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Włodarczyk M, Maryńczak K, Burzyński J, Włodarczyk J, Basak J, Fichna J, Majsterek I, Ciesielski P, Spinelli A, Dziki Ł. The role of miRNAs in the pathogenesis, diagnosis, and treatment of colorectal cancer and colitis-associated cancer. Clin Exp Med 2025; 25:86. [PMID: 40091000 PMCID: PMC11911275 DOI: 10.1007/s10238-025-01582-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/01/2025] [Indexed: 03/19/2025]
Abstract
MicroRNAs (miRNAs) are a group of noncoding single-stranded RNA biomolecules that act in posttranscriptional regulation of gene expression. Their role in the development of inflammatory bowel disease (IBD), colitis-associated cancer (CAC), and colorectal cancer (CRC) is currently under investigation. A few miRNAs present promising results in terms of diagnostic or therapeutic use, for example, miR-21 increases in CRC and inflammation, while also being a possible target for cancer therapy; miR-301a increases in inflammation but only in patients with IBD; miR-31 increases in CRC, especially in advanced stages, namely III-IV in TNM scale; miR-200 family plays a role in carcinogenesis of CRC and other tumors; examined as a group, miR-31-5p, miR-223-3p, and let-7f-5p trigger and exacerbate CAC; miR-19a could potentially be used in therapy and prevention of both CRC and CAC. Here, we discuss available studies and outline future directions concerning the validity of using miRNAs in the diagnosis and/or therapy of IBD, CAC, and CRC. Extensive research confirms that miRNAs play an important role in the pathogenesis of CAC and CRC. Since the significantly altered expression of certain miRNAs is an early prognostic marker for the development of these diseases, miRNAs have the potential to serve as diagnostic tools, enabling quick and straightforward disease detection.
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Affiliation(s)
- Marcin Włodarczyk
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland.
| | - Kasper Maryńczak
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jacek Burzyński
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jakub Włodarczyk
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
- Department of Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Justyna Basak
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Przemysław Ciesielski
- Department of General Surgery, Hospital of Our Lady of Perpetual Help in Wołomin, Wołomin, Poland
| | - Antonino Spinelli
- Colon and Rectal Surgery Division, Humanitas Clinical and Research Center, Milan, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Rozzano, Italy
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
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Li R, Gu B, Lv A. Regulatory Role of IGF2BP2 in Intestinal Mucosal Barrier Dysfunction in Ulcerative Colitis. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2025; 36:269-279. [PMID: 40241612 PMCID: PMC12070433 DOI: 10.5152/tjg.2025.24192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 09/25/2024] [Indexed: 04/18/2025]
Abstract
Background/Aims Ulcerative colitis (UC), an idiopathic and chronic inflammatory disease, primarily targets the mucosal lining of the colon. This research endeavors to reveal the mechanism of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and nuclear receptor coactivator-3 (NCOA3) in UC-induced intestinal mucosal barrier dysfunction. Materials and Methods Dextran sodium sulfate (DSS) was used for UC mouse modeling, followed by an assessment of the disease activity index, intestinal barrier integrity, and intestinal permeability assessment through FITC-glucan assay. microRNA (miR)-222-3p, IGF2BP2, and NCOA3 levels in colon tissues of mice were detected. The targeted binding of miR-222-3p to IGF2BP2 was determined using a dual-luciferase assay. The enrichment of IGF2BP2 or N6-methyladenosine (m6A) on NCOA3 mRNA in YAMC cells was tested by RNA immunoprecipitation and m6A RNA immunoprecipitation assays, and the mRNA stability of NCOA3 was determined after actinomycin D treatment. Results miR-222-3p was increased while IGF2BP2 and NCOA3 were decreased in the colon tissues of UC mice. IGF2BP2 overexpression effectively alleviated intestinal injury and reinstated the functional integrity of the mucosal barrier in DSS mice. IGF2BP2 recognized and bound to the m6A site of NCOA3 and increased mRNA stability, and miR-222-3p negatively regulated IGF2BP2. NCOA3 downregulation abated the beneficial impact of IGF2BP2 overexpression on DSS mice. miR-222-3p downregulation upregulated IGF2BP2/NCOA3 expression to protect against intestinal mucosal barrier dysfunction. Conclusion IGF2BP2 was repressed by miR-222-3p, yet IGF2BP2 increased the stability of NCOA3 mRNA via an m6A-dependent pathway, ultimately leading to attenuation of UC-related intestinal mucosal barrier impairment and UC progression.
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Affiliation(s)
- Ruifan Li
- Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Bin Gu
- Department of Orthopedic, 363 Hospital, Chengdu, China
| | - Anli Lv
- Department of Ultrasound, 363 Hospital, Chengdu, China
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Schemczssen-Graeff Z, Silva CR, de Freitas PNN, Constantin PP, Pileggi SAV, Olchanheski LR, Pileggi M. Probiotics as a strategy for addressing helminth infections in low-income countries: Working smarter rather than richer. Biochem Pharmacol 2024; 226:116363. [PMID: 38871336 DOI: 10.1016/j.bcp.2024.116363] [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: 03/26/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/15/2024]
Abstract
Helminth infections, which affect approximately 1.5 billion individuals worldwide (mainly children), are common in low- and middle-income tropical countries and can lead to various diseases. One crucial factor affecting the occurrence of these diseases is the reduced diversity of the gut microbiome due to antibiotic use. This reduced diversity compromises immune health in hosts and alters host gene expression through epigenetic mechanisms. Helminth infections may produce complex biochemical signatures that could serve as therapeutic targets. Such therapies include next-generation probiotics, live biotherapeutic products, and biochemical drug approaches. Probiotics can bind ferric hydroxide, reducing the iron that is available to opportunistic microorganisms. They also produce short-chain fatty acids associated with immune response modulation, oral tolerance facilitation, and inflammation reduction. In this review, we examine the potential link between these effects and epigenetic changes in immune response-related genes by analyzing methyltransferase-related genes within probiotic strains discussed in the literature. The identified genes were only correlated with methylation in bacterial genes. Various metabolic interactions among hosts, helminth parasites, and intestinal microbiomes can impact the immune system, potentially aiding or hindering worm expulsion through chemical signaling. Implementing a comprehensive strategy using probiotics may reduce the impact of drug-resistant helminth strains.
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Affiliation(s)
- Zelinda Schemczssen-Graeff
- Comparative Immunology Laboratory, Department of Microbiology, Parasitology, and Pathology, Federal University of Paraná, Curitiba, Brazil
| | - Caroline Rosa Silva
- Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, Maringá, Brazil
| | | | - Paola Pereira Constantin
- Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, Maringá, Brazil
| | - Sônia Alvim Veiga Pileggi
- Environmental Microbiology Laboratory, Life Sciences and Health Institute, Structural and Molecular Biology, and Genetics Department, Ponta Grossa State University, Ponta Grossa, Brazil
| | - Luiz Ricardo Olchanheski
- Environmental Microbiology Laboratory, Life Sciences and Health Institute, Structural and Molecular Biology, and Genetics Department, Ponta Grossa State University, Ponta Grossa, Brazil
| | - Marcos Pileggi
- Environmental Microbiology Laboratory, Life Sciences and Health Institute, Structural and Molecular Biology, and Genetics Department, Ponta Grossa State University, Ponta Grossa, Brazil.
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Aravindraja C, Jeepipalli S, Duncan WD, Vekariya KM, Rahaman SO, Chan EKL, Kesavalu L. Streptococcus gordonii Supragingival Bacterium Oral Infection-Induced Periodontitis and Robust miRNA Expression Kinetics. Int J Mol Sci 2024; 25:6217. [PMID: 38892405 PMCID: PMC11172800 DOI: 10.3390/ijms25116217] [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: 04/30/2024] [Revised: 05/24/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Streptococcus gordonii (S. gordonii, Sg) is one of the early colonizing, supragingival commensal bacterium normally associated with oral health in human dental plaque. MicroRNAs (miRNAs) play an important role in the inflammation-mediated pathways and are involved in periodontal disease (PD) pathogenesis. PD is a polymicrobial dysbiotic immune-inflammatory disease initiated by microbes in the gingival sulcus/pockets. The objective of this study is to determine the global miRNA expression kinetics in S. gordonii DL1-infected C57BL/6J mice. All mice were randomly divided into four groups (n = 10 mice/group; 5 males and 5 females). Bacterial infection was performed in mice at 8 weeks and 16 weeks, mice were euthanized, and tissues harvested for analysis. We analyzed differentially expressed (DE) miRNAs in the mandibles of S. gordonii-infected mice. Gingival colonization/infection by S. gordonii and alveolar bone resorption (ABR) was confirmed. All the S. gordonii-infected mice at two specific time points showed bacterial colonization (100%) in the gingival surface, and a significant increase in mandible and maxilla ABR (p < 0.0001). miRNA profiling revealed 191 upregulated miRNAs (miR-375, miR-34b-5p) and 22 downregulated miRNAs (miR-133, miR-1224) in the mandibles of S. gordonii-infected mice at the 8-week mark. Conversely, at 16 weeks post-infection, 10 miRNAs (miR-1902, miR-203) were upregulated and 32 miRNAs (miR-1937c, miR-720) were downregulated. Two miRNAs, miR-210 and miR-423-5p, were commonly upregulated, and miR-2135 and miR-145 were commonly downregulated in both 8- and 16-week-infected mice mandibles. Furthermore, we employed five machine learning (ML) algorithms to assess how the number of miRNA copies correlates with S. gordonii infections in mice. In the ML analyses, miR-22 and miR-30c (8-week), miR-720 and miR-339-5p (16-week), and miR-720, miR-22, and miR-339-5p (combined 8- and 16-week) emerged as the most influential miRNAs.
