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Khidr EG, El-Sayyad GS, Abulsoud AI, Rizk NI, Zaki MB, Raouf AA, Elrebehy MA, Abdel Hady MMM, Elballal MS, Mohammed OA, Abdel-Reheim MA, El-Dakroury WA, Abdel Mageed SS, Al-Noshokaty TM, Doghish AS. Unlocking the Potential of miRNAs in Sepsis Diagnosis and Prognosis: From Pathophysiology to Precision Medicine. J Biochem Mol Toxicol 2025; 39:e70156. [PMID: 39871533 DOI: 10.1002/jbt.70156] [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: 11/23/2024] [Revised: 12/25/2024] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The clinical syndrome appears as a dysregulated host response to infection that results in life-threatening organ dysfunction known as Sepsis. Sepsis is a serious public health concern where for every five deaths in ICU there is one patient who dies with sepsis worldwide. Sepsis is featured as unbalanced inflammation and immunosuppression which is sustained and profound, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and the deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based diagnosis and therapies for sepsis. Yet, the picture is not so straightforward because of miRNAs' versatile and dynamic features. More research is needed to clarify the expression and role of miRNAs in sepsis and promote the use of miRNAs for sepsis management. This study provides an extensive, current, and thorough analysis of the involvement of miRNAs in sepsis. Its purpose is to encourage future research in this area, as tiny miRNAs have the potential to be used for rapid diagnosis, prognosis, and treatment of sepsis.
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Affiliation(s)
- Emad Gamil Khidr
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Gharieb S El-Sayyad
- Medical Laboratory Technology Department, Faculty of Applied Health Sciences Technology, Badr University in Cairo (BUC), Cairo, Egypt
- Drug Microbiology Lab., Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Menoufia National University, Menofia, Egypt
| | - Ahmed Amr Raouf
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Mahmoud A Elrebehy
- Biochemistry Department, Faculty of Pharmacy, Galala University, Suez, Egypt
| | - Manal M M Abdel Hady
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Goyang, Republic of Korea
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | | | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | | | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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2
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Tran PNT, Limothai U, Dinhuzen J, Tachaboon S, Sukmark T, Dokpong C, Roytrakul S, Haake DA, Srisawat N. MicroRNA biomarkers and host response pathways in severe pulmonary hemorrhagic syndrome due to leptospirosis: A multi-omics study. J Infect 2025; 90:106400. [PMID: 39793739 DOI: 10.1016/j.jinf.2024.106400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 12/08/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Severe pulmonary hemorrhagic syndrome (SPHS) remains a fatal complication of leptospirosis with poorly understood mechanisms and an urgent need for effective biomarkers. METHODS A nested case-control analysis was conducted using blood specimens from two previous Thai leptospirosis cohorts. Candidate microRNAs were initially discovered through a global profiling of 798 serum microRNAs in five SPHS and seven non-SPHS patients, and then validated using real-time polymerase chain reactions in 168 patients. Pathways enriched from microRNA targets were compared to those from an integrated transcriptomic-proteomic analysis. Proteins pertaining to the key resulting pathway were measured to validate significance and reveal correlation with microRNA biomarkers. RESULTS Serum microRNA profiling revealed a total of 81 significantly expressed microRNAs, of which seven were selected for further validation in the whole cohort of 168 leptospirosis patients, including 28 in SPHS and 140 nonSPHS groups. Among the selected microRNAs, miR-5010-3p and miR-147b-3p had significantly higher expression in SPHS group compared to nonSPHS group, with consistently higher expression after adjusting for age, sex, days of illness, comorbidity, smoking status or recruitment site. The two had area under the curve (AUC) values of 0.76 (95% CI: 0.67-0.85) and 0.70 (95% CI: 0.56-0.81) for discriminating SPHS, respectively. These microRNAs also exhibited consistent AUC values in patients tested before chest radiograph shadows manifested. Combination of miR-5010-3p with miR-548ai and miR-224-5p, as selected by Bayesian Model Averaging algorithm, substantially boosts the AUC value to 0.86 (95% CI: 0.77-0.94). The miRNA biomarkers also enhanced the predictive values of a previously validated clinical model, increasing AUC value from 0.87 to 0.92 with a significant reclassification net index. Multi-omics pathway analysis incorporating microRNA targets and transcriptomic-proteomic data suggested TNF signaling as among the key pathways. In validation, seven out of ten pathway proteins were significantly different between groups, with principal components correlated with severity and miR-5010-3p. CONCLUSIONS MiR-5010-3p and miR-147b-3p are novel biomarkers with good predictability and potential relevance with TNF signaling pathway, an important host response mechanism in leptospirosis SPHS.
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Affiliation(s)
- Phu Nguyen Trong Tran
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Department of Internal Medicine, Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho, Vietnam
| | - Umaporn Limothai
- Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand
| | - Janejira Dinhuzen
- Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand
| | - Sasipha Tachaboon
- Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand
| | | | | | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani, Thailand
| | - David A Haake
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; The David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Nattachai Srisawat
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand; Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Center for Critical Care Nephrology, The CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Academy of Science, Royal Society of Thailand, Bangkok, Thailand.
