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Frye BM, Negrey JD, Johnson CSC, Kim J, Barcus RA, Lockhart SN, Whitlow CT, Chiou KL, Snyder-Mackler N, Montine TJ, Craft S, Shively CA, Register TC. Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis). Brain Behav Immun 2024; 119:681-692. [PMID: 38636565 PMCID: PMC12051215 DOI: 10.1016/j.bbi.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/17/2024] [Accepted: 04/16/2024] [Indexed: 04/20/2024] Open
Abstract
Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.
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Affiliation(s)
- Brett M Frye
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Biology, Emory and Henry College, Emory, VA, USA; Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA
| | - Jacob D Negrey
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; School of Anthropology, University of Arizona, Tucson, AZ, USA
| | | | - Jeongchul Kim
- Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Richard A Barcus
- Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Samuel N Lockhart
- Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA; Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Christopher T Whitlow
- Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA; Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Kenneth L Chiou
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA; School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Noah Snyder-Mackler
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA; School of Life Sciences, Arizona State University, Tempe, AZ, USA; School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA
| | | | - Suzanne Craft
- Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA; Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Carol A Shively
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA.
| | - Thomas C Register
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA.
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Akkaya-Ulum YZ, Sen B, Akbaba TH, Balci-Peynircioglu B. InflammamiRs in focus: Delivery strategies and therapeutic approaches. FASEB J 2024; 38:e23528. [PMID: 38441434 DOI: 10.1096/fj.202302028r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/22/2024] [Accepted: 02/19/2024] [Indexed: 03/07/2024]
Abstract
microRNAs (miRNAs) are small non-protein-coding RNAs which are essential regulators of host genome expression at the post-transcriptional level. There is evidence of dysregulated miRNA expression patterns in a wide variety of diseases, such as autoimmune and inflammatory conditions. These miRNAs have been termed "inflammamiRs." When working with miRNAs, the method followed, the approach to treat or diagnosis, and the selected biological material are very crucial. Demonstration of the role of miRNAs in particular disease phenotypes facilitates their evaluation as potential and effective therapeutic tools. A growing number of reports suggest the significant utility of miRNAs and other small RNA drugs in clinical medicine. Most miRNAs seem promising therapeutic options, but some features associated with miRNA therapy like off-target effect, effective dosage, or differential delivery methods, mainly caused by the short target's sequence, make miRNA therapies challenging. In this review, we aim to discuss some of the inflammamiRs in diseases associated with inflammatory pathways and the challenge of identifying the most potent therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics. We also discuss the status of inflammamiRs in clinical trials.
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Affiliation(s)
- Yeliz Z Akkaya-Ulum
- Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Basak Sen
- Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Tayfun Hilmi Akbaba
- Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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Toivakka M, Gordon K, Kumar S, Bermudez-Barrientos JR, Abreu-Goodger C, Zamoyska R, Buck AH. miR-7 is recruited to the high molecular weight RNA-induced silencing complex in CD8 + T cells upon activation and suppresses IL-2 signaling. RNA (NEW YORK, N.Y.) 2023; 30:26-36. [PMID: 37879863 PMCID: PMC10726160 DOI: 10.1261/rna.079030.121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/26/2023] [Indexed: 10/27/2023]
Abstract
Increasing evidence suggests mammalian Argonaute (Ago) proteins partition into distinct complexes within cells, but there is still little biochemical or functional understanding of the miRNAs differentially associated with these complexes. In naïve T cells, Ago2 is found almost exclusively in low molecular weight (LMW) complexes which are associated with miRNAs but not their target mRNAs. Upon T-cell activation, a proportion of these Ago2 complexes move into a newly formed high molecular weight (HMW) RNA-induced silencing complex (RISC), which is characterized by the presence of the GW182 protein that mediates translational repression. Here, we demonstrate distinct partitioning of miRNAs and isomiRs in LMW versus HMW RISCs upon antigen-mediated activation of CD8+ T cells. We identify miR-7 as highly enriched in HMW RISC and demonstrate that miR-7 inhibition leads to increased production of IL-2 and up-regulation of the IL-2 receptor, the transferrin receptor, CD71 and the amino acid transporter, CD98. Our data support a model where recruitment of miR-7 to HMW RISC restrains IL-2 signaling and the metabolic processes regulated by IL-2.
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Affiliation(s)
- Matilda Toivakka
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Katrina Gordon
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Sujai Kumar
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - José Roberto Bermudez-Barrientos
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Cei Abreu-Goodger
- Institute of Ecology & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Rose Zamoyska
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Amy H Buck
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
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He Y, Dong X, Yang Q, Liu H, Zhang S, Xie S, Chi S, Tan B. An integrated study of glutamine alleviates enteritis induced by glycinin in hybrid groupers using transcriptomics, proteomics and microRNA analyses. Front Immunol 2023; 14:1301033. [PMID: 38077360 PMCID: PMC10702536 DOI: 10.3389/fimmu.2023.1301033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Glutamine has been used to improve intestinal development and immunity in fish. We previously found that dietary glutamine enhances growth and alleviates enteritis in juvenile hybrid groupers (Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂). This study aimed to further reveal the protective role of glutamine on glycinin-induced enteritis by integrating transcriptome, proteome, and microRNA analyses. Three isonitrogenous and isolipidic trial diets were formulated: a diet containing 10% glycinin (11S group), 10% glycinin diet supplemented with 2% alanine-glutamine (Gln group), and a diet containing neither glycinin nor alanine-glutamine (fishmeal, FM group). Each experimental diet was fed to triplicate hybrid grouper groups for 8 weeks. The analysis of intestinal transcriptomic and proteomics revealed a total of 570 differentially expressed genes (DEGs) and 169 differentially expressed proteins (DEPs) in the 11S and FM comparison group. Similarly, a total of 626 DEGs and 165 DEPs were identified in the Gln and 11S comparison group. Integration of transcriptome and proteome showed that 117 DEGs showed consistent expression patterns at both the transcriptional and translational levels in the Gln and 11S comparison group. These DEGs showed significant enrichment in pathways associated with intestinal epithelial barrier function, such as extracellular matrix (ECM)-receptor interaction, tight junction, and cell adhesion molecules (P < 0.05). Further, the expression levels of genes (myosin-11, cortactin, tenascin, major histocompatibility complex class I and II) related to these pathways above were significantly upregulated at both the transcriptional and translational levels (P < 0.05). The microRNA results showed that the expression levels of miR-212 (target genes colla1 and colla2) and miR-18a-5p (target gene colla1) in fish fed Gln group were significantly lower compared to the 11S group fish (P < 0.05). In conclusion, ECM-receptor interaction, tight junction, and cell adhesion molecules pathways play a key role in glutamine alleviation of hybrid grouper enteritis induced by high-dose glycinin, in which miRNAs and target mRNAs/proteins participated cooperatively. Our findings provide valuable insights into the RNAs and protein profiles, contributing to a deeper understanding of the underlying mechanism for fish enteritis.
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Affiliation(s)
- Yuanfa He
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- College of Fisheries, Southwest University, Chongqing, China
| | - Xiaohui Dong
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
| | - Qihui Yang
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
| | - Hongyu Liu
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
| | - Shiwei Xie
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
| | - Shuyan Chi
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affair, Zhanjiang, China
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Negrey JD, Frye BM, Johnson CSC, Kim J, Barcus RA, Lockhart SN, Whitlow CT, Sutphen C, Chiou KL, Snyder-Mackler N, Montine TJ, Craft S, Shively CA, Register TC. Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.01.565068. [PMID: 37961556 PMCID: PMC10635044 DOI: 10.1101/2023.11.01.565068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
INTRODUCTION Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood. METHODS We assessed the effects of Western vs. Mediterranean-like diets on RNAseq generated transcriptional profiles in temporal cortex and their relationships with changes in MRI neuroimaging phenotypes, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques. RESULTS Diet resulted in differential expression of seven transcripts (FDR<0.05). Cyclin dependent kinase 14 ( CDK14 ), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" ( LFNG ), mannose receptor C type 2 ( MRC2 ), solute carrier family 3 member 2 ( SLCA32 ), butyrophilin subfamily 2 member A1 ( BTN2A1 ), katanin regulatory subunit B1 ( KATNB1 ), and transmembrane protein 268 ( TMEM268 )] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14 , LFNG , MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with monocyte transcript levels, changes in AD-relevant brain volumes determined by MRI over the course of the study, and social isolation and anxiety. CDK14 was positively correlated with monocyte inflammatory transcripts, changes in total brain, gray matter, cortical gray matter volumes, and time alone and anxious behavior, and negatively correlated with changes in total white matter and cerebrospinal fluid (CSF) volumes. In contrast, LFNG , MRC2 , and SLCA32 were negatively correlated with monocyte inflammatory transcripts and changes in total gray matter volume, and positively correlated with CSF volume changes, and SLCA32 was negatively correlated with time alone. DISCUSSION Collectively, our results suggest that relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and behavior.