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Affiliation(s)
- Chairmandurai Aravindraja
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
| | - Syam Jeepipalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
| | - William D. Duncan
- Department of Community Dentistry and Behavioral Science, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
| | - Krishna Mukesh Vekariya
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
| | - Shaik O. Rahaman
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA;
| | - Edward K. L. Chan
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
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de Síbia CDF, Quaglio AEV, de Oliveira ECS, Pereira JN, Ariede JR, Lapa RML, Severino FE, Reis PP, Sassaki LY, Saad-Hossne R. microRNA-mRNA Networks Linked to Inflammation and Immune System Regulation in Inflammatory Bowel Disease. Biomedicines 2024; 12:422. [PMID: 38398024 PMCID: PMC10886709 DOI: 10.3390/biomedicines12020422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/29/2023] [Accepted: 12/02/2023] [Indexed: 02/25/2024] Open
Abstract
UNLABELLED The molecular processes linked to the development and progression of Crohn's disease (CD) and ulcerative colitis (UC) are not completely understood. MicroRNAs (miRNAs) regulate gene expression and are indicated as diagnostic, prognostic, and predictive biomarkers in chronic degenerative diseases. Our objectives included the identification of global miRNA expression in CD and UC, as well as miRNA target genes, miRNA-mRNA interaction networks, and biological functions associated with these different forms of inflammatory bowel disease (IBD). METHODS By performing a comprehensive meta-analysis, we integrated miRNA expression data from nine studies in IBD. We obtained detailed information on significantly deregulated miRNAs (fold change, FC ≥ 2 and p < 0.05), sample type and number, and platform applied for analysis in the training and validation sets. Further bioinformatic analyses were performed to identify miRNA target genes, by using the microRNA Data Integration Portal tool. We also sought to identify statistically enriched pathways of genes regulated by miRNAs using ToppGene Suite. Additional analyses were performed to filter for genes expressed in intestinal tissue using the European Bioinformatics Institute (EBI) database. RESULTS Our findings showed the upregulation of 15 miRNAs in CD and 33 in UC. Conversely, six miRNAs were downregulated in CD, while seven were downregulated in UC. These results indicate a greater deregulation of miRNAs in UC compared to CD. Of note, miRNA target genes were enriched for immune system regulation pathways. Among significantly deregulated miRNAs with a higher number of miRNA-target gene interactions, we identified miR-199a-5p and miR-362-3p altered in CD, while among UC case patients, miRNA-target gene interactions were higher for miR-155-5p. CONCLUSIONS The identified miRNAs play roles in regulating genes associated with immune system regulation and inflammation in IBD. Such miRNAs and their target genes have the potential to serve as clinically relevant biomarkers. These findings hold promise for enhancing the accuracy of diagnoses and facilitating the development of personalized treatment strategies for individuals with various forms of IBD.
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Affiliation(s)
- Carina de F. de Síbia
- Department of Surgery and Orthopedics, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (C.d.F.d.S.); (J.R.A.); (F.E.S.); (P.P.R.)
| | - Ana E. V. Quaglio
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTec), Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18607-440, SP, Brazil;
| | - Ellen C. S. de Oliveira
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (J.N.P.); (L.Y.S.)
| | - Jéssica N. Pereira
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (J.N.P.); (L.Y.S.)
| | - Jovita R. Ariede
- Department of Surgery and Orthopedics, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (C.d.F.d.S.); (J.R.A.); (F.E.S.); (P.P.R.)
- Experimental Research Unity (UNIPEX), Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
| | - Rainer M. L. Lapa
- Facultad de Ingeniería Zootecnista, Agronegocios y Biotecnología, Instituto de Investigación en Ganadería y Biotecnología, Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas, Chachapoyas 01001, Peru;
- Facultad de Ciencias de la Salud, Instituto de Investigación de Salud Integral Intercultural, Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas, Chachapoyas 01001, Peru
| | - Fábio E. Severino
- Department of Surgery and Orthopedics, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (C.d.F.d.S.); (J.R.A.); (F.E.S.); (P.P.R.)
- Experimental Research Unity (UNIPEX), Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
| | - Patricia P. Reis
- Department of Surgery and Orthopedics, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (C.d.F.d.S.); (J.R.A.); (F.E.S.); (P.P.R.)
- Experimental Research Unity (UNIPEX), Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
| | - Lígia Y. Sassaki
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (J.N.P.); (L.Y.S.)
| | - Rogerio Saad-Hossne
- Department of Surgery and Orthopedics, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (C.d.F.d.S.); (J.R.A.); (F.E.S.); (P.P.R.)
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Chen L, Guo S, Zhang D, Li X, Chen J. E2F5 Targeted by Let-7d-5p Facilitates Cell Proliferation, Metastasis and Immune Escape in Gallbladder Cancer. Dig Dis Sci 2024; 69:463-475. [PMID: 38087129 DOI: 10.1007/s10620-023-08209-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 11/24/2023] [Indexed: 02/15/2024]
Abstract
BACKGROUND Gallbladder cancer (GBC) remains a serious cause of cancer-related mortality across the globe. E2F5 has been identified to as a known oncogene in various cancers. However, the special functions of E2F5 have not been investigated in GBC. AIMS To explore the regulatory functions of E2F5 and its related molecular regulatory mechanism in GBC progression. METHODS The expression of genes were examined through qRT-PCR, western blot and IHC assay. The cell proliferation was assessed through CCK-8 and EDU assays. The cytotoxicity was tested through LDH assay. The percentage of CD8+ T cells and cell apoptosis were evaluated through flow cytometry. The binding ability was detected through luciferase reporter assay. The tumor growth was assessed through in vivo assays. RESULTS In this study, it was demonstrated that E2F5 expression was evaluated in GBC, and resulted into poor prognosis. Bioinformatics analysis revealed E2F5 as a target for let-7d-5p, which when overexpressed, suppressed the metastasis and proliferation of GBC through the downregulation of E2F5. It was discovered that E2F5 activates JAK2/STAT3 signaling which is suppressed by let-7d-5p, implicating this pathway as one of the effectors of the oncogenic effects of ESF5 in GBC. E2F5 had been confirmed to aggravate tumor growth in vivo. CONCLUSION E2F5 targeted by let-7d-5p facilitated cell proliferation, metastasis and immune escape in GBC through the JAK2/STAT3 pathway.
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Affiliation(s)
- Lei Chen
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China
| | - Songyi Guo
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China
| | - Dafang Zhang
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China
| | - Xinyu Li
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, 100044, China
| | - Jianfei Chen
- Department of Hepatobiliary Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10, Tieyi Road, Yangfangdian, Haidian District, Beijing, 100038, China.
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Alshahrani SH, Yuliastanti T, Al-Dolaimy F, Korotkova NL, Rasulova I, Almuala AF, Alsaalamy A, Ali SHJ, Alasheqi MQ, Mustafa YF. A glimpse into let-7e roles in human disorders; friend or foe? Pathol Res Pract 2024; 253:154992. [PMID: 38103367 DOI: 10.1016/j.prp.2023.154992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/19/2023]
Abstract
MicroRNAs (miRNAs) have been linked to abnormal expression and regulation in a number of diseases, including cancer. Recent studies have concentrated on miRNA Let-7e's significance in precision medicine for cancer screening and diagnosis as well as its prognostic and therapeutic potential. Differential let-7e levels in bodily fluids have the possibility to enable early detection of cancer utilizing less-invasive techniques, reducing biopsy-related risks. Although Let-7e miRNAs have been described as tumor suppressors, it is crucial to note that there exists proof to support their oncogenic activity in vitro and in in vivo. Let-7e's significance in chemo- and radiation treatment decisions has also been demonstrated. Let-7e can also prevent the synthesis of proinflammatory cytokines in a number of degenerative disorders, including musculoskeletal and neurological conditions. For the first time, an overview of the significance of let-7e in the prevention, detection, and therapy of cancer and other conditions has been given in the current review. Additionally, we focused on the specific molecular processes that underlie the actions of let-7e, more particularly, on malignant cells.
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Affiliation(s)
| | | | | | - Nadezhda L Korotkova
- I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation; Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University" of the Ministry of Health of the Russian Federation, Nizhny Novgorod, Russian Federation
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, 54 Mustaqillik Ave., Tashkent 100007, Uzbekistan; Department of Public Health, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Abbas Firras Almuala
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Saad Hayif Jasim Ali
- Department of Medical Laboratory, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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Abdelazim SA, Shaker OG, Ali O, El-Tawil M, Senousy MA. Differential expression of serum miR-486 and miR-25 in ulcerative colitis and Crohn's disease: Correlations with disease activity, extent, and location. Pathol Res Pract 2023; 252:154910. [PMID: 37939427 DOI: 10.1016/j.prp.2023.154910] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/23/2023] [Accepted: 10/24/2023] [Indexed: 11/10/2023]
Abstract
Novel reliable biomarkers of inflammatory bowel disease (IBD) are clinically imperative due to potential limitations of endoscopic techniques. MicroRNAs (miRNAs) have emerged as non-invasive biomarkers of IBD; however, the full disease-specific miRNAs signature for IBD subtypes remains elusive. We evaluated the diagnostic role of circulating miR-486 and miR-25 in IBD patients and their potential ability to discriminate IBD subtypes; ulcerative colitis (UC) and Crohn's disease (CD). Sixty UC patients, 60 CD patients, and 60 healthy controls were recruited. Serum miRNA expression was determined using RT-qPCR. Bioinformatics was employed for target gene and protein-protein interaction (PPI) network analyses. Serum miR-486 was upregulated in CD patients, but didn't change in UC patients compared to controls. Conversely, serum miR-25 was decreased in both CD and UC patients compared to controls. Only miR-486 was differentially expressed between UC and CD patients. Receiver-operating characteristic analysis revealed that serum miR-486 was superior in CD diagnosis (AUC=0.945) and significantly distinguished CD and UC patients, whereas miR-25 showed discriminative potential for both UC and CD from controls. In the multivariate logistic analysis only miR-486 was associated with the risk of CD diagnosis. Serum miR-486 was correlated with CD activity index and location of disease in CD patients, whereas miR-25 was correlated with the type/extent of UC. PPI network analysis revealed common target genes and signaling pathways for both miRNAs. Conclusively, serum miR-486 and miR-25 might serve as new biomarkers of IBD, with serum miR-486 could be employed in risk stratification of IBD subtypes and has the ground for clinical utility in CD diagnosis, whereas miR-25 has potential for UC and CD diagnosis.