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3
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Yang H, Hua J, Han Y, Chang D, Zheng W. Development and preliminary validation of five miRNAs for lung adenocarcinoma prognostic model associated with immune infiltration. Sci Rep 2025; 15:528. [PMID: 39747924 PMCID: PMC11695782 DOI: 10.1038/s41598-024-84128-2] [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: 01/08/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025] Open
Abstract
Our aim was to investigate the potential value of immune-related miRNA signaling in predicting clinical prognosis and immunotherapy. We first identified immune-related miRNAs in lung adenocarcinoma (LUAD), and then constructed a miRNA-based risk model by lasso regression modeling. Finally, we validated our findings using RT-qPCR in serum from LUAD patients and normal patients. Weighted gene co-expression network analysis (WGCNA) was used to screen the aberrantly expressed genes associated with immune scores, and then correlation analysis and prognostic analysis were used to identify and immune-associated miRNAs, and lasso-cox regression was used to construct an immune-associated 5-miRNA model. Risk score as an independent prognostic factor could accurately predict the prognosis of LUAD patients. Immunotherapy analysis revealed that patients with low-risk scores benefited more from anti-PD-1 and CTLA-4 therapy. Experimental validation showed that only miRNA-200b-3p was significantly differentially expressed in 91 cases of clinically collected cancer tissues and normal tissue serum. We constructed a 5-miRNA model that can be used for risk stratification of LUAD patients. Targeted therapy against miRNA-200b-3p is expected to be a prospective new strategy for the clinical treatment of LUAD.
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Affiliation(s)
- Huanzhang Yang
- Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Jingli Hua
- Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Yanxia Han
- Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Dong Chang
- Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Wenlong Zheng
- Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
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Euler G, Parahuleva M. Monocytic microRNAs-Novel targets in atherosclerosis therapy. Br J Pharmacol 2025; 182:206-219. [PMID: 38575391 DOI: 10.1111/bph.16367] [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: 11/01/2023] [Revised: 02/02/2024] [Accepted: 02/16/2024] [Indexed: 04/06/2024] Open
Abstract
Atherosclerosis is a chronic proinflammatory disease of the vascular wall resulting in narrowing of arteries due to plaque formation, thereby causing reduced blood supply that is the leading cause for diverse end-organ damage with high mortality rates. Monocytes/macrophages, activated by elevated circulating lipoproteins, are significantly involved in the formation and development of atherosclerotic plaques. The imbalance between proinflammatory and anti-inflammatory macrophages, arising from dysregulated macrophage polarization, appears to be a driving force in this process. Proatherosclerotic processes acting on monocytes/macrophages include accumulation of cholesterol in macrophages leading to foam cell formation, as well as dysfunctional efferocytosis, all of which contribute to the formation of unstable plaques. In recent years, microRNAs (miRs) were identified as factors that could modulate monocyte/macrophage function and may therefore interfere with the atherosclerotic process. In this review, we present effects of monocyte/macrophage-derived miRs on atherosclerotic processes in order to reveal new treatment options using miRmimics or antagomiRs. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Affiliation(s)
- Gerhild Euler
- Institute of Physiology, Justus Liebig University, Giessen, Germany
| | - Mariana Parahuleva
- Internal Medicine/Cardiology and Angiology, University Hospital of Giessen and Marburg, Marburg, Germany
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Zhang H, Xie S, Deng W. Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies. Biomolecules 2024; 14:1614. [PMID: 39766321 PMCID: PMC11674137 DOI: 10.3390/biom14121614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/05/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Doxorubicin is a chemotherapeutic drug utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity, including cardiac dilation and heart failure. Mitophagy, a cargo-specific form of autophagy, is specifically used to eliminate damaged mitochondria in autophagosomes through hydrolytic degradation following fusion with lysosomes. Recent advances have unveiled a major role for defective mitophagy in the etiology of DOX-induced cardiotoxicity. Moreover, specific interventions targeting this mechanism to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX-induced cardiotoxicity. However, clinical translation is challenging because of the unclear mechanisms of action and the potential for pharmacological adverse effects. This review aims to offer fresh perspectives on the role of mitophagy in the development of DOX-induced cardiotoxicity and investigate potential therapeutic strategies that focus on this mechanism to improve clinical management.
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Affiliation(s)
- Heng Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (H.Z.); (S.X.)
- Hubei Key Laboratory of Metabolism and Related Chronic Diseases, Wuhan 430060, China
| | - Saiyang Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (H.Z.); (S.X.)
- Hubei Key Laboratory of Metabolism and Related Chronic Diseases, Wuhan 430060, China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (H.Z.); (S.X.)
- Hubei Key Laboratory of Metabolism and Related Chronic Diseases, Wuhan 430060, China
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Iijima N, Yamaguchi M, Hayashi T, Rui Y, Ohira Y, Miyamoto Y, Niino M, Okuno T, Suzuki O, Oka M, Ishii KJ. miR-147-3p in pathogenic CD4 T cells controls chemokine receptor expression for the development of experimental autoimmune diseases. J Autoimmun 2024; 149:103319. [PMID: 39395343 DOI: 10.1016/j.jaut.2024.103319] [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: 09/03/2024] [Accepted: 09/16/2024] [Indexed: 10/14/2024]
Abstract
Incomplete Freund's adjuvant (IFA) has long been used to trigger autoimmune diseases in animal models, such as experimental autoimmune encephalitis and collagen-induced arthritis. However, the molecular mechanisms that control CD4 T cell effector functions and lead to the development of autoimmune diseases are not well understood. A self-antigen and heat-killed Mycobacterium tuberculosis emulsified in IFA augmented the activation of CD4 T cells, leading to the differentiation of pathogenic CD4 T cells in the draining lymph nodes. In contrast, IFA emulsification did not elicit Foxp3+ regulatory T cell expansion. We found that pathogenic Th1 cells expressed miR-147-3p, which targets multiple genes to affect T cell function. Finally, miR-147-3p expressed in CXCR6+SLAMF6- Th1 cells was required for the onset of neurological symptoms through the control of CXCR3 expression. Our findings demonstrate that miR-147-3p expressed in pathogenic CD4 T cells regulates the migratory potential in peripheral tissues and impacts the development of autoimmune diseases.
