.002) and IL-8 (r = 0.154, P = 0.035), while it was negatively correlated with IL-10 (r = -0.289, P < 0.001). miRNA-223 expression in non-survivor was higher than that in survivor (P < 0.001). ROC curve revealed miRNA-223 could distinguish sepsis non-survivor form survivor with AUC of 0.600, 95% CI: 0.505-0.695. Sensitivity and specificity were 83.5% and 38.9% respectively at the best cut-off point.In conclusion, plasma miRNA-223 correlates with disease severity and inflammatory markers levels, and it might serve as a novel diagnostic and prognostic biomarker in sepsis patients.
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The Role of Autophagy and Related MicroRNAs in Inflammatory Bowel Disease. Gastroenterol Res Pract 2018; 2018:7565076. [PMID: 30046303 PMCID: PMC6038472 DOI: 10.1155/2018/7565076] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/26/2018] [Accepted: 05/15/2018] [Indexed: 12/21/2022] Open
Abstract
Accumulating evidence demonstrates that microRNA- (miR-) mediated posttranscriptional regulation plays an important role in autophagy in inflammatory bowel disease (IBD), a disease that is difficult to manage clinically because of the associated chronic recurrent nonspecific inflammation. Research indicates that microRNAs regulate autophagy via different pathways, playing an important role in the IBD process and providing a new perspective for IBD research. Related studies have shown that miR-142-3p, miR-320, miR-192, and miR-122 target NOD2, an IBD-relevant autophagy gene, to modulate autophagy in IBD. miR-142-3p, miR-93, miR-106B, miR-30C, miR-130a, miR-346, and miR-20a regulate autophagy by targeting ATG16L1 through several different pathways. miR-196 can downregulate IRGM and suppress autophagy by inhibiting the accumulation of LC3II. During the endoplasmic reticulum stress response, miR-665, miR-375, and miR-150 modulate autophagy by regulating the unfolded protein response, which may play an important role in IBD intestinal fibrosis. Regarding autophagy-related pathways, miR-146b, miR-221-5p, miR-132, miR-223, miR-155, and miR-21 regulate NF-κB or mTOR signaling to induce or inhibit autophagy in intestinal cells by releasing anti- or proinflammatory factors, respectively.
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40
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Citrobacter rodentium alters the mouse colonic miRNome. Genes Immun 2018; 20:207-213. [PMID: 29728609 DOI: 10.1038/s41435-018-0026-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 02/11/2018] [Accepted: 02/22/2018] [Indexed: 12/12/2022]
Abstract
Citrobacter rodentium is a murine pathogen causing transmissible colonic hyperplasia and colitis with a pathogenic mechanism similar to foodborne enterohaemorrhagic Escherichia coli in humans. Mechanisms underlying intestinal responses to C. rodentium infection are incompletely understood. We identified 24 colonic microRNAs (miRNAs) as significantly deregulated in response to C. rodentium, including miR-7a, -17, -19a, -20a, -20b, -92a, -106a, -132, -200a, and -2137; most of these miRNAs belong to the oncogenic miR-17-92 clusters. Pathways involved in cell cycle, cancers, and immune responses were enriched among the predicted targets of these miRNAs. We further demonstrated that an apoptosis facilitator, Bim, is a candidate gene target of miRNA-mediated host response to the infection. These findings suggest that host miRNAs participate in C. rodentium pathogenesis and may represent novel treatment targets.
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Park EJ, Shimaoka M, Kiyono H. MicroRNA-mediated dynamic control of mucosal immunity. Int Immunol 2018; 29:157-163. [PMID: 28383678 DOI: 10.1093/intimm/dxx019] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 04/01/2017] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal tract is a complex and important physiological and immunological organ embodying the first line of defense by which mucosal immunity regulates the immense number and diversity of naturally encountered antigens and commensal microflora. Effective microRNA (miRNA) control of transcription factors or mediators in mucosal immunity is essential to host defense and homeostasis in both physiologic and pathologic states. MiRNA biology has advanced our understanding of the immune regulatory system network at the level of post-transcriptional gene modification. Increasing knowledge on circulating miRNAs could potentially enhance diagnostic techniques in inflammatory bowel disease (IBD). Furthermore, recent findings on the dynamic role of exosomes vis-à-vis the intercellular transportation of miRNAs may provide insights on the use of miRNA as a target for treating IBD.