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Affiliation(s)
- Samy A Abdelazim
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Olfat G Shaker
- Medical Biochemistry and Molecular Biology department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Omaima Ali
- Department of Biochemistry, Faculty of Pharmacy, Sinai University-Kantara Branch, Ismailia 41636, Egypt; General division for Biological Control and Research, Egyptian Drug Authority, Cairo 12618 Egypt
| | - Mai El-Tawil
- Neurology department, Kasr Al-Ainy Hospital, Cairo, Egypt
| | - Mahmoud A Senousy
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt
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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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10
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Abramczyk J, Milkiewicz M, Hula B, Milkiewicz P, Kempinska-Podhorodecka A. The Role of hsa-miR-125b-5p Interaction with S1P/Ceramide Axis in the Potential Development of Inflammation-Associated Colon Cancer in Primary Sclerosing Cholangitis. Int J Mol Sci 2023; 24:ijms24119175. [PMID: 37298127 DOI: 10.3390/ijms24119175] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis that can lead to MSI-H cancer progression in PSC/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC.
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Affiliation(s)
- Joanna Abramczyk
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Bartosz Hula
- Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland
- Translational Medicine Group, Pomeranian Medical University, 70-111 Szczecin, Poland
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11
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Aggeletopoulou I, Mouzaki A, Thomopoulos K, Triantos C. miRNA Molecules-Late Breaking Treatment for Inflammatory Bowel Diseases? Int J Mol Sci 2023; 24:2233. [PMID: 36768556 PMCID: PMC9916785 DOI: 10.3390/ijms24032233] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
MicroRNAs (miRNAs) are a group of non-coding RNAs that play a critical role in regulating epigenetic mechanisms in inflammation-related diseases. Inflammatory bowel diseases (IBDs), which primarily include ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic recurrent inflammation of intestinal tissues. Due to the multifactorial etiology of these diseases, the development of innovative treatment strategies that can effectively maintain remission and alleviate disease symptoms is a major challenge. In recent years, evidence for the regulatory role of miRNAs in the pathogenetic mechanisms of various diseases, including IBD, has been accumulating. In light of these findings, miRNAs represent potential innovative candidates for therapeutic application in IBD. In this review, we discuss recent findings on the role of miRNAs in regulating inflammatory responses, maintaining intestinal barrier integrity, and developing fibrosis in clinical and experimental IBD. The focus is on the existing literature, indicating potential therapeutic application of miRNAs in both preclinical experimental IBD models and translational data in the context of clinical IBD. To date, a large and diverse data set, which is growing rapidly, supports the potential use of miRNA-based therapies in clinical practice, although many questions remain unanswered.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
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12
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Zhou F, Chen L, Xu S, Si C, Li N, Dong H, Zheng P, Wang W. Upregulation of miR-151-5p promotes the apoptosis of intestinal epithelial cells by targeting brain-derived neurotrophic factor in ulcerative colitis mice. Cell Cycle 2022; 21:2615-2626. [PMID: 35938703 PMCID: PMC9704397 DOI: 10.1080/15384101.2022.2105905] [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: 11/28/2021] [Revised: 06/14/2022] [Accepted: 07/19/2022] [Indexed: 01/09/2023] Open
Abstract
Ulcerative colitis (UC) is the most prevalent form of chronic inflammatory bowel disease, the etiology of which is poorly understood. This study investigated the role of miR-151-5p on UC and explored the role of brain-derived neurotrophic factor (BDNF) in a UC mouse model and cell model. A UC mouse model was engineered by dextran sulfate sodium (DSS) induction. Primary mouse intestinal epithelial cells (IECs) were isolated. Colitis mice were intraperitoneally injected with miR-151-5p antagomir and antagomir negative control, and weight loss, disease activity index, and colon length of mice were measured. Colon tissues of mice were histologically analyzed. A UC cell model was constructed by treating MODE-K cells with DSS. miR-151-5p expression in the cell model was modulated by transfection. The exogenous BDNF effect on the UC cell model and intestinal cell apoptosis, viability and proliferation was detected by flow cytometry, CCK-8 and EdU experiment. The expression of miR-151-5p and apoptosis-related proteins was assessed through q-PCR and western blotting. miR-151-5p was upregulated in the colon tissues and primary IECs of colitis mice. miR-151-5p directly inhibited the expression of BNDF. miR-151-5p upregulation promoted apoptosis in UC MODE-K cells. miR-151-5p upregulation repressed the viability of UC MODE-K cells. Exogenous BNDF treatment reversed the effect of miR-151-5p on UC MODE-K cells. miR-151-5p knockdown improved UC symptoms in mice, including alleviating weight loss, reducing disease activity index and improving colon length and damaged colon tissues. miR-151-5p contributed to intestinal epithelial cells apoptosis in colitis mice via inhibiting BNDF expression.
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Affiliation(s)
- Feng Zhou
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Lipeng Chen
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Shan Xu
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Caijuan Si
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Nan Li
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Hui Dong
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Peifen Zheng
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
| | - Weifeng Wang
- Department of gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang, P.R. China
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13
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MicroRNAs in Inflammatory Bowel Disease and Its Complications. Int J Mol Sci 2022; 23:ijms23158751. [PMID: 35955886 PMCID: PMC9369281 DOI: 10.3390/ijms23158751] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 11/17/2022] Open
Abstract
Inflammatory bowel disease (IBD), classified primarily between Crohn's disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn's disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD. In addition to its role in the well-known progression towards colorectal cancer, we also emphasize how miRNA manifests the many extraintestinal complications in IBD such as cardiovascular diseases; neuropsychiatric conditions such as depression and anxiety disorders; and others, including various musculoskeletal, dermatologic, ocular, and hepatobiliary complications. We conclude through a description of its potential use in bettering diagnostics and the future treatment of IBD and its systemic symptoms.
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14
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Casado-Bedmar M, Viennois E. MicroRNA and Gut Microbiota: Tiny but Mighty-Novel Insights into Their Cross-talk in Inflammatory Bowel Disease Pathogenesis and Therapeutics. J Crohns Colitis 2021; 16:992-1005. [PMID: 34918052 PMCID: PMC9282881 DOI: 10.1093/ecco-jcc/jjab223] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022]
Abstract
MicroRNAs [miRNAs], small non-coding RNAs, have recently been described as crucial contributors to intestinal homeostasis. They can interact with the gut microbiota in a reciprocal manner and deeply affect host health status, leading to several disorders when unbalanced. Inflammatory bowel disease [IBD] is a chronic inflammation of the gastrointestinal tract that co-occurs with alterations of the gut microbiota, and whose aetiology remains largely unclear. On one hand, host miRNA could be playing a relevant role in IBD pathophysiology by shaping the gut microbiota. The gut microbiome, on the other hand, may regulate the expression of host miRNAs, resulting in intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation. Interestingly, it has been hypothesised that their reciprocal impact may be used for therapeutic goals. This review describes the latest research and suggests mechanisms through which miRNA and intestinal microbiota, as joint actors, may participate specifically in IBD pathophysiology. Furthermore, we discuss the diagnostic power and therapeutic potential resulting from their bidirectional communication after faecal transplantation, probiotics intake, or anti-miRNAs or miRNA mimics administration. The current literature is summarised in the present work in a comprehensive manner, hoping to provide a better understanding of the miRNA-microbiota cross-talk and to facilitate their application in IBD.
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Affiliation(s)
- Maite Casado-Bedmar
- INSERM, U1149, Center for Research on Inflammation, Université de Paris, Paris, France
| | - Emilie Viennois
- Corresponding author: Emilie Viennois, INSERM, U1149, Center for Research on Inflammation, Université de Paris, 75018 Paris, France.
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15
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Role of microRNAs in the Pathophysiology of Ulcerative Colitis. IMMUNO 2021. [DOI: 10.3390/immuno1040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Ulcerative colitis (UC) is an intractable disorder characterized by a chronic inflammation of the colon. Studies have identified UC as a multifactorial disorder affected by both genetic and environmental factors; however, the precise mechanism remains unclear. Recent advances in the field of microRNA (miRNA) research have identified an association between this small non-coding RNA in the pathophysiology of UC and altered miRNA expression profiles in patients with UC. Nevertheless, the roles of individual miRNAs are uncertain due to heterogeneity in both research samples and clinical backgrounds. In this review, we focus on miRNA expression in colonic mucosa where inflammation occurs in UC and discuss the potential roles of individual miRNAs in disease development, outlining the pathophysiology of UC.