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MESH Headings
- Animals
- MicroRNAs/genetics
- Mice
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Disease Models, Animal
- Gene Expression Regulation
- Autoimmune Diseases/immunology
- Autoimmune Diseases/genetics
- Receptors, Chemokine/metabolism
- Receptors, Chemokine/genetics
- Th1 Cells/immunology
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Mice, Inbred C57BL
- Lymphocyte Activation/immunology
- Lymphocyte Activation/genetics
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Affiliation(s)
- Norifumi Iijima
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan; Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan.
| | - Masaya Yamaguchi
- Bioinformatics Research Unit, Osaka University Graduate School of Dentistry, Suita Osaka, Japan; Bioinformatics Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Department of Microbiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan; Center for Infectious Diseases Education and Research, Osaka University, Suita, Osaka, Japan
| | - Tomoya Hayashi
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yuxiang Rui
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan
| | - Yuta Ohira
- Central Research Laboratories, Zeria Pharmaceutical Co, Ltd, Kumagaya-shi, Saitama, Japan
| | - Yoichi Miyamoto
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan
| | - Masaaki Niino
- Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Sapporo, Hokkaido, Japan
| | - Tatsusada Okuno
- Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Osamu Suzuki
- Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Asagi Saito, Ibaraki, Osaka, Japan
| | - Masahiro Oka
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan
| | - Ken J Ishii
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka Univerisity, Suita, Osaka, Japan.
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7
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Ran J, Xie Z, Yan L, Ye C, Hou Y, Hu Y, Lu X, Xie C. Oxygen-Propelled Dual-Modular Microneedles with Dopamine-Enhanced RNA Delivery for Regulating Each Stage of Diabetic Wounds. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2404538. [PMID: 39105463 DOI: 10.1002/smll.202404538] [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: 06/04/2024] [Revised: 07/06/2024] [Indexed: 08/07/2024]
Abstract
Diabetic wounds are characterized by the disruption and cessation of essential healing stages, which include hemostasis, inflammation, proliferation, and remodeling. However, traditional treatments for diabetic wounds concentrate on individual stages of the healing process. Herein, this study utilizes mask-mediated sequential polymerization and varied cross-linking techniques to develop dual-modular microneedles (MNs) with fast- and slow-module, exhibiting varying degradation rates tailored for the full spectrum of diabetic wound healing. First, MNs incorporating calcium ions and dopamine synergistically promote rapid hemostasis. Second, fast-module physically cross-linked MNs rapidly D-mannose/dopamine-enhanced tripolyphosphate-quaternized chitosan (mDTC) nanoparticles (NPs) loaded with microRNA-147 (miRNA-147) to manage inflammation and oxidative stress in diabetic wounds. Additionally, dopamine in these NPs enhances their internalization and safeguards miRNA-147 from oxidative stress and RNase degradation. Finally, slow-module chemically cross-linked MNs facilitate the continuous release of deferoxamine (DFO) and dopamine, accelerating angiogenesis and tissue regeneration during the proliferation and remodeling stages. Manganese/dopamine-enhanced calcium peroxide NPs within the MNs initiate a blast-like generation of oxygen bubbles, not only enhancing the delivery of miRNA-mDTC NPs and DFO but also alleviating tissue hypoxia. Consequently, dual-modular MNs are instrumental in promoting rapid and complete healing of diabetic wounds through all stages of healing.
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Affiliation(s)
- Jinhui Ran
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Zhiping Xie
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Liwei Yan
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Chengxinyue Ye
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yue Hou
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Yuelin Hu
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Xiong Lu
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Chaoming Xie
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
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8
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Abobakr S, Shaker O, Hegazy MT, Hany AM. A possible role of lncRNA MEG3 and lncRNA MAFG-AS1 on miRNA 147-b in the pathogenesis of Behcet's disease. Immunogenetics 2024; 76:233-241. [PMID: 38985298 PMCID: PMC11246302 DOI: 10.1007/s00251-024-01346-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024]
Abstract
Behcet's disease (BD) is a multisystem disease with altered Toll-like receptors (TLRs) on macrophages. Long noncoding RNA Maternally expressed gene 3 (lncRNA MEG3) and lncRNA Musculoaponeurotic fibrosarcoma oncogene family, protein G antisense 1 (MAFG-AS1) are regulators of microRNA (miRNA) 147-b, which is induced upon TLR stimulation. We included fifty BD patients, and fifty age and sex-matched controls. Real-time polymerase chain reaction (PCR) was used to measure the expression levels of serum lncRNA MEG3, lncRNA MAFG-AS1, and miRNA 147-b. LncRNA MEG3 and lncRNA MAFG-AS1 were significantly downregulated while miRNA 147-b was significantly upregulated in the BD patients' serum compared to the controls with p-value <0.001. Receiver operation characteristics (ROC) curve analysis revealed that the three biomarkers can discriminate between BD and control subjects with 76%, 100%, and 70% sensitivity respectively, and 100% specificity for all of them. There was a lower expression level of lnc RNA MEG3 among patients who had new eye involvement in the last month in comparison to those without new eye involvement (p-value=0.017). So, LncRNA MEG3, lncRNA MAFG-AS1, and miRNA147-b are promising diagnostic markers and therapeutic targets for BD patients. LncRNA MEG3 can be used as a predictor for new BD ocular involvement.
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Affiliation(s)
- Shimaa Abobakr
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Olfat Shaker
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Tharwat Hegazy
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ayman Mohamed Hany
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
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9
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Abubakar M, Hajjaj M, Naqvi ZEZ, Shanawaz H, Naeem A, Padakanti SSN, Bellitieri C, Ramar R, Gandhi F, Saleem A, Abdul Khader AHS, Faraz MA. Non-Coding RNA-Mediated Gene Regulation in Cardiovascular Disorders: Current Insights and Future Directions. J Cardiovasc Transl Res 2024; 17:739-767. [PMID: 38092987 DOI: 10.1007/s12265-023-10469-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/23/2023] [Indexed: 09/04/2024]
Abstract
Cardiovascular diseases (CVDs) pose a significant burden on global health. Developing effective diagnostic, therapeutic, and prognostic indicators for CVDs is critical. This narrative review explores the role of select non-coding RNAs (ncRNAs) and provides an in-depth exploration of the roles of miRNAs, lncRNAs, and circRNAs in different aspects of CVDs, offering insights into their mechanisms and potential clinical implications. The review also sheds light on the diverse functions of ncRNAs, including their modulation of gene expression, epigenetic modifications, and signaling pathways. It comprehensively analyzes the interplay between ncRNAs and cardiovascular health, paving the way for potential novel interventions. Finally, the review provides insights into the methodologies used to investigate ncRNA-mediated gene regulation in CVDs, as well as the implications and challenges associated with translating ncRNA research into clinical applications. Considering the broader implications, this research opens avenues for interdisciplinary collaborations, enhancing our understanding of CVDs across scientific disciplines.