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Lv W, Sha Y, Liu X, He Y, Hu J, Wang J, Li S, Guo X, Shao P, Zhao F, Li M. Interaction between Rumen Epithelial miRNAs-Microbiota-Metabolites in Response to Cold-Season Nutritional Stress in Tibetan Sheep. Int J Mol Sci 2023; 24:14489. [PMID: 37833936 PMCID: PMC10572940 DOI: 10.3390/ijms241914489] [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: 08/16/2023] [Revised: 09/16/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
Tibetan sheep are already well adapted to cold season nutrient stress on the Tibetan Plateau. Rumen, an important nutrient for metabolism and as an absorption organ in ruminants, plays a vital role in the cold stress adaptations of Tibetan sheep. Ruminal microbiota also plays an indispensable role in rumen function. In this study, combined multiomics data were utilized to comprehensively analyze the interaction mechanism between rumen epithelial miRNAs and microbiota and their metabolites in Tibetan sheep under nutrient stress in the cold season. A total of 949 miRNAs were identified in the rumen epithelium of both cold and warm seasons. A total of 62 differentially expressed (DE) miRNAs were screened using FC > 1.5 and p value < 0.01, and a total of 20,206 targeted genes were predicted by DE miRNAs. KEGG enrichment analysis revealed that DE miRNA-targeted genes were mainly enriched in axon guidance(ko04360), tight junction(ko04530), inflammatory mediator regulation of TRP channels(ko04750) and metabolism-related pathways. Correlation analysis revealed that rumen microbiota, rumen VFAs and DE miRNAs were all correlated. Further study revealed that the targeted genes of cold and warm season rumen epithelial DE miRNAs were coenriched with differential metabolites of microbiota in glycerophospholipid metabolism (ko00564), apoptosis (ko04210), inflammatory mediator regulation of TRP channels (ko04750), small cell lung cancer (ko05222), and choline metabolism in cancer (ko05231) pathways. There are several interactions between Tibetan sheep rumen epithelial miRNAs, rumen microbiota, and microbial metabolites, mainly through maintaining rumen epithelial barrier function and host homeostasis of choline and cholesterol, improving host immunity, and promoting energy metabolism pathways, thus enabling Tibetan sheep to effectively respond to cold season nutrient stress. The results also suggest that rumen microbiota have coevolved with their hosts to improve the adaptive capacity of Tibetan sheep to cold season nutrient stress, providing a new perspective for the study of cold season nutritional stress adaptation in Tibetan sheep.
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Affiliation(s)
- Weibing Lv
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Yuzhu Sha
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Xiu Liu
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Yanyu He
- School of Fundamental Sciences, Massey University, Palmerston North 4410, New Zealand;
| | - Jiang Hu
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Jiqing Wang
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Shaobin Li
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Xinyu Guo
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Pengyang Shao
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Fangfang Zhao
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
| | - Mingna Li
- College of Animal Science and Technology/Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China; (W.L.); (Y.S.); (J.H.); (J.W.); (S.L.); (X.G.); (P.S.); (F.Z.); (M.L.)
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Chen C, Guo M, Zhao X, Zhao J, Chen L, He Z, Xu L, Zha Y. MicroRNA-7: A New Intervention Target for Inflammation and Related Diseases. Biomolecules 2023; 13:1185. [PMID: 37627250 PMCID: PMC10452300 DOI: 10.3390/biom13081185] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/20/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNA that can regulate physiological and pathological processes through post-transcriptional regulatory gene expression. As an important member of the miRNAs family, microRNA-7 (miR-7) was first discovered in 2001 to play an important regulatory role in tissue and organ development. Studies have shown that miR-7 participates in various tissue and organ development processes, tumorigenesis, aging, and other processes by regulating different target molecules. Notably, a series of recent studies have determined that miR-7 plays a key regulatory role in the occurrence of inflammation and related diseases. In particular, miR-7 can affect the immune response of the body by influencing T cell activation, macrophage function, dendritic cell (DC) maturation, inflammatory body activation, and other mechanisms, which has important potential application value in the intervention of related diseases. This article reviews the current regulatory role of miR-7 in inflammation and related diseases, including viral infection, autoimmune hepatitis, inflammatory bowel disease, and encephalitis. It expounds on the molecular mechanism by which miR-7 regulates the occurrence of inflammatory diseases. Finally, the existing problems and future development directions of miR-7-based intervention on inflammation and related diseases are discussed to provide new references and help strengthen the understanding of the pathogenesis of inflammation and related diseases, as well as the development of new strategies for clinical intervention.
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Affiliation(s)
- Chao Chen
- School of Medicine, Guizhou University, Guiyang 550025, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Mengmeng Guo
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Specifc Key Laboratory of Gene Detection and Treatment of Guizhou Province, Zunyi 563000, China
| | - Xu Zhao
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Specifc Key Laboratory of Gene Detection and Treatment of Guizhou Province, Zunyi 563000, China
| | - Juanjuan Zhao
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Specifc Key Laboratory of Gene Detection and Treatment of Guizhou Province, Zunyi 563000, China
| | - Longqing Chen
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Specifc Key Laboratory of Gene Detection and Treatment of Guizhou Province, Zunyi 563000, China
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi 563000, China
| | - Lin Xu
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Specifc Key Laboratory of Gene Detection and Treatment of Guizhou Province, Zunyi 563000, China
| | - Yan Zha
- School of Medicine, Guizhou University, Guiyang 550025, China
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The Current Status of Molecular Biomarkers for Inflammatory Bowel Disease. Biomedicines 2022; 10:biomedicines10071492. [PMID: 35884797 PMCID: PMC9312796 DOI: 10.3390/biomedicines10071492] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 12/12/2022] Open
Abstract
Diagnosis and prognosis of inflammatory bowel disease (IBD)-a chronic inflammation that affects the gastrointestinal tract of patients-are challenging, as most clinical symptoms are not specific to IBD, and are often seen in other inflammatory diseases, such as intestinal infections, drug-induced colitis, and monogenic diseases. To date, there is no gold-standard test for monitoring IBD. Endoscopy and imaging are essential diagnostic tools that provide information about the disease's state, location, and severity. However, the invasive nature and high cost of endoscopy make it unsuitable for frequent monitoring of disease activity in IBD patients, and even when it is possible to replace endoscopy with imaging, high cost remains a concern. Laboratory testing of blood or feces has the advantage of being non-invasive, rapid, cost-effective, and standardizable. Although the specificity and accuracy of laboratory testing alone need to be improved, it is increasingly used to monitor disease activity or to diagnose suspected IBD cases in combination with endoscopy and/or imaging. The literature survey indicates a dearth of summarization of biomarkers for IBD testing. This review introduces currently available non-invasive biomarkers of clinical importance in laboratory testing for IBD, and discusses the trends and challenges in the IBD biomarker studies.
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Casado-Bedmar M, Viennois E. MicroRNA and Gut Microbiota: Tiny but Mighty-Novel Insights into Their Cross-talk in Inflammatory Bowel Disease Pathogenesis and Therapeutics. J Crohns Colitis 2021; 16:992-1005. [PMID: 34918052 PMCID: PMC9282881 DOI: 10.1093/ecco-jcc/jjab223] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022]
Abstract
MicroRNAs [miRNAs], small non-coding RNAs, have recently been described as crucial contributors to intestinal homeostasis. They can interact with the gut microbiota in a reciprocal manner and deeply affect host health status, leading to several disorders when unbalanced. Inflammatory bowel disease [IBD] is a chronic inflammation of the gastrointestinal tract that co-occurs with alterations of the gut microbiota, and whose aetiology remains largely unclear. On one hand, host miRNA could be playing a relevant role in IBD pathophysiology by shaping the gut microbiota. The gut microbiome, on the other hand, may regulate the expression of host miRNAs, resulting in intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation. Interestingly, it has been hypothesised that their reciprocal impact may be used for therapeutic goals. This review describes the latest research and suggests mechanisms through which miRNA and intestinal microbiota, as joint actors, may participate specifically in IBD pathophysiology. Furthermore, we discuss the diagnostic power and therapeutic potential resulting from their bidirectional communication after faecal transplantation, probiotics intake, or anti-miRNAs or miRNA mimics administration. The current literature is summarised in the present work in a comprehensive manner, hoping to provide a better understanding of the miRNA-microbiota cross-talk and to facilitate their application in IBD.
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Affiliation(s)
- Maite Casado-Bedmar
- INSERM, U1149, Center for Research on Inflammation, Université de Paris, Paris, France
| | - Emilie Viennois
- Corresponding author: Emilie Viennois, INSERM, U1149, Center for Research on Inflammation, Université de Paris, 75018 Paris, France.