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16
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Wang YX, Lin C, Cui LJ, Deng TZ, Li QM, Chen FY, Miao XP. Mechanism of M2 macrophage-derived extracellular vesicles carrying lncRNA MEG3 in inflammatory responses in ulcerative colitis. Bioengineered 2021; 12:12722-12739. [PMID: 34895044 PMCID: PMC8810016 DOI: 10.1080/21655979.2021.2010368] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/19/2021] [Accepted: 11/20/2021] [Indexed: 12/20/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. M2 macrophages possess certain anti-inflammation activity. Accordingly, the current study set out to investigate the potential mechanism of M2 macrophage-derived extracellular vesicles (M2-EVs) in UC inflammation. Firstly, mouse peritoneal macrophages were induced to M2 phenotype, and M2-EVs were isolated. , the murine model of UC was established, and the length and weight of the colon, disease activity index (DAI), apoptosis, and inflammatory response of UC mice were measured. Young adult mouse colon (YAMC) cells were induced with the help of lipopolysaccharide. LncRNA maternally expressed 3 (LncRNA MEG3), miR-20b-5p, and cAMP responsive element binding protein 1 (CREB1) expression patterns were detected in UC models. In addition, we analyzed the binding relationship among MEG3, miR-20b-5p, and CREB1. UC mice presented with shortened colon length, lightened weight, increased DAI score, enhanced apoptosis, and significant inflammatory cell infiltration, while M2-EVs reversed these trends. In vitro, M2-EVs increased UC cell viability and reduced inflammation. Mechanistic experimentation revealed that M2-EVs transferred MEG3 into YAMC cells to up-regulate MEG3 expression and promote CREB1 transcription by competitively binding to miR-20b-5p. Moreover, up-regulation of MEG3 in M2-EVs enhanced the protective effect of M2-EVs on UC cells, while over-expression of miR-20b-5p attenuated the aforementioned protective effect of M2-EVs on UC mice and cells. Collectively, our findings revealed that M2-EVs carrying MEG3 enhanced UC cell viability and reduced inflammatory responses via the miR-20b-5p/CREB1 axis, thus alleviating UC inflammation.
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Affiliation(s)
- Yu-Xuan Wang
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
| | - Cheng Lin
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
| | - Lu-Jia Cui
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
| | - Tao-Zhi Deng
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
| | - Qiu-Min Li
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
| | - Feng-Ying Chen
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
| | - Xin-Pu Miao
- Department of Gastroenterology, Hainan General Hospital, Haikou, P.R. China
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17
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The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability. Cells 2021; 10:cells10123358. [PMID: 34943865 PMCID: PMC8699384 DOI: 10.3390/cells10123358] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/15/2022] Open
Abstract
Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability.
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18
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Grillo TG, Quaglio AEV, Beraldo RF, Lima TB, Baima JP, Di Stasi LC, Sassaki LY. MicroRNA expression in inflammatory bowel disease-associated colorectal cancer. World J Gastrointest Oncol 2021; 13:995-1016. [PMID: 34616508 PMCID: PMC8465441 DOI: 10.4251/wjgo.v13.i9.995] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/30/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are non-coding RNA molecules composed of 19-25 nucleotides that regulate gene expression and play a central role in the regulation of several immune-mediated disorders, including inflammatory bowel diseases (IBD). IBD, represented by ulcerative colitis and Crohn's disease, is characterized by chronic intestinal inflammation associated with an increased risk of colorectal cancer (CRC). CRC is one of the most prevalent tumors in the world, and its main risk factors are obesity, physical inactivity, smoking, alcoholism, advanced age, and some eating habits, in addition to chronic intestinal inflammatory processes and the use of immunosuppressants administered to IBD patients. Recent studies have identified miRNAs associated with an increased risk of developing CRC in this population. The identification of miRNAs involved in this tumorigenic process could be useful to stratify cancer risk development for patients with IBD and to monitor and assess prognosis. Thus, the present review aimed to summarize the role of miRNAs as biomarkers for the diagnosis and prognosis of IBD-associated CRC. In the future, therapies based on miRNA modulation could be used both in clinical practice to achieve remission of the disease and restore the quality of life for patients with IBD, and to identify the patients with IBD at high risk for tumor development.
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Affiliation(s)
- Thais Gagno Grillo
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Ana Elisa Valencise Quaglio
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| | - Rodrigo Fedatto Beraldo
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Talles Bazeia Lima
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Julio Pinheiro Baima
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Luiz Claudio Di Stasi
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
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19
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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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20
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Abstract
Inflammatory bowel disease (IBD) as a chronic inflammation in colon and small intestine has two subtypes: ulcerative colitis (UC) and Crohn's disease (CD). Genome studies have shown that UC and CD are related to microRNAs (miRNAs) expression in addition to environmental factors. This article reviews important researches that have recently been done on miRNAs roles in CD and UC disease. First, miRNA is introduced and its biogenesis and function are discussed. Afterward, roles of miRNAs in inflammatory processes involved in IBD are showed. Finally, this review proposes some circulating and tissue-specific miRNAs, which are useful for CD and UC fast diagnosis and grade prediction. As a conclusion, miRNAs are efficient diagnostic molecules especially in IBD subtypes discrimination and can be used by microarray and real time PCR methods for disease detection and classification.
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21
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Xu B, Zhang X, Gao Y, Song J, Shi B. Microglial Annexin A3 promoted the development of melanoma via activation of hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway. J Clin Lab Anal 2021; 35:e23622. [PMID: 33118214 PMCID: PMC7891517 DOI: 10.1002/jcla.23622] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Melanoma, a relatively common malignancy, has become one of the tumors with the fastest rising incidence in recent years. The purpose of this study was to investigate the effect of Microglial Annexin A3 (ANXA3) on melanoma. METHODS Serum samples were obtained from 20 patients with melanoma or 20 healthy controls. Kaplan-Meier survival analysis was performed. Transcriptome were used to analyze the correlation between ANXA3 expression and overall survival in patients with melanoma. Human melanoma cell lines WM-115 cells were transfected with ANXA3, si-ANXA3, ANXA3 + si-hypoxia inducible factor-1α (HIF-1α), si-ANXA3 + HIF-1α, and negative plasmids. Cell proliferation assay, cell invasion assay, and wound healing assay were performed on WM-115 cells. Lactate dehydrogenase (LDH) and caspase-3/9 activities were detected by commercial kits. Western blot and RT-PCR were used to detect the protein and mRNA expression of relation factors. RESULTS ANXA3 expression was up-regulated in patients with melanoma in comparison with healthy controls. Over-expression of ANXA3 promoted cell growth and migration, and reduced cytotoxicity of WM-115 cells. Overall survival (OS) and disease-free survival (DFS) of patients with high ANXA3 expression were both lower than those of patients with low ANXA3 expression. Down-regulation of ANXA3 reduced cell growth and migration, and promoted cytotoxicity of WM-115 cells. ANXA3 induced vascular endothelial growth factor (VEGF) signaling pathway by activation of HIF-1α. CONCLUSION In conclusion, our results indicated that ANXA3 promoted cell growth and migration of melanoma via activation of HIF-1α/VEGF signaling pathway.
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Affiliation(s)
- Bin Xu
- Department of SurgeryZhejiang Rehabilitation Medical CenterHangzhouChina
| | - Xiping Zhang
- Department of Tumor SurgeryZhejiang Cancer HospitalHangzhouChina
| | - Yuan Gao
- Department of SurgeryZhejiang Rehabilitation Medical CenterHangzhouChina
| | - Jianfei Song
- Department of SurgeryZhejiang Rehabilitation Medical CenterHangzhouChina
| | - Bailing Shi
- Department of SurgeryThe Third Affiliated Hospital of ZhejiangChinese Medical UniversityHangzhouChina
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Sun L, Sun M, Ma K, Liu J. Let-7d-5p suppresses inflammatory response in neonatal rats with necrotizing enterocolitis via LGALS3-mediated TLR4/NF-κB signaling pathway. Am J Physiol Cell Physiol 2020; 319:C967-C979. [PMID: 32667865 DOI: 10.1152/ajpcell.00571.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Necrotizing enterocolitis (NEC) is an acute intestinal condition accounting for severe mortality and morbidity in preterm infants. This study aimed to identify the possible roles of let-7d-5p in neonatal rats with NEC. The differentially expressed genes (DEGs) related to NEC were initially screened in silico. After establishment of NEC rat models, measurement of the expression of let-7d-5p, galectin-3 (LGALS3), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) as well as proinflammatory cytokines (TNF-α, IL-1β, and IL-6) was conducted. The interaction between let-7d-5p and LGALS3 or argonaute-2 (AGO2) was identified. Gain- and loss-of-function approaches were then performed in an attempt to investigate the regulatory roles of let-7d-5p and LGALS3 in inflammation and cell apoptosis in NEC neonatal rats. Let-7d-5p was poorly expressed, whereas LGALS3, TLR4, and NF-κB were highly expressed, in the intestinal tissues of NEC rats. Overexpression of let-7d-5p resulted in decreased levels of proinflammatory factors in the intestinal tissues of NEC rats. Through sequential experimentation, let-7d-5p was identified to target LGALS3 and bind to AGO2. In addition, LGALS3 silencing or LPS treatment blocked the TLR4/NF-κB signaling pathway, thereby suppressing intestinal epithelial cell apoptosis and inflammation in NEC. Collectively, let-7d-5p might exercise its inhibitory properties in the inflammatory response and intestinal epithelial cell apoptosis in NEC neonatal rats via inactivation of the LGALS3-dependent TLR4/NF-κB signaling pathway.
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Affiliation(s)
- Liqun Sun
- Department of Pediatric Outpatient, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Meihua Sun
- Department of Pediatric Outpatient, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Ke Ma
- Department of Pediatric Outpatient, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Jiangtao Liu
- Department of Pediatric Outpatient, The First Hospital of Jilin University, Changchun, People's Republic of China
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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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Wajda A, Łapczuk-Romańska J, Paradowska-Gorycka A. Epigenetic Regulations of AhR in the Aspect of Immunomodulation. Int J Mol Sci 2020; 21:E6404. [PMID: 32899152 PMCID: PMC7504141 DOI: 10.3390/ijms21176404] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
Environmental factors contribute to autoimmune disease manifestation, and as regarded today, AhR has become an important factor in studies of immunomodulation. Besides immunological aspects, AhR also plays a role in pharmacological, toxicological and many other physiological processes such as adaptive metabolism. In recent years, epigenetic mechanisms have provided new insight into gene regulation and reveal a new contribution to autoimmune disease pathogenesis. DNA methylation, histone modifications, chromatin alterations, microRNA and consequently non-genetic changes in phenotypes connect with environmental factors. Increasing data reveals AhR cross-roads with the most significant in immunology pathways. Although study on epigenetic modulations in autoimmune diseases is still not well understood, therefore future research will help us understand their pathophysiology and help to find new therapeutic strategies. Present literature review sheds the light on the common ground between remodeling chromatin compounds and autoimmune antibodies used in diagnostics. In the proposed review we summarize recent findings that describe epigenetic factors which regulate AhR activity and impact diverse immunological responses and pathological changes.