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Affiliation(s)
- Muhammad Abubakar
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, Punjab, Pakistan.
| | - Mohsin Hajjaj
- Department of Internal Medicine, Jinnah Hospital, Lahore, Punjab, Pakistan
| | - Zil E Zehra Naqvi
- Department of Internal Medicine, Jinnah Hospital, Lahore, Punjab, Pakistan
| | - Hameed Shanawaz
- Department of Internal Medicine, Windsor University School of Medicine, Cayon, Saint Kitts and Nevis
| | - Ammara Naeem
- Department of Cardiology, Heart & Vascular Institute, Dearborn, Michigan, USA
| | | | | | - Rajasekar Ramar
- Department of Internal Medicine, Rajah Muthiah Medical College, Chidambaram, Tamil Nadu, India
| | - Fenil Gandhi
- Department of Family Medicine, Lower Bucks Hospital, Bristol, PA, USA
| | - Ayesha Saleem
- Department of Internal Medicine, Jinnah Hospital, Lahore, Punjab, Pakistan
| | | | - Muhammad Ahmad Faraz
- Department of Forensic Medicine, Postgraduate Medical Institute, Lahore, Punjab, Pakistan
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10
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Miguel MMV, Shaddox LM. Grade C Molar-Incisor Pattern Periodontitis in Young Adults: What Have We Learned So Far? Pathogens 2024; 13:580. [PMID: 39057807 PMCID: PMC11279578 DOI: 10.3390/pathogens13070580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 06/26/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Grade C molar-incisor pattern periodontitis (C-MIP) is a disease that affects specific teeth with an early onset and aggressive progression. It occurs in systemically healthy patients, mostly African descendants, at an early age, with familial involvement, minimal biofilm accumulation, and minor inflammation. Severe and rapidly progressive bone loss is observed around the first molars and incisors. This clinical condition has been usually diagnosed in children and young adults with permanent dentition under 30 years of age. However, this disease can also affect the primary dentition, which is not as frequently discussed in the literature. Radiographic records have shown that most patients diagnosed in the permanent dentition already presented disease signs in the primary dentition. A hyperresponsive immunological profile is observed in local (gingival crevicular fluid-GCF) and systemic environments. Siblings have also displayed a heightened inflammatory profile even without clinical signs of disease. A. actinomycetemcomitans has been classified as a key pathogen in C-MIP in both dentitions. Scaling and root planning associated with systemic antibiotics is the current gold standard to treat C-MIP, leading to GCF biomarker reduction, some systemic inflammatory response modulation and microbiome profile changes to a healthy-site profile. Further studies should focus on other possible disease-contributing risk factors.
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Affiliation(s)
- Manuela Maria Viana Miguel
- Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, KY 40508, USA;
| | - Luciana Macchion Shaddox
- Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, KY 40508, USA;
- Department of Oral Health Practice, Periodontology Division, College of Dentistry, University of Kentucky, Lexington, KY 40508, USA
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11
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Xiong M, Liu Z, Wang B, Sokolich T, Graham N, Chen M, Wang WL, Boldin MP. The epithelial C15ORF48/miR-147-NDUFA4 axis is an essential regulator of gut inflammation, energy metabolism, and the microbiome. Proc Natl Acad Sci U S A 2024; 121:e2315944121. [PMID: 38917002 PMCID: PMC11228508 DOI: 10.1073/pnas.2315944121] [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: 09/19/2023] [Accepted: 05/13/2024] [Indexed: 06/27/2024] Open
Abstract
Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered C15ORF48/miR-147 as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. C15ORF48/miR-147 encodes two molecular products, C15ORF48 protein and miR-147-3p microRNA, which are predominantly expressed in the intestinal epithelium. C15ORF48/miR-147 ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR-147-3p work together to suppress colonocyte metabolism and inflammation by silencing NDUFA4, a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C-terminal α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. NDUFA4 silencing hinders NF-κB signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the C15ORF48/miR-147-NDUFA4 molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation.
