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Yang L, Li H, Tang M, He L, Yang L. Circular RNAs in inflammatory bowel disease: a review of mechanisms, biomarkers and therapeutic potential. Front Immunol 2025; 16:1540768. [PMID: 40342413 PMCID: PMC12058709 DOI: 10.3389/fimmu.2025.1540768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/02/2025] [Indexed: 05/11/2025] Open
Abstract
Inflammatory bowel disease (IBD) is an autoimmune disease of unknown etiology characterized by recurrent chronic inflammation of the gastrointestinal tract. The incidence of IBD is increasing and has become a focus of research on digestive diseases. Despite advances in understanding its multifactorial etiology, including genetic predisposition, microbiome dysbiosis, and immune dysregulation. However, the molecular mechanisms driving IBD pathogenesis remain incompletely elucidated. Circular RNA (circRNA) is a stable single-stranded RNA with a closed-loop structure and conserved nature. circRNA possesses multiple functions, such as adsorption of microRNAs and RNA-binding proteins, and is involved in the regulation of gene splicing and transcription, as well as protein translation. However, circRNAs in IBD progression and their clinical potential as biomarkers or therapeutic targets are yet to be systematically explored. In this review, we comprehensively synthesize recent advancements in circRNA research related to IBD, integrating evidence from in vitro, in vivo, and clinical studies. We systematically analyze aberrant circRNA expression profiles in IBD tissues (e.g., intestinal mucosa, peripheral blood, and exosomes) and discuss their mechanism of action contributions to inflammation, intestinal epithelial barrier dysfunction, autophagy, intestinal fibrosis, and colitis-associated cancer (CAC). Furthermore, we evaluate methodologies for circRNA detection and therapeutic modulation, including RNA interference, viral vector delivery, and PLGA MSs delivery system strategies. This review highlights the potential of circRNA-focused strategies in the diagnosis and treatment of IBD, offering a scientific foundation for advancing precision medicine in IBD management.
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Affiliation(s)
- Le Yang
- Department of Gastroenterology, Yiyang Central Hospital, Yiyang, China
| | - Huahui Li
- Institute of Biomedical and Health Engineering, Chinese Academy of Sciences Shenzhen Institutes of Advanced Technology, Shenzhen, China
| | - Min Tang
- Department of Pharmacy, Yiyang Medical College, Yiyang, China
| | - Lingnan He
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lijun Yang
- Department of Pharmacy, Yiyang Medical College, Yiyang, China
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Kang Z, Di L, Liu Y, Qu W, Zeng Y, Lu X, Wang L. The Correlation Between the Expression Levels of Serum miR-19b and SOCS-1 mRNA and Clinical Symptoms in Patients with Allergic Rhinitis. J Asthma Allergy 2025; 18:619-627. [PMID: 40292344 PMCID: PMC12032965 DOI: 10.2147/jaa.s518177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 04/07/2025] [Indexed: 04/30/2025] Open
Abstract
Objective To investigate the correlation between the expression levels of microRNA-19b (miR-19b) and suppressor of cytokine signaling 1 messenger RNA (SOCS-1 mRNA) in the serum of patients with allergic rhinitis (AR) and clinical symptoms. Methods This prospective study included a total of 86 patients with allergic rhinitis who were admitted to the People's Hospital Affiliated to Hubei University of Medicine from January 2022 to January 2023. Seventy healthy individuals were included in the control group. The case group was further divided into a mild group (n=45) and a moderate to severe group (n=41) according to the severity of AR. The expression levels of miR-19b and SOCS-1 mRNA in serum samples of the two groups were detected and compared using real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) technique. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were utilized to evaluate the predictive value of miR-19b and SOCS-1 levels for the severity of AR. Results The expression level of miR-19b in the serum of the case group was 1.52±0.36, significantly higher than that of the control group (1.02±0.24, P<0.05). Logistic regression analysis indicated that low levels of serum miR-19b and SOCS-1 mRNA were independent risk factors for moderate to severe AR, with an odds ratio (OR) of 3.575 (95% CI: 1.572-8.133, P<0.001) for miR-19b and 3.725 (95% CI: 1.637-8.473, P<0.001) for SOCS-1 mRNA. ROC curve analysis demonstrated that the levels of serum miR-19b and SOCS-1 mRNA had high accuracy in predicting moderate to severe AR, with AUC values of 0.879 (95% CI: 0.791-0.940) and 0.795 (95% CI: 0.694-0.875), respectively. When combined for prediction, the efficacy was significantly higher than that of individual detection, with an AUC value of 0.923 (95% CI: 0.856-0.967), Z=3.261, P<0.01. Conclusion The expression levels of serum miR-19b and SOCS-1 mRNA are closely related to the severity of clinical symptoms in patients with AR and may serve as new biomarkers for evaluating the condition of AR and guiding treatment.
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Affiliation(s)
- Zhaopeng Kang
- Department of Andrology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China
| | - Lingling Di
- Department of Otolaryngology Head and Neck Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 756099, People’s Republic of China
| | - Yi Liu
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China
| | - Wei Qu
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China
| | - Yi Zeng
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China
| | - Xue Lu
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China
| | - Lixin Wang
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China
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Mo J, Ding Y, Yang J, Zheng Z, Lu J, Luo H, Wang J, Lin F, Chen J, Li Q, Zheng X, Zha L. Milk Exosomes From Gestational Diabetes Mellitus Parturients Demonstrate Weaker Ability to Promote Intestinal Development in Offspring. Mol Nutr Food Res 2025:e70026. [PMID: 40207769 DOI: 10.1002/mnfr.70026] [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: 09/02/2024] [Revised: 01/20/2025] [Accepted: 02/25/2025] [Indexed: 04/11/2025]
Abstract
This study aims to investigate whether human milk exosomes from gestational diabetes mellitus (GDM-EXO) and healthy (HEA-EXO) parturients differ in regulating intestinal development in offspring. The differential miRNAs associated with intestinal development in GDM-EXO and HEA-EXO were verified by using qPCR and their relationships with gut microbiota (GM) in infants were analyzed. C57BL/6J mice were gavaged with 50 mg/kg·BW HEA-EXO or GDM-EXO. The intestinal morphology, gut barriers, ZO-1 and Occludin, and GM were determined by histological staining, Western blotting, and 16S rDNA amplicon sequencing, respectively. Hsa-miR-19b-3p, hsa-miR-148a-3p, and hsa-miR-320a-3p were upregulated, and hsa-miR-429 was decreased in GDM-EXO compared to HEA-EXO. The GDM parturients' infants had increased intestinal Coriobacteriaceae, Clostridiaceae, Erysipelotrichaceae, Erysipelatoclostridiaceae, and fewer Lactobacillaceae than the healthy parturient's infants. The four differential miRNAs in GDM-EXO all correlated with the infants' GM. GDM-EXO- and HEA-EXO-fed mice had greater villus lengths, villus length-to-crypt depth ratios, goblet cell numbers, elevated ZO-1 and Occludin, and lower crypt depths than control mice. HEA-EXO-fed mice had better intestinal morphology and gut barrier integrity than GDM-EXO-fed mice. GDM-EXO-fed mice had significantly decreased Lachnospiraceae and Oscillospiraceae than HEA-EXO-fed mice. GDM-EXO demonstrate weaker ability to promote intestinal development in offspring than HEA-EXO.
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Affiliation(s)
- Jiaqi Mo
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Yudi Ding
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Junyi Yang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
- Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Zhongdaixi Zheng
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Jiazhi Lu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Huiyu Luo
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Jiexian Wang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Fengjuan Lin
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Junbin Chen
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Qing Li
- Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Xiangyi Zheng
- Department of Health Management Medicine, Guangzhou Panyu District Health Management Center (Guangzhou Panyu District Rehabilitation Hospital), Guangzhou, Guangdong, P. R. China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, P. R. China
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Jafari N, Abediankenari S. Role of microRNAs in immunoregulatory functions of epithelial cells. BMC Immunol 2024; 25:84. [PMID: 39707170 PMCID: PMC11662810 DOI: 10.1186/s12865-024-00675-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/27/2024] [Indexed: 12/23/2024] Open
Abstract
Epithelial cells (ECs) provide the first line of defense against microbial threats and environmental challenges. They participate in the host's immune responses via the expression and secretion of various immune-related molecules such as cytokines and chemokines, as well as interaction with immune cells. A growing body of evidence suggests that the dysregulated function of ECs can be involved in the pathophysiology of a broad range of infectious, autoimmune, and inflammatory diseases, including inflammatory bowel disease (IBD), asthma, multiple sclerosis, and rheumatoid arthritis. To maintain a substantial immunoregulatory function of ECs, precise expression of different molecules and their regulatory effects are indispensable. MicroRNAs (miRNAs, miRs) are small non-coding RNAs that regulate gene expression commonly at post-transcriptional level through degradation of target messenger RNAs (mRNAs) or suppression of protein translation. MiRNAs implicate as critical regulators in many cellular processes, including apoptosis, growth, differentiation, and immune response. Due to the crucial roles of miRNAs in such a vast range of biological processes, they have become the spotlight of biological research for more than two decades, but we are still at the beginning stages of the use of miRNA-based therapies in the improvement of human health. Hence, in the present paper, attempts are made to provide a comprehensive overview with regard to the roles of miRNAs in the immunoregulatory functions of ECs. A better understanding of the molecular mechanisms through which immunoregulatory properties of ECs are manifested, could aid the development of efficient strategies to prevent and treat multiple human diseases.
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Affiliation(s)
- Narjes Jafari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abediankenari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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Cheng Z, Zhou Y, Xiong X, Li L, Chen Z, Wu F, Dong R, Liu Q, Zhao Y, Jiang S, Yu Q, Chen G. Traditional herbal pair Portulacae Herba and Granati Pericarpium alleviates DSS-induced colitis in mice through IL-6/STAT3/SOCS3 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155283. [PMID: 38422652 DOI: 10.1016/j.phymed.2023.155283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/01/2023] [Accepted: 12/13/2023] [Indexed: 03/02/2024]
Abstract
BACKGROUND Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain. PURPOSE The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism. METHODS The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot. RESULTS DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration. CONCLUSION PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.