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Affiliation(s)
- Anna Wajda
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland;
| | - Joanna Łapczuk-Romańska
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Agnieszka Paradowska-Gorycka
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland;
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Ghafouri-Fard S, Eghtedarian R, Taheri M. The crucial role of non-coding RNAs in the pathophysiology of inflammatory bowel disease. Biomed Pharmacother 2020; 129:110507. [DOI: 10.1016/j.biopha.2020.110507] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/25/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023] Open
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Alkarkoushi RR, Hui Y, Tavakoli AS, Singh U, Nagarkatti P, Nagarkatti M, Chatzistamou I, Bam M, Testerman TL. Immune and microRNA responses to Helicobacter muridarum infection and indole-3-carbinol during colitis. World J Gastroenterol 2020; 26:4763-4785. [PMID: 32921956 PMCID: PMC7459201 DOI: 10.3748/wjg.v26.i32.4763] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/16/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Indole-3-carbinol (I3C) and other aryl hydrocarbon receptor agonists are known to modulate the immune system and ameliorate various inflammatory and autoimmune diseases in animal models, including colitis induced by dextran sulfate sodium (DSS). MicroRNAs (miRNAs) are also gaining traction as potential therapeutic agents or diagnostic elements. Enterohepatic Helicobacter (EHH) species are associated with an increased risk of inflammatory bowel disease, but little is known about how these species affect the immune system or response to treatment.
AIM To determine whether infection with an EHH species alters the response to I3C and how the immune and miRNA responses of an EHH species compare with responses to DSS and inflammatory bowel disease.
METHODS We infected C57BL/6 mice with Helicobacter muridarum (H. muridarum), with and without DSS and I3C treatment. Pathological responses were evaluated by histological examination, symptom scores, and cytokine responses. MiRNAs analysis was performed on mesenteric lymph nodes to further evaluate the regional immune response.
RESULTS H. muridarum infection alone caused colonic inflammation and upregulated proinflammatory, macrophage-associated cytokines in the colon similar to changes seen in DSS-treated mice. Further upregulation occurred upon treatment with DSS. H. muridarum infection caused broad changes in mesenteric lymph node miRNA expression, but colitis-associated miRNAs were regulated similarly in H. muridarum-infected and uninfected, DSS-treated mice. In spite of causing colitis exacerbation, H. muridarum infection did not prevent disease amelioration by I3C. I3C normalized both macrophage- and T cell-associated cytokines.
CONCLUSION Thus, I3C may be useful for inflammatory bowel disease patients regardless of EHH infection. The miRNA changes associated with I3C treatment are likely the result of, rather than the cause of immune response changes.
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Affiliation(s)
- Rasha Raheem Alkarkoushi
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Yvonne Hui
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Abbas S Tavakoli
- College of Nursing, University of South Carolina, University of South Carolina, Columbia, SC 29208, United States
| | - Udai Singh
- Department of Medicine, Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Ioulia Chatzistamou
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Marpe Bam
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Traci L Testerman
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
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Faridi A, Afgar A, Mousavi SM, Nasibi S, Mohammadi MA, Farajli Abbasi M, Fasihi Harandi M. Intestinal Expression of miR-130b, miR-410b, and miR-98a in Experimental Canine Echinococcosis by Stem-Loop RT-qPCR. Front Vet Sci 2020; 7:507. [PMID: 33005638 PMCID: PMC7480022 DOI: 10.3389/fvets.2020.00507] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/03/2020] [Indexed: 12/19/2022] Open
Abstract
Echinococcus granulosus is a zoonotic cestode dwelling in the small intestine of canid definitive hosts. Intermediate hosts are a wide range of domestic and wild ungulates. Human infection with the larval stage causes cystic echinococcosis. Understanding the nature and extent of molecular mechanisms involved in host–parasite interactions helps to answer some very basic questions in the biology of cestode parasites with significant implications in the management and control of cystic echinococcosis. Little is known on the miRNAs expression in the intestinal tissues of dogs infected with E. granulosus. In the present study, expression of a selected profile of miRNAs was evaluated in experimental canine echinococcosis. MiRNAs were extracted from 20 different parts of small intestinal tract of two sibling 3-months-old mix-breed dogs. Complementary DNA was specifically synthesized using an optimized stem-loop system. Intestinal expression of four miRNAs (cfa-let7g, cfa-miR-98, cfamiR-410, cfa-miR-130b) was evaluated using RT-qPCR. The results of the study indicate a significant difference between test and control dogs in cfamiR-130b, cfa-miR-98, and cfa-miR-410 (P ≤ 0.05); however, there was no significant difference for cfa-let7g. The most upregulated miRNAs were cfamiR-130b and cfa-miR-98. An increasing trend for cfa-let7g and a declining trend for cfa-miR-98, cfa-miR-410, and cfamiR-130b were found toward the distal segments of the small intestine. Our study revealed that cfa-miR-98, cfa-miR-410, and cfamiR-130b are involved in the definitive host response in canine echinococcosis. The study provides new information on the molecular basis of interactions between E. granulosus and dogs in terms of miRNA expression and showed that E. granulosus infection could increase the expression of some pro-inflammatory miRNAs at the cellular level in the definitive host.
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Affiliation(s)
- Ashkan Faridi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran.,Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Afgar
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Seyed Mohammad Mousavi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Saeid Nasibi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Ali Mohammadi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Farajli Abbasi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Fasihi Harandi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
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Upregulation of microRNA-219-5p relieves ulcerative colitis through balancing the differentiation of Treg/Th17 cells. Eur J Gastroenterol Hepatol 2020; 32:813-820. [PMID: 32175983 PMCID: PMC7269018 DOI: 10.1097/meg.0000000000001712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This study aimed to investigate the specific regulatory roles of microRNA-219-5p (miR-219-5p) on ulcerative colitis (UC), and reveal the potential mechanisms relating with the differentiation of Treg/Th17 cells. METHODS The mouse model of chronic UC was established by oral administration of 3% dextran sodium sulfate for three cycles. After intravenous injected with lentivirus (LV)-miR-219-5p for 24 h, the disease activity index (DAI), colon length, as well as the serum levels of Interleukin (IL)-6, -17A, -21, and -23 were measured. In addition, the histopathological changes in colon tissues were observed by Hematoxylin-eosin staining. The differentiation of Treg/Th17 cells was detected by Flow cytometry, and the expression of retinoic acid-related orphan receptor (RORrt), signal transducer and activator of transcription 3 (STAT3), and forkhead box p3 (Foxp3) were detected by quantitative real-time PCR and Western blot. RESULTS MiR-219-5p was downregulated in colonic mucosal tissues of UC mice (P < 0.05). UC mice injected with LV-miR-219-5p exhibited significantly relieved histopathological changes of colon tissues, increased colon length, decreased DAI, as well as decreased serum levels of IL-6, -17A, -21, and -23 (P < 0.05). In addition, the injection of LV-miR-219-5p significantly increased the percentage of Treg cells via upregulating Foxp3, and decreased the percentage of Th17 cells via downregulating RORrt and STAT3 in UC mice (P < 0.05). CONCLUSION The upregulation of miR-219-5p relieved the colonic damage and inflammation of UC through balancing the differentiation of Treg/Th17 cells.
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Chen Q, Fang X, Yao N, Wu F, Xu B, Chen Z. Suppression of miR-330-3p alleviates DSS-induced ulcerative colitis and apoptosis by upregulating the endoplasmic reticulum stress components XBP1. Hereditas 2020; 157:18. [PMID: 32386518 PMCID: PMC7211341 DOI: 10.1186/s41065-020-00135-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 04/30/2020] [Indexed: 11/29/2022] Open
Abstract
Background This study aimed to explore the biological activities of miR-330-3p in dextan sulphate sodium (DSS)-induced ulcerative colitis and apoptosis and the direct target of miR-330-3p in this process. HT-29 cells and male C57BL/6 mice were used to examine the function of miR-330-3p in vitro and in vivo, respectively. Expression of miRNA and mRNA was measured using quantitative real time PCR (qRT-PCR). Western blotting was used to measure the change of protein expression. Flow cytometry was used to determine cell apoptosis and luciferase assay was used to confirm the direct target of miR-330-3p. Results miR-330-3p expression was increased by DSS in both HT-29 cells and mice. Upregulation miR-330-3p induced cell apoptosis, mice weight loss and ulcerative colitis in vivo, which could prevent by suppression of miR-330-3p. Cell apoptosis related protein expression, cleaved caspase-3 and cleaved PARP was also inhibited by miR-330-3p overexpression and elevated by miR-330-3p inhibition both in vitro and in vivo. Luciferase assay confirmed that 3′ untranslated region (3′-UTR) of XBP1 is the directed target of miR-330-3p and Western blotting results have showed that protein expression of XBP1 was decreased by miR-330-3p mimics and increased by miR-330-3p inhibitor. Conclusion miR-330-3p is upregulated by DSS in both HT-29 cells and mice and promoted ulcerative colitis and cell apoptosis by targeting of 3′-UTR of XBP1, which is a key component of ER stress. Inhibition of miR-330-3p prevent DSS-induced ulcerative colitis and cell apoptosis mediated by upregulation of XBP1 expression.