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Affiliation(s)
- Min Xiong
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA91010
| | - Ze Liu
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA90033
| | - Bintao Wang
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA91010
| | - Thomas Sokolich
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA91010
| | - Natalie Graham
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA91010
| | - Meirong Chen
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu210009, China
| | - Wei-Le Wang
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA91010
| | - Mark P. Boldin
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA91010
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12
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Zhang N, Song GY, Yu QH, Fan XM, Zhang WS, Hu YJ, Chao TZ, Wu YY, Duan SY, Wang F, Du RP, Xu P. Evaluation of the lncRNA-miRNA-mRNA ceRNA network in lungs of miR-147 -/- mice. Front Pharmacol 2024; 15:1335374. [PMID: 38510653 PMCID: PMC10953689 DOI: 10.3389/fphar.2024.1335374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024] Open
Abstract
Background: Previous studies have documented important roles for microRNA-147 (miR-147) in inflammation, radiation-induced injury, cancer, and a range of other diseases. Murine lungs exhibit high levels of miRNA, mRNA, and lncRNA expression. However, very little research to date has focused on the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks associated with miR-147, and the regulation of lncRNAs and miRNAs in this setting remains poorly understood. Methods: After establishing a miR-147-/- model mouse, samples of lung tissue were harvested for RNA-sequencing, and differentially expressed lncRNAs, miRNAs, and mRNAs were identified. The miRNA targets of these lncRNAs and the identified miRNAs were first overlapped to facilitate the prediction of target mRNAs, with analyses then examining the overlap between these targets and mRNAs that were differentially expressed. Then, these target mRNAs were subjected to pathway enrichment analyses. These results were ultimately used to establish a miR-147-related ceRNA network. Results: Relative to wild-type mice, the lungs of miR-147-/- mice exhibited 91, 43, and 71 significantly upregulated lncRNAs, miRNAs, and mRNAs, respectively, together with 114, 31, and 156 that were significantly downregulated. The lncRNA-miRNA-mRNA network established based on these results led to the identification of Kcnh6 as a differentially expressed hub gene candidate and enabled the identification of a range of regulatory relationships. KEGG pathway enrichment showed that the mRNA targets of differentially expressed lncRNAs and miRNAs in the mice were associated with tumor-related signaling, endometrial cancer, bladder cancer, and ErbB signaling. Conclusion: These results suggest that the identified ceRNA network in miR-147-/- mice shapes tumor-associated signaling activity, with miR-147 potentially regulating various lncRNAs and miRNAs through Kcnh6, ultimately influencing tumorigenesis. Future studies of the lncRNA, miRNA, and mRNA regulatory targets shown to be associated with miR-147 in the present study may ultimately lead to the identification of novel clinically relevant targets through which miR-147 shapes the pathogenesis of cancer and other diseases.
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Affiliation(s)
- Nan Zhang
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Gui-Yuan Song
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Qing-Hua Yu
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
- School of Public Health, Weifang Medical University, Weifang, Shandong, China
| | - Xin-Ming Fan
- Department of Radiotherapy, Zaozhuang Municipal Hospital, Zaozhuang, Shandong, China
| | - Wen-Shuo Zhang
- Department of Radiotherapy, Zaozhuang Municipal Hospital, Zaozhuang, Shandong, China
| | - Yong-Jian Hu
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China
| | - Tian-Zhu Chao
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Yao-Yao Wu
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Shu-Yan Duan
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Fei Wang
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Rui-Peng Du
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
| | - Ping Xu
- Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China
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13
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Talepoor AG, Doroudchi M. Regulatory RNAs in immunosenescence. Immun Inflamm Dis 2024; 12:e1209. [PMID: 38456619 PMCID: PMC10921898 DOI: 10.1002/iid3.1209] [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: 10/22/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND Immunosenescence is a multifactorial stress response to different intrinsic and extrinsic insults that cause immune deterioration and is accompanied by genomic or epigenomic perturbations. It is now widely recognized that genes and proteins contributing in the process of immunosenescence are regulated by various noncoding (nc) RNAs, including microRNAs (miRNAs), long ncRNAs, and circular RNAs. AIMS This review article aimed to evaluate the regulatore RNAs roles in the process of immunosenescence. METHODS We analyzed publications that were focusing on the different roles of regulatory RNAs on the several aspects of immunosenescence. RESULTS In the immunosenescence setting, ncRNAs have been found to play regulatory roles at both transcriptional and post-transcriptional levels. These factors cooperate to regulate the initiation of gene expression programs and sustaining the senescence phenotype and proinflammatory responses. CONCLUSION Immunosenescence is a complex process with pivotal alterations in immune function occurring with age. The extensive network that drive immunosenescence-related features are are mainly directed by a variety of regulatory RNAs such as miRNAs, lncRNAs, and circRNAs. Latest findings about regulation of senescence by ncRNAs in the innate and adaptive immune cells as well as their role in the immunosenescence pathways, provide a better understanding of regulatory RNAs function in the process of immunosenescence.
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Affiliation(s)
- Atefe Ghamar Talepoor
- Department of Immunology, School of MedicineShiraz University of Medical SciencesShirazIran
- Autoimmune Diseases Research CenterUniversity of Medical SciencesShirazIran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of MedicineShiraz University of Medical SciencesShirazIran
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14
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Takakura Y, Machida M, Terada N, Katsumi Y, Kawamura S, Horie K, Miyauchi M, Ishikawa T, Akiyama N, Seki T, Miyao T, Hayama M, Endo R, Ishii H, Maruyama Y, Hagiwara N, Kobayashi TJ, Yamaguchi N, Takano H, Akiyama T, Yamaguchi N. Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity. Nat Commun 2024; 15:953. [PMID: 38296961 PMCID: PMC10831050 DOI: 10.1038/s41467-024-45206-1] [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: 03/21/2023] [Accepted: 01/18/2024] [Indexed: 02/02/2024] Open
Abstract
Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.
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Affiliation(s)
- Yuki Takakura
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Moeka Machida
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - Natsumi Terada
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - Yuka Katsumi
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - Seika Kawamura
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - Kenta Horie
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Maki Miyauchi
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Tatsuya Ishikawa
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Nobuko Akiyama
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Takao Seki
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Takahisa Miyao
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Mio Hayama
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Rin Endo
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Hiroto Ishii
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Yuya Maruyama
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan
| | - Naho Hagiwara
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Tetsuya J Kobayashi
- Institute of Industrial Science, The University of Tokyo, Tokyo, 153-8505, Japan
| | - Naoto Yamaguchi
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - Hiroyuki Takano
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - Taishin Akiyama
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
- Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan.