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10
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Zheng C, Lu T, Fan Z. miR-200b-3p alleviates TNF-α-induced apoptosis and inflammation of intestinal epithelial cells and ulcerative colitis progression in rats via negatively regulating KHDRBS1. Cytotechnology 2021; 73:727-743. [PMID: 34629748 DOI: 10.1007/s10616-021-00490-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 08/18/2021] [Indexed: 12/20/2022] Open
Abstract
Ulcerative colitis (UC) is difficult to be treated. miRNAs are a group of gene regulators. Study demonstrated that miR-200b-3p is involved in the development of UC, but the specific molecular mechanism is still unclear. A UC model was established by injecting acetic acid into rectum of rats, which were then treated with miR-200b-3p antagonists and agonists. Weight change, fecal viscosity and fecal bleeding were measured to determine disease activity index. The ratio of colon length to weight was measured. Colon lesions were detected by H&E staining. ELISA was used to detect the expression of TGF-β in colon tissues and IL-10/CRP in serum. Intestinal epithelial cells (NCM460) were treated by TNF-α to create an inflammatory environment. MRNA and protein levels of miR-200b-3p, KHDRBS1, IL-10, IL-6, IL-1β, TGF-β, Bcl-2, Bax and C-capase-3 were detected by qRT-PCR and Western blot, respectively. TargetScan database and dual-luciferase reporter assay were conducted to predict the targeting relationship between miR-200b-3p and KHDRBS1. MTT and flow cytometry were respectively performed to detect cell proliferation and apoptosis. MiR-200b-3p expression was inhibited, leading to increased disease activity index and colonic length-weight ratio, and aggravation of lesions of the UC rat model. Up-regulation of miR-200b-3p can relieve inflammation and apoptosis of immune cells in UC rats. MiR-200b-3p targeted KHDRBS1 and inhibited its expression. Moreover, KHDRBS1 reversed the effects of miR-200b-3p on apoptosis, proliferation and inflammation of intestinal epithelial cells. MiR-200b-3p alleviates UC by negatively regulating KHDRBS1.
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Affiliation(s)
- Chunju Zheng
- Department of Anorectal, Huai'an TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Huai'an, China
| | - Ting Lu
- Department of Anorectal, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, 157 Daming Road, Qinhuai District, Nanjing, 210001 Jiangsu China
| | - Zhimin Fan
- Department of Anorectal, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, 157 Daming Road, Qinhuai District, Nanjing, 210001 Jiangsu China
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11
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Liu P, Gao C, Chen H, Vong CT, Wu X, Tang X, Wang S, Wang Y. Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies. Acta Pharm Sin B 2021; 11:2798-2818. [PMID: 34589398 PMCID: PMC8463263 DOI: 10.1016/j.apsb.2020.11.003] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/01/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.
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Key Words
- ACQ, aggregation-caused quenching
- ADR, adverse drug reaction
- AIE, aggregation-induced emission
- Active target
- BSA, bovine serum albumin
- CAM, cell adhesion molecule
- CD, Crohn's disease
- CRD, cysteine-rich domain
- CS, chondroitin sulfate
- CT, computed tomography
- CTLD, c-type lectin-like domain
- Cell adhesion molecule
- Crohn's disease
- DCs, dendritic cells
- DSS, dextran sulfate sodium salt
- Drug delivery
- EGF, epidermal growth factor
- EPR, enhanced permeability and retention
- FNII, fibronectin type II domain
- FR, folate receptor
- FRET, fluorescence resonance energy transfer
- GIT, gastrointestinal tract
- HA, hyaluronic acid
- HUVEC, human umbilical vein endothelial cells
- IBD, inflammatory bowel disease
- ICAM, intercellular adhesion molecule
- Inflammatory bowel disease
- LMWC, low molecular weight chitosan
- LPS, lipopolysaccharide
- MAP4K4, mitogen-activated protein kinase kinase kinase kinase 4
- MGL, macrophage galactose lectin
- MPO, myeloperoxidase
- MPS, mononuclear phagocyte system
- MR, mannose receptor
- MRI, magnetic resonance imaging
- PAMAM, poly(amidoamine)
- PEI, polyethylenimine
- PSGL-1, P-selectin glycoprotein ligand-1
- PepT1, peptide transporter 1
- QDs, quantum dots
- RES, reticuloendothelial system
- Receptor-mediated target
- Targeted therapy
- TfR, transferrin receptor
- UC, ulcerative colitis
- Ulcerative colitis
- VCAM, vascular cell adhesion molecule
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12
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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: 32] [Impact Index Per Article: 8.0] [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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13
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Abstract
Inflammatory bowel disease (IBD) as a chronic inflammation in colon and small intestine has two subtypes: ulcerative colitis (UC) and Crohn's disease (CD). Genome studies have shown that UC and CD are related to microRNAs (miRNAs) expression in addition to environmental factors. This article reviews important researches that have recently been done on miRNAs roles in CD and UC disease. First, miRNA is introduced and its biogenesis and function are discussed. Afterward, roles of miRNAs in inflammatory processes involved in IBD are showed. Finally, this review proposes some circulating and tissue-specific miRNAs, which are useful for CD and UC fast diagnosis and grade prediction. As a conclusion, miRNAs are efficient diagnostic molecules especially in IBD subtypes discrimination and can be used by microarray and real time PCR methods for disease detection and classification.
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14
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Kahya U, Köseer AS, Dubrovska A. Amino Acid Transporters on the Guard of Cell Genome and Epigenome. Cancers (Basel) 2021; 13:E125. [PMID: 33401748 PMCID: PMC7796306 DOI: 10.3390/cancers13010125] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.
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Affiliation(s)
- Uğur Kahya
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
| | - Ayşe Sedef Köseer
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Anna Dubrovska
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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15
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Jacob EM, Borah A, Pillai SC, Kumar DS. Inflammatory Bowel Disease: The Emergence of New Trends in Lifestyle and Nanomedicine as the Modern Tool for Pharmacotherapy. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2460. [PMID: 33316984 PMCID: PMC7764399 DOI: 10.3390/nano10122460] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/08/2023]
Abstract
The human intestine, which harbors trillions of symbiotic microorganisms, may enter into dysbiosis when exposed to a genetic defect or environmental stress. The naissance of chronic inflammation due to the battle of the immune system with the trespassing gut bacteria leads to the rise of inflammatory bowel disease (IBD). Though the genes behind the scenes and their link to the disease are still unclear, the onset of IBD occurs in young adults and has expanded from the Western world into the newly industrialized countries. Conventional drug deliveries depend on a daily heavy dosage of immune suppressants or anti-inflammatory drugs targeted for the treatment of two types of IBD, ulcerative colitis (UC) and Crohn's disease (CD), which are often associated with systemic side effects and adverse toxicities. Advances in oral delivery through nanotechnology seek remedies to overcome the drawbacks of these conventional drug delivery systems through improved drug encapsulation and targeted delivery. In this review, we discuss the association of genetic factors, the immune system, the gut microbiome, and environmental factors like diet in the pathogenesis of IBD. We also review the various physiological concerns required for oral delivery to the gastrointestinal tract (GIT) and new strategies in nanotechnology-derived, colon-targeting drug delivery systems.
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Affiliation(s)
| | | | | | - D. Sakthi Kumar
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama 350-8585, Japan; (E.M.J.); (A.B.); (S.C.P.)