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Affiliation(s)
- Qifeng Chen
- Department of Gastroenterology Surgery, Shulan(hangzhou) Hospital, No. 848, Road Dongxin, District Xiacheng, Hangzhou City, 310000, Zhejiang Province, China.
| | - Xiaoming Fang
- Department of General Surgery, 903th hospital of PLA, Hangzhou City, 310000, Zhejiang Province, China
| | - Ning Yao
- Department of General Surgery, 903th hospital of PLA, Hangzhou City, 310000, Zhejiang Province, China
| | - Fang Wu
- Department of Gastroenterology Surgery, Shulan(hangzhou) Hospital, No. 848, Road Dongxin, District Xiacheng, Hangzhou City, 310000, Zhejiang Province, China
| | - Biao Xu
- Department of Gastroenterology Surgery, Shulan(hangzhou) Hospital, No. 848, Road Dongxin, District Xiacheng, Hangzhou City, 310000, Zhejiang Province, China
| | - Zhengguang Chen
- Department of Gastroenterology Surgery, Shulan(hangzhou) Hospital, No. 848, Road Dongxin, District Xiacheng, Hangzhou City, 310000, Zhejiang Province, China
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Valmiki S, Ahuja V, Puri N, Paul J. miR-125b and miR-223 Contribute to Inflammation by Targeting the Key Molecules of NFκB Pathway. Front Med (Lausanne) 2020; 6:313. [PMID: 32039213 PMCID: PMC6990118 DOI: 10.3389/fmed.2019.00313] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022] Open
Abstract
The contribution of miRNA in the pathogenesis of ulcerative colitis (UC) has emerged in the past few decades. Differential miRNA expression has been demonstrated in UC patients, and their ability to target the genes involved in inflammatory pathway has also been explored in recent years. miR-125b and miR-223 have been demonstrated to get upregulated within the colonic mucosa of UC patients. Here, we explored the biological relevance of miR-125b and miR-223 altered expression during UC by identifying the potential gene targets for miR-125b and miR-223. TRAF6 and A20, the signaling molecules involved in the NFκB pathway, were identified as target genes for miR-125b while IKKα was identified as a gene target for miR-223. The colonic mucosal samples from UC patients exhibited a significant rise in miR-125b and miR-223 expression while a subsequent downregulation was observed in the expression of TRAF6, A20, and IKKα. This negative correlation between miRNAs and their respective target genes was validated by co-transfecting miR-125b and miR-223 in HT29 cells. Co-transfection with miR-125b resulted in a marked decline in the expression of TRAF6 and A20, while the miR-223 co-transfected cells exhibited lower IKKα expression levels. Additionally, co-transfection with miR-125b or miR-223 in HT29 cells caused higher p65 and pro-inflammatory cytokines (IL-8 and IL-1β) expression upon LPS stimulation. From our findings, we highlight the possible contribution of miR-125b and miR-223 in regulating the inflammatory response during UC by negatively regulating the expression of TRAF6, A20, and IKKα. Therefore, we conclude that these two miRNAs could be considered as potential candidates for developing promising biomarkers for screening and diagnosis of UC.
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Affiliation(s)
- Swati Valmiki
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Niti Puri
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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Qiu Y, Cheng R, Liang C, Yao Y, Zhang W, Zhang J, Zhang M, Li B, Xu C, Zhang R. MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca 2+ Cross-Talk. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:1343-1356. [PMID: 32160705 PMCID: PMC7036712 DOI: 10.1016/j.omtn.2020.01.017] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/26/2019] [Accepted: 01/13/2020] [Indexed: 12/14/2022]
Abstract
MicroRNA (miRNA) and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca2+ handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca2+ cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-the-art techniques. The results demonstrated that Mfn2 was downregulated and miR-20b was upregulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-20b or miR-20b antisense inhibitor (AMO-20b). The deleterious action of miR-20b on Mfn2 expression/function and mitochondrial ATP synthesis was observed and reversed by rAAV9-anti-miR-20b or AMO-20b. The targeted regulation of miR-20b on Mfn2 was confirmed by luciferase reporter and miRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca2+ into mitochondria, manifested as enhanced histamine-mediated Ca2+ release from mitochondrial, suggesting that Ca2+ reuptake/buffering capability of mitochondria to cytosolic Ca2+ is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca2+ overload and cardiac hypertrophy through Ca2+ signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through downregulation of Mfn2 and cytosolic Ca2+ overload by weakening the buffering capability of mitochondria.
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Affiliation(s)
- Yue Qiu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Rongchao Cheng
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Chaoqi Liang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yuan Yao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Wenhao Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Jie Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Mingyu Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Baiyan Li
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Chaoqian Xu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China; Department of Pharmacology, Mudanjiang Medical University, Mudanjiang 157011, China.
| | - Rong Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
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Hossian AKMN, Mackenzie GG, Mattheolabakis G. miRNAs in gastrointestinal diseases: can we effectively deliver RNA-based therapeutics orally? Nanomedicine (Lond) 2019; 14:2873-2889. [PMID: 31735124 DOI: 10.2217/nnm-2019-0180] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nucleic acid-based therapeutics are evaluated for their potential of treating a plethora of diseases, including cancer and inflammation. Short nucleic acids, such as miRNAs, have emerged as versatile regulators for gene expression and are studied for therapeutic purposes. However, their inherent instability in vivo following enteral and parenteral administration has prompted the development of novel methodologies for their delivery. Although research on the oral delivery of siRNAs is progressing, with the development and utilization of promising carrier-based methodologies for the treatment of a plethora of gastrointestinal diseases, research on miRNA-based oral therapeutics is lagging behind. In this review, we present the potential role of miRNAs in diseases of the GI tract, and analyze current research and the cardinal features of the novel carrier systems used for nucleic acid oral delivery that can be expanded for oral miRNA administration.
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Affiliation(s)
- A K M Nawshad Hossian
- School of Basic Pharmaceutical & Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
| | | | - George Mattheolabakis
- School of Basic Pharmaceutical & Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
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Zhu X. MiR-125b but not miR-125a is upregulated and exhibits a trend to correlate with enhanced disease severity, inflammation, and increased mortality in sepsis patients. J Clin Lab Anal 2019; 34:e23094. [PMID: 31696556 PMCID: PMC7083454 DOI: 10.1002/jcla.23094] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/02/2019] [Accepted: 10/16/2019] [Indexed: 12/11/2022] Open
Abstract
Objective This study aimed to investigate the correlation of miR‐125a/b expressions with disease risk, progression, and prognosis of sepsis. Methods MiR‐125a/b expressions and inflammatory cytokines were detected by RT‐qPCR and ELISA assays in plasma samples from 120 sepsis patients. Besides, blood biochemical indexes, disease severity scores, and in‐hospital mortality of sepsis patients were recorded. Meanwhile, miR‐125a/b expressions in plasma from 120 health controls (HCs) were also detected by RT‐qPCR. Results MiR‐125b was elevated in sepsis patients compared with HCs, and ROC curve revealed that miR‐125b could well distinguish sepsis patients from HCs with AUC 0.658. MiR‐125b positively correlated with APACHE II score, SOFA score, Scr, CRP, PCT, TNF‐α, and IL‐6 levels. Most interestingly, miR‐125b was greatly decreased in survivors compared with non‐survivors, and multivariate analysis revealed that miR‐125b independently predicted higher mortality risk in sepsis patients. Besides, miR‐125a showed no significant correlation with sepsis risk, disease severity, or prognosis. Conclusion MiR‐125b but not miR‐125a is upregulated and exhibits a trend to correlate with enhanced disease severity, inflammation, and increased mortality in sepsis patients.
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Affiliation(s)
- Xiaoping Zhu
- Departments of Anesthesia, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Zeng Z, Mukherjee A, Zhang H. From Genetics to Epigenetics, Roles of Epigenetics in Inflammatory Bowel Disease. Front Genet 2019; 10:1017. [PMID: 31737035 PMCID: PMC6834788 DOI: 10.3389/fgene.2019.01017] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 09/24/2019] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a destructive, recurrent, and heterogeneous disease. Its detailed pathogenesis is still unclear, although available evidence supports that IBD is caused by a complex interplay between genetic predispositions, environmental factors, and aberrant immune responses. Recent breakthroughs with regard to its genetics have offered valuable insights into the sophisticated genetic basis, but the identified genetic factors only explain a small part of overall disease variance. It is becoming increasingly apparent that epigenetic factors can mediate the interaction between genetics and environment, and play a fundamental role in the pathogenesis of IBD. This review outlines recent genetic and epigenetic discoveries in IBD, with a focus on the roles of epigenetics in disease susceptibility, activity, behavior and colorectal cancer (CRC), and their potential translational applications.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | | | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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35
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Soroosh A, Rankin CR, Polytarchou C, Lokhandwala ZA, Patel A, Chang L, Pothoulakis C, Iliopoulos D, Padua DM. miR-24 Is Elevated in Ulcerative Colitis Patients and Regulates Intestinal Epithelial Barrier Function. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1763-1774. [PMID: 31220450 PMCID: PMC6723227 DOI: 10.1016/j.ajpath.2019.05.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/01/2019] [Accepted: 05/28/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease is characterized by high levels of inflammation and loss of barrier integrity in the colon. The intestinal barrier is a dynamic network of proteins that encircle intestinal epithelial cells. miRNAs regulate protein-coding genes. In this study, miR-24 was found to be elevated in colonic biopsies and blood samples from ulcerative colitis (UC) patients compared with healthy controls. In the colon of UC patients, miR-24 is localized to intestinal epithelial cells, which prompted an investigation of intestinal epithelial barrier function. Two intestinal epithelial cell lines were used to study the effect of miR-24 overexpression on barrier integrity. Overexpression of miR-24 in both cell lines led to diminished transepithelial electrical resistance and increased dextran flux, suggesting an effect on barrier integrity. Overexpression of miR-24 did not induce apoptosis or affect cell proliferation, suggesting that the effect of miR-24 on barrier function was due to an effect on cell-cell junctions. Although the tight junctions in cells overexpressing miR-24 appeared normal, miR-24 overexpression led to a decrease in the tight junction-associated protein cingulin. Loss of cingulin compromised barrier formation; cingulin levels negatively correlated with disease severity in UC patients. Together, these data suggest that miR-24 is a significant regulator of intestinal barrier that may be important in the pathogenesis of UC.