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Affiliation(s)
- Zhe Cheng
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yi Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xinyu Xiong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lingli Li
- Department of Traditional Chinese Medicine, Wuhan Fourth Hospital, Wuhan 430033, China
| | - Zekai Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fan Wu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ruolan Dong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qiong Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yan Zhao
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shujun Jiang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qin Yu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guang Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Aggeletopoulou I, Kalafateli M, Tsounis EP, Triantos C. Exploring the role of IL-1β in inflammatory bowel disease pathogenesis. Front Med (Lausanne) 2024; 11:1307394. [PMID: 38323035 PMCID: PMC10845338 DOI: 10.3389/fmed.2024.1307394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 01/11/2024] [Indexed: 02/08/2024] Open
Abstract
Interleukin 1β (IL-1β) is a significant mediator of inflammation and tissue damage in IBD. The balance between IL-1β and its endogenous inhibitor-IL-1Ra-, plays a critical role in both initiation and regulation of inflammation. However, the precise role of IL-1β as a causative factor in IBD or simply a consequence of inflammation remains unclear. This review summarizes current knowledge on the molecular and cellular characteristics of IL-1β, describes the existing evidence on the role of this cytokine as a modulator of intestinal homeostasis and an activator of inflammatory responses, and also discusses the role of microRNAs in the regulation of IL-1β-related inflammatory responses in IBD. Current evidence indicates that IL-1β is involved in several aspects during IBD as it greatly contributes to the induction of pro-inflammatory responses through the recruitment and activation of immune cells to the gut mucosa. In parallel, IL-1β is involved in the intestinal barrier disruption and modulates the differentiation and function of T helper (Th) cells by activating the Th17 cell differentiation, known to be involved in the pathogenesis of IBD. Dysbiosis in the gut can also stimulate immune cells to release IL-1β, which, in turn, promotes inflammation. Lastly, increasing evidence pinpoints the central role of miRNAs involvement in IL-1β-related signaling during IBD, particularly in the maintenance of homeostasis within the intestinal epithelium. In conclusion, given the crucial role of IL-1β in the promotion of inflammation and immune responses in IBD, the targeting of this cytokine or its receptors represents a promising therapeutic approach. Further research into the IL-1β-associated post-transcriptional modifications may elucidate the intricate role of this cytokine in immunomodulation.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Kalafateli
- Department of Gastroenterology, General Hospital of Patras, Patras, Greece
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
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Beňačka R, Szabóová D, Guľašová Z, Hertelyová Z, Radoňak J. Non-Coding RNAs in Human Cancer and Other Diseases: Overview of the Diagnostic Potential. Int J Mol Sci 2023; 24:16213. [PMID: 38003403 PMCID: PMC10671391 DOI: 10.3390/ijms242216213] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/07/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are abundant single-stranded RNA molecules in human cells, involved in various cellular processes ranging from DNA replication and mRNA translation regulation to genome stability defense. MicroRNAs are multifunctional ncRNA molecules of 18-24 nt in length, involved in gene silencing through base-pair complementary binding to target mRNA transcripts. piwi-interacting RNAs are an animal-specific class of small ncRNAs sized 26-31 nt, responsible for the defense of genome stability via the epigenetic and post-transcriptional silencing of transposable elements. Long non-coding RNAs are ncRNA molecules defined as transcripts of more than 200 nucleotides, their function depending on localization, and varying from the regulation of cell differentiation and development to the regulation of telomere-specific heterochromatin modifications. The current review provides recent data on the several forms of small and long non-coding RNA's potential to act as diagnostic, prognostic or therapeutic target for various human diseases.
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Affiliation(s)
- Roman Beňačka
- Department of Pathophysiology, Medical Faculty, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (R.B.); (D.S.)
| | - Daniela Szabóová
- Department of Pathophysiology, Medical Faculty, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (R.B.); (D.S.)
| | - Zuzana Guľašová
- Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (Z.G.); (Z.H.)
| | - Zdenka Hertelyová
- Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (Z.G.); (Z.H.)
| | - Jozef Radoňak
- 1st Department of Surgery, Faculty of Medicine, Louis Pasteur University Hospital (UNLP) and Pavol Jozef Šafarik University, 04011 Košice, Slovakia
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Won Lee J, Kyu Shim M, Kim H, Jang H, Lee Y, Hwa Kim S. RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges. Adv Drug Deliv Rev 2023; 201:115073. [PMID: 37657644 DOI: 10.1016/j.addr.2023.115073] [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: 04/27/2023] [Revised: 07/31/2023] [Accepted: 08/20/2023] [Indexed: 09/03/2023]
Abstract
The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.
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Affiliation(s)
- Jong Won Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Man Kyu Shim
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Hyosuk Kim
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Hochung Jang
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Yuhan Lee
- Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Accelerated Medical Innovation & Center for Nanomedicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Sun Hwa Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
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Datta N, Johnson C, Kao D, Gurnani P, Alexander C, Polytarchou C, Monaghan TM. MicroRNA-based therapeutics for inflammatory disorders of the microbiota-gut-brain axis. Pharmacol Res 2023; 194:106870. [PMID: 37499702 DOI: 10.1016/j.phrs.2023.106870] [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: 03/11/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.
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Affiliation(s)
- Neha Datta
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Charlotte Johnson
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Pratik Gurnani
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Cameron Alexander
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Christos Polytarchou
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science & Technology, Nottingham Trent University, Nottingham, UK.
| | - Tanya M Monaghan
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
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Han L, Chen S, Luan Z, Fan M, Wang Y, Sun G, Dai G. Immune function of colon cancer associated miRNA and target genes. Front Immunol 2023; 14:1203070. [PMID: 37465677 PMCID: PMC10351377 DOI: 10.3389/fimmu.2023.1203070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/15/2023] [Indexed: 07/20/2023] Open
Abstract
Introduction Colon cancer is a complex disease that involves intricate interactions between cancer cells and theimmune microenvironment. MicroRNAs (miRNAs) have recently emerged as critical regulators of gene expression in cancer, including colon cancer. There is increasing evidence suggesting that miRNA dysregulation plays a crucial role in modulating the immune microenvironment of intestinal cancer. In particular, miRNAs regulate immune cell activation, differentiation, and function, as well as cytokine and chemokine production in intestinal cancer. It is urgent to fully investigate the potential role of intestinal cancer-related miRNAs in shaping the immune microenvironment. Methods Therefore, this paper aims to identify miRNAs that are potentially associated with colon cancer and regulate a large number of genes related to immune function. We explored the role of these genes in colon cancer patient prognosis, immune infiltration, and tumor purity based on data of 174 colon cancer patients though convolutional neural network, survival analysis and multiple analysis tools. Results Our findings suggest that miRNA regulated genes play important roles in CD4 memory resting cells, macrophages.M2, and Mast cell activated cells, and they are concentrated in the cytokinecytokine receptor interaction pathway. Discussion Our study enhances our understanding of the underlying mechanisms of intestinal cancer and provides new insights into the development of effective therapies. Additionally, identification of miRNA biomarkers could aid in diagnosis and prognosis, as well as guide personalized treatment strategies for patients with intestinal cancer.
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Affiliation(s)
- Lu Han
- Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Shiyun Chen
- Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Zhe Luan
- Department of Gastroenterology and Hepatology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Mengjiao Fan
- Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Yanrong Wang
- Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Gang Sun
- Department of Gastroenterology and Hepatology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Guanghai Dai
- Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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Lu Y, Chai Y, Qiu J, Zhang J, Wu M, Fu Z, Wang Y, Qin C. Integrated omics analysis reveals the epigenetic mechanism of visceral hypersensitivity in IBS-D. Front Pharmacol 2023; 14:1062630. [PMID: 37007011 PMCID: PMC10064328 DOI: 10.3389/fphar.2023.1062630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Background and objective: IBS-D is a common functional bowel disease with complex etiology and without biomarker. The pathological and physiological basis of IBS-D focuses on visceral hypersensitivity. However, its epigenetic mechanism remains elusive. Our study aimed to integrate the relationship between differentially expressed miRNAs, mRNAs and proteins in IBS-D patients in order to reveal epigenetic mechanism of visceral hypersensitivity from transcription and protein levels and provide the molecular basis for discovering biomarkers of IBS-D.Methods: The intestinal biopsies from IBS-D patients and healthy volunteers were obtained for high-throughput sequencing of miRNAs and mRNAs. The differential miRNAs were selected and verified by q-PCR experiment followed by target mRNA prediction. Biological functions were respectively analyzed for target mRNAs, differential mRNAs and the previously identified differential proteins in order to explore the characteristic involved visceral hypersensitivity. At last, interaction analysis of miRNAs, mRNAs and proteins was performed for the epigenetic regulation mechanism from transcription and protein levels.Results: Thirty-three miRNAs were found to be differentially expressed in IBS-D and five of them were further confirmed, including upregulated hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p and downregulated hsa-miR-219a-5p, hsa-miR-19b-1-5p. In addition, 3,812 differential mRNAs were identified. Thirty intersecting molecules were found from the analysis on the target mRNAs of miRNAs and mRNAs. Fourteen intersecting molecules were obtained from the analysis on the target mRNAs and proteins, and thirty-six intersecting molecules were identified from analysis on the proteins and different mRNAs. According to the integrated analysis of miRNA-mRNA-protein, we noticed two new molecules COPS2 regulated by hsa-miR-19b-1-5p and MARCKS regulated by hsa-miR-641. Meanwhile some critical signaling pathways in IBS-D were found such as MAPK, GABAergic synapse, Glutamatergic synapse, and Adherens junction.Conclusion: The expressions of hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p, hsa-miR-219a-5p, and hsa-miR-19b-1-5p in the intestinal tissues of IBS-D patients were significantly different. Moreover, they could regulate a variety of molecules and signaling pathways, which were involved in the multifaceted and multilevel mechanism of visceral hypersensitivity of IBS-D.
