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Thomas P, Ramani P, Ramasubramanian A, Sekar D. Characterizing
miR-20a-3p
Expression in the Progression of Oral Squamous Cell Carcinoma. JOURNAL OF ADVANCED ORAL RESEARCH 2025; 16:34-42. [DOI: 10.1177/23202068241307076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
Aim:
This study aims to elucidate the role of
miR-20a-3p
in the inhibition of tumor suppressor genes, thereby enhancing the development and advancement of oral squamous cell carcinoma (OSCC) by fostering the proliferation and viability of tumor cells. Additionally, the study seeks to evaluate the potential of
miR-20a-3p
as a prognostic biomarker for more effective treatment strategies in OSCC patients.
Materials and Methods:
This observational, analytical study utilized a convenience sampling method, involving a total of 63 OSCC biopsy samples and corresponding nontumor oral tissues from the same patients. The expression levels of
miR-20a-3p
were quantified using quantitative real-time polymerase chain reaction. Clinical information, including tumor stage, and grade was obtained. Statistical analysis included unpaired Student’s
t
tests to compare
miR-20a-3p
expression levels between normal and OSCC samples, and one-way ANOVA to compare expression across different grades and stages of the tumor, using SPSS version 19.
Results:
Our findings demonstrate that
miR-20a-3p
expression was significantly downregulated in OSCC samples compared to healthy controls (
p
< .001). Additionally, we observed a correlation between
miR-20a-3p
downregulation and OSCC histological grade and staging.
miR-20a-3p
expression levels were significantly different across different grades of OSCC, particularly between well-differentiated squamous cell carcinoma (WDSCC) and poorly differentiated squamous cell carcinoma (PDSCC) (
p
< .006) and moderately differentiated squamous cell carcinoma and PDSCC (
p
< .008). There was a significant difference in
miR-20a-3p
expression between normal tissues and Stage II (
p
< .006) and Stage IV (
p
< .001) OSCC.
Conclusion:
The study confirms that
miR-20a-3p
acts as a tumor suppressor in OSCC and holds potential as a biomarker for prognosis and personalized treatment strategies. miR-20a-3p expression is significantly reduced in OSCC tissues compared to normal tissues, and its levels vary with tumor grade and stage. These findings underscore the importance of further research into miRNAs as therapeutic targets.
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Affiliation(s)
- Priya Thomas
- Annoor Dental College, Muvattupuzha, Kerala, India
- Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
| | - Pratibha Ramani
- Department of Oral Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Abilasha Ramasubramanian
- Department of Oral Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Durairaj Sekar
- Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
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2
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Liu F, Liu B, Xu S, Ni Y, Liu X. MicroRNA-122 protects against interferon-α-induced hepatic inflammatory response via the Janus kinase-signal transducer and activator of transcription pathway. Endocr J 2025; 72:53-67. [PMID: 39358210 PMCID: PMC11778391 DOI: 10.1507/endocrj.ej24-0317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Significant overlap in the epidemiology and coinfection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) has been identified, which accelerates the development of severe liver cirrhosis and hepatocellular carcinoma worldwide. Interferon-α (IFN-α), a cytokine with antiviral properties, exerts profound physiological effects on innate immunity by regulating interferon-stimulated genes (ISGs) within cells. However, the underlying mechanism of IFN-α in hepatic inflammation remains to be fully elucidated. Here, we utilized LO2 cells treated with the recombinant IFN-α protein and conducted microRNA (miR) sequencing. MiR-122-3p and miR-122-5p_R+1 were the most enriched miRNAs involved in the pathogenesis of IFN-α-induced inflammatory responses and were significantly downregulated by IFN-α treatment. Furthermore, we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) as a potential target gene of miR-122. IFN-α markedly increased the expression of proinflammatory cytokines and fibrogenic genes but decreased the mRNA expression of ISGs. Additionally, IFN-α significantly activated the NF-κB p-p65, MAPK p-p38, and Jak/STAT pathways to trigger inflammation. Importantly, supplementation with a miR-122 mimic significantly alleviated IFN-α-induced inflammation and induced IFIT1 expression in LO2 cells. Conversely, the suppression of miR-122 markedly exacerbated the inflammatory response triggered by IFN-α. Furthermore, silencing IFIT1 via an siRNA elicited an inflammatory response, whereas IFIT1 overexpression ameliorated hepatic inflammation and fibrosis in a manner comparable to that induced by IFN-α treatment. Taken together, our findings suggest that miR-122 and its target, IFIT1, reciprocally regulate the inflammatory response associated with IFN through the Jak/STAT pathway.
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Affiliation(s)
- Fanwei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Bowen Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Shanshan Xu
- Department of Anesthesia, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
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Harshithkumar R, Kaul M, Chandane-Tak M, Siddiqi NJ, Malik A, Khan AA, Mukherjee A. Harnessing miRNA dynamics in HIV-1-infected macrophages: Unveiling new targeted therapeutics using systems biology. Comput Struct Biotechnol J 2025; 27:1754-1771. [DOI: 10.1016/j.csbj.2025.04.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
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Guo S, Liu Q, Tan T, Chen X. MiR-24 regulates obstructive pulmonary disease in rats via S100A8. Exp Lung Res 2024; 50:172-183. [PMID: 39390946 DOI: 10.1080/01902148.2024.2411852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 09/05/2024] [Accepted: 09/28/2024] [Indexed: 10/12/2024]
Abstract
PURPOSE Chronic obstructive pulmonary disease (COPD) is a persistent inflammatory disorder characterized by minor airway inflammation and emphysema involving various cell types and cytokines. MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of lung diseases. This study investigates the impact of microRNA-24 (miR-24) on airway inflammatory responses in a rat model of COPD. MATERIALS AND METHODS The model was established by combining cigarette smoke exposure and lipopolysaccharide stimulation, and rat lung tissues were transfected with adeno-associated viruses overexpressing miR-24. Pathological changes in the lung were assessed using hematoxylin and eosin staining. Levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6, and interleukin-8, were measured using enzyme-linked immunosorbent assay. Expression of miR-24 and S100A8 was detected through quantitative reverse transcription PCR, while protein levels of S100A8, Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) were assessed using western blotting. Bioinformatics analysis and dual-luciferase reporter assay were performed to determine the relationship between S100A8 and miR-24. RESULTS The results demonstrated the downregulation of miR-24 in rats with COPD, and its overexpression resulted in a significant decrease in S1008 mRNA levels. Additionally, the protein level of S100A8 was significantly increased in the lung tissues of COPD rats. The upregulation of miR-24, however, not only inhibited the protein expression of S100A8, TLR4, and MyD88 in lung tissues but also reduced the release of pro-inflammatory cytokines in the plasma and bronchoalveolar lavage fluid, thereby attenuating inflammatory responses and pathological injuries in the lung. CONCLUSIONS Our data suggest that miR-24 attenuates airway inflammatory responses in COPD by inhibiting the TLR4/MyD88 pathway via targeting S100A8.
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Affiliation(s)
- Sha Guo
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Qin Liu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Tingting Tan
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xiaoju Chen
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
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5
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Li J, Hu H, Fu P, Yang Q, Wang P, Gao X, Yang J, Gun S, Huang X. Pig Milk Exosome Packaging ssc-miR-22-3p Alleviates Pig Intestinal Epithelial Cell Injury and Inflammatory Response by Targeting MAPK14. Int J Mol Sci 2024; 25:10715. [PMID: 39409044 PMCID: PMC11476862 DOI: 10.3390/ijms251910715] [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: 09/12/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024] Open
Abstract
Inflammatory diseases of the intestinal tract in piglets severely impair the economic performance of pig farms. Pig milk exosomes can encapsulate miRNAs which can then enter the piglet intestine to play an immunomodulatory role. Previously, we comparatively analyzed and identified exosomal miRNAs in the colostrum and mature milk of Bamei and Landrace pigs, and we screened for ssc-miR-22-3p, which is associated with inflammation and immune response; however, the role played by ssc-miR-22-3p in the immune response in IPEC-J2 cells is not yet clear. In this study, we first constructed a pig intestinal inflammatory response model using Lipopolysaccharide (LPS) and Polyinosinic-polycytidylic acid (Poly (I:C)), and we investigated the role of ssc-miR-22-3p targeting MAPK14 in the regulation of LPS and Poly (I:C)-induced inflammatory injury in IPEC-J2 cells by RT-qPCR, cell counting kit-8 (CCK-8), EdU staining, lactate dehydrogenase (LDH) activity assay, and dual luciferase reporter gene assay. We successfully established LPS and Poly (I:C)-induced cell damage models in IPEC-J2 cells. The immune response of IPEC-J2 cells was stimulated by induction of IPEC-J2 cells at 10 μg/mL LPS and 20 μg/mL Poly (I:C) for 24 h. Overexpression of ssc-miR-22-3p decreased cytokine expression and promoted cell viability and proliferation. The functional enrichment analysis revealed that ssc-miR-22-3p targets genes enriched in the pathways of negative regulation of inflammatory response and bacterial invasion of epithelial cells. The validity of the binding site of ssc-miR-22-3p to MAPK14 was tested by a dual luciferase reporter gene. Pig milk exosome ssc-miR-22-3p promotes cell viability and proliferation by targeting MAPK14, and it alleviates LPS and Poly (I:C)-induced inflammatory responses in IPEC-J2 cells.
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Affiliation(s)
- Jie Li
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Huihui Hu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Panpan Fu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Xiaoli Gao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Jiaojiao Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
- Gansu Research Center for Swine Production Engineering and Technology, Lanzhou 730070, China
| | - Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
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Iacomino N, Tarasco MC, Berni A, Ronchi J, Mantegazza R, Cavalcante P, Foti M. Non-Coding RNAs in Myasthenia Gravis: From Immune Regulation to Personalized Medicine. Cells 2024; 13:1550. [PMID: 39329732 PMCID: PMC11430632 DOI: 10.3390/cells13181550] [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: 08/07/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder characterized by altered neuromuscular transmission, which causes weakness and fatigability in the skeletal muscles. The etiology of MG is complex, being associated with multiple genetic and environmental factors. Over recent years, progress has been made in understanding the immunological alterations implicated in the disease, but the exact pathogenesis still needs to be elucidated. A pathogenic interplay between innate immunity and autoimmunity contributes to the intra-thymic MG development. Epigenetic changes are critically involved in both innate and adaptive immune response regulation. They can act as (i) pathological factors besides genetic predisposition and (ii) co-factors contributing to disease phenotypes or patient-specific disease course/outcomes. This article reviews the role of non-coding RNAs (ncRNAs) as epigenetic factors implicated in MG. Particular attention is dedicated to microRNAs (miRNAs), whose expression is altered in MG patients' thymuses and circulating blood. The long ncRNA (lncRNA) contribution to MG, although not fully characterized yet, is also discussed. By summarizing the most recent and fast-growing findings on ncRNAs in MG, we highlight the therapeutic potential of these molecules for achieving immune regulation and their value as biomarkers for the development of personalized medicine approaches to improve disease care.