| | - Noritaka Yamaguchi
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
- Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
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15
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Hamley M, Leyk S, Casar C, Liebold I, Jawazneh AA, Lanzloth C, Böttcher M, Haas H, Richardt U, Rothlin CV, Jacobs T, Huber S, Adlung L, Pelczar P, Henao-Mejia J, Bosurgi L. Nmes1 is a novel regulator of mucosal response influencing intestinal healing potential. Eur J Immunol 2024; 54:e2350434. [PMID: 37971166 DOI: 10.1002/eji.202350434] [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: 02/15/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 11/19/2023]
Abstract
The initiation of tissue remodeling following damage is a critical step in preventing the development of immune-mediated diseases. Several factors contribute to mucosal healing, leading to innovative therapeutic approaches for managing intestinal disorders. However, uncovering alternative targets and gaining mechanistic insights are imperative to enhance therapy efficacy and broaden its applicability across different intestinal diseases. Here we demonstrate that Nmes1, encoding for Normal Mucosa of Esophagus-Specific gene 1, also known as Aa467197, is a novel regulator of mucosal healing. Nmes1 influences the macrophage response to the tissue remodeling cytokine IL-4 in vitro. In addition, using two murine models of intestinal damage, each characterized by a type 2-dominated environment with contrasting functions, the ablation of Nmes1 results in decreased intestinal regeneration during the recovery phase of colitis, while enhancing parasitic egg clearance and reducing fibrosis during the advanced stages of Schistosoma mansoni infection. These outcomes are associated with alterations in CX3CR1+ macrophages, cells known for their wound-healing potential in the inflamed colon, hence promising candidates for cell therapies. All in all, our data indicate Nmes1 as a novel contributor to mucosal healing, setting the basis for further investigation into its potential as a new target for the treatment of colon-associated inflammation.
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Affiliation(s)
- Madeleine Hamley
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Stephanie Leyk
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Bioinformatics Core, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Imke Liebold
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Amirah Al Jawazneh
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Clarissa Lanzloth
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Marius Böttcher
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ulricke Richardt
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Carla V Rothlin
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas Jacobs
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lorenz Adlung
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Penelope Pelczar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jorge Henao-Mejia
- The Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lidia Bosurgi
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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16
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Ganguly T, Laha S, Senapati S, Chatterjee G, Chatterjee R. Serum miRNA profiling identified miRNAs associated with disease severity in psoriasis. Exp Dermatol 2024; 33:e14973. [PMID: 37926911 DOI: 10.1111/exd.14973] [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: 07/12/2023] [Revised: 09/27/2023] [Accepted: 10/21/2023] [Indexed: 11/07/2023]
Abstract
Psoriasis vulgaris is a chronic, autoimmune skin disease involving a complex interplay of epidermal keratinocytes, dermal fibroblast and infiltrating immune cells. Differential expressions of miRNAs are observed in psoriasis and the deregulated miRNAs are sometimes associated with disease severity. This study aims to identify miRNAs altered in the serum of psoriasis patients that are associated with the Psoriasis Area and Severity Index (PASI). In order to assess miRNA levels in the serum of psoriasis patients, we selected 24 differentially expressed miRNAs in the psoriatic skin are possibly derived from the skin and immune cells, as well as five miRNAs that are enriched in other tissues. We identified 16 miRNAs that exhibited significantly (p < 0.05) altered levels in the serum of psoriasis patients compared to healthy individuals. Among these, 13 miRNAs showed similar expression pattern in the serum of psoriasis patients as also observed in the psoriatic skin tissues. Ten miRNAs showed an accuracy of greater than 75% in classifying the psoriasis patients from healthy individuals. Further analysis of differential miRNA levels between the low PASI group and the high PASI group identified three miRNAs (miR-147b, miR-3614-5p, and miR-125a-5p) with significantly altered levels between the low severity and the high severity psoriasis patients. Our systematic investigation of skin and immune cell-derived miRNAs in the serum of psoriasis patients revealed alteration in miRNA levels to be associated with disease severity, which may help in monitoring the disease progression and therapeutic response.
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Affiliation(s)
- Torsa Ganguly
- Human Genetics Unit, Indian Statistical Institute, Kolkata, West Bengal, India
| | - Sayantan Laha
- Human Genetics Unit, Indian Statistical Institute, Kolkata, West Bengal, India
| | | | - Gobinda Chatterjee
- Department of Dermatology, IPGMER/SSKM Hospital, Kolkata, West Bengal, India
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17
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Parsamanesh N, Poudineh M, Siami H, Butler AE, Almahmeed W, Sahebkar A. RNA interference-based therapies for atherosclerosis: Recent advances and future prospects. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 204:1-43. [PMID: 38458734 DOI: 10.1016/bs.pmbts.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.
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Affiliation(s)
- Negin Parsamanesh
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Haleh Siami
- School of Medicine, Islamic Azad University of Medical Science, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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18
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Li S, Li H, Kong H, Wu SY, Cheng CK, Xu J. Endogenous and microbial biomarkers for periodontitis and type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1292596. [PMID: 38149100 PMCID: PMC10750125 DOI: 10.3389/fendo.2023.1292596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/20/2023] [Indexed: 12/28/2023] Open
Abstract
It has been well documented that there is a two-way relationship between diabetes mellitus and periodontitis. Diabetes mellitus represents an established risk factor for chronic periodontitis. Conversely, chronic periodontitis adversely modulates serum glucose levels in diabetic patients. Activated immune and inflammatory responses are noted during diabetes and periodontitis, under the modulation of similar biological mediators. These activated responses result in increased activity of certain immune-inflammatory mediators including adipokines and microRNAs in diabetic patients with periodontal disease. Notably, certain microbes in the oral cavity were identified to be involved in the occurrence of diabetes and periodontitis. In other words, these immune-inflammatory mediators and microbes may potentially serve as biomarkers for risk assessment and therapy selection in diabetes and periodontitis. In this review, we briefly provide an updated overview on different potential biomarkers, providing novel diagnostic and therapeutic insights on periodontal complications and diabetes mellitus.