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Affiliation(s)
- Yaoyao Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuna Chai
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Yuna Chai, ; Yongfu Wang, ; Chongzhen Qin,
| | - Jianli Qiu
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jingmin Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Menglin Wu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhe Fu
- Department of General Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yongfu Wang
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Yuna Chai, ; Yongfu Wang, ; Chongzhen Qin,
| | - Chongzhen Qin
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Yuna Chai, ; Yongfu Wang, ; Chongzhen Qin,
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Ribeiro BE, Breves J, de Souza HSP. Pathogenesis: Crohn’s disease and ulcerative colitis. NATURAL PLANT PRODUCTS IN INFLAMMATORY BOWEL DISEASES 2023:9-46. [DOI: 10.1016/b978-0-323-99111-7.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Li T, Ge H, Yang Q, Wang J, Yin Q, Wang H, Hou G. Oncogenic role of microRNA-19b-3p-mediated SOCS3 in glioma through activation of JAK-STAT pathway. Metab Brain Dis 2022; 38:945-960. [PMID: 36484970 DOI: 10.1007/s11011-022-01136-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 11/25/2022] [Indexed: 12/14/2022]
Abstract
The altered expression of microRNA (miRNA) has been implicated in glioma. Here, the current study aimed to clarify the oncogenic effects of miR-19b-3p on cellular processes of glioma and to elucidate the underlying mechanism associated with SOCS3 and the JAK-STAT signaling pathway. Differentially expressed genes related to glioma were initially identified via microarray analysis. Twenty-five glioma patients were selected for clinical data collection, while additional 12 patients with traumatic brain injuries were selected as controls. Cell senescence was assessed by β-galactosidase staining, proliferation by MTT assay and apoptosis by flow cytometry following gain- and/or loss-of-function of miR-19b-3p or SOCS3. Glioma xenograft mouse model was developed through subcutaneous injection to nude mice to provide evidence in vivo. The glioma patients exhibited overexpressed miR-19b-3p and poorly-expressed SOCS3. SOCS3 was identified as a target gene of miR-19b-3p through dual-luciferase reporter gene assay. miR-19b-3p repressed SOCS3 expression and activated the JAK-STAT signaling pathway. Furthermore, miR-19b-3p inhibition promoted apoptosis and senescence, and suppressed cell proliferation through inactivation of the JAK-STAT signaling pathway and up-regulation of SOCS3. The reported regulatory axis was validated in nude mice as evidenced by suppressed tumor growth. Taken together, this study demonstrates that miR-19b-3p facilitates glioma progression via activation of the JAK-STAT signaling pathway by targeting SOCS3, highlighting a novel therapeutic target for glioma treatment.
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Affiliation(s)
- Tao Li
- The Second Department of Neurosurgery, Affiliated Hospital of Hebei Engineering University, No. 81, Congtai Road, Congtai District, 056000, Handan, Hebei Province, P. R. China
| | - Hong Ge
- Personnel Department, Handan Psychiatric Hospital, 056000, Handan, P. R. China
| | - Qingyan Yang
- Department of Otolaryngology, Affiliated Hospital of Hebei Engineering University, 056000, Handan, P. R. China
| | - Junmei Wang
- The Fourth Department of Neurosurgery, Handan Central Hospital, 056000, Handan, P. R. China
| | - Qian Yin
- Department of Laboratory Medicine, Han Gang Hospital, 056000, Handan, P. R. China
| | - Hongbin Wang
- Department of Neurosurgery, Affiliated Hospital of Hebei Engineering University, 056000, Handan, P. R. China
| | - Gaolei Hou
- The Second Department of Neurosurgery, Affiliated Hospital of Hebei Engineering University, No. 81, Congtai Road, Congtai District, 056000, Handan, Hebei Province, P. R. China.
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Therapeutic Efficacy of Novel HDAC Inhibitors SPA3052 and SPA3074 against Intestinal Inflammation in a Murine Model of Colitis. Pharmaceuticals (Basel) 2022; 15:ph15121515. [PMID: 36558966 PMCID: PMC9785328 DOI: 10.3390/ph15121515] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are digestive tract disorders that involve chronic inflammation with frequent recurrences. This study aimed to evaluate the efficacy of two novel histone deacetylase 8 (HDAC8) inhibitors, namely, SPA3052 and SPA3074, against dextran sulfate sodium (DSS)-induced experimental colitis. Male C57BL/6N mice were subjected to two cycles of 1.5% DSS followed by treatment with suberoylanilide hydroxamic acid (SAHA), SPA3052, or SPA3074 for 14 days. Our results showed that SPA3074 administration increased (>50%) the expression of occludin, a tight junction protein, which was significantly decreased (>100%) after DSS treatment. Moreover, SPA3074 upregulated suppressor of cytokine signaling 1 (SOCS1) protein expression, which is known to be a key suppressor of T-helper cell differentiation and pro-inflammatory cytokines expression. Furthermore, we observed a decrease in SOCS1-associated Akt phosphorylation and an increase in lower extracellular signal-regulated kinase 1 and 2 phosphorylation, which contributed to lower nuclear factor-kappa B activation. Th2 effector cytokines, especially interleukin-13, were also downregulated by SPA3074 treatment. This study suggests that HDAC8 might be a promising novel target for the development of IBD treatments and that the novel HDAC8 inhibitor SPA3074 is a new candidate for IBD therapeutics.
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15
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Li Y, Tan S, Shen Y, Guo L. miR‑146a‑5p negatively regulates the IL‑1β‑stimulated inflammatory response via downregulation of the IRAK1/TRAF6 signaling pathway in human intestinal epithelial cells. Exp Ther Med 2022; 24:615. [PMID: 36160881 PMCID: PMC9468834 DOI: 10.3892/etm.2022.11552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022] Open
Abstract
The primary pathophysiological alteration caused by inflammatory bowel disease (IBD) is prolonged, excessive inflammatory response to stimulation factors, which leads to intestinal mucosal lesions. microRNA (miR)-146a-5p is broadly activated in the mucosal immune response. At present, the biogenesis, function and role of miR-146a-5p in intestinal epithelial cells (IECs) during the pathogenesis of IBD remain elusive. The human colon cancer epithelial Caco-2 cell line was cultured with 10 ng/ml recombinant human IL-1β for 3 h to establish an in vitro IECs inflammatory model. Relative levels of miR-146a-5p and inflammatory factors (IL-6, IL-1β, TNF-α and IP-10) were measured by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. Transfection of miR-146a-5p mimic or inhibitor into Caco-2 cells was performed to identify the influence of miR-146a-5p on Caco-2 cell inflammatory factors expression. The targeting relationship between miR-146a-5p and interleukin 1 receptor associated kinase 1 (IRAK1)/tumor necrosis factor receptor-associated factor 6 (TRAF6) was predicted by TargetScan 8.0. The present study demonstrated that miR-146a-5p and inflammatory factors (IL-6, IL-1β, TNF-α and IP-10) were upregulated in a dose- and time-dependent manner in IL-1β-stimulated Caco-2 cells. Moreover, upregulation of miR-146a-5p negatively regulated the expression of inflammatory factors, but the downregulation of miR-146a-5p increased their expression. The results of the present study demonstrated that miR-146a-5p decreased the expression of the inflammatory factors through targeted downregulation of IRAK1/TRAF6. These results suggest that miR-146a-5p negatively regulates the IL-1β-stimulated inflammatory response via downregulation of the IRAK1/TRAF6 signaling pathway in human IECs. Therefore, miR-146a-5p may act as an important diagnostic biomarker and treatment target of IBD.
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Affiliation(s)
- Yanli Li
- Department of Medical Microbiology and Immunology, College of Basic Medicine, Dali University, Dali, Yunnan 671003, P.R. China
| | - Shilian Tan
- Department of Medical Microbiology and Immunology, College of Basic Medicine, Dali University, Dali, Yunnan 671003, P.R. China
| | - Yuanying Shen
- Department of Medical Microbiology and Immunology, College of Basic Medicine, Dali University, Dali, Yunnan 671003, P.R. China
| | - Le Guo
- Department of Medical Microbiology and Immunology, College of Basic Medicine, Dali University, Dali, Yunnan 671003, P.R. China
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16
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Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications. Cells 2022; 11:cells11101708. [PMID: 35626744 PMCID: PMC9139855 DOI: 10.3390/cells11101708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/30/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023] Open
Abstract
Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways makes development of a “clean” AhR therapeutically challenging. Ligand promiscuity and diversity in context-specific AhR activation further complicates targeting the AhR for drug development due to limitations surrounding clinical translatability. Despite these concerns, several approaches to target the AhR have been explored such as small molecules, microbials, PROTACs, and oligonucleotide-based approaches. These various chemical modalities are not without safety liabilities and require unique de-risking strategies to parse out toxicities. Collectively, these programs can benefit from in silico and in vitro methodologies that investigate specific AhR pathway activation and have the potential to implement thresholding parameters to categorize AhR ligands as “high” or “low” risk for sustained AhR activation. Exploration into transcriptomic signatures for AhR safety assessment, incorporation of physiologically-relevant in vitro model systems, and investigation into chronic activation of the AhR by structurally diverse ligands will help address gaps in our understanding regarding AhR-dependent toxicities. Here, we review the role of the AhR within the GI tract, novel therapeutic modality approaches to target the AhR, key AhR-dependent safety liabilities, and relevant strategies that can be implemented to address drug safety concerns. Together, this review discusses the emerging therapeutic landscape of modalities targeting the AhR for inflammatory GI indications and offers a safety roadmap for AhR drug development.
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Kang M, Huang CC, Gajendrareddy P, Lu Y, Shirazi S, Ravindran S, Cooper LF. Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration. Front Immunol 2022; 13:878194. [PMID: 35585987 PMCID: PMC9108364 DOI: 10.3389/fimmu.2022.878194] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/07/2022] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal stem cells show remarkable versatility and respond to extracellular and micro environmental cues by altering their phenotype and behavior. In this regard, the MSC's immunomodulatory properties in tissue repair are well documented. The paracrine effects of MSCs in immunomodulation are, in part, attributable to their secreted extracellular vesicles (EVs). When MSCs migrate to the wound bed, they are exposed to a myriad of inflammatory signals. To understand their response to an inflammatory environment from an EV perspective, we sought to evaluate the effects of the inflammatory cytokine TNFα on MSC EV mediated immunomodulation. Our results indicate that while the physical characteristics of the EVs remain unchanged, the TNFα preconditioned MSC EVs possess enhanced immunomodulatory properties. In vitro experiments using polarized (M1 and M2) primary mouse macrophages indicated that the preconditioned MSC EVs suppressed pro-inflammatory (M1) markers such as IL-1β and iNOS and elevated reparatory (M2) markers such as Arg1 and CD206. When evaluated in vivo in a rat calvarial defect model, the TNFα preconditioned MSC EVs reduced inflammation at 1-, 3- and 7-days post wounding resulting in the subsequent enhanced bone formation at 4- and 8-weeks post wounding possibly by modulation of oncostatin M (OSM) expression. An analysis of EV miRNA composition revealed significant changes to anti-inflammatory miRNAs in the preconditioned MSC EVs hinting at a possible role for EV derived miRNA in the enhanced immunomodulatory activity. Overall, these results indicate that MSC exposure to inflammatory signals influence the MSC EV's immunomodulatory function in the context of tissue repair. The specific function of TNFα preconditioned MSC EV miRNAs in immunomodulatory control of bone regeneration merits further investigation.