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Affiliation(s)
- Nicola Iacomino
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Maria Cristina Tarasco
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
- Ph.D. Program in Neuroscience, University of Milano-Bicocca, 20900 Monza, Italy;
| | - Alessia Berni
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Jacopo Ronchi
- Ph.D. Program in Neuroscience, University of Milano-Bicocca, 20900 Monza, Italy;
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
- BicOMICs, University of Milano-Bicocca, 20900 Monza, Italy
| | - Renato Mantegazza
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Paola Cavalcante
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Maria Foti
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
- BicOMICs, University of Milano-Bicocca, 20900 Monza, Italy
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7
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Vahidi Z, Saghi E, Mahmoudi M, RezaieYazdi Z, Esmaeili SA, Zemorshidi F, Samadi M, Rastin M. Lactobacillus rhamnosus and Lactobacillus delbrueckii Ameliorate the Expression of miR-125a and miR-146a in Systemic Lupus Erythematosus Patients. Appl Biochem Biotechnol 2024; 196:6330-6341. [PMID: 38351428 DOI: 10.1007/s12010-023-04827-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2023] [Indexed: 11/29/2024]
Abstract
The microRNAs are non-coding RNA molecules involved in physiological and pathological processes, causing autoimmune diseases such as systemic lupus erythematosus (SLE). Probiotics are living microorganisms that possess beneficial effects on the host immune system and modulate it. The effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii on the expression of miR-125a and miR-146a was studied in peripheral blood mononuclear cells (PBMCs) from newly diagnosed lupus patients in this in vitro study. During this study, 20 recently diagnosed SLE patients and 20 healthy individuals participated. Ficoll method was used to isolate the PBMCs from whole blood, which were cultured for 48 h with Lactobacillus rhamnosus and Lactobacillus delbrueckii. In the next step, total RNA containing microRNA was extracted. cDNA was synthesized for miR-125a and miR-146a genes and analyzed by real-time PCR. Results were presented as fold changes. As compared to healthy controls, SLE patients expressed lower levels of miR-125a and miR-146a. PBMCs treated with Lactobacillus rhamnosus, Lactobacillus delbrueckii, or both probiotics had significantly higher levels of miR-125a and miR-146a compared to the untreated group. Treatment of PBMCs with both L. rhamnosus and L. delbrueckii upregulated the expression of miR-125a and miR-146a in treated cells compared with untreated cells in SLE patients (p = 0.02, p = 0.001). Lactobacillus rhamnosus and Lactobacillus delbrueckii modify lupus patients' immune responses and disease effects by regulating miR-125a and miR-146a.
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Affiliation(s)
- Zohreh Vahidi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Effat Saghi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Departments, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra RezaieYazdi
- Rheumatic Diseases Research Center, Ghaem Hospital, Internal Medicine Section, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Departments, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariba Zemorshidi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Morteza Samadi
- Department of Immunology, Faculty of Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Maryam Rastin
- Immunology Departments, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yang H, Thompson B. Widespread changes to the translational landscape in a maize microRNA biogenesis mutant. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2024; 119:1986-2000. [PMID: 38963711 DOI: 10.1111/tpj.16902] [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: 11/19/2023] [Revised: 06/08/2024] [Accepted: 06/17/2024] [Indexed: 07/06/2024]
Abstract
MicroRNAs are short, non-coding RNAs that repress gene expression in both plants and animals and have diverse functions related to growth, development, and stress responses. The ribonuclease, DICER-LIKE1 (DCL1) is required for two steps in plant miRNA biogenesis: cleavage of the primary miRNAs (pri-miRNAs) to release a hairpin structure, called the precursor miRNA (pre-miRNA) and cleavage of the pre-miRNA to generate the miRNA/miRNA* duplex. The mature miRNA guides the RNA-induced silencing complex to target RNAs with complementary sequences, resulting in translational repression and/or RNA cleavage of target mRNAs. However, the relative contribution of translational repression versus mRNA degradation by miRNAs remains unknown at the genome-level in crops, especially in maize. The maize fuzzy tassel (fzt) mutant contains a hypomorphic mutation in DCL1 resulting in broad developmental defects. While most miRNAs are reduced in fzt, the levels of miRNA-targeted mRNAs are not dramatically increased, suggesting that translational regulation by miRNAs may be common. To gain insight into the repression mechanism of plant miRNAs, we combined ribosome profiling and RNA-sequencing to globally survey miRNA activities in maize. Our data indicate that translational repression contributes significantly to regulation of most miRNA targets and that approximately one-third of miRNA targets are regulated primarily at the translational level. Surprisingly, ribosomes appear altered in fzt mutants suggesting that DCL1 may also have a role in ribosome biogenesis. Thus, DICER-LIKE1 shapes the translational landscape in plants through both miRNA-dependent and miRNA-independent mechanisms.
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Affiliation(s)
- Hailong Yang
- Biology Department, East Carolina University, Greenville, North Carolina, USA
| | - Beth Thompson
- Biology Department, East Carolina University, Greenville, North Carolina, USA
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Zhang Y, Zhang F, Zhang Y, Wang M, Gao Y, Li H, Sun J, Xie Z. Investigating the therapeutic mechanism of Jiedu-Quyu-Ziyin Fang on systemic lupus erythematosus through the ERα-miRNA-TLR7 immune axis. Heliyon 2024; 10:e32752. [PMID: 38948043 PMCID: PMC11209013 DOI: 10.1016/j.heliyon.2024.e32752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 07/02/2024] Open
Abstract
Jiedu-Quyu-Ziyin Fang (JQZF) is a formula that has been empirically used for the treatment of SLE in clinical practice. JQZF has become an approved hospital prescription in China. Fifteen MRL/lpr mice were randomly divided into three groups: Model, JQZF, and JQZF + GC, with five mice in each group. Five MRL/MPJ mice were used as the Blank group. After 8 weeks of administration, peripheral blood serum was collected to detect anti-dsDNA antibodies and complement C3 levels. Spleen B cells were collected to detect the expression of TLR7 and NF-κBp65 mRNA, and correlation analysis was performed. Transcriptome sequencing analysis was also performed on spleen B cells. Further, key miRNA and key gene mRNA expression were detected by RT-qPCR, and key protein expression levels were detected by Western blot method. Bioinformatics methods predicted that ESR1 is a key target of JQZF action on SLE, hsa-miR-146a-5p is one of the key miRNAs, and KEGG pathway analysis showed that NF-κB signaling pathway is its key signaling pathway. Transcriptome sequencing of MRL/lpr mouse spleen B cells revealed that the differential genes between the JQZF and Model groups were enriched in Toll-like receptor signaling pathway, NF-κB signaling pathway, Estrogen signaling pathway, etc. Animal studies show that JQZF treatment significantly boosts serum C3 and lowers anti-dsDNA antibodies (P < 0.01). On the molecular level, JQZF suppresses TLR7 and NF-κBp65 mRNA in spleen B cells, with TLR7 mRNA positively linked to anti-dsDNA titers and negatively to serum C3. Further cellular work demonstrates that JQZF reverses the increased IRAK1 and TRAF6 expression seen after miR146a inhibition. Additionally, post-ERα inhibition, JQZF continues to upregulate miR146a and more significantly reduces TLR7 mRNA expression (P < 0.01), pointing to ERα's pivotal role in the miR146a-TLR7 axis. These results indicate JQZF alleviates SLE by adjusting the ERα-miR146a-TLR7 loop, showcasing its mechanism and therapeutic potential for SLE.
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Affiliation(s)
| | | | | | - MeiJiao Wang
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang Province, China
| | - Yan Gao
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang Province, China
| | - HaiChang Li
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang Province, China
| | - Jing Sun
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang Province, China
| | - ZhiJun Xie
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang Province, China
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10
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Liu X, Xiong W, Ye M, Lu T, Yuan K, Chang S, Han Y, Wang Y, Lu L, Bao Y. Non-coding RNAs expression in SARS-CoV-2 infection: pathogenesis, clinical significance, and therapeutic targets. Signal Transduct Target Ther 2023; 8:441. [PMID: 38057315 PMCID: PMC10700414 DOI: 10.1038/s41392-023-01669-0] [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: 12/09/2022] [Revised: 09/12/2023] [Accepted: 09/28/2023] [Indexed: 12/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has been looming globally for three years, yet the diagnostic and treatment methods for COVID-19 are still undergoing extensive exploration, which holds paramount importance in mitigating future epidemics. Host non-coding RNAs (ncRNAs) display aberrations in the context of COVID-19. Specifically, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) exhibit a close association with viral infection and disease progression. In this comprehensive review, an overview was presented of the expression profiles of host ncRNAs following SARS-CoV-2 invasion and of the potential functions in COVID-19 development, encompassing viral invasion, replication, immune response, and multiorgan deficits which include respiratory system, cardiac system, central nervous system, peripheral nervous system as well as long COVID. Furthermore, we provide an overview of several promising host ncRNA biomarkers for diverse clinical scenarios related to COVID-19, such as stratification biomarkers, prognostic biomarkers, and predictive biomarkers for treatment response. In addition, we also discuss the therapeutic potential of ncRNAs for COVID-19, presenting ncRNA-based strategies to facilitate the development of novel treatments. Through an in-depth analysis of the interplay between ncRNA and COVID-19 combined with our bioinformatic analysis, we hope to offer valuable insights into the stratification, prognosis, and treatment of COVID-19.
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Affiliation(s)
- Xiaoxing Liu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191, Beijing, China
| | - Wandi Xiong
- Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, 570228, Haikou, China
| | - Maosen Ye
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, 650204, Kunming, Yunnan, China
| | - Tangsheng Lu
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
| | - Kai Yuan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191, Beijing, China
| | - Suhua Chang
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191, Beijing, China
| | - Ying Han
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
| | - Yongxiang Wang
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, Shandong, China.
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
| | - Lin Lu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191, Beijing, China.
- Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China.
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China.
| | - Yanping Bao
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China.
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, Shandong, China.
- School of Public Health, Peking University, 100191, Beijing, China.
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11
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Maroso F, Padovani G, Muñoz Mora VH, Giannelli F, Trucchi E, Bertorelle G. Fitness consequences and ancestry loss in the Apennine brown bear after a simulated genetic rescue intervention. CONSERVATION BIOLOGY : THE JOURNAL OF THE SOCIETY FOR CONSERVATION BIOLOGY 2023; 37:e14133. [PMID: 37259604 DOI: 10.1111/cobi.14133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 03/14/2023] [Accepted: 03/22/2023] [Indexed: 06/02/2023]
Abstract
Reduction in population size, with its predicted effects on population fitness, is the most alarming anthropogenic impact on endangered species. By introducing compatible individuals, genetic rescue (GR) is a promising but debated approach for reducing the genetic load unmasked by inbreeding and for restoring the fitness of declining populations. Although GR can improve genetic diversity and fitness, it can also produce loss of ancestry, hampering local adaptation, or replace with introduced variants the unique genetic pools evolved in endemic groups. We used forward genetic simulations based on empirical genomic data to assess fitness benefits and loss of ancestry risks of GR in the Apennine brown bear (Ursus arctos marsicanus). There are approximately 50 individuals of this isolated subspecies, and they have lower genetic diversity and higher inbreeding than other European brown bears, and GR has been suggested to reduce extinction risks. We compared 10 GR scenarios in which the number and genetic characteristics of migrants varied with a non-GR scenario of simple demographic increase due to nongenetic factors. The introduction of 5 individuals of higher fitness or lower levels of deleterious mutations than the target Apennine brown bear from a larger European brown bear population produced a rapid 10-20% increase in fitness in the subspecies and up to 22.4% loss of ancestry over 30 generations. Without a contemporary demographic increase, fitness started to decline again after a few generations. Doubling the population size without GR gradually increased fitness to a comparable level, but without losing ancestry, thus resulting in the best strategy for the Apennine brown bear conservation. Our results highlight the importance for management of endangered species of realistic forward simulations grounded in empirical whole-genome data.