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Affiliation(s)
- Songjun Li
- Longgang Ear-Nose-Throat (ENT) Hospital, Institute of Ear-Nose-Throat (ENT) and Shenzhen Key Laboratory of Ear-Nose-Throat (ENT), Shenzhen, China
| | - Hongwen Li
- Longgang Ear-Nose-Throat (ENT) Hospital, Institute of Ear-Nose-Throat (ENT) and Shenzhen Key Laboratory of Ear-Nose-Throat (ENT), Shenzhen, China
- Shenzhen Longgang Institute of Stomatology, Longgang Ear-Nose-Throat (ENT) Hospital, Shenzhen, China
| | - Haiying Kong
- Longgang Ear-Nose-Throat (ENT) Hospital, Institute of Ear-Nose-Throat (ENT) and Shenzhen Key Laboratory of Ear-Nose-Throat (ENT), Shenzhen, China
| | - Shang Ying Wu
- Department of Laboratory Medicine, Shenzhen Hospital, Peking University, Shenzhen, China
| | - Chak Kwong Cheng
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
| | - Jian Xu
- Longgang Ear-Nose-Throat (ENT) Hospital, Institute of Ear-Nose-Throat (ENT) and Shenzhen Key Laboratory of Ear-Nose-Throat (ENT), Shenzhen, China
- Shenzhen Longgang Institute of Stomatology, Longgang Ear-Nose-Throat (ENT) Hospital, Shenzhen, China
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19
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Roy S, Saha P, Bose D, Trivedi A, More M, Xiao S, Diehl AM, Chatterjee S. Hepatic NLRP3-Derived Hsp70 Binding to TLR4 Mediates MASLD to MASH Progression upon Inhibition of PP2A by Harmful Algal Bloom Toxin Microcystin, a Second Hit. Int J Mol Sci 2023; 24:16354. [PMID: 38003543 PMCID: PMC10671242 DOI: 10.3390/ijms242216354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Harmful algal bloom toxin microcystin has been associated with metabolic dysfunction-associated steatotic liver disease (MASLD) progression and hepatocellular carcinoma, though the mechanisms remain unclear. Using an established mouse model of MASLD, we show that the NLRP3-Hsp70-TLR4 axis drives in part the inflammation of the liver lobule that results in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH). Results showed that mice deficient in NLRP3 exhibited decreased MASH pathology, blocked Hsp70 expression, and co-binding with NLRP3, a crucial protein component of the liver inflammasome. Hsp70, both in the liver lobule and extracellularly released in the liver vasculature, acted as a ligand to TLR4 in the liver, primarily in hepatocytes to activate the NF-κB pathway, ultimately leading to hepatic cell death and necroptosis, a crucial pathology of MASH progression. The above studies show a novel insight into an inflammasome-triggered Hsp70-mediated inflammation that may have broader implications in MASLD pathology. MASLD to MASH progression often requires multiple hits. One of the mediators of progressive MASLD is environmental toxins. In this research report, we show for the first time a novel mechanism where microcystin-LR, an environmental toxin, advances MASLD to MASH by triggering the release of Hsp70 as a DAMP to activate TLR4-induced inflammation in the liver.
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Affiliation(s)
- Subhajit Roy
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (S.R.); (P.S.); (D.B.); (A.T.)
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (S.R.); (P.S.); (D.B.); (A.T.)
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (S.R.); (P.S.); (D.B.); (A.T.)
| | - Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (S.R.); (P.S.); (D.B.); (A.T.)
| | - Madhura More
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (S.R.); (P.S.); (D.B.); (A.T.)
| | - Shuo Xiao
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA;
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USA;
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (S.R.); (P.S.); (D.B.); (A.T.)
- Division of Infectious Diseases, School of Medicine, University of California, Irvine, CA 92697, USA
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20
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Jiang X, Shi R, Ma R, Tang X, Gong Y, Yu Z, Shi Y. The role of microRNA in psoriasis: A review. Exp Dermatol 2023; 32:1598-1612. [PMID: 37382420 DOI: 10.1111/exd.14871] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023]
Abstract
Psoriasis is a chronic immune-mediated inflammatory skin disease that involves a complex interplay between infiltrated immune cells and keratinocytes. Great progress has been made in the research on the molecular mechanism of coding and non-coding genes, which has helped in clinical treatment. However, our understanding of this complex disease is far from clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that are involved in post-transcriptional regulation, characterised by their role in mediating gene silencing. Recent studies on miRNAs have revealed their important role in the pathogenesis of psoriasis. We reviewed the current advances in the study of miRNAs in psoriasis; the existing research has found that dysregulated miRNAs in psoriasis notably affect keratinocyte proliferation and/or differentiation processes, as well as inflammation progress. In addition, miRNAs also influence the function of immune cells in psoriasis, including CD4+ T cells, dendritic cells, Langerhans cells and so on. In addition, we discuss possible miRNA-based therapy for psoriasis, such as the topical delivery of exogenous miRNAs, miRNA antagonists and miRNA mimics. Our review highlights the potential role of miRNAs in the pathogenesis of psoriasis, and we expect more research progress with miRNAs in the future, which will help us understand this complex skin disease more accurately.
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Affiliation(s)
- Xingyu Jiang
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Rongcan Shi
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Rui Ma
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Xinyi Tang
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Yu Gong
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Zengyang Yu
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Yuling Shi
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
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21
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Wang C, Wang X, Zhang D, Sun X, Wu Y, Wang J, Li Q, Jiang G. The macrophage polarization by miRNAs and its potential role in the treatment of tumor and inflammation (Review). Oncol Rep 2023; 50:190. [PMID: 37711048 PMCID: PMC10523439 DOI: 10.3892/or.2023.8627] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 08/18/2023] [Indexed: 09/16/2023] Open
Abstract
The characteristics of monocyte/macrophage lineage are diversity and plasticity, mainly manifested by M1 and M2 subtypes in the body tissues, and playing different roles in the immunity. In the polarization process of macrophages, the classic molecular mechanism is related to sequential transcription factors. Whether in tumor or inflammatory local microenvironment, the pathological factors of the local microenvironment often affect the polarization of M1 and M2 macrophages, and participate in the occurrence and development of these pathological processes. In recent years, a growing number of research results demonstrated that non‑coding RNA (ncRNA) also participates in the polarization process of macrophages, in addition to traditional cytokines and transcriptional regulation signal pathway molecules. Among numerous ncRNAs, microRNAs (miRNAs) have attracted more attention from scholars both domestically and internationally, and significant progress has been made in basic and clinical research. Therefore, for improved understanding of the molecular mechanism of miRNAs in macrophage polarization and analysis of the potential value of this regulatory pathway in tumor and inflammatory intervention therapy, a comprehensive review of the progress of relevant literature research was conducted and some viewpoints and perspectives were proposed.