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Affiliation(s)
- Miya Kang
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Chun-Chieh Huang
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Praveen Gajendrareddy
- Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Yu Lu
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Sajjad Shirazi
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Lyndon F. Cooper
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
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Li T, Liu W, Hui W, Shi T, Liu H, Feng Y, Gao F. Integrated Analysis of Ulcerative Colitis Revealed an Association between PHLPP2 and Immune Infiltration. DISEASE MARKERS 2022; 2022:4983471. [PMID: 35308140 PMCID: PMC8931176 DOI: 10.1155/2022/4983471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/08/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a progressive intestine inflammatory disease that is prone to recur. Herein, we utilize microarray technology and bioinformatics to reveal the underlying pathogenesis of UC and provide novel markers. Colonic biopsies were taken from eight UC patients and eight healthy controls. Three differentially expressed miRNAs (DEMIs) and 264 differentially expressed genes (DEGs) were screened using mRNA and miRNA microarray. Most DEGs were significantly associated with immune response and were markedly enriched in the IL-17 signaling pathway. Among the target genes of DEMIs, PHLPP2 overlapped with DEGs and the downregulation of PHLPP2 group was mainly involved in the epithelial-mesenchymal transition. PHLPP2 was downregulated in UC patients, which was validated in 5 GEO datasets and qRT-PCR. The ROC curve demonstrated that PHLPP2 has a perfect ability to distinguish UC patients from healthy controls. Moreover, PHLPP2 was low expression in patients with active UC. CIBERSORT algorithm indicated that the abundance of gamma delta T cells (P = 0.04), M0 macrophages (P = 0.01), and activated mast cells (P < 0.01) was significantly greater than that of the control group. The Spearman correlation analysis showed that PHLPP2 was positively correlated with the proportion of activated NK cells (rho = 0.62, P = 0.013) and Tregs (rho = 0.55, P = 0.03), but negatively correlated with those of activated mast cells (rho = -0.8, P < 0.01) and macrophages (rho = -0.73, P < 0.01). These results indicate that PHLPP2 is associated with immune cells in the pathogenesis of UC, as well as provide new prospects and future directions of investigation.
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Affiliation(s)
- Ting Li
- Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Weidong Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Wenjia Hui
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Tian Shi
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Huan Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Feng Gao
- Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
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Long noncoding RNA KIF9-AS1 promotes cell apoptosis by targeting the microRNA-148a-3p/suppressor of cytokine signaling axis in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2021; 33:e922-e932. [PMID: 34750325 PMCID: PMC8734634 DOI: 10.1097/meg.0000000000002309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Inflammatory bowel disease (IBD) is a chronic intestinal disease. This study was attempted to investigate the effects of long noncoding RNA KIF9-AS1 (KIF9-AS1) on the development of IBD and its underlying mechanism of action. METHODS Quantitative real time PCR (qRT-PCR) was implemented to examine the expression of KIF9-AS1 and microRNA-148a-3p (miR-148a-3p). The IBD mouse model was induced by dextran sulfate sodium (DSS). The body weight, disease activity index (DAI) score, colon length and histological injury were used to evaluate the colon injury. The levels of proinflammatory cytokines were measured by ELISA. In vitro, IBD was simulated by DSS treatment in colonic cells. Then the apoptosis of colonic cells was detected by flow cytometry assay. Furthermore, a dual-luciferase reporter assay was used to demonstrate the interactions among KIF9-AS1, miR-148a-3p and suppressor of cytokine signaling (SOCS3). RESULTS KIF9-AS1 expression was upregulated in IBD patients, DSS-induced IBD mice and DSS-induced colonic cells, whereas miR-148a-3p expression was downregulated. KIF9-AS1 silencing attenuated the apoptosis of DSS-induced colonic cells in vitro and alleviated colon injury and inflammation in DSS-induced IBD mice in vivo. Additionally, the mechanical experiment confirmed that KIF9-AS1 and SOCS3 were both targeted by miR-148a-3p with the complementary binding sites at 3'UTR. Moreover, miR-148a-3p inhibition or SOCS3 overexpression reversed the suppressive effect of KIF9-AS1 silencing on the apoptosis of DSS-induced colonic cells. CONCLUSION KIF9-AS1 silencing hampered the colon injury and inflammation in DSS-induced IBD mice in vivo, and restrained the apoptosis of DSS-induced colonic cells by regulating the miR-148a-3p/SOCS3 axis in vitro, providing a new therapeutic target for IBD.
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Loss of Setd2 associates with aberrant microRNA expression and contributes to inflammatory bowel disease progression in mice. Genomics 2021; 113:2441-2454. [PMID: 34052319 DOI: 10.1016/j.ygeno.2021.05.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022]
Abstract
Both SETD2-mediated H3K36me3 and miRNAs play critical epigenetic roles in inflammatory bowel disease (IBD) and involve in the dysfunctional intestinal barrier. However, little is known about cross-talk between these two types of regulators in IBD progression. We performed small RNA sequencing of Setd2 epithelium-specific knockout mice (Setd2Vil-KO) and wild-type controls, both with DSS-induced colitis, and designed a framework for integrative analysis. Firstly, we integrated the downloaded ChIP-seq data with miRNA expression profiles and identified a significant intersection of pre-miRNA expression and H3K36me3 modification. A significant inverse correlation was detected between changes of H3K36me3 modification and expression of the 171 peak-covered miRNAs. We further integrated RNA-seq data with predicted miRNA targets to screen negatively regulated miRNA-mRNA pairs and found the H3K36me3-associated differentially expressed microRNAs significantly enriched in cell-cell junction and signaling pathways. Using network analysis, we identified ten hub miRNAs, among which six are H3K36me3-associated, suggesting therapeutic targets for IBD patients with SETD2-deficiency.
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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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22
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Xu Y, Xu X, Ocansey DKW, Cao H, Qiu W, Tu Q, Mao F. CircRNAs as promising biomarkers of inflammatory bowel disease and its associated-colorectal cancer. Am J Transl Res 2021; 13:1580-1593. [PMID: 33841681 PMCID: PMC8014397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/18/2020] [Indexed: 06/12/2023]
Abstract
In recent years, research on the pathogenesis of inflammatory bowel disease (IBD) and its associated-colorectal cancer has been well documented to involve environmental, genetic, immune, and intestinal microbiota factors. Evidence indicates that, regardless of the current high global incidence of IBD with over 3.5 million cases in Europe and North America only, it continues to emerge in newly industrialized countries across Asia, Middle East, and South America. Individuals with IBD have significant increased risk of gastrointestinal and extra-intestinal malignancies, particularly, colorectal cancer (CRC) and lymphomas. Among the significant areas of exploration in IBD and its associated-CRC is the search for effective and reliable diagnostic and prognostic markers, and treatment targets. To this effect, the role of non-coding RNAs in IBD and its associated-CRC has attracted research attention, among which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) get more detailed exploration while little is known about circular RNAs (circRNAs). This review focuses on the emerging role of circRNAs in the diagnosis, prognosis, and treatment of IBD and its associated-CRC. It introduces the biogenesis of circRNAs and brings an up-to-date report on those found within IBD and CRC environment, as well as their participation toward the promotion or suppression of the conditions, and their diagnostic potentials.
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Affiliation(s)
- Yuting Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, China
| | - Xinwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, China
- Directorate of University Health Services, University of Cape CoastGhana
| | - Hua Cao
- Nanjing Jiangning HospitalNanjing 211100, Jiangsu, China
| | - Wei Qiu
- Nanjing Jiangning HospitalNanjing 211100, Jiangsu, China
| | - Qiang Tu
- Nanjing Jiangning HospitalNanjing 211100, Jiangsu, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, China
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23
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Liu Y, Wang Y, Wang C, Shi R, Zhou X, Li Z, Sun W, Zhao L, Yuan L. Maternal obesity increases the risk of fetal cardiac dysfunction via visceral adipose tissue derived exosomes. Placenta 2021; 105:85-93. [PMID: 33556718 DOI: 10.1016/j.placenta.2021.01.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 01/20/2021] [Accepted: 01/27/2021] [Indexed: 01/02/2023]
Abstract
INTRODUCTION There is a strong association between gestational obesity and fetal cardiac dysfunction, while the exact mechanisms remain largely unknown. The purpose of this study was to investigate the role of exosomes from maternal visceral adipose tissue in abnormal embryonic development in obese pregnancy. METHODS Female C57BL/6J obese mice were induced by a high-fat diet (containing 60% fat). Fetal cardiac function and morphology were examined by echocardiography and histology. The placenta was extracted for histological examination. miRNA expression in exosomes from the visceral adipose tissue was profiled by RNA-seq. Gene expression of inflammatory factors was analyzed by qPCR. RESULTS In the obese pregnant mice, there were obvious inflammation and lipid droplets in the placenta. And the fetal cardiac function in obese pregnancy was also compromised. Moreover, injection of the visceral adipose tissue exosomes from the obese mice significantly decreased the fetal cardiac function in the normal lean pregnant mice. Mechanistically, the decreased expression of miR-19b might be responsible for the enhanced inflammation in the placenta. DISCUSSION Exosomes derived from visceral adipose tissue in obese mice contribute to fetal heart dysfunction, at least partially via affecting the function of the placenta.