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Affiliation(s)
- Francesco Maroso
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
- Department of Biology, University of Padova, Padova, Italy
| | - Giada Padovani
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | | | - Francesco Giannelli
- Department of Life and Environmental Science, Marche Polytechnic University, Ancona, Italy
| | - Emiliano Trucchi
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
- Department of Life and Environmental Science, Marche Polytechnic University, Ancona, Italy
| | - Giorgio Bertorelle
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
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12
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Sakalli-Tecim E, Gur-Dedeoglu B, Guray NT. Systems biology based miRNA-mRNA expression pattern analysis of Emodin in breast cancer cell lines. Pathol Res Pract 2023; 249:154780. [PMID: 37633004 DOI: 10.1016/j.prp.2023.154780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/20/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
Breast cancer has been among the most prominent cancers with high mortality. Currently most of the offered therapeutics are toxic; hence, less toxic therapeutic intervention is required. Here, we studied the molecular mechanisms of the effect of a phytoestrogen Emodin on estrogen receptor positive MCF-7 and negative MDA-MB-231 cells by carrying out a comprehensive network assessment. Differentially expressed microRNAs along with their previously identified differentially expressed mRNAs were analyzed through microarrays by using integrative systems biology approach. For each cell line miRNA-target gene networks were built, gene ontology and pathway enrichment analyses were performed, enrichment maps were constructed and the potential key genes, miRNAs and miRNA-gene interactions were studied.
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Affiliation(s)
- Elif Sakalli-Tecim
- Department of Biotechnology, Middle East Technical University, Ankara, Turkiye
| | | | - N Tulin Guray
- Department of Biotechnology, Middle East Technical University, Ankara, Turkiye; Department of Biological Sciences, Middle East Technical University, Ankara, Turkiye.
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13
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Soltani-Zangbar MS, Hajivalili M, Daneshdoust D, Ghadir S, Savari G, Zolfaghari M, Aghebati-Maleki L, Oloufi S, Nouri N, Amini N, Mehdizadeh A, Ghasemi Moghadam H, Mahmoodpoor A, Ahmadian Heris J, Yousefi M. SARS-CoV2 infection induce miR-155 expression and skewed Th17/Treg balance by changing SOCS1 level: A clinical study. Cytokine 2023; 169:156248. [PMID: 37307689 PMCID: PMC10247889 DOI: 10.1016/j.cyto.2023.156248] [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: 09/27/2022] [Revised: 03/18/2023] [Accepted: 05/27/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND One of the regulators in severe acute respiratory syndrome coronavirus2 (SARS-CoV2) infection is miRNAs. In COVID-19 patients, immunological responses to SARS-CoV2 infection may be impacted by miR-155, a miRNA associated to inflammation. MATERIALS AND METHODS Peripheral blood mononuclear cells (PBMCs) of 50 confirmed COVID-19 patients /Healthy Controls (HCs) was isolated by Ficoll. The frequency of T helper 17 and regulatory T cells was analyzed by flowcytometry. The RNA was extracted from each sample and after synthesis of c-DNA, the relative expression of miR-155, suppressor of cytokine signaling (SOCS-1), Signal transducer and activator of transcription 3(STAT3), and Fork Head Box Protein 3 (FoxP3) was evaluated by real-time PCR. The protein level of STAT3, FoxP3 and RORγT in the isolated PBMCs measured by western blotting. The serum level of IL-10, TGF-β, IL-17 and IL21 was assessed by ELISA method. RESULTS The population of Th17 cells showed a significant rise, whereas Treg cells reduced in COVID-19 cases. The master transcription factor of Treg (FoxP3) and Th17 (RORγT) relative expression showed the same pattern as flowcytometry. STAT3 level of expression at RNA and protein level increased in COVID-19 cases. FOXP3 and SOCS-1 proteins were down-regulated. The relative expression of miR-155, up-regulated in PBMC of COVID-19 patients and revealed a negative correlation with SOCS-1. The serum cytokine profile showed a reduction in TGF-β, on the other hand an increase was seen in IL-17, IL-21 and IL-10 in COVID-19 cases toward control group. CONCLUSION Based on the studies conducted in this field, it can be suggested that Th17/Treg in covid-19 patients can be affected by miR-155 and it can be considered a valuable diagnostic and prognostic factor in this disease.
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Affiliation(s)
- Mohammad Sadegh Soltani-Zangbar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Sara Ghadir
- Student Research Committee, Faculty of Medical Sciences, Babol University of Medical Sciences, Babol, Iran
| | - Golaleh Savari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Solmaz Oloufi
- School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Narjes Nouri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Naser Amini
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Institute of Regenerative Medicine, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ata Mahmoodpoor
- Department of Anesthesiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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14
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Shokati E, Safari E. The immunomodulatory role of exosomal microRNA networks in the crosstalk between tumor-associated myeloid-derived suppressor cells and tumor cells. Int Immunopharmacol 2023; 120:110267. [PMID: 37276829 DOI: 10.1016/j.intimp.2023.110267] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/07/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are considered a heterogeneous group of immature myeloid cells engaging in aggressive tumor progression and metastasis in the tumor microenvironment (TME) of patients diagnosed with cancer, through downregulation of anti-tumor immune responses. Exosomes are small vesicles carrying specific cargos, including proteins, lipids, and MicroRNA (miRNAs). Such exosomal miRNAs delivered by MDSCs and tumor cells are short noncoding RNAs mediating some of the immunosuppressive characteristics of MDSCs in the TME. However, when it comes to cancer diseases, how these miRNAs interact with MDSCs and encourage MDSCs differentiation and function need further investigations. In this review, we discuss MDSC-derived exosomal miRNAs and those derived from tumor cells (TDE) could modulate anti-tumor immunity and regulate the interaction between tumor cells and MDSCs in the TME. Afterward, we focus on dividing miRNAs, as an important substance interacting with MDSCs and tumor cells in the TME, into those have an immunosuppressive or stimulating effect not only on MDSCs expansion, differentiation, and suppressive function but also on tumor evasion.
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Affiliation(s)
- Elham Shokati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
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15
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Millán O, Ruiz P, Julian J, Lizana A, Fundora Y, Crespo G, Colmenero J, Navasa M, Brunet M. A plasmatic score using a miRNA signature and CXCL-10 for accurate prediction and diagnosis of liver allograft rejection. Front Immunol 2023; 14:1196882. [PMID: 37325660 PMCID: PMC10265684 DOI: 10.3389/fimmu.2023.1196882] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/17/2023] [Indexed: 06/17/2023] Open
Abstract
Introduction The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort. Methods A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort. Results Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity). Conclusion These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.
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Affiliation(s)
- Olga Millán
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Pablo Ruiz
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Judit Julian
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Biochemistry and Molecular Genetics, Biomedical Diagnostic Center, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Ana Lizana
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Yiliam Fundora
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Department of General and Digestive Surgery, Hospital Clínic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Gonzalo Crespo
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jordi Colmenero
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Miquel Navasa
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Mercè Brunet
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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16
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Silva Grijó Farani P, Iandra da Silva Ferreira B, Begum K, Vilar-Pereira G, Pereira IR, Fernández-Figueroa EA, Cardenas-Ovando RA, Almeida IC, Roy S, Lannes-Vieira J, Moreira OC. Treatment with benznidazole and pentoxifylline regulates microRNA transcriptomic profile in a murine model of Chagas chronic cardiomyopathy. PLoS Negl Trop Dis 2023; 17:e0011223. [PMID: 36972298 PMCID: PMC10121046 DOI: 10.1371/journal.pntd.0011223] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 04/21/2023] [Accepted: 03/07/2023] [Indexed: 03/29/2023] Open
Abstract
Chronic Chagas cardiomyopathy (CCC) is one of the leading causes of morbidity and mortality due to cardiovascular disorders in endemic areas of Chagas disease (CD), a neglected tropical illness caused by the protozoan parasite Trypanosoma cruzi. CCC is characterized by parasite persistence and inflammatory response in the heart tissue, which occur parallel to microRNA (miRNA) alterations. Here, we investigated the miRNA transcriptome profiling in the cardiac tissue of chronically T. cruzi-infected mice treated with a suboptimal dose of benznidazole (Bz), the immunomodulator pentoxifylline alone (PTX), or the combination of both (Bz+PTX), following the CCC onset. At 150 days post-infection, Bz, PTX, and Bz+PTX treatment regimens improved electrocardiographic alterations, reducing the percentage of mice afflicted by sinus arrhythmia and second-degree atrioventricular block (AVB2) when compared with the vehicle-treated animals. miRNA Transcriptome profiling revealed considerable changes in the differential expression of miRNAs in the Bz and Bz+PTX treatment groups compared with the control (infected, vehicle-treated) group. The latter showed pathways related to organismal abnormalities, cellular development, skeletal muscle development, cardiac enlargement, and fibrosis, likely associated with CCC. Bz-Treated mice exhibited 68 differentially expressed miRNAs related to signaling pathways like cell cycle, cell death and survival, tissue morphology, and connective tissue function. Finally, the Bz+PTX-treated group revealed 58 differentially expressed miRNAs associated with key signaling pathways related to cellular growth and proliferation, tissue development, cardiac fibrosis, damage, and necrosis/cell death. The T. cruzi-induced upregulation of miR-146b-5p, previously shown in acutely infected mice and in vitro T. cruzi-infected cardiomyocytes, was reversed upon Bz and Bz+PTX treatment regimens when further experimentally validated. Our results further our understanding of molecular pathways related to CCC progression and evaluation of treatment response. Moreover, the differentially expressed miRNAs may serve as drug targets, associated molecular therapy, or biomarkers of treatment outcomes.
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Affiliation(s)
- Priscila Silva Grijó Farani
- Real-Time PCR Platform RPT09A, Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Laboratory of Biology of the Interactions, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Beatriz Iandra da Silva Ferreira
- Real-Time PCR Platform RPT09A, Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Khodeza Begum
- Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America
| | - Glaucia Vilar-Pereira
- Laboratory of Biology of the Interactions, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Isabela Resende Pereira
- Laboratory of Biology of the Interactions, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Edith A. Fernández-Figueroa
- Computational and Integrative Genomics, Instituto Nacional de Medicina Genómica, Arenal Tepepan, Mexico City, Mexico
| | | | - Igor C. Almeida
- Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America
| | - Sourav Roy
- Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America
| | - Joseli Lannes-Vieira
- Laboratory of Biology of the Interactions, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Otacilio Cruz Moreira
- Real-Time PCR Platform RPT09A, Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- * E-mail:
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17
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Rossi GP, Barton M, Dhaun N, Rizzoni D, Seccia TM. Challenges in the evaluation of endothelial cell dysfunction: a statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors. J Hypertens 2023; 41:369-379. [PMID: 36728915 DOI: 10.1097/hjh.0000000000003314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Endothelial cell function is mediated by different mechanisms in different vascular beds. Moreover, in humans, endothelial cell dysfunction triggers and accelerates the progression of cardiovascular and chronic kidney diseases. Progression of such diseases can be in part mitigated by the control of cardiovascular risk factors and drugs targeting different systems, including endothelin receptor antagonists (ERAs), renin-angiotensin aldosterone antagonists and agents affecting glucose metabolism, all of which were shown to improve endothelial cell function. In recent years, the microRNAs, which are endogenous regulators of gene expression, have been identified as transmitters of information from endothelial cells to vascular smooth muscle cells, suggesting that they can entail tools to assess the endothelial cell dysfunction in arterial hypertension and target for pharmacologic intervention. This article critically reviews current challenges and limitations of available techniques for the invasive and noninvasive assessment of endothelial cell function, and also discusses therapeutic aspects as well as directions for future research in the areas of endothelial cell biology and pathophysiology in humans.