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16
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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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17
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Morris NL, Cannon AR, Li X, Choudhry MA. Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury. J Leukoc Biol 2020; 109:1121-1130. [PMID: 32964503 DOI: 10.1002/jlb.3a0820-323rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/17/2020] [Accepted: 08/22/2020] [Indexed: 12/15/2022] Open
Abstract
Ethanol remains a confounder in postburn pathology, which is associated with an impaired intestinal barrier. Previously, we demonstrated that ethanol and burn injury reduce intestinal oxygen delivery (hypoxia) and alters microRNA (miR) expression in small intestinal epithelial cells. Hypoxia has been shown to influence expression of miRs and miR biogenesis components. Therefore, we examined whether hypoxia influences expression of miR biogenesis components (drosha, dicer, and argonaute-2 [ago-2]) and miRs (-7a and -150) and whether these changes impacted other parameters following ethanol and burn injury. Mice were gavaged with ethanol (∼2.9 g/kg) 4 h before receiving a ∼12.5% total body surface full thickness burn. Mice were resuscitated at the time of injury with normal saline with or without 5 mg/kg PX-478, a hypoxia-inducible factor-1α inhibitor. One day following injury mice were euthanized, and the expression of miRs and their biogenesis components as well as bacterial growth, tight junction proteins, intestinal transit, and permeability were assessed. Ethanol combined with burn injury significantly reduced expression of drosha, ago-2, miRs (-7a and -150), occludin, zonula occludens-1, claudin-4, zonula occludens-1, mucins-2 and -4, and intestinal transit compared to shams. Furthermore, there was an increase in intestinal permeability, total bacteria, and Enterobacteriaceae populations following the combined injury compared to shams. PX-478 treatment improved expression of drosha, ago-2, miRs (-7a and -150), occludin, claudin-4, zonula occludens-1, and mucin-2. PX-478 treatment also improved intestinal transit and reduced dysbiosis and permeability. These data suggest that PX-478 improves miR biogenesis and miR expression, and restores barrier integrity while reducing bacterial dysbiosis following ethanol and burn injury.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA.,Current address: Department of Medicine, Pulmonary, Allergy, Critical Care and Sleep, Emory University/Atlanta VA Medical Center, Decatur, Georgia, USA
| | - Abigail R Cannon
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA
| | - Xiaoling Li
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA.,Department of Microbiology and Immunology, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA
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18
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He Y, Ye G, Chi S, Tan B, Dong X, Yang Q, Liu H, Zhang S. Integrative Transcriptomic and Small RNA Sequencing Reveals Immune-Related miRNA-mRNA Regulation Network for Soybean Meal-Induced Enteritis in Hybrid Grouper, Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂. Front Immunol 2020; 11:1502. [PMID: 32903657 PMCID: PMC7438716 DOI: 10.3389/fimmu.2020.01502] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
A 10-week feeding experiment was conducted to reveal the immune mechanism for soybean meal-induced enteritis (SBMIE) in hybrid grouper, Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂. Four isonitrogenous and isolipidic diets were formulated by replacing 0, 10, 30, and 50% fish meal protein with soybean meal (namely FM, SBM10, SBM30, and SBM50, respectively). The weight gain rate of the SBM50 group was significantly lower than those of the other groups. Plica height, muscular layer thickness, and goblet cells of the distal intestine in the SBM50 group were much lower than those in the FM group. The intestinal transcriptomic data, including the transcriptome and miRNAome, showed that a total of 6,390 differentially expressed genes (DEGs) and 92 DEmiRNAs were identified in the SBM50 and FM groups. DEmiRNAs (10 known and 1 novel miRNAs) and their DE target genes were involved in immune-related phagosome, natural killer cell-mediated cytotoxicity, Fc gamma R-mediated phagocytosis, and the intestinal immune network for IgA production pathways. Our study is the first to offer transcriptomic and small RNA profiling for SBMIE in hybrid grouper. Our findings offer important insights for the understanding of the RNA profile and further elucidation of the underlying molecular immune mechanism for SBMIE in carnivorous fish.
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Affiliation(s)
- Yuanfa He
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Guanlin Ye
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Shuyan Chi
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangdong Ocean University, Zhanjiang, China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Xiaohui Dong
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Qihui Yang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Hongyu Liu
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Aquatic Animals Precision Nutrition and High-Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
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19
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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20
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Khare T, Palakurthi SS, Shah BM, Palakurthi S, Khare S. Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:E3956. [PMID: 32486445 PMCID: PMC7312938 DOI: 10.3390/ijms21113956] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.
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Affiliation(s)
- Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
| | - Sushesh Srivatsa Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Brijesh M. Shah
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Srinath Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
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21
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Ding S, Liu G, Jiang H, Fang J. MicroRNA Determines the Fate of Intestinal Epithelial Cell Differentiation and Regulates Intestinal Diseases. Curr Protein Pept Sci 2019; 20:666-673. [PMID: 30678626 DOI: 10.2174/1389203720666190125110626] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 12/30/2018] [Accepted: 01/10/2019] [Indexed: 12/19/2022]
Abstract
The rapid self-renewal of intestinal epithelial cells enhances intestinal function, promotes the nutritional needs of animals and strengthens intestinal barrier function to resist the invasion of foreign pathogens. MicroRNAs (miRNAs) are a class of short-chain, non-coding RNAs that regulate stem cell proliferation and differentiation by down-regulating hundreds of conserved target genes after transcription via seed pairing to the 3' untranslated regions. Numerous studies have shown that miRNAs can improve intestinal function by participating in the proliferation and differentiation of different cell populations in the intestine. In addition, miRNAs also contribute to disease regulation and therefore not only play a vital role in the gastrointestinal disease management but also act as blood or tissue biomarkers of disease. As changes to the levels of miRNAs can change cell fates, miRNA-mediated gene regulation can be used to update therapeutic strategies and approaches to disease treatment.
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Affiliation(s)
- Sujuan Ding
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China.,Hunan Province Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, Hunan, China.,Academician Workstation of Hunan Baodong Farming Co., Ltd., Hunan 422001, China
| | - Gang Liu
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China.,Hunan Province Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, Hunan, China
| | - Hongmei Jiang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
| | - Jun Fang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
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22
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23
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Stolwijk JA, Wegener J. Impedance-Based Assays Along the Life Span of Adherent Mammalian Cells In Vitro: From Initial Adhesion to Cell Death. BIOANALYTICAL REVIEWS 2019. [DOI: 10.1007/11663_2019_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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24
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Han MK, Baker M, Zhang Y, Yang C, Zhang M, Garg P, Viennois E, Merlin D. Overexpression of CD98 in intestinal epithelium dysregulates miRNAs and their targeted proteins along the ileal villus-crypt axis. Sci Rep 2018; 8:16220. [PMID: 30385787 PMCID: PMC6212412 DOI: 10.1038/s41598-018-34474-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/07/2018] [Indexed: 01/19/2023] Open
Abstract
CD98 has been implicated in the experimental model of inflammatory bowel disease. We have previously shown that IEC-specific overexpression of CD98 mediates intestinal inflammation and intestinal epithelial barrier dysfunction. Mice overexpressing CD98 exhibited severe colitis and a greater susceptibility to CAC. Here we demonstrated CD98 overexpression to dysregulate homeostatic gradient profile of miRNA and protein expression along the ileal villus-crypt axis. Using miRNA-target gene prediction module, we observed differentially expressed miRNAs to target proteins of villus and crypt profoundly affected by CD98 overexpression. We have utilized online bioinformatics as methods to further scrutinize the biological meanings of miRNA-target data. We identified significant interactions among the differentially regulated proteins targeted by altered miRNAs in Tg mice. The biological processes affected by the predicted targets of miRNAs deviate from the homeostatic functions of the miRNA-gene-protein axis of the wildtype mice. Our results emphasize a dynamic perturbation of miRNA and protein expression in villus-crypt axis contributing to potential biological consequences of altering CD98 expression. Our findings also suggest the need for a consideration of arrays of interacting biological entities (i.e. miRNAs-mRNAs, protein-protein interaction) or a combination comparison for a better understanding of the disease pathology which is necessary for an effective therapeutic target development.
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Affiliation(s)
- Moon K Han
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA.
| | - Mark Baker
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA
| | - Yuchen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA
| | - Chunhua Yang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA
| | - Mingzhen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA
| | - Pallavi Garg
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA
| | - Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Center for Inflammation, Immunity and Infection, Digestive Disease Research Group, Georgia State University, Atlanta, 30303, USA.,Atlanta Veterans Affairs Medical Center, Decatur, 30033, USA
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25
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Zakeri A, Hansen EP, Andersen SD, Williams AR, Nejsum P. Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles. Front Immunol 2018; 9:2349. [PMID: 30369927 PMCID: PMC6194161 DOI: 10.3389/fimmu.2018.02349] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022] Open
Abstract
Helminth parasites are masters at manipulating host immune responses, using an array of sophisticated mechanisms. One of the major mechanisms enabling helminths to establish chronic infections is the targeting of pattern recognition receptors (PRRs) including toll-like receptors, C-type lectin receptors, and the inflammasome. Given the critical role of these receptors and their intracellular pathways in regulating innate inflammatory responses, and also directing adaptive immunity toward Th1 and Th2 responses, recognition of the pathways triggered and/or modulated by helminths and their products will provide detailed insights about how helminths are able to establish an immunoregulatory environment. However, helminths also target PRRs-independent mechanisms (and most likely other yet unknown mechanisms and pathways) underpinning the battery of different molecules helminths produce. Herein, the current knowledge on intracellular pathways in antigen presenting cells activated by helminth-derived biomolecules is reviewed. Furthermore, we discuss the importance of helminth-derived vesicles as a less-appreciated components released during infection, their role in activating these host intracellular pathways, and their implication in the development of new therapeutic approaches for inflammatory diseases and the possibility of designing a new generation of vaccines.