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Affiliation(s)
- Yunnan Liu
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Yixiao Wang
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Chen Wang
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Ruijing Shi
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Xueying Zhou
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Zhelong Li
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Wenqi Sun
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Lianbi Zhao
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China
| | - Lijun Yuan
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
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24
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Hardesty JE, Warner JB, Song YL, Rouchka EC, Chen CY, Kang JX, McClain CJ, Warner DR, Kirpich IA. Transcriptional signatures of the small intestinal mucosa in response to ethanol in transgenic mice rich in endogenous n3 fatty acids. Sci Rep 2020; 10:19930. [PMID: 33199802 PMCID: PMC7670449 DOI: 10.1038/s41598-020-76959-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/04/2020] [Indexed: 12/19/2022] Open
Abstract
The intestine interacts with many factors, including dietary components and ethanol (EtOH), which can impact intestinal health. Previous studies showed that different types of dietary fats can modulate EtOH-induced changes in the intestine; however, mechanisms underlying these effects are not completely understood. Here, we examined intestinal transcriptional responses to EtOH in WT and transgenic fat-1 mice (which endogenously convert n6 to n3 polyunsaturated fatty acids [PUFAs]) to identify novel genes and pathways involved in EtOH-associated gut pathology and discern the impact of n3 PUFA enrichment. WT and fat-1 mice were chronically fed EtOH, and ileum RNA-seq and bioinformatic analyses were performed. EtOH consumption led to a marked down-regulation of genes encoding digestive and xenobiotic-metabolizing enzymes, and transcription factors involved in developmental processes and tissue regeneration. Compared to WT, fat-1 mice exhibited a markedly plastic transcriptome response to EtOH. Cell death, inflammation, and tuft cell markers were downregulated in fat-1 mice in response to EtOH, while defense responses and PPAR signaling were upregulated. This transcriptional reprogramming may contribute to the beneficial effects of n3 PUFAs on EtOH-induced intestinal pathology. In summary, our study provides a reference dataset of the intestinal mucosa transcriptional responses to chronic EtOH exposure for future hypothesis-driven mechanistic studies.
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Affiliation(s)
- Josiah E Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Jeffrey B Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Ying L Song
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
| | - Eric C Rouchka
- Department of Computer Science and Engineering, Speed School of Engineering, University of Louisville, Louisville, KY, USA
| | - Chih-Yu Chen
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA
- Robley Rex Veterans Medical Center, Louisville, KY, USA
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA.
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25
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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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26
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Luo R, Li L, Hu Y, Xiao F. LncRNA H19
inhibits high glucose‐induced inflammatory responses of human retinal epithelial cells by targeting
miR
‐19b to increase
SIRT1
expression. Kaohsiung J Med Sci 2020; 37:101-110. [PMID: 33022863 DOI: 10.1002/kjm2.12302] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 07/17/2020] [Accepted: 08/30/2020] [Indexed: 12/12/2022] Open
Affiliation(s)
- Rong Luo
- Department of Ophthalmology Jiangxi Provincial People's Hospital Affiliated to Nanchang University Nanchang China
| | - Lan Li
- Department of Ophthalmology Jiangxi Provincial People's Hospital Affiliated to Nanchang University Nanchang China
| | - Yu‐Xiang Hu
- Department of Ophthalmology Jiangxi Provincial People's Hospital Affiliated to Nanchang University Nanchang China
| | - Fan Xiao
- Department of Ophthalmology Jiangxi Provincial People's Hospital Affiliated to Nanchang University Nanchang China
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27
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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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28
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Liang H, Jiao Z, Rong W, Qu S, Liao Z, Sun X, Wei Y, Zhao Q, Wang J, Liu Y, Chen X, Wang T, Zhang CY, Zen K. 3'-Terminal 2'-O-methylation of lung cancer miR-21-5p enhances its stability and association with Argonaute 2. Nucleic Acids Res 2020; 48:7027-7040. [PMID: 32542340 PMCID: PMC7367198 DOI: 10.1093/nar/gkaa504] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 06/01/2020] [Accepted: 06/04/2020] [Indexed: 12/21/2022] Open
Abstract
Methylation of miRNAs at the 2'-hydroxyl group on the ribose at 3'-end (2'-O-methylation, 2'Ome) is critical for miRNA function in plants and Drosophila. Whether this methylation phenomenon exists for mammalian miRNA remains unknown. Through LC-MS/MS analysis, we discover that majority of miR-21-5p isolated from human non-small cell lung cancer (NSCLC) tissue possesses 3'-terminal 2'Ome. Predominant 3'-terminal 2'Ome of miR-21-5p in cancer tissue is confirmed by qRT-PCR and northern blot after oxidation/β-elimination procedure. Cancerous and the paired non-cancerous lung tissue miRNAs display different pattern of 3'-terminal 2'Ome. We further identify HENMT1 as the methyltransferase responsible for 3'-terminal 2'Ome of mammalian miRNAs. Compared to non-methylated miR-21-5p, methylated miR-21-5p is more resistant to digestion by 3'→5' exoribonuclease polyribonucleotide nucleotidyltransferase 1 (PNPT1) and has higher affinity to Argonaute-2, which may contribute to its higher stability and stronger inhibition on programmed cell death protein 4 (PDCD4) translation, respectively. Our findings reveal HENMT1-mediated 3'-terminal 2'Ome of mammalian miRNAs and highlight its role in enhancing miRNA's stability and function.
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Affiliation(s)
- Hongwei Liang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Zichen Jiao
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weiwei Rong
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Shuang Qu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Zhicong Liao
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Xinlei Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Yao Wei
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Quan Zhao
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Jun Wang
- Department of Emergency Medicine, Nanjing Drum Tower Hospital, Medical School, Nanjing University, 210008 Nanjing, China
| | - Yuan Liu
- Center for Inflammation, Immunity and Infectious Diseases, Georgia State University, Atlanta, GA 30032, USA
| | - Xi Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Tao Wang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chen-Yu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China
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29
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Which long noncoding RNAs and circular RNAs contribute to inflammatory bowel disease? Cell Death Dis 2020; 11:456. [PMID: 32541691 PMCID: PMC7295799 DOI: 10.1038/s41419-020-2657-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), a chronic relapsing gastrointestinal inflammatory disease, mainly comprises ulcerative colitis (UC) and Crohn’s disease (CD). Although the mechanisms and pathways of IBD have been widely examined in recent decades, its exact pathogenesis remains unclear. Studies have focused on the discovery of new therapeutic targets and application of precision medicine. Recently, a strong connection between IBD and noncoding RNAs (ncRNAs) has been reported. ncRNAs include microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). The contributions of lncRNAs and circRNAs in IBD are less well-studied compared with those of miRNAs. However, lncRNAs and circRNAs are likely to drive personalized therapy for IBD. They will enable accurate diagnosis, prognosis, and prediction of therapeutic responses and promote IBD therapy. Herein, we briefly describe the molecular functions of lncRNAs and circRNAs and provide an overview of the current knowledge of the altered expression profiles of lncRNAs and circRNAs in patients with IBD. Further, we discuss how these RNAs are involved in the nosogenesis of IBD and are emerging as biomarkers.
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30
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Qin YJ, Lin TY, Lin XL, Liu Y, Zhao WT, Li XY, Lian M, Chen HW, Li YL, Zhang XL, Xiao D, Jia JS, Sun Y. Loss of PDK4 expression promotes proliferation, tumorigenicity, motility and invasion of hepatocellular carcinoma cells. J Cancer 2020; 11:4397-4405. [PMID: 32489458 PMCID: PMC7255379 DOI: 10.7150/jca.43459] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 03/27/2020] [Indexed: 02/07/2023] Open
Abstract
Although the roles and underlying mechanisms of other PDK family members (i.e., PDK1, PDK2 and PDK3) in tumor progression have been extensively investigated and are well understood, the functions and underlying molecular mechanisms of pyruvate dehydrogenase kinase 4 (PDK4) in the tumorigenesis and progression of various cancers [including hepatocellular carcinoma (HCC)] remain largely unknown. In this study, we examined the expression profile of PDK4 in HCC clinical tissue specimens and the roles of PDK4 in the proliferation, tumorigenicity, motility and invasion of HCC cells. The immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) results revealed that PDK4 was significantly downregulated in the cohort of HCC clinical specimens. Additionally, PDK4 protein was found in both the nucleus and cytoplasm of HCC cells based on an immunofluorescence (ICC) assay, and PDK4 protein was also found in the nucleus and cytoplasm of cancer cells contained in HCC clinical specimens based on IHC. The CCK-8 assay and cell colony formation assay demonstrated that stable depletion of endogenous PDK4 by lentivirus-mediated RNA interference (RNAi) markedly promoted the proliferation of HCC cell lines (i.e., BEL-7402 and BEL-7404 cells) in vitro, while PDK4 silencing significantly enhanced the tumorigenic ability of BEL-7404 cells in vivo. In addition to enhance proliferation and tumorigenesis induced by PDK4 silencing, additional studies demonstrated that knockdown of PDK4 led to increase migration and invasion of BEL-7402 and BEL-7404 cells in vitro. Taken together, these findings suggest that the loss of PDK4 expression contributes to HCC malignant progression.
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Affiliation(s)
- Yu-Juan Qin
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
- Department of Radiology, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, China
| | - Tao-Yan Lin
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Lin Lin
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yu Liu
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Wen-Tao Zhao
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
| | - Xiao-Yan Li
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Mei Lian
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Heng-Wei Chen
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Yong-Long Li
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Ling Zhang
- Department of Physiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
| | - Dong Xiao
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Jun-Shuang Jia
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yan Sun
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
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31
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Zhang H, Wang Y, Li S, Tang X, Liang R, Yang X. SOCS3 protects against neonatal necrotizing enterocolitis via suppressing NLRP3 and AIM2 inflammasome activation and p65 nuclear translocation. Mol Immunol 2020; 122:21-27. [PMID: 32278838 DOI: 10.1016/j.molimm.2020.03.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/11/2020] [Accepted: 03/27/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) is an acquired disorder of mucosal damage characterized by the diffuse or local necrosis of the intestine. The suppressor of cytokine signaling 3 (SOCS3) has been demonstrated to possess anti-inflammatory action in gastritis, ulcerative colitis and other inflammatory diseases. The present study aims to explore the effects of SOCS3 on LPS-induced colonic cell model of NEC, and investigate the underlying mechanisms. METHODS Expression of SOCS3 in tissue samples of NEC and LPS-induced enterocytes were evaluated by real-time quantitative PCR (RT-qPCR). Western blotting and enzyme-linked immunosorbent assay (ELISA) were applied to examine the effect of SOCS3 on inflammatory molecules. Co-immunoprecipitation assay were devoted to explore the relation between SOCS3 and TLR4. RESULTS We proved that SOCS3 was expressed at a low level in tissue samples of NEC and LPS-induced enterocytes, and LPS inhibited SOCS3 expression via JAK2/STAT3 pathway. Overexpression of SOCS3 weaken the LPS-induced inflammatory response in FHC and CACO2 cells. Moreover, SOCS3 downregulates proinflammatory cytokines by targeting TLR4, thus mediating the p65 nuclear translocation, and the activation of NLR family pyrin domain containing 3/absent in melanoma-2 (NLRP3/AIM2) inflammasome, ultimately reveals its anti-inflammatory effects. CONCLUSIONS Taken together, our data revealed that LPS inhibited SOCS3 expression via JAK2/STAT3 pathway, and SOCS3 protects enterocytes against NEC through mediating p65 nuclear translocation and NLRP3/AIM2 inflammasome activation in a TLR4 dependent manner.