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Affiliation(s)
- Eun Jeong Park
- Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.,Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan
| | - Hiroshi Kiyono
- Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.,International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.,Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8670, Japan
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Guo TM, Yan Y, Cao WN, Liu Q, Zhu HY, Yang L, Gao MC, Xing YL. Predictive value of microRNA-132 and its target gene NAG-1 in evaluating therapeutic efficacy of non-steroidal anti-inflammatory drugs treatment in patients with ankylosing spondylitis. Clin Rheumatol 2018; 37:1281-1293. [PMID: 29497899 DOI: 10.1007/s10067-018-4017-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 12/29/2017] [Accepted: 01/29/2018] [Indexed: 12/14/2022]
Abstract
Ankylosing spondylitis (AS) is a common chronic rheumatic disorder, accompanied by the differential expression of various microRNAs (miRNAs) in patients suffering from the condition, some of which have the potential to serve as novel complementary AS biomarkers. During this study, AS patients were recruited in connection with our investigation into the correlation of microRNA-132 (miR-132) in peripheral blood and its target gene NAG-1 expressions in relation with the clinical efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) treatment in patients with AS. A total of 218 AS patients who had been previously treated with oral diclofenac sodium and were placed into either the response (n = 175) or non-response groups (n = 43) following a 16-week period of therapeutic evaluation. An additional 113 healthy patients were also recruited for the purposes of the study. AS patient peripheral blood samples were obtained at the 0th, 8th, and 16th week, with the corresponding samples of the healthy patients collected at week 0. The expressions of miR-132 and NAG-1 were detected by RT-qPCR and analyzed using a ROC curve for the elucidation of the diagnostic value of peripheral blood miR-132 expressions as well as their predictive value among AS patients undergoing NSAIDs treatment. The targeting relations of miR-132 and NAG-1 were validated by microRNA.org and luciferase assay. Greater levels of peripheral blood miR-132 expression were observed among AS patients prior to treatment, in comparison to the healthy patients in the study. Prior to treatment, the area under the miR-132 ROC curve (AUC) of AS patients was 0.965, with a critical point of 2.605. The sensitivity and specificity of miR-132 were 91.7 and 97.3%, respectively, in regard to the AS diagnostic clinical efficacy. In comparison with the non-response group, the miR-132 expression of patients in the response group exhibited descended levels while the mRNA expression of NAG-1 increased. The ROC results indicated that the AUC of miR-132 was 0.876 with its sensitivity and specificity observed to be 95.3 and 80.0%, respectively. The AUC of NAG-1 was 0.912 with its sensitivity and specificity observed to be 76.6 and 79.1%, respectively. In comparison with the high miR-132 expression group and the low NAG-1 mRNA expression group, significantly improved blood biochemistry indexes, sign indexes, blood indexes, and adverse reaction rate were observed among the low miR-132 expression group and the high NAG-1 mRNA expression group. The microRNA.org and luciferase assay revealed NAG-1 to be a target of miR-132. Based on the results of this study, it was concluded that the expressions of MiR-132 and NAG-1 could serve as biological markers in the prediction of the therapeutic efficiency of NSAID treatment in AS patients.
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Affiliation(s)
- Tuan-Mao Guo
- The Second Department of Orthopaedics, Xianyang Central Hospital, Xianyang, 712000, People's Republic of China
| | - Yong Yan
- The Second Department of Orthopaedics, Shaanxi Traditional Chinese Medicine Hospital, Xi'an, 710003, People's Republic of China
| | - Wei-Ning Cao
- The Second Department of Orthopaedics, Xianyang Central Hospital, Xianyang, 712000, People's Republic of China
| | - Qiang Liu
- The First Department of Orthopaedics, Xianyang Central Hospital, Xianyang, 712000, People's Republic of China
| | - Hai-Yun Zhu
- Xianyang Central Hospital, Xianyang, 712000, People's Republic of China
| | - Lan Yang
- Xianyang Central Hospital, Xianyang, 712000, People's Republic of China
| | - Mai-Cang Gao
- Department of Critical Care Medicine, the First Affiliated Hospital, Shaanxi University of Chinese Medicine, No. 2, Weicheng West Road, Xianyang, 712000, Shaanxi Province, People's Republic of China.
| | - Yan-Li Xing
- Pharmaceutical Preparation Section, Xianyang Central Hospital, No. 78, Renmin East Road, Xianyang, 712000, Shaanxi Province, People's Republic of China.
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Tili E, Michaille JJ, Piurowski V, Rigot B, Croce CM. MicroRNAs in intestinal barrier function, inflammatory bowel disease and related cancers-their effects and therapeutic potentials. Curr Opin Pharmacol 2017; 37:142-150. [PMID: 29154194 PMCID: PMC5938753 DOI: 10.1016/j.coph.2017.10.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/13/2017] [Accepted: 10/13/2017] [Indexed: 12/17/2022]
Abstract
The initiation and development or inflammatory bowel disease (IBD) and associated colorectal cancers, have been linked to inflammation. MicroRNAs are non-coding regulators of gene expression that have gained great attention due to their capability to regulate the expression of a number of target transcripts. It is now generally admitted that microRNAs are instrumental in gut pathologies, in particular through their targeting of transcripts encoding proteins of the intestinal barrier (IB) and their regulators. Intense research is conducted to identify microRNAs susceptible to be used as biomarkers and to design new therapeutic approaches based upon using synthetic microRNA mimics and inhibitors as well as finding new drugs capable to restore or modify microRNA expression in the context of gut pathologies.