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Affiliation(s)
- Amin Zakeri
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Eline P. Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Sidsel D. Andersen
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Andrew R. Williams
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Peter Nejsum
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
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26
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Fukata T, Mizushima T, Nishimura J, Okuzaki D, Wu X, Hirose H, Yokoyama Y, Kubota Y, Nagata K, Tsujimura N, Inoue A, Miyoshi N, Haraguchi N, Takahashi H, Hata T, Matsuda C, Kayama H, Takeda K, Doki Y, Mori M, Yamamoto H. The Supercarbonate Apatite-MicroRNA Complex Inhibits Dextran Sodium Sulfate-Induced Colitis. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 12:658-671. [PMID: 30092402 PMCID: PMC6083010 DOI: 10.1016/j.omtn.2018.07.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 07/07/2018] [Accepted: 07/10/2018] [Indexed: 01/02/2023]
Abstract
The incidence of inflammatory bowel disease (IBD) is increasing. Nucleic acid-based medicine has potential as a next-generation treatment, but it is rarely successful with IBD. The aim of this study was to establish a microRNA-based therapy in an IBD model. For this purpose, we used microRNA-29 (miR-29) and a supercarbonate apatite (sCA) nanoparticle as a drug delivery system. Injection of sCA-miR-29a-3p or sCA-miR-29b-3p into mouse tail veins markedly prevented and restored inflammation because of dextran sulfate sodium (DSS)-induced colitis. RNA sequencing analysis revealed that miR-29a and miR-29b could inhibit the interferon-associated inflammatory cascade. Subcutaneous injection of sCA-miR-29b also potently inhibited inflammation, and it efficiently targeted CD11c+ dendritic cells (DCs) among various types of immune cells in the inflamed mucosa. RT-PCR analysis indicated that the miR-29 RNAs in CD11c+ DCs suppressed the production of interleukin-6 (IL-6), transforming growth factor β (TGF-β), and IL-23 subunits in DSS-treated mice. This may inhibit Th17 differentiation and subsequent activation, which is critical in IBD pathogenesis. In vivo experiments using a non-natural artificial microRNA sequence revealed that targeting of DCs in the inflamed colon is an exceptional feature of sCA. This study suggests that sCA-miR-29s may open a new avenue in nucleic acid-based medicine for IBD treatment.
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Affiliation(s)
- Tadafumi Fukata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Junichi Nishimura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita City, Osaka, Japan
| | - Xin Wu
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City, Osaka, Japan
| | - Haruka Hirose
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City, Osaka, Japan
| | - Yuhki Yokoyama
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City, Osaka, Japan
| | - Yui Kubota
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City, Osaka, Japan
| | - Kazuya Nagata
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City, Osaka, Japan
| | - Naoto Tsujimura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Akira Inoue
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Taishi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Hisako Kayama
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Yamadaoka 2-2, Suita City, Osaka, Japan; Laboratory of Mucosal Immunology, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka3-1, Suita City, Osaka, Japan
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Yamadaoka 2-2, Suita City, Osaka, Japan; Laboratory of Mucosal Immunology, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka3-1, Suita City, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, Japan; Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City, Osaka, Japan.
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27
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Uhr K, Sieuwerts AM, de Weerd V, Smid M, Hammerl D, Foekens JA, Martens JWM. Association of microRNA-7 and its binding partner CDR1-AS with the prognosis and prediction of 1 st-line tamoxifen therapy in breast cancer. Sci Rep 2018; 8:9657. [PMID: 29941867 PMCID: PMC6018428 DOI: 10.1038/s41598-018-27987-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/12/2018] [Indexed: 12/12/2022] Open
Abstract
The large number of non-coding RNAs (ncRNAs) and their breadth of functionalities has fuelled many studies on their roles in cancer. We previously linked four microRNAs to breast cancer prognosis. One of these microRNAs, hsa-miR-7, was found to be regulated by another type of ncRNA, the circular non-coding RNA (circRNA) CDR1-AS, which contains multiple hsa-miR-7 binding sites. Based on this finding, we studied the potential clinical value of this circRNA on breast cancer prognosis in a cohort based on a cohort that was previously analysed for hsa-miR-7 and in an adjuvant hormone-naïve cohort for 1st-line tamoxifen treatment outcomes, in which we also analysed hsa-miR-7. A negative correlation was observed between hsa-miR-7 and CDR1-AS in both cohorts. Despite associations with various clinical metrics (e.g., tumour grade, tumour size, and relapse location), CDR1-AS was neither prognostic nor predictive of relevant outcomes in our cohorts. However, we did observe stromal CDR1-AS expression, suggesting a possible cell-type specific interaction. Next to the known association of hsa-miR-7 expression with poor prognosis in primary breast cancer, we found that high hsa-miR-7 expression was predictive of an adverse response to tamoxifen therapy and poor progression-free and post-relapse overall survival in patients with recurrent disease.
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Affiliation(s)
- K Uhr
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - A M Sieuwerts
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
| | - V de Weerd
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - M Smid
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - D Hammerl
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - J A Foekens
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
| | - J W M Martens
- Erasmus MC Cancer Institute, Erasmus University Medical Centre, Department of Medical Oncology and Cancer Genomics, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
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28
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Cron MA, Maillard S, Delisle F, Samson N, Truffault F, Foti M, Fadel E, Guihaire J, Berrih-Aknin S, Le Panse R. Analysis of microRNA expression in the thymus of Myasthenia Gravis patients opens new research avenues. Autoimmun Rev 2018; 17:588-600. [DOI: 10.1016/j.autrev.2018.01.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 01/02/2018] [Indexed: 12/16/2022]
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29
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Zhong T, Hu J, Xiao P, Zhan S, Wang L, Guo J, Li L, Zhang H, Niu L. Identification and Characterization of MicroRNAs in the Goat ( Capra hircus) Rumen during Embryonic Development. Front Genet 2017; 8:163. [PMID: 29123545 PMCID: PMC5662549 DOI: 10.3389/fgene.2017.00163] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 10/13/2017] [Indexed: 12/19/2022] Open
Abstract
The rumen is an important digestive organ in ruminants. Numerous regulatory factors including microRNAs (miRNAs) are involved in embryonic organ development. In the present study, miRNAs expressed in the rumens of goats (Capra hircus) and their potential roles in the pathways involved in rumen development were identified using high-throughput sequencing. Histological morphology revealed a distinct difference in each layer of rumen during the period from embryonic day 60 (E60) to embryonic day 135 (E135). We determined the expression profiles of miRNAs in the goat rumen, and identified 423 known miRNAs and 559 potentially novel miRNAs in the E60 and E135 embryonic rumen, respectively. Bioinformatics analysis annotated the 42 differentially expressed miRNAs and the top 10 most highly expressed miRNAs of the two libraries to 48 and 38 gene ontology categories, as well as to 168 and 71 Kyoto Encyclopedia of Genes and Genomes pathways, respectively. The expression patterns of eight randomly selected miRNAs were validated by stem-loop quantitative reverse transcription PCR, suggesting that the sequencing data were reliable. We profiled the genome-wide expression of rumen-expressed miRNAs at different prenatal stages of rumen tissues, revealing that a subset of miRNAs might play important roles in the formation of the rumen layers. Taken together, these findings will aid the investigation of dominant rumen-related miRNA sets and help understand the genetic control of rumen development in goats.
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Affiliation(s)
- Tao Zhong
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Jiangtao Hu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Ping Xiao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Siyuan Zhan
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Linjie Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Jiazhong Guo
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Li Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Hongping Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Lili Niu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
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30
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Guo J, Sun M, Teng X, Xu L. MicroRNA‑7‑5p regulates the expression of TFF3 in inflammatory bowel disease. Mol Med Rep 2017; 16:1200-1206. [PMID: 28627600 PMCID: PMC5562002 DOI: 10.3892/mmr.2017.6730] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 02/24/2017] [Indexed: 12/17/2022] Open
Abstract
Trefoil factor 3 (TFF3) serves an important role in intestinal mucosal damage and healing, and contributes to the pathogenesis and treatment of inflammatory bowel disease (IBD). The aim of the present study was to determine the association between TFF3 and microRNA‑7‑5p (miR‑7‑5p) in IBD. Tissue immunohistochemistry was applied to evaluate the relative expression of TFF3, and reverse transcription‑quantitative polymerase chain reaction was performed to determine the expression of miR‑7‑5p in lesional tissue obtained from patients with IBD and healthy control tissues. A dual‑luciferase reporter assay was used to investigate whether TFF3 was a target of miR‑7‑5p, and western blotting was performed to determine the expression of TFF3 when miR‑7‑5p was overexpressed or suppressed. The protein expression levels of TFF3 were decreased and miR‑7‑5p was overexpressed in the lesional tissue of patients with IBD compared with in healthy control tissues. TFF3 was identified as a target of miR‑7‑5p, and TFF3 protein expression was negatively regulated by miR‑7‑5p in human colonic epithelial LS174T cells. The present study demonstrated a negative association between the expression of miR‑7‑5p and TFF3 in IBD lesional tissues and normal tissues. In conclusion, TFF3 was identified as a novel target of miR‑7‑5p and miR‑7‑5p may serve as a promising therapeutic target for IBD.