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Affiliation(s)
- Hua Zhang
- Pediatric intensive care unit, The Affiliated Children's Hospital of Xi'an Jiaotong University, 69 Xijuyuan Lane, Xi'an, Shaanxi, 710003, China
| | - Yi Wang
- Neonatal Intensive Care Unit, The Affiliated Children's Hospital of Xi'an Jiaotong University, 69 Xijuyuan Lane, Xi'an, Shaanxi, 710003, China
| | - Sixiu Li
- Neonatal Intensive Care Unit, The Affiliated Children's Hospital of Xi'an Jiaotong University, 69 Xijuyuan Lane, Xi'an, Shaanxi, 710003, China
| | - Xiaojing Tang
- Neonatal Intensive Care Unit, The Affiliated Children's Hospital of Xi'an Jiaotong University, 69 Xijuyuan Lane, Xi'an, Shaanxi, 710003, China
| | - Ruobing Liang
- Neonatal Intensive Care Unit, The Affiliated Children's Hospital of Xi'an Jiaotong University, 69 Xijuyuan Lane, Xi'an, Shaanxi, 710003, China
| | - Xuefeng Yang
- Neonatal Intensive Care Unit, The Affiliated Children's Hospital of Xi'an Jiaotong University, 69 Xijuyuan Lane, Xi'an, Shaanxi, 710003, China.
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32
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Xu H, Liu X, Ni H. Clinical significance of miR-19b-3p in patients with sepsis and its regulatory role in the LPS-induced inflammatory response. Eur J Med Res 2020; 25:9. [PMID: 32188465 PMCID: PMC7079357 DOI: 10.1186/s40001-020-00408-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Background MicroRNAs (miRNAs) play important roles in the development and progression of sepsis. This study investigated the clinical value of miR-19b-3p in sepsis patients, and explored its role in regulating inflammatory responses in HUVECs cells. Methods 103 patients with sepsis and 98 healthy individuals were recruited. qRT-PCR was used for the measurement of miR-19b-3p level. Cell viability was evaluated using CCK-8. The protein levels of TNF-α and IL-6 were measured using ELISA. Receiver operating characteristic (ROC) curve and logistic regression analysis were constructed to evaluate the diagnostic and prognostic values of miR-19b-3p in sepsis patients. Results MiR-19b-3p level was significantly reduced in the serum from patients with sepsis compared with healthy controls (P < 0.001). Sepsis patients in the survival group had significantly high miR-19b-3p levels compared with the non-survival group (P < 0.001). MiR-19b-3p was of a good value in predicting sepsis risk, and was an independent prognostic factor for 28-day survival in sepsis patients (OR = 3.226, 95% CI 1.076–9.670, P = 0.037). MiR-19b-3p level was negatively associated with serum levels of IL-6 (r = − 0.852, P < 0.001) and TNF-α (r = − 0.761, P < 0.001). Overexpression of miR-19b-3p alleviated LPS-induced inflammatory response of HUVECs, which was reflected by the decrease of the levels of IL-6 and TNF-α induced by LPS treatment (P < 0.001). Conclusion MiR-19b-3p might be a potential biomarker for the early diagnosis and prognosis of sepsis patients. Overexpression of miR-19b-3p alleviated sepsis-induced inflammatory responses.
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Affiliation(s)
- Huimin Xu
- Department of Infectious Diseases, Linyi People's Hospital, Linyi, 276034, Shandong, China
| | - Xiuwu Liu
- Department of Internal Medicine, Linyi People's Hospital, Linyi, 276034, Shandong, China
| | - Huaijun Ni
- Department of Surgery, Linyi People's Hospital, No. 233, Fenghuang Street, Linyi, 276034, Shandong, China.
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Shi Y, Dai S, Qiu C, Wang T, Zhou Y, Xue C, Yao J, Xu Y. MicroRNA-219a-5p suppresses intestinal inflammation through inhibiting Th1/Th17-mediated immune responses in inflammatory bowel disease. Mucosal Immunol 2020; 13:303-312. [PMID: 31628427 DOI: 10.1038/s41385-019-0216-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 09/11/2019] [Accepted: 09/28/2019] [Indexed: 02/04/2023]
Abstract
MicroRNA (miR)-219a-5p has been implicated in the development of numerous progression of carcinoma and autoimmune diseases. However, whether miR-219a-5p is involved in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. In this study, we demonstrated that miR-219a-5p expression was significantly decreased in the inflamed intestinal mucosa and peripheral blood (PB)-CD4+ T cells from patients with IBD. Proinflammatory cytokines (e.g., IL-6, IL-12, IL-23 and TNF-α) inhibited miR-219a-5p expression in CD4+ T cells in vitro. Lentivirus-mediated miR-219a-5p downregulation facilitated Th1/Th17 cell differentiation, whereas miR-219a-5p overexpression exerted an opposite effect. Luciferase assays confirmed that ETS variant 5 (ETV5) was a functional target of miR-219a-5p and ETV5 expression was significantly increased in the inflamed intestinal mucosa and PB-CD4+ T cells from IBD patients. ETV5 overexpression enhanced Th1/Th17 immune response through upregulating the phosphorylation of STAT3 and STAT4. Importantly, supplementation of miR-219a-5p ameliorated TNBS-induced intestinal mucosal inflammation, characterized by decreased IFN-γ+ CD4+ T cells and IL-17A+ CD4+ T cells infiltration in the colonic lamina propria. Our data thus reveal a novel mechanism whereby miR-219a-5p suppresses intestinal inflammation through inhibiting Th1/Th17-mediated immune responses. miR-219a-5p might be a target for the treatment of IBD.
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Affiliation(s)
- Yan Shi
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
| | - Shenglan Dai
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
| | - Caiyu Qiu
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
| | - Tao Wang
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
| | - Yong Zhou
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
| | - Cuihua Xue
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
| | - Jun Yao
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China.
| | - Yaping Xu
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China.
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34
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Liu F, Wang X, Geng H, Bu HF, Wang P, De Plaen IG, Yang H, Qian J, Tan XD. Interferon-γ inhibits sirtuin 6 gene expression in intestinal epithelial cells through a microRNA-92b-dependent mechanism. Am J Physiol Cell Physiol 2020; 318:C732-C739. [PMID: 32049548 DOI: 10.1152/ajpcell.00335.2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sirtuin 6 (Sirt6) is predominantly expressed in epithelial cells in intestinal crypts. It plays an important role in protecting intestinal epithelial cells against inflammatory injury. Previously, we found that colitis is associated with the downregulation of Sirt6 protein in the intestines. Here, we report that murine interferon-γ (Ifnγ) inhibits Sirt6 protein but not mRNA expression in young adult mouse colonocytes (YAMC, a mouse colonic epithelial cell line) in a dose- and time-dependent manner. Using microRNA array analysis, we showed that Ifnγ induces expression of miR-92b in YAMC cells. With in silico analysis, we found that the Sirt6 3'-untranslated region (UTR) contains a putative binding site for miR-92b. Luciferase assay showed that Ifnγ inhibited Sirt6 3'-UTR activity and this effect was mimicked by miR-92b via directly targeting the miR-92b seed site in the 3'-UTR of Sirt6 mRNA. Furthermore, Western blot demonstrated that miR-92b downregulated Sirt6 protein expression in YAMC cells. Blocking miR-92b with a specific inhibitor attenuated the inhibitory effect of Ifnγ on Sirt6 protein expression in the cells. Collectively, our data suggest that Ifnγ inhibits Sirt6 protein expression in intestinal epithelial cells via a miR-92b-mediated mechanism. miR-92b may be a novel therapeutic target for rescuing Sirt6 protein levels in intestinal epithelial cells, thereby protecting against intestinal mucosal injury caused by inflammation.
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Affiliation(s)
- Fangyi Liu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.,Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Xiao Wang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Hua Geng
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Heng-Fu Bu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Peng Wang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Isabelle G De Plaen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.,Division of Neonatology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Xiao-Di Tan
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.,Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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35
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Li J, Lin TY, Chen L, Liu Y, Dian MJ, Hao WC, Lin XL, Li XY, Li YL, Lian M, Chen HW, Jia JS, Zhang XL, Xiao SJ, Xiao D, Sun Y. miR-19 regulates the expression of interferon-induced genes and MHC class I genes in human cancer cells. Int J Med Sci 2020; 17:953-964. [PMID: 32308549 PMCID: PMC7163354 DOI: 10.7150/ijms.44377] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/19/2020] [Indexed: 01/13/2023] Open
Abstract
MicroRNA-19 (miR-19) is identified as the key oncogenic component of the miR-17-92 cluster. When we explored the functions of the dysregulated miR-19 in lung cancer, microarray-based data unexpectedly demonstrated that some immune and inflammatory response genes (i.e., IL32, IFI6 and IFIT1) were generally down-regulated by miR-19 overexpression in A549 cells, which prompted us to fully investigate whether the miR-19 family (i.e., miR-19a and miR-19b-1) was implicated in regulating the expression of immune and inflammatory response genes in cancer cells. In the present study, we observed that miR-19a or miR-19b-1 overexpression by miRNA mimics in the A549, HCC827 and CNE2 cells significantly downregulated the expression of interferon (IFN)-regulated genes (i.e., IRF7, IFI6, IFIT1, IFITM1, IFI27 and IFI44L). Furthermore, the ectopic miR-19a or miR-19b-1 expression in the A549, HCC827, CNE2 and HONE1 cells led to a general downward trend in the expression profile of major histocompatibility complex (MHC) class I genes (such as HLA-B, HLA-E, HLA-F or HLA-G); conversely, miR-19a or miR-19b-1 inhibition by the miRNA inhibitor upregulated the aforementioned MHC Class I gene expression, suggesting that miR-19a or miR-19b-1 negatively modulates MHC Class I gene expression. The miR-19a or miR-19b-1 mimics reduced the expression of interleukin (IL)-related genes (i.e., IL1B, IL11RA and IL6) in the A549, HCC827, CNE2 or HONE1 cells. The ectopic expression of miR-19a or miR-19b-1 downregulated IL32 expression in the A549 and HCC827 cells and upregulated IL32 expression in CNE2 and HONE1 cells. In addition, enforced miR-19a or miR-19b-1 expression suppressed IL-6 production by lung cancer and nasopharyngeal carcinoma (NPC) cells. Taken together, these findings demonstrate, for the first time, that miR-19 can modulate the expression of IFN-induced genes and MHC class I genes in human cancer cells, suggesting a novel role of miR-19 in linking inflammation and cancer, which remains to be fully characterized.