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Affiliation(s)
- Artin Soroosh
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Carl R Rankin
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Christos Polytarchou
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Zulfiqar A Lokhandwala
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Ami Patel
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Charalabos Pothoulakis
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Dimitrios Iliopoulos
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - David M Padua
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California; Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
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Sun J, Liang W, Yang X, Li Q, Zhang G. Cytoprotective effects of galacto-oligosaccharides on colon epithelial cells via up-regulating miR-19b. Life Sci 2019; 231:116589. [DOI: 10.1016/j.lfs.2019.116589] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 02/07/2023]
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Zhao J, Wang H, Dong L, Sun S, Li L. miRNA-20b inhibits cerebral ischemia-induced inflammation through targeting NLRP3. Int J Mol Med 2018; 43:1167-1178. [PMID: 30628668 PMCID: PMC6365032 DOI: 10.3892/ijmm.2018.4043] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 11/19/2018] [Indexed: 12/15/2022] Open
Abstract
The present study was designed to investigate the role of microRNA (miRNA)-20b in the inflammatory response during cerebral ischemia and the underlying mechanism following cerebral ischemia. A reverse transcription quantitative polymerase chain reaction assay was used to measure the expression of miRNA-20b, and tumor necrosis factor α, interleukin (IL)-6, IL-18 and IL-1β levels were measured using ELISA. In addition, the protein expression levels of NOD-like receptor pyrin domain containing 3 (NLRP3), caspase-1, IL-1β and IL-18 were determined by western blot analysis. It was determined that the expression of miRNA-20b during cerebral ischemia was increased compared with the control group. The overexpression of miRNA-20b increased the levels of IL-1β and IL-18 in the cerebral ischemia group through activation of the NLRP3 signaling pathway. Conversely, the downregulation of miRNA-20b suppressed IL-1β and IL-18 levels in cerebral ischemia via suppression of the NLRP3 signaling pathway. Additionally, the overexpression of miRNA-20b increased the levels of adenosine 5′-triphosphate (ATP) and reactive oxygen species (ROS) in the cerebral ischemia group, which were decreased following the downregulation of miRNA-20b. The inhibition of NLRP3 decreased the pro-inflammatory effects of miRNA-20b in cerebral ischemia. Suppression of ATP decreases the pro-inflammatory effects of miRNA-20b in cerebral ischemia. Suppression of ROS also decreases the pro-inflammatory effects of miRNA-20b in cerebral ischemia. Collectively, the present study provided novel insight into the role of miRNA-20b upregulation in the promotion of inflammation following cerebral infarction, suggesting that the miRNA-20b/NLRP3 axis may be a putative therapeutic target in cerebral ischemia.
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Affiliation(s)
- Jingru Zhao
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Hebo Wang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Lipeng Dong
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Sujuan Sun
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Litao Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
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Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
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Aberrantly Expressed Genes and miRNAs in Slow Transit Constipation Based on RNA-Seq Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2617432. [PMID: 30186855 PMCID: PMC6112260 DOI: 10.1155/2018/2617432] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/26/2018] [Accepted: 07/18/2018] [Indexed: 02/06/2023]
Abstract
Background This study aims to identify the key genes and miRNAs in slow transit constipation (STC). Methods MRNA and miRNA expression profiling were obtained. Differentially expressed genes (DEGs) and miRNAs were identified followed by the regulatory network construction. Functional annotation analysis and protein-protein interaction (PPI) network were conducted. The electronic validation was performed. Results Hsa-miR-2116-3p, hsa-miR-3622a-5p, hsa-miR-424-5p, and hsa-miR-1273-3p covered most DEGs. HLA-DRB1, HLA-DRB5, C3, and ICAM were significantly involved in staphylococcus aureus infection. The PPI network generated several hub proteins including ZBTB16, FBN1, CCNF, and CDK1. Electronic validation of HLA-DRB1, PTGDR, MKI67, BIRC5, CCNF, and CDK1 was consistent with the RNA-sequencing analysis. Conclusion Our study might be helpful in understanding the pathology of STC at the molecular level.
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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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Janszky N, Süsal C. Circulating and urinary microRNAs as possible biomarkers in kidney transplantation. Transplant Rev (Orlando) 2017; 32:110-118. [PMID: 29366537 DOI: 10.1016/j.trre.2017.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 12/03/2017] [Accepted: 12/14/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Noémi Janszky
- Transplantation Immunology, Institute of Immunology, University of Heidelberg, Germany.
| | - Caner Süsal
- Transplantation Immunology, Institute of Immunology, University of Heidelberg, Germany
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Tanaka H, Hazama S, Iida M, Tsunedomi R, Takenouchi H, Nakajima M, Tokumitsu Y, Kanekiyo S, Shindo Y, Tomochika S, Tokuhisa Y, Sakamoto K, Suzuki N, Takeda S, Yamamoto S, Yoshino S, Ueno T, Hamamoto Y, Fujita Y, Tanaka H, Tahara K, Shimizu R, Okuno K, Fujita K, Kuroda M, Nakamura Y, Nagano H. miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. Cancer Sci 2017; 108:2229-2238. [PMID: 28859241 PMCID: PMC5666028 DOI: 10.1111/cas.13390] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/24/2017] [Accepted: 08/27/2017] [Indexed: 12/17/2022] Open
Abstract
Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse‐transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR‐125b‐1 in cancer cells (P = 0.040), and miR‐378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR‐378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027–7.585; P = 0.044). In conclusion, miR‐125b‐1 and miR‐378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer.
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Affiliation(s)
- Hironori Tanaka
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.,Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Ube, Japan
| | - Michihisa Iida
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hiroko Takenouchi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masao Nakajima
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yukio Tokumitsu
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shinsuke Kanekiyo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shinobu Tomochika
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yoshihiro Tokuhisa
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Kazuhiko Sakamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Nobuaki Suzuki
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shigeru Takeda
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shigeru Yamamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | | | - Tomio Ueno
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yoshihiko Hamamoto
- Division of Electrical, Electronic and Information Engineering, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Ube, Japan
| | - Yusuke Fujita
- Division of Electrical, Electronic and Information Engineering, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Ube, Japan
| | - Hiroaki Tanaka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ko Tahara
- Department of Surgery, Kure-Kyosai Hospital, Kure, Japan
| | - Ryoichi Shimizu
- Department of Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan
| | - Kiyotaka Okuno
- Department of Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan
| | - Koji Fujita
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Yusuke Nakamura
- Department of Medicine and Surgery, The University of Chicago, Chicago, USA
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
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Entwistle LJ, Wilson MS. MicroRNA-mediated regulation of immune responses to intestinal helminth infections. Parasite Immunol 2017; 39. [PMID: 27977850 DOI: 10.1111/pim.12406] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/02/2016] [Indexed: 12/12/2022]
Abstract
Intestinal helminth infections are highly prevalent in the developing world, often resulting in chronic infection and inflicting high host morbidity. With the emergence of drug-resistant parasites, a limited number of chemotherapeutic drugs available and stalling vaccine efforts, an increased understanding of antihelminth immunity is essential to provide new avenues to therapeutic intervention. MicroRNAs are a class of small, nonprotein coding RNAs which negatively regulate mRNA translation, thus providing finite control over gene expression in a plethora of biological settings. The miRNA-mediated coordinated control of gene expression has been shown to be essential in infection and immunity, in promoting and fine-tuning the appropriate immune response. This review gathers together and discusses observations of miRNA-mediated effects on the immune system and the subsequent impact on our understanding of antihelminth immunity.
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Affiliation(s)
- L J Entwistle
- Allergy and Anti-Helminth Laboratory, The Francis Crick Institute, London, UK
| | - M S Wilson
- Allergy and Anti-Helminth Laboratory, The Francis Crick Institute, London, UK
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Majumdar I, Ahuja V, Paul J. Altered expression of Tumor Necrosis Factor Alpha -Induced Protein 3 correlates with disease severity in Ulcerative Colitis. Sci Rep 2017; 7:9420. [PMID: 28842689 PMCID: PMC5572729 DOI: 10.1038/s41598-017-09796-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/28/2017] [Indexed: 01/07/2023] Open
Abstract
Ulcerative colitis (UC), an inflammatory disorder of the colon arises from dysregulated immune response towards gut microbes. Transcription factor NFκB is a major regulatory component influencing mucosal inflammation. We evaluated expression of Tumor Necrosis Factor Alpha Induced Protein3 (TNFAIP3), the inhibitor of NFκB activation and its associated partners ITCH, RNF11 and Tax1BP1 in inflamed mucosa of UC patients. We found highly significant up-regulated mRNA expression of TNFAIP3 that negatively correlated with disease activity in UC. mRNA levels of ITCH, RNF11 and Tax1BP1 were significantly down-regulated. Significant positive correlation with disease activity was noted for Tax1BP1. All four genes showed significant down-regulation at protein level. mRNA levels of inducers of TNFAIP3 expression, NFκB p65 subunit and MAST3 was determined. There was significant increase in p65 mRNA expression and down-regulated MAST3 expression. This suggested that increase in NFκB expression regulates TNFAIP3 levels. Deficiency of TNFAIP3 expression resulted in significant up-regulation of NFκB p65 sub-unit as well as its downstream genes such as iNOS, an inflammatory marker, inhibitors of apoptosis like cIAP2 and XIAP and mediators of anti-apoptotic signals TRAF1 and TRAF2. Taken together, decreased expression of TNFAIP3 and its partners contribute to inflammation and up-regulation of apoptosis inhibitors that may create microenvironment for colorectal cancer.