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Affiliation(s)
- Jing Guo
- Department of Pediatrics, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Mei Sun
- Department of Pediatrics, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xu Teng
- Department of Pediatrics, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Lingfen Xu
- Department of Pediatrics, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China
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31
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Smith KN, Starmer J, Miller SC, Sethupathy P, Magnuson T. Long Noncoding RNA Moderates MicroRNA Activity to Maintain Self-Renewal in Embryonic Stem Cells. Stem Cell Reports 2017; 9:108-121. [PMID: 28579393 PMCID: PMC5511051 DOI: 10.1016/j.stemcr.2017.05.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 05/02/2017] [Accepted: 05/03/2017] [Indexed: 12/22/2022] Open
Abstract
Of the thousands of long noncoding RNAs expressed in embryonic stem cells (ESCs), few have known roles and fewer have been functionally implicated in the regulation of self-renewal and pluripotency, or the reprogramming of somatic cells to the pluripotent state. In ESCs, Cyrano is a stably expressed long intergenic noncoding RNA with no previously assigned role. We demonstrate that Cyrano contributes to ESC maintenance, as its depletion results in the loss of hallmarks of self-renewal. Delineation of Cyrano's network through transcriptomics revealed widespread effects on signaling pathways and gene expression networks that contribute to ESC maintenance. Cyrano shares unique sequence complementarity with the differentiation-associated microRNA, mir-7, and mir-7 overexpression reduces expression of a key self-renewal factor to a similar extent as Cyrano knockdown. This suggests that Cyrano functions to restrain the action of mir-7. Altogether, we provide a view into the multifaceted function of Cyrano in ESC maintenance.
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Affiliation(s)
- Keriayn N Smith
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Joshua Starmer
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Sarah C Miller
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Praveen Sethupathy
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Terry Magnuson
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
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32
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Viennois E, Zhao Y, Han MK, Xiao B, Zhang M, Prasad M, Wang L, Merlin D. Serum miRNA signature diagnoses and discriminates murine colitis subtypes and predicts ulcerative colitis in humans. Sci Rep 2017; 7:2520. [PMID: 28566745 PMCID: PMC5451415 DOI: 10.1038/s41598-017-02782-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 04/19/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is difficult to diagnose due to nonspecific and variable symptoms, and lack of reliable diagnostic tests. Current methods are invasive, non-sensitive, non-predictive, and do not easily discriminate between its two main forms. Consequently, there remains a great need for reliable serum markers for IBD. Here, using a longitudinal study of various mouse models of colitis, we identified a serum miRNA signature that indicated the development of colitis and discriminated between inflammations of various origins (colitis from arthritis). Unlike the existing biomarkers, the newly identified signature also serves to distinguish individuals at risk, predict the type of inflammation, and evaluate the response to therapeutics. Moreover, the miRNA signature identified in mice predicted ulcerative colitis with 83.3% accuracy. In future, the signature identified herein could play a central role in monitoring inflammatory disorders and therapeutic responses in patients, thereby paving the way for personalized medicine.
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Affiliation(s)
- Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.
| | - Yuan Zhao
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Moon Kwon Han
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - Bo Xiao
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Institute for Clean Energy and Advanced Materials, Faculty for Materials and Energy, Southwest University, Chongqing, 400715, China
| | - Mingzhen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
| | - Meena Prasad
- Veterans Affairs Medical Center, Decatur, GA, USA.,Emory University, Department of Medicine, Atlanta, GA, USA
| | - Lixin Wang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Veterans Affairs Medical Center, Decatur, GA, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.,Veterans Affairs Medical Center, Decatur, GA, USA
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Zhu Y, Wang W, Yuan T, Fu L, Zhou L, Lin G, Zhao S, Zhou H, Wu G, Wang J. MicroRNA-29a mediates the impairment of intestinal epithelial integrity induced by intrauterine growth restriction in pig. Am J Physiol Gastrointest Liver Physiol 2017; 312:G434-G442. [PMID: 28280141 DOI: 10.1152/ajpgi.00020.2017] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/22/2017] [Accepted: 03/06/2017] [Indexed: 01/31/2023]
Abstract
An important characteristic of intrauterine growth restricted (IUGR) neonate is the impaired intestinal barrier function. With the use of a pig model, this study was conducted to identify the responsible microRNA (miRNA) for the intestinal damage in IUGR neonates through comparing the miRNA profile of IUGR and normal porcine neonates and to investigate the regulation mechanism. Compared with the normal ones, we identified 83 upregulated and 76 downregulated miRNAs in the jejunum of IUGR pigs. Notably, IUGR is associated with profoundly increasesd miR-29 family and decreased expression of extracellular matrix (ECM) and tight junction (TJ) proteins in the jejunum. Furthermore, in vitro study using theporcine intestinal epithelial cell line (IPEC-1) showed that inhibition of miR-29a expression could improve the monolayer integrity by increasing cell proliferation and transepithelial resistance. Also, overexpression/inhibition of miR-29a in IPEC-1 cells can suppress/increase the expression of integrin-β1, collagen I, collagen IV, fibronectin, and claudin 1, both at transcriptional and translational levels. Subsequent luciferase reporter assay confirmed a direct interaction between miR-29a and the 3'-untranslated regions of these genes. In conclusion, this study reveals that IUGR-impaired intestinal barrier function is associated with downregulated ECM and TJ protein expression mediated by the upregulation of miR-29a.NEW & NOTEWORTHY Intrauterine growth restricted (IUGR) remains a major problem for both human health and animal production due to its association with high rates of preweaning morbidity and mortality. We have identified the abnormal expression of microRNA-29a (miR-29a) in the small intestine of IUGR neonates, as well as its targets and mechanisms. These results provide new information about biological characteristics of IUGR-affected intestinal dysfunction and can lead to the development of potentially solution for preventing and treating IUGR in the future.
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Affiliation(s)
- Yuhua Zhu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China
| | - Wei Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China
| | - Taolin Yuan
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China
| | - Liangliang Fu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Lian Zhou
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Gang Lin
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China
| | - Shuhong Zhao
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Huaijun Zhou
- Department of Animal Science, University of California, Davis, California; and
| | - Guoyao Wu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China.,Department of Animal Science, Texas A&M University, College Station, Texas
| | - Junjun Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China;
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Gabbani T, Deiana S, Marocchi M, Annese V. Genetic risk variants as therapeutic targets for Crohn's disease. Expert Opin Ther Targets 2017; 21:381-390. [PMID: 28281904 DOI: 10.1080/14728222.2017.1296431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/14/2017] [Indexed: 02/06/2023]
Abstract
The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.
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Affiliation(s)
- Tommaso Gabbani
- a Gastroenterology UO , Azienda Unita Sanitaria Locale della Romagna , Forlì , Italy
| | - Simona Deiana
- b Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Margherita Marocchi
- c Division of Gastroenterology , AOU Modena University Hospital , Modena , Italy
| | - Vito Annese
- d Department of Gastroenterology , Valiant Clinic , Dubai , UAE
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Abstract
Maintaining intestinal homeostasis is a key prerequisite for a healthy gut. Recent evidence points out that microRNAs (miRNAs) act at the epicenter of the signaling networks regulating this process. The fine balance in the interaction between gut microbiota, intestinal epithelial cells, and the host immune system is achieved by constant transmission of signals and their precise regulation. Gut microbes extensively communicate with the host immune system and modulate host gene expression. On the other hand, sensing of gut microbiota by the immune cells provides appropriate tolerant responses that facilitate the symbiotic relationships. While the role of many regulatory proteins, receptors and their signaling pathways in the regulation of the intestinal homeostasis is well documented, the involvement of non-coding RNA molecules in this process has just emerged. This review discusses the most recent knowledge about the contribution of miRNAs in the regulation of the intestinal homeostasis.
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Affiliation(s)
- Antoaneta Belcheva
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
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Canup BSB, Song H, Le Ngo V, Meng X, Denning TL, Garg P, Laroui H. CD98 siRNA-loaded nanoparticles decrease hepatic steatosis in mice. Dig Liver Dis 2017; 49:188-196. [PMID: 27939923 PMCID: PMC6475075 DOI: 10.1016/j.dld.2016.11.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/07/2016] [Accepted: 11/08/2016] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid hepatic accumulation. Here, we investigated whether a reduction of CD98 expression mediated by CD98 siRNA-loaded nanoparticles (NPs) could attenuate liver disease markers in a mouse model of NAFLD. NPs were generated using a double emulsion/solvent evaporation technique. Mice fed a high fat diet for 8 weeks to induce fatty liver were treated with vein tail injections of CD98 siRNA-loaded NPs. In vitro, HepG2 treated with CD98 siRNA-loaded NPs showed significant downregulation of CD98 leading to a significant decrease of major pro-inflammatory cytokines and markers. In vivo, CD98 siRNA-loaded NPs strongly decreased all markers of NAFLD, including the blood levels of ALT and lipids accumulation, fibrosis evidence and pro-inflammatory cytokines. In conclusion, our results indicate that CD98 appears to function as a key actor/inducer in NAFLD, and that our NPs approach may offer a new targeted therapeutic for this disease.