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Affiliation(s)
- Gian Paolo Rossi
- Emergency Medicine Unit and European Society of Hypertension Specialized Center of Excellence for Hypertension, Department of Medicine-DIMED, University of Padua, Padova, Italy
| | - Matthias Barton
- Molecular Internal Medicine, University of Zürich, and Andreas Grüntzig Foundation, Zürich, Switzerland
| | - Neeraj Dhaun
- University/British Heart Foundation Centre of Research Excellence, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Damiano Rizzoni
- Department of Clinical and Experimental Sciences, University of Brescia and Division of Medicine, Istituto Clinico Città di Brescia, Brescia, Italy
| | - Teresa M Seccia
- Emergency Medicine Unit and European Society of Hypertension Specialized Center of Excellence for Hypertension, Department of Medicine-DIMED, University of Padua, Padova, Italy
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18
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Liang S, Ma J, Gong H, Shao J, Li J, Zhan Y, Wang Z, Wang C, Li W. Immune regulation and emerging roles of noncoding RNAs in Mycobacterium tuberculosis infection. Front Immunol 2022; 13:987018. [PMID: 36311754 PMCID: PMC9608867 DOI: 10.3389/fimmu.2022.987018] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/29/2022] [Indexed: 05/10/2024] Open
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, engenders an onerous burden on public hygiene. Congenital and adaptive immunity in the human body act as robust defenses against the pathogens. However, in coevolution with humans, this microbe has gained multiple lines of mechanisms to circumvent the immune response to sustain its intracellular persistence and long-term survival inside a host. Moreover, emerging evidence has revealed that this stealthy bacterium can alter the expression of demic noncoding RNAs (ncRNAs), leading to dysregulated biological processes subsequently, which may be the rationale behind the pathogenesis of tuberculosis. Meanwhile, the differential accumulation in clinical samples endows them with the capacity to be indicators in the time of tuberculosis suffering. In this article, we reviewed the nearest insights into the impact of ncRNAs during Mycobacterium tuberculosis infection as realized via immune response modulation and their potential as biomarkers for the diagnosis, drug resistance identification, treatment evaluation, and adverse drug reaction prediction of tuberculosis, aiming to inspire novel and precise therapy development to combat this pathogen in the future.
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Affiliation(s)
- Shufan Liang
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Jiechao Ma
- Artificial Intelligence (AI) Lab, Deepwise Healthcare, Beijing, China
| | - Hanlin Gong
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jun Shao
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Jingwei Li
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Yuejuan Zhan
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Zhoufeng Wang
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Chengdi Wang
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine, Med-X Center for Manufacturing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
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19
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You X, Liu M, Liu Q, Li H, Qu Y, Gao X, Huang C, Luo G, Cao G, Xu D. miRNA let-7 family regulated by NEAT1 and ARID3A/NF-κB inhibits PRRSV-2 replication in vitro and in vivo. PLoS Pathog 2022; 18:e1010820. [PMID: 36215225 PMCID: PMC9550049 DOI: 10.1371/journal.ppat.1010820] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/21/2022] [Indexed: 11/05/2022] Open
Abstract
Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating diseases affecting the swine industry worldwide. To investigate the role of miRNAs in the infection and susceptibility of PRRS virus (PRRSV), twenty-four miRNA libraries were constructed and sequenced from PRRSV-infected and mock-infected Porcine alveolar macrophages (PAMs) of Meishan, Landrace, Pietrain and Qingping pigs at 9 hours post infection (hpi), 36 hpi, and 60 hpi. The let-7 family miRNAs were significantly differentially expressed between PRRSV-infected and mock-infected PAMs from 4 pig breeds. The let-7 family miRNAs could significantly inhibit PRRSV-2 replication by directly targeting the 3’UTR of the PRRSV-2 genome and porcine IL6, which plays an important role in PRRSV replication and lung injury. NEAT1 acts as a competing endogenous lncRNA (ceRNA) to upregulate IL6 by attaching let-7 in PAMs. EMSA and ChIP results confirmed that ARID3A could bind to the promoter region of pri-let-7a/let-7f/let-7d gene cluster and inhibit the expression of the let-7 family. Moreover, the NF-κB signaling pathway inhibits the expression of the let-7 family by affecting the nuclear import of ARID3A. The pEGFP-N1-let-7 significantly reduced viral infections and pathological changes in PRRSV-infected piglets. Taken together, NEAT1/ARID3A/let-7/IL6 play significant roles in PRRSV-2 infection and may be promising therapeutic targets for PRRS. There are significant differences in susceptibility/resistance to PRRSV among different pig breeds. Especially the local pig breeds in China had strong resistance to PRRSV. However, due to the complexity of the interaction mechanism between pigs and PRRSV, the genetic mechanism leading to PRRSV susceptibility/resistance in different pig breeds is still unclear. MiRNAs play a vital regulatory role in immune response and development of PRRS. In this study, we found that the expression of miRNA let-7 family members were significantly different in PRRSV-infected/mock-infected PAMs from Pietrain, Qingping, Meishan, and Landrace pigs. Our findings illustrated that NEAT1/ARID3A/let-7/IL6 had a significant role in PRRSV-2 infection. What’s more, let-7 family could significantly reduce PRRSV infection and pathological changes in vitro and in vivo. This discovery provided a new idea for breeding PRRSV resistant pigs by revealing the molecular mechanism of PRRSV susceptibility in different pig breeds. Altogether, let-7 family have significant roles in PRRSV infection and may be promising therapeutic targets for PRRS.
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Affiliation(s)
- Xiangbin You
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Animal Science & Technology, Huazhong Agricultural University, Wuhan, China
- College of Animal Science & Technology, Henan University of Science and Technology, Luoyang, China
| | - Min Liu
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Qian Liu
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Animal Science & Technology, Henan University of Science and Technology, Luoyang, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Huijuan Li
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Animal Science & Technology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Yilin Qu
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Xiaoxiao Gao
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Chengyu Huang
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Gan Luo
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Animal Science & Technology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Gang Cao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Dequan Xu
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
- College of Animal Science & Technology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, China
- * E-mail:
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Shen H, Jiang W, Yu Y, Feng Y, Zhang T, Liu Y, Guo L, Zhou N, Huang X. microRNA-146a mediates distraction osteogenesis via bone mesenchymal stem cell inflammatory response. Acta Histochem 2022; 124:151913. [PMID: 35759812 DOI: 10.1016/j.acthis.2022.151913] [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: 02/14/2022] [Revised: 05/09/2022] [Accepted: 05/24/2022] [Indexed: 11/20/2022]
Abstract
Distraction osteogenesis (DO) is a widely used surgical technique to repair bone defects, partly owing to its high efficiency in inducing osteogenesis; however, the process of osteogenesis is complex, and the precise mechanism is still unclear. Among the factors identified for an effective DO procedure, well-controlled inflammation is essential. We aimed to explore how microRNA(miR)-146a, a negative regulator of inflammation, influences osteogenesis in DO. First, we established canine right mandibular DO and bone fracture models to evaluate the expression level of miR-146a in response to these procedures. Second, bone marrow mesenchymal stem cells (BMSCs) were isolated from healthy puppies and cultured with lipopolysaccharide (LPS) to observe how inflammation affects osteogenesis. Finally, the osteogenesis activity of BMSCs transfected with lentiviral vector either overexpressing (miR-146a-up) or inhibited for miR-146a expression was evaluated. miR-146a-up-transfected BMSCs were injected locally into the distraction gaps of the DO model canines. On days 42 and 56 post-surgery, the bone volume/tissue volume and bone mineral density values were evaluated via using micro-computed tomography, and newly formed tissues were harvested and evaluated via histological staining. The expression of miR-146a in both the DO canine model and LPS-stimulated BMSCs increased. Overexpression of miR-146a enhanced cell proliferation, migration, and osteogenic differentiation. Additionally, the newly formed callus was improved in canine mandibles injected with miR-146a-up-transfected BMSCs. In summary, miR-146a regulates mandibular DO by improving osteogenesis, and can serve as a potential target to shorten the therapy period of DO.
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Affiliation(s)
- Huijuan Shen
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Weidong Jiang
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Yangyang Yu
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Yuan Feng
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Tao Zhang
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Yan Liu
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Lina Guo
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Nuo Zhou
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China.
| | - Xuanping Huang
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China.
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MicroRNAs (miRNAs) in Cardiovascular Complications of Rheumatoid Arthritis (RA): What Is New? Int J Mol Sci 2022; 23:ijms23095254. [PMID: 35563643 PMCID: PMC9101033 DOI: 10.3390/ijms23095254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 02/08/2023] Open
Abstract
Rheumatoid Arthritis (RA) is among the most prevalent and impactful rheumatologic chronic autoimmune diseases (AIDs) worldwide. Within a framework that recognizes both immunological activation and inflammatory pathways, the exact cause of RA remains unclear. It seems however, that RA is initiated by a combination between genetic susceptibility, and environmental triggers, which result in an auto-perpetuating process. The subsequently, systemic inflammation associated with RA is linked with a variety of extra-articular comorbidities, including cardiovascular disease (CVD), resulting in increased mortality and morbidity. Hitherto, vast evidence demonstrated the key role of non-coding RNAs such as microRNAs (miRNAs) in RA, and in RA-CVD related complications. In this descriptive review, we aim to highlight the specific role of miRNAs in autoimmune processes, explicitly on their regulatory roles in the pathogenesis of RA, and its CV consequences, their main role as novel biomarkers, and their possible role as therapeutic targets.
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The Association between Circulating microRNAs and the Risk of Active Disease Development from Latent Tuberculosis Infection: a Nested Case-Control Study. Microbiol Spectr 2022; 10:e0262521. [PMID: 35435753 PMCID: PMC9241859 DOI: 10.1128/spectrum.02625-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Tuberculosis (TB) remains one of the deadliest communicable diseases. Biomarkers predicting the risk of active disease development from latent tuberculosis infection (LTBI) are urgently needed for precise intervention. This study aimed to identify potential circulating microRNAs (miRNAs) playing such a role in Chinese population. Based on a prospective study aiming to track the development of active TB among rural residents with LTBI, the baseline levels of circulating miRNAs were retrospectively compared between those who developed TB (case group) and those age-gender matched controls remain free of TB (contraol group) during the follow-up. Agilent human miRNA microarray were used to select differently expressed circulating miRNAs and verified by subsequent real-time quantitative PCR (RT-qPCR). Six candidate miRNAs were expressed at statistically significant levels between the two groups at the baseline, as determined by microarray. Following verification among 150 study participants by RT-qPCR, the levels of hsa-miR-16-5p (P < 0.001) and hsa-miR-451a (P < 0.001) were found to be significantly lower in case group compared to control group. The combined areas under curves (AUCs) and precision-recall curves (PRCs) were 0.84, 0.86 and 0.85, 0.87 for hsa-miR-16-5p and hsa-miR-451a, respectively. hsa-miR-451a combined with body mass index (BMI) and prior history of TB presented the best performance, with a sensitivity of 80.82% and an acceptable specificity of 79.22%. After adjusting the two co-variables, the AUC of hsa-miR-451a was 0.78. Circulating levels of hsa-miR-451a showed potential to predict development of active TB from LTBI in a Chinese population. Further studies are warranted to verify these findings in varied study settings. IMPORTANCE Approximately a quarter of the world population are infected with M. tuberculosis and about 5% to 10% of these might develop active disease in their lifetime. Preventive treatment could effectively protect individuals at a high risk of developing active disease from LTBI, and is regarded as a critical component of End TB Strategies. Biomarkers which could accurately identify high-risk population and predict the risk of disease development are urgently needed for developing local guidelines of LTBI management and precise intervention. A nested case-control study was designed to explore possible microRNAs related with TB occurrence based on a previous prospective study, which aimed to track the development of active TB among rural residents with LTBI. The baseline circulating levels of hsa-miR-16-5p and hsa-miR-451a were significantly lower in TB cases compared to those in LTBI controls. Further receiver operator characteristic (ROC) curve analysis found that hsa-miR-451a showed considerable potential to predict the development of active TB from LTBI.