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Affiliation(s)
- Ishani Majumdar
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
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Palmieri O, Creanza TM, Bossa F, Latiano T, Corritore G, Palumbo O, Martino G, Biscaglia G, Scimeca D, Carella M, Ancona N, Andriulli A, Latiano A. Functional Implications of MicroRNAs in Crohn's Disease Revealed by Integrating MicroRNA and Messenger RNA Expression Profiling. Int J Mol Sci 2017; 18:E1580. [PMID: 28726756 PMCID: PMC5536068 DOI: 10.3390/ijms18071580] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Revised: 07/12/2017] [Accepted: 07/16/2017] [Indexed: 12/11/2022] Open
Abstract
Crohn's disease (CD) is a debilitating inflammatory bowel disease (IBD) that emerges due to the influence of genetic and environmental factors. microRNAs (miRNAs) have been identified in the tissue and sera of IBD patients and may play an important role in the induction of IBD. Our study aimed to identify differentially expressed miRNAs and miRNAs with the ability to alter transcriptome activity by comparing inflamed tissue samples with their non-inflamed counterparts. We studied changes in miRNA-mRNA interactions associated with CD by examining their differential co-expression relative to normal mucosa from the same patients. Correlation changes between the two conditions were incorporated into scores of predefined gene sets to identify biological processes with altered miRNA-mediated control. Our study identified 28 miRNAs differentially expressed (p-values < 0.01), of which 14 are up-regulated. Notably, our differential co-expression analysis highlights microRNAs (i.e., miR-4284, miR-3194 and miR-21) that have known functional interactions with key mechanisms implicated in IBD. Most of these miRNAs cannot be detected by differential expression analysis that do not take into account miRNA-mRNA interactions. The identification of differential miRNA-mRNA co-expression patterns will facilitate the investigation of the miRNA-mediated molecular mechanisms underlying CD pathogenesis and could suggest novel drug targets for validation.
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Affiliation(s)
- Orazio Palmieri
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Teresa Maria Creanza
- Institute of Intelligent Systems for Automation, National Research Council, CNR-ISSIA, 70126 Bari, Italy.
- Center for Complex Systems in Molecular Biology and Medicine, University of Turin, 10124 Turin, Italy.
| | - Fabrizio Bossa
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Tiziana Latiano
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Giuseppe Corritore
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Orazio Palumbo
- IRCCS 'Casa Sollievo della Sofferenza', Division of Medical Genetics, 71013 San Giovanni Rotondo, Italy.
| | - Giuseppina Martino
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Giuseppe Biscaglia
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Daniela Scimeca
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Massimo Carella
- IRCCS 'Casa Sollievo della Sofferenza', Division of Medical Genetics, 71013 San Giovanni Rotondo, Italy.
| | - Nicola Ancona
- Institute of Intelligent Systems for Automation, National Research Council, CNR-ISSIA, 70126 Bari, Italy.
| | - Angelo Andriulli
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
| | - Anna Latiano
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.
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Cao B, Zhou X, Ma J, Zhou W, Yang W, Fan D, Hong L. Role of MiRNAs in Inflammatory Bowel Disease. Dig Dis Sci 2017; 62:1426-1438. [PMID: 28391412 DOI: 10.1007/s10620-017-4567-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 04/01/2017] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBD), mainly including Crohn's disease and ulcerative colitis, are characterized by chronic inflammation of the gastrointestinal tract. Despite improvements in detection, drug treatment and surgery, the pathogenesis of IBD has not been clarified. A number of miRNAs have been found to be involved in the initiation, development and progression of IBD, and they may have the potential to be used as biomarkers and therapeutic targets. Here, we have summarized the recent advances about the roles of miRNAs in IBD and analyzed the contribution of miRNAs to general diagnosis, differential diagnosis and activity judgment of IBD. Furthermore, we have also elaborated the promising role of miRNAs in IBD-related cancer prevention and prognosis prediction.
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Affiliation(s)
- Bo Cao
- The First Brigade of Student, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Xin Zhou
- The First Brigade of Student, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Jiaojiao Ma
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Wei Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Wanli Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Liu Hong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
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Viennois E, Zhao Y, Han MK, Xiao B, Zhang M, Prasad M, Wang L, Merlin D. Serum miRNA signature diagnoses and discriminates murine colitis subtypes and predicts ulcerative colitis in humans. Sci Rep 2017; 7:2520. [PMID: 28566745 PMCID: PMC5451415 DOI: 10.1038/s41598-017-02782-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 04/19/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is difficult to diagnose due to nonspecific and variable symptoms, and lack of reliable diagnostic tests. Current methods are invasive, non-sensitive, non-predictive, and do not easily discriminate between its two main forms. Consequently, there remains a great need for reliable serum markers for IBD. Here, using a longitudinal study of various mouse models of colitis, we identified a serum miRNA signature that indicated the development of colitis and discriminated between inflammations of various origins (colitis from arthritis). Unlike the existing biomarkers, the newly identified signature also serves to distinguish individuals at risk, predict the type of inflammation, and evaluate the response to therapeutics. Moreover, the miRNA signature identified in mice predicted ulcerative colitis with 83.3% accuracy. In future, the signature identified herein could play a central role in monitoring inflammatory disorders and therapeutic responses in patients, thereby paving the way for personalized medicine.
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Affiliation(s)
- Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.
| | - Yuan Zhao
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Moon Kwon Han
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - Bo Xiao
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Institute for Clean Energy and Advanced Materials, Faculty for Materials and Energy, Southwest University, Chongqing, 400715, China
| | - Mingzhen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - Meena Prasad
- Veterans Affairs Medical Center, Decatur, GA, USA.,Emory University, Department of Medicine, Atlanta, GA, USA
| | - Lixin Wang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Veterans Affairs Medical Center, Decatur, GA, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Veterans Affairs Medical Center, Decatur, GA, USA
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Duvoisin G, Lopez RN, Day AS, Lemberg DA, Gearry RB, Leach ST. Novel Biomarkers and the Future Potential of Biomarkers in Inflammatory Bowel Disease. Mediators Inflamm 2017; 2017:1936315. [PMID: 28522897 PMCID: PMC5410373 DOI: 10.1155/2017/1936315] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 03/21/2017] [Indexed: 12/19/2022] Open
Abstract
There is increasing importance placed upon noninvasive assessment of gut inflammation. These tools are likely to be the key in differentiating intestinal inflammatory disease from functional disorders and in monitoring the response to intervention in individuals with known inflammatory conditions. Although various noninvasive markers are currently available, they have limitations and do not provide ideal utility. This review focuses on emerging markers of gut inflammation, highlighting the potential of specific markers.
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Affiliation(s)
- Gilles Duvoisin
- Department of Paediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Gastroenterology, Sydney Children's Hospital Randwick, Sydney, Australia
| | - Robert N. Lopez
- Department of Gastroenterology, Sydney Children's Hospital Randwick, Sydney, Australia
| | - Andrew S. Day
- Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand
| | - Daniel A. Lemberg
- Department of Gastroenterology, Sydney Children's Hospital Randwick, Sydney, Australia
| | - Richard B. Gearry
- Department of Paediatrics, University of Otago, Christchurch, Christchurch, New Zealand
| | - Steven T. Leach
- School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
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Béres NJ, Kiss Z, Sztupinszki Z, Lendvai G, Arató A, Sziksz E, Vannay Á, Szabó AJ, Müller KE, Cseh Á, Boros K, Veres G. Altered mucosal expression of microRNAs in pediatric patients with inflammatory bowel disease. Dig Liver Dis 2017; 49:378-387. [PMID: 28077249 DOI: 10.1016/j.dld.2016.12.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 12/15/2016] [Accepted: 12/18/2016] [Indexed: 12/11/2022]
Abstract
INTRODUCTION MicroRNAs (miRs) came recently into focus as promising novel research targets offering new insights into the pathogenesis of inflammatory bowel diseases (IBD). AIMS The aim of our study was to identify a pediatric IBD (pIBD) characteristic miR profile serving as potential Crohn's disease (CD) and ulcerative colitis (UC) specific diagnostic pattern and to further analyze the related target genes. METHODS Small RNA sequencing was performed on inflamed and intact colonic biopsies of CD, and control patients. Selected miRs were further investigated by RT-PCR, complemented with an UC group, in order to address the differential diagnostic potential of miRs in the two IBD subtypes. To analyze network connection of differentially expressed miRs and their target genes MiRTarBase database and previous transcriptome sequencing data from pediatric patient groups were used. RESULTS Sequencing analysis identified 170 miRs with altered expression. RT-PCR analysis revealed altered expression of miR-31, -125a, -142-3p, and -146a discriminating between the inflamed mucosa of CD and UC. In the intact mucosa of CD patients the expression of miR-18a, -20a, -21, -31, -99a, -99b, -100, -125a, -126, -142-5p, -146a, -185, -204, -221, and -223 was elevated compared to the controls. The expression of miR-20a, -204 and -221 was elevated exclusively in the intact region of CD patients compared to the controls. Enrichment analysis identified main IBD-related functional groups. CONCLUSIONS We demonstrated a characteristic colonic miR pattern in pIBD that could facilitate deeper understanding of the pathomechanism of IBD and may serve as a diagnostic tool.
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Affiliation(s)
- Nóra Judit Béres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Zoltán Kiss
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | | | - Gábor Lendvai
- MTA-SE Tumor Progression Research Group, Budapest, Hungary
| | - András Arató
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Erna Sziksz
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | - Ádám Vannay
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | - Attila J Szabó
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | | | - Áron Cseh
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Kriszta Boros
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Gábor Veres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
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