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Affiliation(s)
- Brandon S B Canup
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Heliang Song
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Vu Le Ngo
- Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Xiangxiao Meng
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Timothy L Denning
- Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Pallavi Garg
- Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Hamed Laroui
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA; Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
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Abstract
Despite advances in our understanding of the pathophysiology underlying inflammatory bowel disease, there remains a significant need for biomarkers that can differentiate between Crohn's disease and ulcerative colitis with high sensitivity and specificity, in a cost-efficient manner. As the focus on personalized approaches to the delivery of medical treatment increases, new biomarkers are being developed to predict an individual's response to therapy and their overall disease course. In this review, we will outline many of the existing and recently developed biomarkers, detailing their role in the assessment of patients with inflammatory bowel disease. We will identify opportunities for improvement in our biomarkers, including better differentiation between the subtypes of inflammatory bowel disease. We will also discuss new targets and strategies in biomarker development, including combining modalities to create biomarker signatures to improve the ability to predict disease courses and response to therapy among individual patients.
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38
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CD98 signals controlling tumorigenesis. Int J Biochem Cell Biol 2016; 81:148-150. [PMID: 27840151 DOI: 10.1016/j.biocel.2016.11.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 11/07/2016] [Accepted: 11/09/2016] [Indexed: 11/23/2022]
Abstract
CD98 is implicated in a large number of cancers. CD98 regulates amino acid transport and integrin signaling, which are key drivers in tumor progression. The light chain in the CD98 heterodimer functions as an amino acid exchanger. Alongside the light chain, the heavy chain forms a heterocomplex at the plasma membrane to mediate signaling pathways. In this article, we review various approaches to blocking CD98 activity, which may lead to novel opportunities in cancer therapeutics.
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Gabbani T, Deiana S, Annese AL, Lunardi S, Annese V. The genetic burden of inflammatory bowel diseases: implications for the clinic? Expert Rev Gastroenterol Hepatol 2016; 10:1109-1117. [PMID: 27258545 DOI: 10.1080/17474124.2016.1196131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation. Their etiology is multifactorial, with complex interactions between genetic and environmental factors, which are still largely unclear. Areas covered: The influence of genetics is clearly demonstrated by important epidemiological data, including familial aggregation and concordance in twins. In 2001, the first genetic susceptibility gene for IBD, the NOD2 gene, was identified. Currently, thanks to genetic wide association studies, over 200 susceptibility genetic markers are know. Expert commentary: However, clinically highly relevant gene associations are still very limited and the usefulness of these information in the current clinical strategies for treatment and surveillance of IBD is weak. Nevertheless, the recent identification of some genetic risk variants has clarified some newbiological pathways of these diseases thus paving the way for the discoveries in the near future of new targeted therapies.
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Affiliation(s)
- Tommaso Gabbani
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Simona Deiana
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Antonio Luca Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Sarah Lunardi
- b Division of Internal Medicine 4 , AOU Careggi University Hospital , Florence , Italy
| | - Vito Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
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40
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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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Si XY, Merlin D, Xiao B. Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease. World J Gastroenterol 2016; 22:7718-7726. [PMID: 27678353 PMCID: PMC5016370 DOI: 10.3748/wjg.v22.i34.7718] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 07/11/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy, and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting, sustained drug release, and decreased adverse effects. Here, we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition, the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.
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Analysis of microRNA Levels in Intestinal Epithelial Cells. Methods Mol Biol 2016. [PMID: 27246025 DOI: 10.1007/978-1-4939-3603-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
The field of microRNA (miRNA) research is expanding rapidly with the crucial role of miRNAs in almost every biological process and their implication in many diseases. The role of miRNAs in modulating inflammatory responses in the gut has attracted many research groups including us. Here, we first briefly summarize our current understanding of the role of miRNAs in maintaining and regulating gut physiopathology and in inflammatory bowel diseases. We then describe in detail our techniques to analyze miRNA levels with notes that we have collected and summarized during our experiments.
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Bragazzi Cunha J, Wobus CE. Select membrane proteins modulate MNV-1 infection of macrophages and dendritic cells in a cell type-specific manner. Virus Res 2016; 222:64-70. [PMID: 27264433 DOI: 10.1016/j.virusres.2016.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 05/31/2016] [Accepted: 06/01/2016] [Indexed: 10/21/2022]
Abstract
Noroviruses cause gastroenteritis in humans and other animals, are shed in the feces, and spread through the fecal-oral route. Host cellular expression of attachment and entry receptors for noroviruses is thought to be a key determinant of cell tropism and the strict species-specificity. However, to date, only carbohydrates have been identified as attachment receptors for noroviruses. Thus, we investigated whether host cellular proteins play a role during the early steps of norovirus infection. We used murine norovirus (MNV) as a representative norovirus, since MNV grows well in tissue culture and is a frequently used model to study basic aspects of norovirus biology. Virus overlay protein binding assay followed by tandem mass spectrometry analysis was performed in two permissive cell lines, RAW264.7 (murine macrophages) and SRDC (murine dendritic cells) to identify four cellular membrane proteins as candidates. Loss-of-function studies revealed that CD36 and CD44 promoted MNV-1 binding to primary dendritic cells, while CD98 heavy chain (CD98) and transferrin receptor 1 (TfRc) facilitated MNV-1 binding to RAW 264.7 cells. Furthermore, the VP1 protruding domain of MNV-1 interacted directly with the extracellular domains of recombinant murine CD36, CD98 and TfRc by ELISA. Additionally, MNV-1 infection of RAW 264.7 cells was enhanced by soluble rCD98 extracellular domain. These studies demonstrate that multiple membrane proteins can promote efficient MNV-1 infection in a cell type-specific manner. Future studies are needed to determine the molecular mechanisms by which each of these proteins affect the MNV-1 infectious cycle.
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Affiliation(s)
- Juliana Bragazzi Cunha
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA
| | - Christiane E Wobus
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA.
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Yu Q, Zhang S, Chao K, Feng R, Wang H, Li M, Chen B, He Y, Zeng Z, Chen M. E3 Ubiquitin ligase RNF183 Is a Novel Regulator in Inflammatory Bowel Disease. J Crohns Colitis 2016; 10:713-25. [PMID: 26818663 DOI: 10.1093/ecco-jcc/jjw023] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 01/04/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Specific members of the RING finger [RNF] protein family serve as E3 ubiquitin ligases and play important roles in the regulation of inflammation. However, their roles in the pathogenesis of inflammatory bowel disease [IBD] have not been explored. METHODS Genomic microarray of inflamed colon samples from Crohn's disease [CD] patients was performed to identify potential up-regulated genes. Expression of the identified highly up-regulated RNF183 gene was subsequently examined by quantitative reverse transcription polymerase chain reaction [qRT-PCR], western blotting and immunohistochemistry of the intestinal tissues of IBD patients and the colons of trinitrobenzene sulphonic acid [TNBS]-induced colitic mice. RNF183-mediated interaction with the NF-κB pathway and ubiquitination of IκBα were examined by siRNA, plasmid transfection, and immunoprecipitation. The miRNA predicted to target RNF183 was explored and its role in the RNF183/ NF-κB pathway was investigated. RESULTS RNF183 was up-regulated in intestinal epithelial cells in IBD patients and in colitic mice. RNF183 promoted intestinal inflammation via the activation of the NF-κB pathway by increasing the ubiquitination and degradation of IκBα. Computational analysis identified putative binding of miR-7 to RNF183. Transfection of intestinal cells with a miR-7 mimic or inhibitor confirmed its negative regulatory effect on RNF183 expression and ubiquitination of IκBα. miR-7 was down-regulated in inflamed colon tissues of IBD patients and colitic mice. CONCLUSIONS RNF183, which is negatively regulated by miR-7, is a novel regulator promoting intestinal inflammation by increasing the ubiquitination and degradation of IκBα, thereby inducing NF-κB activation. The interaction between RNF183-mediated ubiquitination and miRNA may be an important novel epigenetic mechanism in the pathogenesis of IBD.