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Matz A, Qu L, Karlinsey K, Zhou B. Impact of microRNA Regulated Macrophage Actions on Adipose Tissue Function in Obesity. Cells 2022; 11:1336. [PMID: 35456015 PMCID: PMC9024513 DOI: 10.3390/cells11081336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/12/2022] [Accepted: 04/12/2022] [Indexed: 02/06/2023] Open
Abstract
Obesity-induced adipose tissue dysfunction is bolstered by chronic, low-grade inflammation and impairs systemic metabolic health. Adipose tissue macrophages (ATMs) perpetuate local inflammation but are crucial to adipose tissue homeostasis, exerting heterogeneous, niche-specific functions. Diversified macrophage actions are shaped through finely regulated factors, including microRNAs, which post-transcriptionally alter macrophage activation. Numerous studies have highlighted microRNAs' importance to immune function and potential as inflammation-modulatory. This review summarizes current knowledge of regulatory networks governed by microRNAs in ATMs in white adipose tissue under obesity stress.
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Affiliation(s)
- Alyssa Matz
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
| | - Lili Qu
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
| | - Keaton Karlinsey
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
| | - Beiyan Zhou
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (A.M.); (L.Q.); (K.K.)
- Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
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24
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miR-142-3p Suppresses Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Infection by Directly Targeting Rac1. Vet Microbiol 2022; 269:109434. [DOI: 10.1016/j.vetmic.2022.109434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/23/2022] [Accepted: 04/10/2022] [Indexed: 11/20/2022]
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Safarzadeh M, Mohammadi-Yeganeh S, Ghorbani-Bidkorbeh F, Haji Molla Hoseini M. Chitosan based nanoformulation expressing miR-155 as a promising adjuvant to enhance Th1-biased immune responses. Life Sci 2022; 297:120459. [PMID: 35248524 DOI: 10.1016/j.lfs.2022.120459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/18/2022] [Accepted: 03/01/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIM MiR-155 could act as a key modulator of different aspects of immune system including Th1 responses. In this study, we designed chitosan nanoparticles containing miR-155-expressing plasmid and explored their effects as an adjuvant to enhance Th1 responses for potential future application against intracellular pathogens. METHODS Nanoparticles were formulated by complex coacervation method and characterized for physicochemical and functional characteristics. Transfection efficiency in Raw 264.7 cells, effects on miR-155 target genes and NO production were evaluated. The prepared nanoparticles were co-administered as an adjuvant with ovalbumin to immunize mice and finally production of IFN-γ and IL-4 were measured by ELISA in splenocyte recall responses. RESULTS The prepared nanoparticles had the mean size of 244 nm and zeta potential of +17 mV, respectively. Electrophoresis analysis indicated the high capability of nanoparticles to protect the plasmid from DNaseI degradation. Furthermore, nanoparticles showed an appropriate transfection efficiency in Raw 264.7 cells and could downregulate the expression of miR-155 target genes and also upregulate NO production. In vivo immunization examinations revealed successful shift of T cell responses toward Th1. CONCLUSION Our data suggests the high potential of chitosan nanoparticles containing miR-155-expressing plasmid as an adjuvant for significantly enhanced Th1-biased immune responses upon immunization with a given antigen.
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Affiliation(s)
- Mehrnoush Safarzadeh
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghorbani-Bidkorbeh
- Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Haji Molla Hoseini
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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26
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Zhang X, Xu Z, Wen X, Huang G, Nian S, Li L, Guo X, Ye Y, Yuan Q. The onset, development and pathogenesis of severe neutrophilic asthma. Immunol Cell Biol 2022; 100:144-159. [PMID: 35080788 DOI: 10.1111/imcb.12522] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/02/2021] [Accepted: 01/23/2022] [Indexed: 12/12/2022]
Abstract
Bronchial asthma is divided into Th2 high, Th2 low and mixed types. The Th2 high type is dominated by eosinophils while the Th2 low type is divided into neutrophilic and paucigranulocytic types. Eosinophilic asthma has gained increased attention recently, and its pathogenesis and treatment are well understood. However, severe neutrophilic asthma requires more in-depth research because its pathogenesis is not well understood, and no effective treatment exists. This review looks at the advances made in asthma research, the pathogenesis of neutrophilic asthma, the mechanisms of progression to severe asthma, risk factors for asthma exacerbations, and biomarkers and treatment of neutrophilic asthma. The pathogenesis of neutrophilic asthma is further discussed from four aspects: Th17-type inflammatory response, inflammasomes, exosomes and microRNAs. This review provides direction for the mechanistic study, diagnosis and treatment of neutrophilic asthma. The treatment of neutrophilic asthma remains a significant challenge for clinical therapists and is an important area of future clinical research.
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Affiliation(s)
- Xingli Zhang
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Zixi Xu
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Xue Wen
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Guoping Huang
- Zigong Hospital of Woman and Children Healthcare, Sichuan, China
| | - Siji Nian
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Lin Li
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Xiyuan Guo
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Yingchun Ye
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
| | - Qing Yuan
- Public Center of Experimental Technology, Immune Mechanism and Therapy of Major Diseases of Luzhou Key Laboratory, School of Basic Medical Science of Southwest Medical University, Luzhou, Sichuan, China
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27
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Roffel MP, Maes T, Brandsma CA, van den Berge M, Vanaudenaerde BM, Joos GF, Brusselle GG, Heijink IH, Bracke KR. MiR-223 is increased in lungs of patients with COPD and modulates cigarette smoke-induced pulmonary inflammation. Am J Physiol Lung Cell Mol Physiol 2021; 321:L1091-L1104. [PMID: 34668437 DOI: 10.1152/ajplung.00252.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Since microRNA (miR)-223-3p modulates inflammatory responses and COPD is associated with amplified pulmonary inflammation, we hypothesized that miR-223-3p plays a role in COPD pathogenesis. Expression of miR-223-3p was measured in lung tissue of 2 independent cohorts with COPD GOLD stage II-IV patients, never smokers and smokers without COPD. The functional role of miR-223-3p was studied in deficient mice and upon overexpression in airway epithelial cells from COPD and controls. We observed higher miR-223-3p levels in patients with COPD stage II-IV compared to (non)-smoking controls, and levels were associated with higher neutrophil numbers in bronchial biopsies of COPD patients. MiR-223-3p expression was also increased in lungs and bronchoalveolar lavage of cigarette smoke (CS)-exposed mice. CS-induced neutrophil and monocyte lung infiltration was stronger in miR-223 deficient mice upon acute (5 days) exposure, but attenuated upon sub-chronic (4 weeks) exposure. Additionally, miR-223 deficiency attenuated acute and sub-chronic CS-induced lung infiltration of dendritic cells and T lymphocytes. Finally, in vitro overexpression of miR-223-3p in non-COPD airway epithelial cells suppressed CXCL8 and GM-CSF secretion and gene expression of the pro-inflammatory transcription factor TRAF6. Importantly, this suppressive effect of miR-223-3p was compromised in COPD-derived cultures. In conclusion, we demonstrate that miR-223-3p is increased in lungs of COPD patients and CS-exposed mice, and is associated with neutrophilic inflammation. In vivo data indicate that miR-223 acts as negative regulator of acute CS-induced neutrophilic and monocytic inflammation. In vitro data suggests that miR-223-3p does so by suppressing pro-inflammatory airway epithelial responses, which is less effective in COPD epithelium.
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Affiliation(s)
- Mirjam P Roffel
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, The Netherlands.,Ghent University, Ghent University Hospital, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent, Belgium
| | - Tania Maes
- Ghent University, Ghent University Hospital, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent, Belgium
| | - Corry-Anke Brandsma
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, The Netherlands
| | - Maarten van den Berge
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, The Netherlands.,University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands
| | - Bart M Vanaudenaerde
- Laboratory for Respiratory Diseases, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Guy F Joos
- Ghent University, Ghent University Hospital, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent, Belgium
| | - Guy G Brusselle
- Ghent University, Ghent University Hospital, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent, Belgium
| | - Irene H Heijink
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, The Netherlands.,University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands
| | - Ken R Bracke
- Ghent University, Ghent University Hospital, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent, Belgium
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Usuelli V, Ben Nasr M, D'Addio F, Liu K, Vergani A, El Essawy B, Yang J, Assi E, Uehara M, Rossi C, Solini A, Capobianco A, Rigamonti E, Potena L, Venturini M, Sabatino M, Bottarelli L, Ammirati E, Frigerio M, Castillo‐Leon E, Maestroni A, Azzoni C, Loretelli C, Joe Seelam A, Tai AK, Pastore I, Becchi G, Corradi D, Visner GA, Zuccotti GV, Chau NB, Abdi R, Pezzolesi MG, Fiorina P. miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy. Am J Transplant 2021; 21:3280-3295. [PMID: 33764625 PMCID: PMC8518036 DOI: 10.1111/ajt.16581] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/19/2021] [Accepted: 03/09/2021] [Indexed: 01/25/2023]
Abstract
Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.
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Affiliation(s)
- Vera Usuelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Moufida Ben Nasr
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Francesca D'Addio
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Kaifeng Liu
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Andrea Vergani
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Basset El Essawy
- Department of MedicineAl‐Azhar UniversityCairoEgypt,Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Jun Yang
- Institute of Organ TransplantationTongji Hospital and Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Emma Assi
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Mayuko Uehara
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Chiara Rossi
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Anna Solini
- Department of SurgicalMedical, Molecular and Critical Area PathologyUniversity of PisaPisaItaly
| | - Annalisa Capobianco
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Elena Rigamonti
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Luciano Potena
- Heart Failure and Heart Transplant ProgramS. Orsola‐Malpighi HospitalAlma‐Mater University of BolognaBolognaItaly
| | | | - Mario Sabatino
- Department of Cardiothoracic, Transplantation and Vascular SurgeryS. Orsola‐Malpighi HospitalAlma Mater‐University of BolognaBolognaItaly
| | | | - Enrico Ammirati
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Maria Frigerio
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Eduardo Castillo‐Leon
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Anna Maestroni
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Cinzia Azzoni
- Department of Medicine and SurgeryUniversity of ParmaParmaItaly
| | - Cristian Loretelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Andy Joe Seelam
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Albert K. Tai
- Tufts University Core Facility (TUCF) Genomics CoreTufts University School of MedicineBostonMassachusetts
| | - Ida Pastore
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| | | | | | - Gary A. Visner
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Gian V. Zuccotti
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Department of PediatricsBuzzi Children's HospitalMilanItaly
| | | | - Reza Abdi
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Marcus G. Pezzolesi
- Division of Nephrology and Hypertension, Diabetes and Metabolism CenterUniversity of UtahSalt Lake CityUtah
| | - Paolo Fiorina
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts,Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
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Boštjančič E, Večerić-Haler Ž, Kojc N. The Role of Immune-Related miRNAs in the Pathology of Kidney Transplantation. Biomolecules 2021; 11:biom11081198. [PMID: 34439863 PMCID: PMC8393721 DOI: 10.3390/biom11081198] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 01/04/2023] Open
Abstract
MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation.
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Affiliation(s)
- Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Željka Večerić-Haler
- Department of Nephrology, University Medical Centre, 1000 Ljubljana, Slovenia;
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- Correspondence: ; Tel.: +386-154-371-25
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MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission. Sci Rep 2021; 11:15676. [PMID: 34344968 PMCID: PMC8333426 DOI: 10.1038/s41598-021-95028-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 07/16/2021] [Indexed: 11/09/2022] Open
Abstract
Modulation of miRNAs and neutrophil extracellular traps (NETs) formation are both implicated in inflammatory disorders. Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease with neutrophilic leukocytosis and unknown etiology. Although the NETs formation is elevated in AOSD patients, the regulatory roles of miRNAs in NETs formation in AOSD remains unclear. We revealed that the circulating levels of IL-18, NETs, and miR-223 were significantly higher in active AOSD patients, compared with inactive AOSD patients or healthy controls (P < 0.005). Moreover, IL-18 increased calcium influx into neutrophils, which led to mitochondrial ROS (mROS) production and NETs formation. Elevated levels of NETs-DNA could induce miR-223 expression in neutrophils through activating Toll-like receptor 9. The upregulated miR-223 expression in neutrophils suppressed mROS production by blocking calcium influx, and subsequently inhibited IL-18-mediated NETs formation. Besides, the increased neutrophil-derived exosomal miR-223 levels were observed in active AOSD patients compared with healthy controls (P < 0.005). Our in vitro assays demonstrated that the neutrophil-derived small extracellular vesicles carried miR-223, which could repress IL-18 production in macrophages. Together, these results suggest a fine-tuned mechanism between inflammatory (IL-18 induced NETs) and anti-inflammatory (miR-223) factors in AOSD. MiR-223, mROS inhibitors, and calcium channel blockers are the potential therapeutics for autoinflammatory diseases such as AOSD.