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Affiliation(s)
- Esmerina Tili
- Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA; Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
| | - Jean-Jacques Michaille
- Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA; BioPerox-IL, UB-INSERM IFR #100, Faculté Gabriel, Université de Bourgogne-Franche Comté, Dijon, France
| | - Victoria Piurowski
- Department of Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA
| | - Brooke Rigot
- Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
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Che F, Du H, Zhang W, Cheng Z, Tong Y. MicroRNA-132 modifies angiogenesis in patients with ischemic cerebrovascular disease by suppressing the NF‑κB and VEGF pathway. Mol Med Rep 2017; 17:2724-2730. [PMID: 29207094 DOI: 10.3892/mmr.2017.8138] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 06/15/2017] [Indexed: 11/06/2022] Open
Abstract
In the present study, the expression of microRNA (miR)‑132 and the mechanism by which it modifies angiogenesis in patients with ischemic cerebrovascular disease (ICD) was investigated. RNA isolation and reverse transcription‑quantitative polymerase chain reaction were used to measure miR‑132 expression in patients with ICD. Inflammatory factors were measured using ELISA kits and western blotting measured B‑cell lymphoma‑2 (Bcl‑2)‑associated X/Bcl‑2 ratio (Bax/Bcl‑2 ratio), nuclear factor (NF)‑κB p65, matrix metalloproteinase‑9 (MMP‑9), vascular cell adhesion molecule‑1 (VCAM‑1) and protein expression of inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) protein expression. miR‑132 expression in patients with ICD was lower compared with healthy volunteers. PC12 cells were used to create an oxygen glucose deprivation (OGD) model. miR‑132 overexpression in an in vitro model was able to reduce tumor necrosis factor‑a, interleukin (IL)‑1β, IL‑6, IL‑8, cyclooxygenase‑2, caspase‑3 and caspase‑9 levels, suppress Bax/Bcl‑2 ratio, NF‑κB p65, MMP‑9, VCAM‑1, iNOS, VEGF protein expression. The results suggested that miR‑132 may modify angiogenesis in patients with ICD by suppressing the NF‑κB pathway and promoting the VEGF pathway, and may develop into a therapy for ICD in future research.
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Affiliation(s)
- Fengli Che
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101145, P.R. China
| | - Huishan Du
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101145, P.R. China
| | - Weidong Zhang
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101145, P.R. China
| | - Zhe Cheng
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101145, P.R. China
| | - Yanna Tong
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101145, P.R. China
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Xiong Y, Shi L, Wang L, Zhou Z, Wang C, Lin Y, Luo D, Qiu J, Chen D. Activation of sirtuin 1 by catalpol-induced down-regulation of microRNA-132 attenuates endoplasmic reticulum stress in colitis. Pharmacol Res 2017; 123:73-82. [DOI: 10.1016/j.phrs.2017.05.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 05/23/2017] [Accepted: 05/23/2017] [Indexed: 02/06/2023]
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Jin X, Chen D, Zheng RH, Zhang H, Chen YP, Xiang Z. miRNA-133a-UCP2 pathway regulates inflammatory bowel disease progress by influencing inflammation, oxidative stress and energy metabolism. World J Gastroenterol 2017; 23:76-86. [PMID: 28104982 PMCID: PMC5221288 DOI: 10.3748/wjg.v23.i1.76] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/09/2016] [Accepted: 11/15/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and energy metabolism. METHODS C57BL/6 mice were fed dextran sulfate sodium (DSS) liquid for 7 consecutive days, followed by the administration of saline to the DSS group, UCP2 siRNA to the UCP2 group and a miR-133a mimic to the miR-133a group on days 8 and 11. Body weight, stool consistency and rectal bleeding were recorded daily, and these composed the disease activity index (DAI) score for the assessment of disease severity. After cervical dislocation was performed on day 14, the length of the colon in each mouse was measured, and colonic tissue was collected for further study, which included the following: haematoxylin and eosin staining, UCP2 and miR-133a detection by immunohistochemical staining, western blot and quantitative real-time PCR, measurement of apoptosis by TUNEL assay, and the assessment of inflammation (TNF-α, IL-1β, IL-6 and MCP1), oxidative stress (H2O2 and MDA) and metabolic parameters (ATP) by ELISA and colorimetric methods. RESULTS An animal model of IBD was successfully established, as shown by an increased DAI score, shortened colon length and specific pathologic changes, along with significantly increased UCP2 and decreased miR-133a levels. Compared with the DSS group, the severity of IBD was alleviated in the UCP2 and the miR-133a groups after successful UCP2 knockdown and miR-133a overexpression. The extent of apoptosis, as well as the levels of TNF-α, IL-1β, MDA and ATP, were significantly increased in both the UCP2 and miR-133a groups compared with the DSS group. CONCLUSION The miR-133a-UCP2 pathway participates in IBD by altering downstream inflammation, oxidative stress and markers of energy metabolism, which provides novel clues and potential therapeutic targets for IBD.
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