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Affiliation(s)
- Qiao Yu
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Shenghong Zhang
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Kang Chao
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Rui Feng
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Huiling Wang
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Manying Li
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Baili Chen
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Yao He
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Zhirong Zeng
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Minhu Chen
- IBD Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
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45
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Xu XM, Zhang HJ. miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation. World J Gastroenterol 2016; 22:2206-2218. [PMID: 26900285 PMCID: PMC4734997 DOI: 10.3748/wjg.v22.i7.2206] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 09/28/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract, and includes two major phenotypes: ulcerative colitis and Crohn’s disease. The pathogenesis of IBD is not fully understood as of yet. It is believed that IBD results from complicated interactions between environmental factors, genetic predisposition, and immune disorders. miRNAs are a class of small non-coding RNAs that can regulate gene expression by targeting the 3′-untranslated region of specific mRNAs for degradation or translational inhibition. miRNAs are considered to play crucial regulatory roles in many biologic processes, such as immune cellular differentiation, proliferation, and apoptosis, and maintenance of immune homeostasis. Recently, aberrant expression of miRNAs was revealed to play an important role in autoimmune diseases, including IBD. In this review, we discuss the current understanding of how miRNAs regulate autoimmunity and inflammation by affecting the differentiation, maturation, and function of various immune cells. In particular, we focus on describing specific miRNA expression profiles in tissues and peripheral blood that may be associated with the pathogenesis of IBD. In addition, we summarize the opportunities for utilizing miRNAs as new biomarkers and as potential therapeutic targets in IBD.
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46
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Chen WQ, Hu L, Chen GX, Deng HX. Role of microRNA-7 in digestive system malignancy. World J Gastrointest Oncol 2016; 8:121-127. [PMID: 26798443 PMCID: PMC4714141 DOI: 10.4251/wjgo.v8.i1.121] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 11/19/2015] [Indexed: 02/05/2023] Open
Abstract
There are several malignancies of the digestive system (including gastric, pancreatic and colorectal cancers, and hepatocellular carcinoma), which are the most common types of cancer and a major cause of death worldwide. MicroRNA (miR)-7 is abundant in the pancreas, playing an important role in pancreatic development and endocrine function. Expression of miR-7 is downregulated in digestive system malignancies compared with normal tissue. Although there are contrasting results for miR-7 expression, almost all research reveals that miR-7 is a tumor suppressor, by targeting various genes in specific pathways. Moreover, miR-7 can target different genes simultaneously in different malignancies of the digestive system. By acting on many cytokines, miR-7 is also involved in many gastrointestinal inflammatory diseases as a significant carcinogenic factor. Consequently, miR-7 might be a biomarker or therapeutic target gene in digestive system malignancies.
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47
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Youshia J, Lamprecht A. Size-dependent nanoparticulate drug delivery in inflammatory bowel diseases. Expert Opin Drug Deliv 2015; 13:281-94. [PMID: 26637060 DOI: 10.1517/17425247.2016.1114604] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a chronic autoimmune disease, whose main forms are Crohn's disease and ulcerative colitis. The main treatment of IBD includes oral administration of anti-inflammatory or immunosuppressive agents enclosed in traditional dosage forms, intended to release the active ingredient in the large intestine. However, most of them have been designed based on the physiology of healthy colon, which differs distinctly from conditions met in IBD patients risking adverse effects and patient intolerance. The use of nanoparticles as a drug carrier for treatment of IBD is a promising approach that is capable of solving this problem. Previous studies have shown a size-dependent behavior, where reducing the particle size, increases the targeting efficacy and the residence time compared to healthy controls. AREAS COVERED This review covers the utilization of nanoparticles as drug delivery carriers for treating IBD. They can reach the inflamed colonic sites either by endothelial or epithelial delivery employing passive and active targeting strategies. The effect of particle size is analyzed in detail while elucidating other essential parameters such as the particle surface properties. EXPERT OPINION One of the most important advantages of nanoparticles is their passive targeting to the inflamed colonic tissues due to their size. Recent findings underline that this size-dependent bioadhesion behavior can be further enhanced by selecting smart surface properties to help in penetrating the mucus and reach the inflamed sites.
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Affiliation(s)
- John Youshia
- a Department of Pharmaceutics , Institute of Pharmacy, University of Bonn , Bonn , Germany.,b Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Ain Shams University , Cairo , Egypt
| | - Alf Lamprecht
- a Department of Pharmaceutics , Institute of Pharmacy, University of Bonn , Bonn , Germany.,c Laboratory of Pharmaceutical Engineering, EA 4267 , University of Franche-Comté , Besançon , France
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Fisher K, Lin J. MicroRNA in inflammatory bowel disease: Translational research and clinical implication. World J Gastroenterol 2015; 21:12274-12282. [PMID: 26604636 PMCID: PMC4649112 DOI: 10.3748/wjg.v21.i43.12274] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 08/04/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
Idiopathic inflammatory bowel disease (IBD) predominantly includes ulcerative colitis and Crohn’s disease. The pathogenesis of IBD is complex and not completely understood. MicroRNAs belong to a class of noncoding small RNAs that post-transcriptionally regulate gene expression. Unique microRNA expression profiles have been explored in IBD. In this review, we focus on the unique microRNA expression pattern in both tissue and peripheral blood from IBD patients and emphasize the potential diagnostic and therapeutic applications. The discovery of microRNAs has contributed to our understanding of IBD pathogenesis and might lead to clinical advance in new therapeutics.
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Meir M, Flemming S, Burkard N, Bergauer L, Metzger M, Germer CT, Schlegel N. Glial cell line-derived neurotrophic factor promotes barrier maturation and wound healing in intestinal epithelial cells in vitro. Am J Physiol Gastrointest Liver Physiol 2015; 309:G613-G624. [PMID: 26294673 DOI: 10.1152/ajpgi.00357.2014] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 07/20/2015] [Indexed: 01/31/2023]
Abstract
Recent data suggest that neurotrophic factors from the enteric nervous system are involved in intestinal epithelial barrier regulation. In this context the glial cell line-derived neurotrophic factor (GDNF) was shown to affect gut barrier properties in vivo directly or indirectly by largely undefined processes in a model of inflammatory bowel disease (IBD). We further investigated the potential role and mechanisms of GDNF in the regulation of intestinal barrier functions. Immunostaining of human gut specimen showed positive GDNF staining in enteric neuronal plexus and in enterocytes. In Western blots of the intestinal epithelial cell lines Caco2 and HT29B6, significant amounts of GDNF were detected, suggesting that enterocytes represent an additional source of GDNF. Application of recombinant GDNF on Caco2 and HT29B6 cells for 24 h resulted in significant epithelial barrier stabilization in monolayers with immature barrier functions. Wound-healing assays showed a significantly faster closure of the wounded areas after GDNF application. GDNF augmented cAMP levels and led to significant inactivation of p38 MAPK in immature cells. Activation of p38 MAPK signaling by SB-202190 mimicked GDNF-induced barrier maturation, whereas the p38 MAPK activator anisomycin blocked GDNF-induced effects. Increasing cAMP levels had adverse effects on barrier maturation, as revealed by permeability measurements. However, increased cAMP augmented the proliferation rate in Caco2 cells, and GDNF-induced proliferation of epithelial cells was abrogated by the PKA inhibitor H89. Our data show that enterocytes represent an additional source of GDNF synthesis. GDNF contributes to wound healing in a cAMP/PKA-dependent manner and promotes barrier maturation in immature enterocytes cells by inactivation of p38 MAPK signaling.
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Affiliation(s)
- Michael Meir
- Department of Surgery I, University of Wuerzburg, Oberduerrbacherstrasse 6, Wuerzburg, Germany; and
| | - Sven Flemming
- Department of Surgery I, University of Wuerzburg, Oberduerrbacherstrasse 6, Wuerzburg, Germany; and
| | - Natalie Burkard
- Department of Surgery I, University of Wuerzburg, Oberduerrbacherstrasse 6, Wuerzburg, Germany; and
| | - Lisa Bergauer
- Department of Surgery I, University of Wuerzburg, Oberduerrbacherstrasse 6, Wuerzburg, Germany; and
| | - Marco Metzger
- Department for Tissue Engineering and Regenerative Medicine, University Hospital Wuerzburg, Roentgenring 11, Wuerzburg, Germany
| | - Christoph-Thomas Germer
- Department of Surgery I, University of Wuerzburg, Oberduerrbacherstrasse 6, Wuerzburg, Germany; and
| | - Nicolas Schlegel
- Department of Surgery I, University of Wuerzburg, Oberduerrbacherstrasse 6, Wuerzburg, Germany; and
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Abstract
Diagnostics of inflammatory bowel diseases (IBDs) currently relies on a combination of biological and morphological tests. The current method of diagnostic remains a critical challenge for physicians in part due to their invasiveness and also for their limitations in term of diagnosis, prognosis, disease activity and severity assessment, and therapeutic outcomes. Laboratory biomarkers can be used in the diagnosis and management of IBD, but none of them has been proven to be ideal. Increasing efforts are being made to discover new biomarkers that can discriminate between the types of IBD, predict future responses to treatment, and aid in differential diagnosis, treatment planning, and prognosis prediction. This review addresses the potential for current biomarkers and the emergence of the concept of biomarker signatures in IBD diagnostic and personalized medicine.
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