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Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease. Mediators Inflamm 2021; 2021:9999146. [PMID: 34158806 PMCID: PMC8187052 DOI: 10.1155/2021/9999146] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/04/2021] [Indexed: 12/14/2022] Open
Abstract
The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.
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Zhang H, Li M, Kaboli PJ, Ji H, Du F, Wu X, Zhao Y, Shen J, Wan L, Yi T, Wen Q, Li X, Cho CH, Li J, Xiao Z. Identification of cluster of differentiation molecule-associated microRNAs as potential therapeutic targets for gastrointestinal cancer immunotherapy. Int J Biol Markers 2021; 36:22-32. [PMID: 33788641 DOI: 10.1177/17246008211005473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Cluster of differentiation molecules are markers of immune cells that have been identified as a potential immunotherapeutic target for cancer treatment. MicroRNAs are small non-coding RNAs that act as tumor suppressors or oncogenes whose importance in diagnosis, prognosis, and treatment of gastric and colorectal cancers has been widely reported. However, their association with cluster of differentiation molecules in gastrointestinal cancers has not been well studied. Therefore, our study aimed to analyze the relationship between microRNAs and cluster of differentiation molecules in gastrointestinal cancers, and to identify cluster of differentiation molecule-associated microRNAs as prognostic biomarkers for gastrointestinal cancer patients. METHODS Targetscan, Starbase, DIANA microT, and miRDB were used to investigate microRNA profiles that might be correlated with cluster of differentiation molecules in gastrointestinal cancers. Moreover, The Cancer Genome Atlas data analysis was used to investigate the association between cluster of differentiation molecules and microRNA expression in patients with gastric, colon, rectal, pancreatic, and esophageal cancers. The Kaplan-Meier plotter was used to identify the association between overall survival and cluster of differentiation molecule-associated microRNA expression in gastrointestinal cancer patients. RESULTS miR-200a, miR-559, and miR-1236 were negatively associated with CD86, CD81, and CD160, respectively, in almost all types of gastrointestinal cancers, which were further verified in the in vitro studies by transfecting microRNA mimics in gastric cancer, colon cancer, pancreatic, and esophageal cell lines. CONCLUSION Our study showed that miR-200a, miR-1236, and miR-559 are identified as cluster of differentiation-associated microRNAs in gastrointestinal cancers, providing a novel perspective to identify new therapeutic targets for cancer immunotherapy in gastrointestinal cancer patients.
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Affiliation(s)
- Hanyu Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Parham Jabbarzadeh Kaboli
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Huijiao Ji
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Lin Wan
- Department of Hematology and Oncology, The Children's Hospital of Soochow, Suzhou, Jiangsu, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, PR China
| | - Xiang Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Jing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China.,Department of Oncology and Hematology, Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
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Circulating MicroRNAs as Potential Biomarkers in the Diagnosis of Neurosyphilis: A Case Control Study. INTERNATIONAL JOURNAL OF DERMATOLOGY AND VENEREOLOGY 2021. [DOI: 10.1097/jd9.0000000000000127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Feiz Haddad MH, Rezvan H, Nourian A, Habibpour H. Expression of MicroRNA of Macrophages Infected with Attenuated Leishmania major Parasite. J PEDIAT INF DIS-GER 2021. [DOI: 10.1055/s-0041-1724021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Abstract
Objective Leishmaniasis has been proposed as one of the neglected vector-borne diseases due to an obligate intracellular parasite of the genus Leishmania. MicroRNAs (miRNAs) with a length of 22-nucleotide are known as the noncoding small RNAs. MiRNAs contribute to many biological and cellular approaches. Therefore, the present study evaluated expressing mmu-miR-721, mmu-miR-294–3p, mmu-miR-155–3p, and mmu-miR-30a in murine macrophages infected with attenuated Leishmania major parasites on 3 days after infection.
Methods Attenuated promastigotes have been achieved after 20 passages of Leishmania major parasites. Cell line J774A.1 (murine macrophage) has been used for in vitro experiments. The stationary phase of attenuated L. major promastigotes has been chosen to infect the cells, and then their incubation has been performed with 5% CO2 at 37°C for 3 days. The real-time polymerase chain reaction (PCR) has also been performed with SYBR Green master-mix Kit for measuring the level of mmu-miR-721, mmu-miR-294–3p, mmu-miR-30a, and mmu-miR-155-3p expression. Uninfected macrophages have been considered as a control group.
Results Real-time PCR demonstrated overexpression of mmu-miR-155-3p, mmu-miR-294–3p, and, mmu-miR-721 in the infected cells with Leishmania parasites after 3 days. Results showed no statistically significant difference in the mmu-miR-30a expression between infected macrophages and the uninfected control group.
Conclusion Our findings suggested the significant contribution of the alterations in the miRNA levels to the regulation of macrophage functions following the creation of intracellular parasites like Leishmania. These data could help to understand better the genes' expression in the host cells in the course of leishmaniasis.
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Affiliation(s)
- Mohammad Hossein Feiz Haddad
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Parasitology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Rezvan
- Department of Pathobiology, Faculty of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Alireza Nourian
- Department of Pathobiology, Faculty of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Habib Habibpour
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Parasitology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Inhibition of anti-inflammatory cytokines, IL-10 and TGF-β, in Leishmania major infected macrophage by miRNAs: A new therapeutic modality against leishmaniasis. Microb Pathog 2021; 153:104777. [PMID: 33592260 DOI: 10.1016/j.micpath.2021.104777] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/18/2020] [Accepted: 01/28/2021] [Indexed: 01/03/2023]
Abstract
Leishmania major (L. major) applies several mechanisms to escape the immune system. Interleukin-10 (IL-10) and Transforming Growth Factor (TGF-β) downregulate nitric oxide synthase (iNOS) leading to the survival of Leishmania within macrophages. The miRNAs are known as the modulators of the immune system. The present study was conducted to assess the effect of synthetic miR-340 mimic on cytokines (IL-10 and TGF-β1) involved in L. major infected macrophages. The miRNAs targeting of IL-10 and TGF-β1 was predicted using bioinformatic tools. Relative expression of predicted miRNA, IL-10, and TGF-β1 was measured by RT-qPCR before and after synthetic miRNA mimic transfection. Concentration of IL-10 and TGF-β was measured in posttreatment condition using ELISA method. Also, infectivity was assessed by Giemsa staining. mmu-miR-340 received the highest score for targeting cytokines. The expression of miR-340 was downregulated in L. major infected macrophages. By contrast, expression of IL-10 and TGF-β1 was upregulated in infected macrophages. After miRNA transfection, TGF-β1 and IL-10 were both downregulated and interestingly, the combination of miR-340 and miR-27a had a stronger effect on the downregulation of target genes. This research revealed that transfection of infected macrophages with miR-340 alone or in combination with miR-27a mimic can reduce macrophage infectivity and might be introduced as a novel therapeutic agent for cutaneous leishmaniasis.
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Progressive Control of Streptococcus agalactiae-Induced Innate Inflammatory Response Is Associated with Time Course Expression of MicroRNA-223 by Neutrophils. Infect Immun 2020; 88:IAI.00563-20. [PMID: 32958526 DOI: 10.1128/iai.00563-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/10/2020] [Indexed: 12/19/2022] Open
Abstract
Group B streptococcus (GBS) is a human-pathogenic bacterium inducing a strong inflammatory response that may be detrimental for host tissues if not finely regulated. The inflammatory response can be modulated by different molecular mechanisms, among which growing evidence points toward the crucial role of microRNAs (miRNAs). Regarding innate inflammatory response, studies have reported that miR-223 is essential for the control of granulocyte proliferation and activation. Moreover, a number of investigations on miRNA expression profiling performed in various inflammatory settings have revealed that miR-223 is among the top differentially expressed miRNAs. Yet the dynamic pattern of expression of miR-223 in vivo with respect to the evolution of the inflammatory process, especially in microbial infection, remains elusive. In this study, we analyzed the kinetic expression of miR-223 in an inflammatory model of GBS-induced murine pneumonia and looked for correlates with inflammatory markers, including innate cell infiltrates. We found that miR-223 expression is rapidly induced at very early time points (3 to 6 h postinfection [p.i.]) mainly by lung-infiltrating neutrophils. Interestingly, the level of miR-223 accumulating in the lungs remains higher at later stages of infection (24 h and 48 h p.i.), and this correlates with reduced expression of primary inflammatory cytokines and chemokines and with a shift in infiltrating monocyte and macrophage subtypes toward a regulatory phenotype. Transient inhibition of miR-223 by an antagomir resulted in significant increase of CXCL2 expression and partial enhancement of infiltrating neutrophils in GBS-infected lung tissues. This suggests the potential contribution of miR-223 to the resolution phase of GBS-induced acute inflammation.
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MiRNA-574-3p inhibits cell progression by directly targeting CCND2 in colorectal cancer. Biosci Rep 2020; 39:221158. [PMID: 31729531 PMCID: PMC6911158 DOI: 10.1042/bsr20190976] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 11/05/2019] [Accepted: 11/14/2019] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) remains the candidate for one of the typical types of malignant tumors of in gastrointestinal tract all around the world, which leads to tremendous death and ranks as the top leading death of cancer. Recently, microRNAs have emerged as double-edged sword in numerous cancers. This investigation aims to discuss the regulative role of microRNA-574-3p (miR-574-3p), elucidating its molecular mechanism and clinical significance in CRC. Herein, it revealed to us that miR-574-3p was lowly expressed in CRC tissues in comparison with the matched paracarcinoma tissues. In addition, transfection of SW480 and HT29 cells with miR-574-3p mimics prohibited the post-transcriptional expression of Cyclin D2 (CCND2), which then significantly blocked cell growth and cell migration, yet triggered cell apoptosis. Also, dual-luciferase reporter assays proved the role of CCND2 as the targeted gene for miR-574-3p. miR-574-3p overexpression prohibited the activity of CCND2 in SW480 and HT29 cells. Silencing of CCND2 in SW480 and HT29 CRC cell lines leading to reduced cell proliferative and migrative rates, and enhanced apoptotic rate. The suppressive effects of elevation of miR-574-3p on the proliferation of the human CRC cells and promotive effects on cell apoptosis by targeting CCND2 were further illustrated in the in vitro studies. Thus, we hypothesize that miR-574-3p may be served as a prospective therapeutic candidate for CRC.