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Affiliation(s)
- Jing Li
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Radiotherapy Center, the First People's Hospital of Chenzhou, Chenzhou 423000, China
| | - Tao-Yan Lin
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Lin Chen
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Yu Liu
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Mei-Juan Dian
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Wei-Chao Hao
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Lin Lin
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Yan Li
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Yong-Long Li
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Mei Lian
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Heng-Wei Chen
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Jun-Shuang Jia
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Ling Zhang
- Department of Physiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
| | - Sheng-Jun Xiao
- Department of Pathology, the Second Affiliated Hospital, Guilin Medical University, Guilin 541199, China
| | - Dong Xiao
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Yan Sun
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, 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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Ye YL, Yin J, Hu T, Zhang LP, Wu LY, Pang Z. Increased circulating circular RNA_103516 is a novel biomarker for inflammatory bowel disease in adult patients. World J Gastroenterol 2019; 25:6273-6288. [PMID: 31749597 PMCID: PMC6848015 DOI: 10.3748/wjg.v25.i41.6273] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/23/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Increasing evidence demonstrates that by acting as microRNA sponges modulating gene expression at the transcriptional or post-transcriptional level, circular RNAs (circRNAs) participate in the pathogenesis of a variety of diseases and are considered ideal biomarkers of human disease.
AIM To examine the expression of circRNA_103516 in inflammatory bowel disease (IBD) and its associations with clinical phenotypes and inflammatory cytokines.
METHODS Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IBD, healthy controls (HCs), and patient controls (PCs). Expression of circRNA_103516 and hsa-miR-19b-1-5p was assessed by quantitative reverse transcription-polymerase chain reaction. Crohn's disease activity index (CDAI), Mayo score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were measured. To assess the inflammatory cytokines tumour necrosis factor α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10), blood samples were analysed by flow cytometry.
RESULTS Ninety Crohn’s disease (CD) and 90 ulcerative colitis (UC) patients, 80 HCs, and 35 PCs were included in the study. CircRNA_103516 was upregulated in CD and UC patients compared with HCs and PCs (P < 0.05). The area under the curve of circRNA_103516 for diagnosing CD and UC was 0.790 and 0.687, respectively. In addition, circRNA_103516 levels were increased in active CD and UC compared with remittent groups (P = 0.027, P = 0.045). Furthermore, in CD, circRNA_103516 correlated positively with CDAI (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNFα (P < 0.001), and IFN-γ (P < 0.001) and negatively correlated with IL-10 (P = 0.006). In UC patients, circRNA_103516 correlated with Mayo score (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNFα (P < 0.001), IFN-γ (P =0.011), and IL-10 (P = 0.002). Additionally, circRNA_103516 correlated positively with stricturing (P = 0.018) and penetrating (P = 0.031) behaviour. Moreover, hsa-miR-19b-1-5p correlated negatively with circRNA_103516 in CD.
CONCLUSION CircRNA_103516 levels in PBMCs can be considered an ideal candidate biomarker for diagnosing IBD. Dysregulation of circRNA_103516 may participate in the molecular mechanism of IBD through hsa-miR-19b-1-5p sponging.
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Affiliation(s)
- Yu-Lan Ye
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Juan Yin
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Tong Hu
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Li-Ping Zhang
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Long-Yun Wu
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Zhi Pang
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
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38
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Cruz-Gil S, Sánchez-Martínez R, Wagner-Reguero S, Stange D, Schölch S, Pape K, Ramírez de Molina A. A more physiological approach to lipid metabolism alterations in cancer: CRC-like organoids assessment. PLoS One 2019; 14:e0219944. [PMID: 31339921 PMCID: PMC6655698 DOI: 10.1371/journal.pone.0219944] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 07/03/2019] [Indexed: 12/17/2022] Open
Abstract
Precision medicine might be the response to the recent questioning of the use of metformin as an anticancer drug in colorectal cancer (CRC). Thus, in order to establish properly its benefits, metformin application needs to be assayed on the different progression stages of CRC. In this way, intestinal organoids imply a more physiological tool, representing a new therapeutic opportunity for CRC personalized treatment to assay tumor stage-dependent drugs. The previously reported lipid metabolism-related axis, Acyl-CoA synthetases/ Stearoyl-CoA desaturase (ACSLs/SCD), stimulates colon cancer progression and metformin is able to rescue the invasive and migratory phenotype conferred to cancer cells upon this axis overexpression. Therefore, we checked ACSL/SCD axis status, its regulatory miRNAs and the effect of metformin treatment in intestinal organoids with the most common acquired mutations in a sporadic CRC (CRC-like organoids) as a model for specific and personalized treatment. Despite ACSL4 expression is upregulated progressively in CRC-like organoids, metformin is able to downregulate its expression, especially in the first two stages (I, II). Besides, organoids are clearly more sensitive in the first stage (Apc mutated) to metformin than current chemotherapeutic drugs such as fluorouracil (5-FU). Metformin performs an independent "Warburg effect" blockade to cancer progression and is able to reduce crypt stem cell markers expression such as LGR5+. These results suggest a putative increased efficiency of the use of metformin in early stages of CRC than in advanced disease.
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Affiliation(s)
- Silvia Cruz-Gil
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
| | - Ruth Sánchez-Martínez
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
| | - Sonia Wagner-Reguero
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
| | - Daniel Stange
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sebastian Schölch
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Cancer Consortium (DKTK), Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kristin Pape
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ana Ramírez de Molina
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
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Feng Y, Zhang Y, Zhou D, Chen G, Li N. MicroRNAs, intestinal inflammatory and tumor. Bioorg Med Chem Lett 2019; 29:2051-2058. [PMID: 31213403 DOI: 10.1016/j.bmcl.2019.06.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) is the third most malignant tumor. Inflammatory bowel disease (IBD) can increase the risk of colorectal cancer. And colitis-associated cancer (CAC) is a CRC subtype, representing the inflammation-related colorectal cancer. For the past decades, we have known that ectopic microRNA (miRNA) expression was involved in the pathogenesis of IBD and CRC, playing a pivotal role in the progression of inflammation to colorectal cancer. Thus, this review provides the recent advances in altered human tissue-specific miRNAs that contribute to IBD, CRC and CAC pathogenesis, diagnosis and treatment. Meanwhile, the potential utilization of miRNAs as novel therapeutic targets for the prevention of CRC was also discussed.
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Affiliation(s)
- Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China
| | - Yuan Zhang
- Tianjin Vocational College of Bioengineering, Tianjin 300462, China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China.
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China.
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40
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Chon HS, Sehovic M, Marchion D, Walko C, Xiong Y, Extermann M. Biologic Mechanisms Linked to Prognosis in Ovarian Cancer that May Be Affected by Aging. J Cancer 2019; 10:2604-2618. [PMID: 31258768 PMCID: PMC6584919 DOI: 10.7150/jca.29611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 04/27/2019] [Indexed: 12/20/2022] Open
Abstract
The increase of both life expectancy of the Western industrialized population and cancer incidence with aging is expected to result in a rapid expansion of the elderly cancer population, including patients with epithelial ovarian cancer (EOC). Although the survival of patients with EOC has generally improved over the past three decades, this progress has yet to provide benefits for elderly patients. Compared with young age, advanced age has been reported as an adverse prognostic factor influencing EOC. However, contradicting results have been obtained, and the mechanisms underlying this observation are poorly defined. Few papers have been published on the underlying biological mechanisms that might explain this prognosis trend. We provide an extensive review of mechanisms that have been linked to EOC prognosis and/or aging in the published literature and might underlie this relationship in humans.
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Affiliation(s)
- Hye Sook Chon
- Department of Gynecology Oncology, Moffitt Cancer Center and Research Institute, Tampa FL, USA
- University of South Florida, Tampa FL, USA
| | - Marina Sehovic
- Senior Adult Oncology Program, Moffitt Cancer Center and Research Institute, Tampa FL, USA
- Department of Individualized Cancer Management, Moffitt Cancer Center and Research Institute, Tampa FL, USA
| | - Douglas Marchion
- Department of Pathology, Moffitt Cancer Center and Research Institute, Tampa FL, USA
| | - Christine Walko
- Department of Individualized Cancer Management, Moffitt Cancer Center and Research Institute, Tampa FL, USA
| | - Yin Xiong
- Department of Pathology, Moffitt Cancer Center and Research Institute, Tampa FL, USA
| | - Martine Extermann
- Senior Adult Oncology Program, Moffitt Cancer Center and Research Institute, Tampa FL, USA
- Department of Individualized Cancer Management, Moffitt Cancer Center and Research Institute, Tampa FL, USA
- University of South Florida, Tampa FL, USA
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41
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Moein S, Vaghari-Tabari M, Qujeq D, Majidinia M, Nabavi SM, Yousefi B. MiRNAs and inflammatory bowel disease: An interesting new story. J Cell Physiol 2018; 234:3277-3293. [PMID: 30417350 DOI: 10.1002/jcp.27173] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.
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Affiliation(s)
- Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mostafa Vaghari-Tabari
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Irantab.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Bahman Yousefi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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42
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Heat Shock Factor 1 Inhibits the Expression of Suppressor of Cytokine Signaling 3 in Cerulein-Induced Acute Pancreatitis. Shock 2018; 50:465-471. [DOI: 10.1097/shk.0000000000001071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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43
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Yang Y, Alderman C, Sehlaoui A, Xiao Y, Wang W. MicroRNAs as Immunotherapy Targets for Treating Gastroenterological Cancers. Can J Gastroenterol Hepatol 2018; 2018:9740357. [PMID: 30046565 PMCID: PMC6038585 DOI: 10.1155/2018/9740357] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 05/02/2018] [Indexed: 01/17/2023] Open
Abstract
Gastroenterological cancers are the most common cancers categorized by systems and are estimated to comprise 18.4% of all cancers in the United States in 2017. Gastroenterological cancers are estimated to contribute 26.2% of cancer-related death in 2017. Gastroenterological cancers are characterized by late diagnosis, metastasis, high recurrence, and being refractory to current therapies. Since the current targeted therapies provide limited benefit to the overall response and survival, there is an urgent need for developing novel therapeutic strategy to improve the outcome of gastroenterological cancers. Immunotherapy has been developed and underwent clinical trials, but displayed limited therapeutic benefit. Since aberrant expressions of miRNAs are found in gastroenterological cancers and miRNAs have been shown to regulate antitumor immunity, the combination therapy combining the traditional antibody-based immunotherapy and novel miRNA-based immunotherapy is promising for achieving clinical success. This review summarizes the current knowledge about the miRNAs and long noncoding RNAs that exhibit immunoregulatory roles in gastroenterological cancers and precancerous diseases of digestive system, as well as the miRNA-based clinical trials for gastroenterological cancers. This review also analyzes the ongoing challenge of identifying appropriate therapy candidates for complex and dynamic tumor microenvironment, ensuring efficient and targeted delivery to specific cancer tissues, and developing strategy for avoiding off-target effect.
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Affiliation(s)
- Yixin Yang
- College of Natural, Applied and Health Sciences, Kean University, 100 Morris Avenue, Union, NJ 07083, USA
| | - Christopher Alderman
- School of Medicine, University of Colorado, 13001 E 17th Pl, Aurora, CO 80045, USA
| | - Ayoub Sehlaoui
- Department of Biological Sciences, Emporia State University, 1 Kellogg Circle, Emporia, KS 66801, USA
| | - Yuan Xiao
- Department of Biological Sciences, Emporia State University, 1 Kellogg Circle, Emporia, KS 66801, USA
| | - Wei Wang
- Department of Thoracic Surgery III, Cancer Hospital of China Medical University, No. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning 110042, China
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44
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Wu Y, Wan X, Ji F, Song Z, Fang X. Serum miR-658 induces metastasis of gastric cancer by activating PAX3-MET pathway: A population-based study. Cancer Biomark 2018; 22:111-118. [PMID: 29630524 DOI: 10.3233/cbm-171045] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This article has been retracted, and the online PDF replaced with this retraction notice.
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Affiliation(s)
- Yuanyu Wu
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaoyu Wan
- Department of Breast and Thyroid Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Fujian Ji
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Zheyu Song
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Xuedong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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45
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Li C, Li S, Zhang F, Wu M, Liang H, Song J, Lee C, Chen H. Endothelial microparticles-mediated transfer of microRNA-19b promotes atherosclerosis via activating perivascular adipose tissue inflammation in apoE−/− mice. Biochem Biophys Res Commun 2018; 495:1922-1929. [DOI: 10.1016/j.bbrc.2017.11.195] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 11/29/2017] [Indexed: 11/25/2022]
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46
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Shi T, Xie Y, Fu Y, Zhou Q, Ma Z, Ma J, Huang Z, Zhang J, Chen J. The signaling axis of microRNA-31/interleukin-25 regulates Th1/Th17-mediated inflammation response in colitis. Mucosal Immunol 2017; 10:983-995. [PMID: 27901018 DOI: 10.1038/mi.2016.102] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 10/01/2016] [Indexed: 02/04/2023]
Abstract
Interleukin-25 (IL-25) is an important regulatory cytokine that has a key role on mucosal immune tolerance during inflammation response. However, the molecular mechanism that regulates the colonic IL-25 expression in Crohn's disease (CD) remains unclear. In this study, IL-25 level was proved to decrease in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice and IL-10 knockout (KO) spontaneous colitis mice. An inverse correlation between IL-25 and miR-31 was discovered in the colons from model mice and CD patients. Furthermore, target validation analysis demonstrated that miR-31 directly regulated IL-25 expression by binding to its messenger RNA 3'-untranslated region. Changing colonic miR-31 level in the colitis mice could affect the mucosal IL-12/23-mediated Th1/Th17 pathway and lead to either amelioration or aggravation of colonic inflammation. In addition, the therapeutic effects of anti-miR-31 in TNBS-induced colitis were abolished by colonic treatment with IL-25 antibody or colonic down-expression of IL-25. Our findings demonstrated that IL-25 could be a crucial anti-inflammatory cytokine in TNBS-induced colitis and the signaling of miR-31 targeting IL-25 might be a possible mechanism that regulates IL-12/23-mediated Th1/Th17 inflammatory responses during colonic inflammation process. Restoring colonic IL-25 expression and blocking Th1/Th17 responses via intracolonic administration of miR-31 inhibitor may represent a promising approach for CD treatment.
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Affiliation(s)
- T Shi
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Y Xie
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Y Fu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Q Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Z Ma
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - J Ma
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Z Huang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - J Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.,State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - J Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.,State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, Jiangsu, China
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Abstract
PURPOSE OF REVIEW Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), represent chronic diseases of unknown cause, and they are regarded as prototypical complex diseases. Despite all the recent advances, a complete appreciation of the pathogenesis of IBD is still limited. In this review, we present recent information contributing to a better understanding of mechanisms underlying IBD. RECENT FINDINGS Here, we attempt to highlight novel environmental triggers, data on the gut microbiota, its interaction with the host, and the potential influence of diet and food components. We discuss recent findings on defective signaling pathways and the potential effects on the immune response, and we present new data on epigenetic changes, inflammasome, and damage-associated molecular patterns associated with IBD. SUMMARY The continuing identification of several epigenetic, transcriptomic, proteomic, and metabolomic alterations in patients with IBD reflects the complex nature of the disease and suggests the need for innovative approaches such as systems biology for identifying novel relevant targets in IBD.
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Affiliation(s)
- Heitor S P de Souza
- aServiço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro bD'Or Institute for Research and Education (IDOR), Rio de Janeiro, Rio de Janeiro, Brazil
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48
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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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49
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Ruan GF, Zheng L, Huang JS, Huang WX, Gong BD, Fang XX, Zhang XY, Tang JP. Effect of mesenchymal stem cells on Sjögren-like mice and the microRNA expression profiles of splenic CD4+ T cells. Exp Ther Med 2017; 13:2828-2838. [PMID: 28587347 PMCID: PMC5450633 DOI: 10.3892/etm.2017.4313] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 12/09/2016] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) serve immuno-regulatory functions and offer a promising novel treatment for certain autoimmune diseases. The present study investigated the therapeutic effect of mice bone marrow (BM)-MSCs on mice with relatively late stage of Sjögren-like disease and the impact of BM-MSCs on the microRNA (miRNA) expression profiles of splenic CD4+ T cells. Female NOD/Ltj mice were randomized into two groups: The disease group (n=8) and the MSC-treated group (n=8). Female ICR mice served as the healthy control group (n=8). The MSC-treated group received an injection of MSCs when they were 26 weeks old. Water intake, blood glucose and salivary flow rate were measured and submandibular glands were resected and stained with hematoxylin and eosin to calculate the focus score. The concentrations of interleukin (IL)-2, IL-6, hepatocyte growth factor, interferon γ, IL-10, prostaglandin E2, transforming growth factor β1 and tumor necrosis factor-α in serum were measured using ELISA. The expression of miRNAs in splenic CD4+ T cells were measured using deep sequencing. The results demonstrated that treatment with BM-MSCs prevented a decline in the salivary flow rate and lymphocyte infiltration in the salivary glands of NOD mice, indicating that MSC-treatment had a therapeutic effect on NOD mice with relatively late stage of Sjögren-like disease. ELISA and deep sequencing results showed that the three groups of mice had different serum concentrations of cytokines/growth factors and different miRNA expression profiles of splenic CD4+ T cells. This implies that the alteration in serum levels of cytokines/growth factors and miRNA expression profiles of splenic CD4+ T cells may explain the therapeutic effect MSCs have on Sjögren's syndrome.
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Affiliation(s)
- Guang-Feng Ruan
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Ling Zheng
- Department of Respiratory Medicine, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Jia-Shu Huang
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Wan-Xue Huang
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Bang-Dong Gong
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Xing-Xing Fang
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Xiao-Yu Zhang
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
| | - Jian-Ping Tang
- Department of Rheumatology, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China
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50
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Jin HY, Oda H, Chen P, Yang C, Zhou X, Kang SG, Valentine E, Kefauver JM, Liao L, Zhang Y, Gonzalez-Martin A, Shepherd J, Morgan GJ, Mondala TS, Head SR, Kim PH, Xiao N, Fu G, Liu WH, Han J, Williamson JR, Xiao C. Differential Sensitivity of Target Genes to Translational Repression by miR-17~92. PLoS Genet 2017; 13:e1006623. [PMID: 28241004 PMCID: PMC5348049 DOI: 10.1371/journal.pgen.1006623] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 03/13/2017] [Accepted: 02/08/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. MicroRNAs (miRNAs) are small RNAs encoded by our genome. Each miRNA binds hundreds of target mRNAs and performs specific functions. It is thought that miRNAs exert their function by reducing the expression of all these target genes and each to a small degree. However, these target genes often have very diverse functions. It has been unclear how small changes in hundreds of target genes with diverse functions are translated into the specific function of a miRNA. Here we take advantage of recent technical advances to globally examine the mRNA and protein levels of 868 target genes regulated by miR-17~92, the first oncogenic miRNA, in mutant mice with transgenic overexpression or deletion of this miRNA gene. We show that miR-17~92 regulates target gene expression mainly at the protein level, with little effect on mRNA. Surprisingly, only a small fraction of target genes respond to miR-17~92 expression changes. Further studies show that the sensitivity of target genes to miR-17~92 is determined by a non-coding region of target mRNA. Our findings demonstrate that not every target gene is equal, and suggest that the function of a miRNA is mediated by a small number of key target genes.
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Affiliation(s)
- Hyun Yong Jin
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Hiroyo Oda
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Pengda Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Chao Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Xiaojuan Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Seung Goo Kang
- Division of Biomedical Convergence/Institute of Bioscience & Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Elizabeth Valentine
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jennifer M. Kefauver
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Lujian Liao
- Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Life Sciences, East China Normal University, Shanghai, China
| | - Yaoyang Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Alicia Gonzalez-Martin
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jovan Shepherd
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Gareth J. Morgan
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
| | - Tony S. Mondala
- Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, United States of America
| | - Steven R. Head
- Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, United States of America
| | - Pyeung-Hyeun Kim
- Department of Molecular Bioscience/Institute of Bioscience & Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Nengming Xiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Guo Fu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Wen-Hsien Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jiahuai Han
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - James R. Williamson
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Changchun Xiao
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- * E-mail:
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