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Zhang G, Hu Y, Yuan W, Qiu H, Yu H, Du J. miR-519d-3p Overexpression Inhibits P38 and PI3K/AKT Pathway via Targeting VEGFA to Attenuate the Malignant Biological Behavior of Non-Small Cell Lung Cancer. Onco Targets Ther 2020; 13:10257-10266. [PMID: 33116606 PMCID: PMC7568445 DOI: 10.2147/ott.s252795] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Background Non-small cell lung cancer (NSCLC) is a heterogeneous tumor that accounts for approximately 85% of all lung cancer cases worldwide. microRNAs (miRNAs) are believed to play an important role in regulating a variety of biological processes, including immunity and cancer. We investigated the effect of miR-519d-3p on the mitigation of NSCLC in vitro and in vivo. Methods RT-PCR or immunohistochemical assays were used to assess the expression of miR-519d-3p. Colony formation, flow cytometry, and transwell assay were respectively used to detect proliferation, apoptosis, and invasion of A549 and NCI-H661 cell lines. Luciferase reporter assay was used to verify targeting the relationship between mir-519d-3p and VEGFA. Western blot was used to examine the expression of Ki67, caspase-3, E-cadherin, N-cadherin, VEGF, P38, and PI3K/AKT. Animal models were established by BABL/c mice to research the effect of mir-519d-3p overexpression in vivo. Results In vitro, miR-519d-3p overexpression inhibited A549 and NCI-H661 cells proliferation, invasion, and also promoted apoptosis. In addition, miR-519d-3p overexpression downregulated VEGFA expression and decreased the P38 and PI3K/AKT phosphorylation level. In vivo, miR-519d-3p overexpression significantly restrained tumor volume (2087±265 mm3 vs 599±135 mm3, *P< 0.05) and tumor weight (0.45±0.08 g vs 0.13±0.06 g, *P<0.05) compared with the control group. Overexpression of miR-519d-3p downregulated levels of Ki67 and N-cadherin significantly. Conclusion The data indicated that miR-519d-3p could be a novel therapy or adjuvant against NSCLC.
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Affiliation(s)
- Guangzhao Zhang
- Department of Minimally Invasive Surgery, Henan Chest Hospital, Zhengzhou, Henan 450003, People's Republic of China
| | - Yanlei Hu
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan 451464, People's Republic of China
| | - Wuying Yuan
- Department of Minimally Invasive Surgery, Henan Chest Hospital, Zhengzhou, Henan 450003, People's Republic of China
| | - Hongli Qiu
- Department of Minimally Invasive Surgery, Henan Chest Hospital, Zhengzhou, Henan 450003, People's Republic of China
| | - Haifeng Yu
- Department of Minimally Invasive Surgery, Henan Chest Hospital, Zhengzhou, Henan 450003, People's Republic of China
| | - Jiahui Du
- Department of Minimally Invasive Surgery, Henan Chest Hospital, Zhengzhou, Henan 450003, People's Republic of China
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miR-369-3p modulates inducible nitric oxide synthase and is involved in regulation of chronic inflammatory response. Sci Rep 2020; 10:15942. [PMID: 32994523 PMCID: PMC7525504 DOI: 10.1038/s41598-020-72991-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 09/10/2020] [Indexed: 11/08/2022] Open
Abstract
Dendritic cells are the most important antigen-presenting cells that link the innate and acquired immune system. In our previous study, we identified that the upregulation of miR-369-3p suppresses the LPS-induced inflammatory response, reducing C/EBP-β, TNFα and IL-6 production. With the aim of gaining further insight into the biological function of miR-369-3p during acute inflammatory response, in the present study we identified novel gene targets of miR-369-3p and demonstrated the suppressive ability of these genes on the inflammatory dendritic cells. Bioinformatic analyses revealed that iNOS is a potential target of miR-369-3p. We demonstrated that the ectopic induction of miR-369-3p markedly reduced iNOS mRNA and protein as well as NO production. Moreover, we found that the upregulation of miR-369-3p decreased the release of TNFα, IL-6, IL-12, IL-1α, IL-1β in response to LPS, and increased the production of anti-inflammatory cytokines such as IL-10 and IL-1RA. In addition, LPS-induced nuclear translocation of NF-kB was inhibited by miR-369-3p. Levels of miR-369-3p were decreased in human inflamed regions of human intestine obtained from IBD patients. Our results provide novel additional information on miR-369-3p as a potential core of the signaling regulating the inflammatory response. These findings suggest that miR-369-3p should be considered as a potential target for the future development of new molecular therapeutic approaches.
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Mechanism of miRNA-based Aconitum leucostomum Worosch. Monomer inhibition of bone marrow-derived dendritic cell maturation. Int Immunopharmacol 2020; 88:106791. [PMID: 32871480 DOI: 10.1016/j.intimp.2020.106791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 06/15/2020] [Accepted: 07/06/2020] [Indexed: 11/24/2022]
Abstract
Delvestidine (DLTD) is a monomeric compound isolated from Aconitum leucostomum Worosch, a widely used medicine for local treatment of rheumatoid arthritis (RA). Studies have shown that Aconitum leucostomum Worosch. can inhibit maturation of bone marrow-derived dendritic cells (BMDCs). Further, microRNAs (miRNAs) have regulatory effects on DC maturity and function. However, the mechanism underlying DLTD effects on DC maturity and RA remains to be elucidated. This study investigated whether DLTD-mediated inhibition of DC maturation is regulated by miRNAs. LPS-induced mature BMDCs were treated with DLTD for 48 h. CD80 and CD86 expression on BMDCs was detected by flow cytometry, and levels of inflammatory factors IL-6, IL-23, IL-1β, and TNF-α were detected by ELISA and PCR. Further, gene expression and miRNA expression profiles were investigated by bioinformatics analysis and verified by PCR. DLTD was found to inhibit CD80 and CD86 expression on the surface of BMDCs and secretion of inflammatory factors IL-6, IL-23, IL-1β, and TNF-α. In total, 54 differentially expressed miRNAs were detected, including 29 up-regulated and 25 down-regulated miRNAs after DLTD treatment. Analysis of biological information revealed that the differentially expressed target genes mainly regulated biological processes, including cell differentiation, cell cycle, and protein kinase complexes. Additionally, miR-511-3p downstream targets Calcr, Fzd10, and Eps8, were closely related to BMDCs maturation. DLTD may induce BMDCs maturity through regulation of miRNAs that affect Calcr, Fzd10, and Eps8 gene signals.
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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: 25] [Impact Index Per Article: 5.0] [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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Di Stefano AB, Pappalardo M, Moschella F, Cordova A, Toia F. MicroRNAs in solid organ and vascularized composite allotransplantation: Potential biomarkers for diagnosis and therapeutic use. Transplant Rev (Orlando) 2020; 34:100566. [PMID: 32682704 DOI: 10.1016/j.trre.2020.100566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/23/2020] [Accepted: 06/30/2020] [Indexed: 12/24/2022]
Abstract
Nowadays, solid organ transplantation (SOT) is an established treatment for patients with end-organ dysfunction, which dramatically improves the quality-of-life. Vascularized composite allotransplants (VCAs) including hand and face have been reported worldwide over the last 20 years. However, VCAs, differently to SOT, are life-enhancing instead of life-saving and are not routinely performed due to the risk of immune rejection and the adverse effects of immunosuppression. Over the past decade, although considerable improvements in short-term outcomes after allotransplantation have been registered, these results have not been translated into major progress in long-term allograft acceptance and patient survival. Recently active researches in the field of biomarker discovery have been conducted to develop individualized therapies for allograft recipients. MicroRNAs (miRNAs) are a small noncoding RNAs functioning as critical regulators of gene and protein expression by RNA interference. They have been connected in numerous biological processes and diseases. Due to their immunomodulatory functions, miRNAs have been amended as potential diagnostic and prognostic biomarker for the detection of rejection in allotransplantation. Due to their specific circulating expression profile, they could act as noninvasive predictive tools for rejection that may help clinicians in an early adjustment of the immunosuppression protocol during acute rejections episodes. Indeed, specific anti-sense oligonucleotides suppressing miRNAs expressed in rejection could reduce the rejection rate in allografts and decrease the use of immunosuppressants. We present a literature review of the immunomodulatory properties and characteristics of miRNAs. We will summarize the current knowledge on miRNAs as potential biomarkers for allograft rejection and possible application in allotransplantation monitoring. Finally, we will discuss the advances in preclinical miRNA-based therapies for immunosuppression.
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Affiliation(s)
- Anna Barbara Di Stefano
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Marco Pappalardo
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Francesco Moschella
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Adriana Cordova
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
| | - Francesca Toia
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
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Zheng J, Wang W, Hong T, Yang S, Shen J, Liu C. Suppression of microRNA-155 exerts an anti-inflammatory effect on CD4+ T cell-mediated inflammatory response in the pathogenesis of atherosclerosis. Acta Biochim Biophys Sin (Shanghai) 2020; 52:654-664. [PMID: 32372074 DOI: 10.1093/abbs/gmaa040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/27/2022] Open
Abstract
In the current study, we aimed to investigate the effects of miR-155 on CD4+ T cell-mediated immune response in the pathogenesis of atherosclerosis. CD34+ hematopoietic stem cells, CD4+ T lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) were harvested from the same donor. Knockdown of miR-155 in the CD4+ T cells was achieved by lentiviral transfection, whereas control RNA-transfected or untransfected lymphocytes were used as controls. The transfected CD4+ T cells were activated by incubating with oxidized low-density lipoprotein-treated dendritic cells. The proliferative capacities, phenotype distribution, and cytokine secretion profiles of the activated CD4+ T cells from different groups were evaluated. The activated lymphocytes were used to treat ECs co-cultivated with VSMCs. The ability of the CD4+ T cells to induce the apoptosis of the ECs and to promote the proliferation of the VSMCs was investigated. Inhibition of miR-155 was found to significantly reduce the proliferation rate of the transfected CD4+ T cells. CD4+ T lymphocytes transfected with the miR-155 inhibitor showed increased populations of T helper type 2 and regulatory T cells, as well as more production of anti-inflammatory cytokines. MiR-155 knockdown was also shown to significantly hamper the ability to CD4+ T cells to induce EC apoptosis and to promote the growth of VSMCs. Our data suggested that inhibition of miR-155 in CD4+ T cells could slow down the formation of atherosclerotic plaques. These results lay the groundwork for future research on the therapeutic potential of miR-155 against atherosclerosis-associated cardiovascular diseases.
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Affiliation(s)
- Jiayu Zheng
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenshuo Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Tao Hong
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shouguo Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jinqiang Shen
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chen Liu
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Abstract
20-Hydroxyecdysone (20-HE) plays essential roles in coordinating developmental transitions of insects through responsive protein-coding genes and microRNAs (miRNAs). The involvement of single miRNAs in the ecdysone-signalling pathways has been extensively explored, but the interplay between ecdysone and the majority of miRNAs still remains largely unknown. Here, by small RNA sequencing, we systematically investigated the genome-wide responses of miRNAs to 20-HE in the embryogenic cell lines of Bombyx mori and Drosophila melanogaster. Over 60 and 70 20-HE-responsive miRNAs were identified in the BmE cell line and S2 cell line, respectively. The response of miRNAs to ecdysone exhibited a time-dependent pattern, and the response intensity increased with extending exposure to 20-HE. The relationship between ecdysone and the miRNAs was further explored through knockdown of ecdysone-signalling pathway genes. Specifically, ecdysone regulated the cluster miR-275 and miR-305 through the coordination of BmEcR-B and downstream BmE75B, and the interaction between BmEcR and miR-275 cluster was strengthened by the feedback regulation of BmE75B. Ecdysone induced miR-275-3p and miR-305-5p through the ecdysone response effectors (EcREs) at the upstream of the pre-miR-275 cluster. Overall, the results might help us further understand the relationship between ecdysone signalling pathways and small RNAs in the development and metamorphosis of insects.
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Affiliation(s)
- Xiaoli Jin
- State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University , Chongqing, PR China
| | - Xiaoyan Wu
- State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University , Chongqing, PR China
| | - Lanting Zhou
- State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University , Chongqing, PR China
| | - Ting He
- State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University , Chongqing, PR China
| | - Quan Yin
- State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University , Chongqing, PR China
| | - Shiping Liu
- State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University , Chongqing, PR China.,College of Life Science, China West Normal University , Nanchong, PR China
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Nimsarkar P, Ingale P, Singh S. Systems Studies Uncover miR-146a as a Target in Leishmania major Infection Model. ACS OMEGA 2020; 5:12516-12526. [PMID: 32548436 PMCID: PMC7271362 DOI: 10.1021/acsomega.0c01502] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 05/04/2020] [Indexed: 06/11/2023]
Abstract
Leishmaniasis, the second most neglected tropical disease, has been reported to affect approximately 12 million people worldwide. The causative protozoan parasite Leishmania has shown drug resistance to available chemotherapies, owing to which we need to look for better approaches to deal with the clinical situations. As per recent reports, several miRNAs have been found to be differentially expressed during Leishmania major infection in host macrophages. We aim to evaluate the impact of miRNA-mediated gene regulation on the key players of inflammation and macrophage dysfunction. The origin of Leishmania miRNAs and their processing is a questionable phenomenon as of yet. Through our study, we aim to provide a framework of their characterization. We amalgamate chemical systems biology and synthetic biology approaches to identify putative miRNA targets and unravel the complexity of host-pathogen gene regulatory networks.
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Lu H, Hu J, Li J, Lu W, Deng X, Wang X. miR-328-3p overexpression attenuates the malignant proliferation and invasion of liver cancer via targeting Endoplasmic Reticulum Metallo Protease 1 to inhibit AKT phosphorylation. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:754. [PMID: 32647679 PMCID: PMC7333113 DOI: 10.21037/atm-20-3749] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Liver cancer is one of the most common cancers worldwide. microRNAs (miRNAs) have been recognized as minimally invasive prognostic markers for distinct types of cancer. This study evaluates the mitigation role of miR-328-3p on liver cancer in vitro and in vivo. Methods Liver cancer cell line Huh-7 and HepG2 were used for in vitro experiments. Compared with the control group, miR-328-3p overexpression inhibited the proliferation, invasion, and promoted apoptosis of Huh-7 cells. miR-328-3p and endoplasmic reticulum metalloprotease 1 (ERMP1) had an excellent targeting relationship. Compared with the pcDNA-ERMP1 transfection group, the ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR in miR-328-3p mimic and pcDNA-ERMP1 co-transfection group were significantly decreased. Animal models were set up using four-week-old immunodeficient BABL/c female nude mice. Huh-7 cells transfected with lentivirus holding miR-328-3p or empty vector were injected into the right dorsal side of BABL/c nude mice, respectively. Tumor volume was measured every five days. After one month, animals were sacrificed, xenograft tumors were dissected and weighed for RT-PCR and immunohistochemical assays. Results Compared with control group, miR-328-3p overexpression significantly inhibited tumor weight (0.46±0.07 vs. 0.11±0.05 g, P<0.05) and tumor volume (1876±321 vs. 543±168 mm3, P<0.05) after thirty days. miR-328-3p overexpression significantly downregulated the percentage of Ki67 positive cells, N-cadherin positive cells and vimentin positive cells. Conclusions These findings suggested that miR-328-3p could be a new treatment or a novel marker for liver cancer prognosis.
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Affiliation(s)
- Hua Lu
- Anesthesia Operation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Jiali Hu
- Department of Pain, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Jianping Li
- Department of Geriatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Weifeng Lu
- Anesthesia Operation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiaofan Deng
- Organ Transplant Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xu Wang
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
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Parihar A, Tembhre M, Sharma V, Gupta S, Chattopadhyay P, Deepak K. Effect of narrowband ultraviolet B treatment on micro
RNA
expression in active nonsegmental generalized vitiligo. Br J Dermatol 2020; 183:167-169. [DOI: 10.1111/bjd.18890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- A.S. Parihar
- Department of Dermatology and Venereology AIIMS New Delhi India
| | - M.K. Tembhre
- Department of Cardiac Biochemistry AIIMS New Delhi India
| | - V.K. Sharma
- Department of Dermatology and Venereology AIIMS New Delhi India
| | - S. Gupta
- Department of Dermatology and Venereology AIIMS New Delhi India
| | | | - K.K. Deepak
- Department of Physiology AIIMS New Delhi India
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Hernández-Walias FJ, Vázquez E, Pacheco Y, Rodríguez-Fernández JM, Pérez-Elías MJ, Dronda F, Casado JL, Moreno A, Hermida JM, Quereda C, Hernando A, Tejerina-Picado F, Asensi V, Galindo MJ, Leal M, Moreno S, Vallejo A. Risk, Diagnostic and Predictor Factors for Classical Hodgkin Lymphoma in HIV-1-Infected Individuals: Role of Plasma Exosome-Derived miR-20a and miR-21. J Clin Med 2020; 9:jcm9030760. [PMID: 32168859 PMCID: PMC7141191 DOI: 10.3390/jcm9030760] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/27/2020] [Accepted: 03/08/2020] [Indexed: 02/07/2023] Open
Abstract
The incidence of classical Hodgkin lymphoma (cHL) in the HIV-1 setting has increased 5–25-fold compared to that observed in the general population. This study aimed to determine whether selected micro RNAs (miRs) and other soluble biomarkers and cellular subsets are dysregulated in cHL and could be used as biomarkers. This was a retrospective and longitudinal matched case-control study of 111 Caucasian, HIV-1-infected adult individuals, including 37 individuals with cHL and 74 with no type of cancer. Immunovirological data, plasma exosome-derived miR-16, miR-20a, miR-21, miR-221, miR-223, miR-106a, miR-185, miR-23, miR-30d, miR-222, miR-146a and miR-324, plasma IL-6, sCD14, sCD27, sCD30, sIL-2R, TNFR1, and cell phenotyping of T and B lymphocytes and natural killer (NK) cells were analyzed. Before cHL diagnosis, miR-20a, miR-21, and sCD30 were higher in cHL (p = 0.008, p = 0.009 and p = 0.042, respectively), while miR-16 was down-regulated (p = 0.040). miR-20a and miR-21 were independently associated with cHL (p = 0.049 and p = 0.035, respectively). The combination of miR-20a and miR-21 showed a good AUC value of 0.832 with a moderate likelihood ratio positive (LR+) value of 5.6 and a slight likelihood ratio negative (LR−) value of 0.23. At cHL diagnosis, miR-20a, miR-21 and miR-324 were overexpressed in cHL (p = 0.005, p = 0.024, and p = 0.001, respectively), while miR-223, miR-16, miR-185 and miR-106a were down regulated (p = 0.042, p = 0.007, p = 0.006, and p = 0.002, respectively). In addition, sCD14, sCD27, sCD30 and IL2R levels were higher in these individuals (p = 0.038, p = 0.010, p = 0.030, p = 0.006, respectively). miR-20a was independently associated with cHL (p = 0.011). The diagnostic value of miR-20a showed good AUC value of 0.754 (p = 0.074) with a slight LR+ value of 2 and a slight LR− of 0.25. After chemotherapy, miR-20a was higher in those individuals who had an adverse outcome (p < 0.001), while sCD14 and sCD30 were higher (p < 0.001). A specific signature of miRs and cytokines associated with a subsequent cHL diagnosis was found in this study, especially miR-20a and miR-21. Also, another biomarker signature was found at cHL diagnosis, with a relevant discriminant disease value for miR-20a. Of note, miR-20a expression was higher in those individuals who had an adverse clinical outcome after chemotherapy.
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Affiliation(s)
- Francisco J. Hernández-Walias
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Esther Vázquez
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Yolanda Pacheco
- Biomedicine Institute of Seville (IBiS), University Hospital Virgen del Rocío, 41013 Seville, Spain; (Y.P.); (M.L.)
| | | | - María J. Pérez-Elías
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Fernando Dronda
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - José L. Casado
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Ana Moreno
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - José M. Hermida
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Carmen Quereda
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Asunción Hernando
- Department of Medicine, 12 de Octubre University Hospital, Universidad European University of Madrid, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
| | | | - Víctor Asensi
- Infectious Diseases Department, Central University Hospital of Asturias, University Medical School, 33011 Oviedo, Spain;
- Group of Translational Research in Infectious Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | | | - Manuel Leal
- Biomedicine Institute of Seville (IBiS), University Hospital Virgen del Rocío, 41013 Seville, Spain; (Y.P.); (M.L.)
- Department of Internal Medicine and Infectious Diseases, Viamed Hospital, Santa Ángela de la Cruz, 41014 Seville, Spain
| | - Santiago Moreno
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
| | - Alejandro Vallejo
- Laboratory of Immunovirology, Infectious Diseases Department, Health Research Institute Ramon y Cajal (IRyCIS), Ramon y Cajal University Hospital, 28034 Madrid, Spain; (F.J.H.-W.); (E.V.); (M.J.P.-E.); (F.D.); (J.L.C.); (A.M.); (J.M.H.); (C.Q.); (S.M.)
- Correspondence:
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New signatures of poor CD4 cell recovery after suppressive antiretroviral therapy in HIV-1-infected individuals: involvement of miR-192, IL-6, sCD14 and miR-144. Sci Rep 2020; 10:2937. [PMID: 32076107 PMCID: PMC7031287 DOI: 10.1038/s41598-020-60073-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 02/05/2020] [Indexed: 02/08/2023] Open
Abstract
Up to 40% of newly diagnosed cases of HIV-1 infection are late diagnoses, with a profound decrease in CD4 cell counts in many cases. One-third of these individuals do not achieve optimal CD4 cell recovery (OR) after suppressive antiretroviral treatment (ART). This retrospective/longitudinal study of poor recovery (PR) included 79 HIV-1-infected individuals with CD4 count <200 cells/mm3 (25 PR and 54 OR) before ART. After suppressive ART, 21 PR and 24 OR individuals were further analysed, including paired samples. Selected miRs and plasma inflammatory markers were determined to investigate their potential predictive/diagnostic value for poor recovery. miR-192, IL-6 and sCD14 were independently associated with CD4 recovery before ART (p = 0.031, p = 0.007, and p = 0.008, respectively). The combination of these three factors returned a good discrimination (predictive value for PR) value of 0.841 (AUC, p < 0.001). After suppressive ART, miR-144 was independently associated with CD4 recovery (p = 0.017), showing a moderate discrimination value of 0.730 (AUC, p = 0.008) for PR. Our study provides new evidence on the relationship between miRs and HIV-1 infection that could help improve the management of individuals at HIV-1 diagnosis. These miRs and cytokines signature sets provide novel tools to predict CD4 cell recovery and its progression after ART.
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Lawson KS, Prasad A, Groopman JE. Methamphetamine Enhances HIV-1 Replication in CD4 + T-Cells via a Novel IL-1β Auto-Regulatory Loop. Front Immunol 2020; 11:136. [PMID: 32117283 PMCID: PMC7025468 DOI: 10.3389/fimmu.2020.00136] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 01/20/2020] [Indexed: 12/19/2022] Open
Abstract
Methamphetamine (Meth) abuse is a worldwide public health problem and contributes to HIV-1 pathobiology and poor adherence to anti-retroviral therapies. Specifically, Meth is posited to alter molecular mechanisms to provide a more conducive environment for HIV-1 replication and spread. Enhanced expression of inflammatory cytokines, such as Interleukin-1β (IL-1β), has been shown to be important for HIV-1 pathobiology. In addition, microRNAs (miRNAs) play integral roles in fine-tuning the innate immune response. Notably, the effects of Meth abuse on miRNA expression are largely unknown. We studied the effects of Meth on IL-1β and miR-146a, a well-characterized member of the innate immune signaling network. We found that Meth induces miR-146a and triggers an IL-1β auto-regulatory loop to modulate innate immune signaling in CD4+ T-cells. We also found that Meth enhances HIV-1 replication via IL-1 signaling. Our results indicate that Meth activates an IL-1β feedback loop to alter innate immune pathways and favor HIV-1 replication. These observations offer a framework for designing targeted therapies in HIV-infected, Meth using hosts.
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Affiliation(s)
- Kaycie S Lawson
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Anil Prasad
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Jerome E Groopman
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
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