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Affiliation(s)
- Chaozhe Wang
- Department of Immunology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 2640032, P.R. China
| | - Xidi Wang
- Department of Laboratory Medicine, Zhangqiu People's Hospital, Jinan, Shandong 250200, P.R. China
| | - Danfeng Zhang
- Department of Laboratory Medicine, Lixia People's Hospital, Jinan, Shandong 250013, P.R. China
| | - Xiaolin Sun
- Department of Laboratory Medicine, Zibo First Hospital, Zibo, Shandong 255200, P.R. China
| | - Yunhua Wu
- Department of Immunology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 2640032, P.R. China
| | - Jing Wang
- Department of Immunology, Shandong Yinfeng Academy of Life Science, Jinan, Shandong 250013, P.R. China
| | - Qing Li
- Department of Laboratory Medicine, Zibo First Hospital, Zibo, Shandong 255200, P.R. China
| | - Guosheng Jiang
- Department of Immunology, College of Basic Medicine, Binzhou Medical University, Yantai, Shandong 2640032, P.R. China
- Department of Laboratory Medicine, Zibo First Hospital, Zibo, Shandong 255200, P.R. China
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22
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Iskusnykh IY, Fattakhov N, Li Y, Bihannic L, Kirchner MK, Steshina EY, Northcott PA, Chizhikov VV. Lmx1a is a master regulator of the cortical hem. eLife 2023; 12:e84095. [PMID: 37725078 PMCID: PMC10508884 DOI: 10.7554/elife.84095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 09/05/2023] [Indexed: 09/21/2023] Open
Abstract
Development of the nervous system depends on signaling centers - specialized cellular populations that produce secreted molecules to regulate neurogenesis in the neighboring neuroepithelium. In some cases, signaling center cells also differentiate to produce key types of neurons. The formation of a signaling center involves its induction, the maintenance of expression of its secreted molecules, and cell differentiation and migration events. How these distinct processes are coordinated during signaling center development remains unknown. By performing studies in mice, we show that Lmx1a acts as a master regulator to orchestrate the formation and function of the cortical hem (CH), a critical signaling center that controls hippocampus development. Lmx1a co-regulates CH induction, its Wnt signaling, and the differentiation and migration of CH-derived Cajal-Retzius neurons. Combining RNAseq, genetic, and rescue experiments, we identified major downstream genes that mediate distinct Lmx1a-dependent processes. Our work revealed that signaling centers in the mammalian brain employ master regulatory genes and established a framework for analyzing signaling center development.
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Affiliation(s)
- Igor Y Iskusnykh
- Department of Anatomy and Neurobiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Nikolai Fattakhov
- Department of Anatomy and Neurobiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Yiran Li
- Department of Developmental Neurobiology, St. Jude Children's Research HospitalMemphisUnited States
| | - Laure Bihannic
- Department of Developmental Neurobiology, St. Jude Children's Research HospitalMemphisUnited States
| | - Matthew K Kirchner
- Department of Anatomy and Neurobiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Ekaterina Y Steshina
- Department of Anatomy and Neurobiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Paul A Northcott
- Department of Developmental Neurobiology, St. Jude Children's Research HospitalMemphisUnited States
| | - Victor V Chizhikov
- Department of Anatomy and Neurobiology, University of Tennessee Health Science CenterMemphisUnited States
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23
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Yang Y, GuangXuan H, GenMeng W, MengHuan L, Bo C, XueJie Y. Idiopathic inflammatory myopathy and non-coding RNA. Front Immunol 2023; 14:1227945. [PMID: 37744337 PMCID: PMC10512060 DOI: 10.3389/fimmu.2023.1227945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/11/2023] [Indexed: 09/26/2023] Open
Abstract
Idiopathic inflammatory myopathies (IIMs) are common autoimmune diseases that affect skeletal muscle quality and function. The lack of an early diagnosis and treatment can lead to irreversible muscle damage. Non-coding RNAs (ncRNAs) play an important role in inflammatory transfer, muscle regeneration, differentiation, and regulation of specific antibody levels and pain in IIMs. ncRNAs can be detected in blood and hair; therefore, ncRNAs detection has great potential for diagnosing, preventing, and treating IIMs in conjunction with other methods. However, the specific roles and mechanisms underlying the regulation of IIMs and their subtypes remain unclear. Here, we review the mechanisms by which micro RNAs and long non-coding RNA-messenger RNA networks regulate IIMs to provide a basis for ncRNAs use as diagnostic tools and therapeutic targets for IIMs.
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Affiliation(s)
- Yang Yang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Hu GuangXuan
- School of Physical Education, Liaoning Normal University, Dalian, Liaoning, China
| | - Wan GenMeng
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
| | - Li MengHuan
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
| | - Chang Bo
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
| | - Yi XueJie
- Social Science Research Center, Shenyang Sport University, Shenyang, Liaoning, China
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24
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Fang A, Yuan Y, Sui B, Wang Z, Zhang Y, Zhou M, Chen H, Fu ZF, Zhao L. Inhibition of miR-200b-3p confers broad-spectrum resistance to viral infection by targeting TBK1. mBio 2023; 14:e0086723. [PMID: 37222520 PMCID: PMC10470528 DOI: 10.1128/mbio.00867-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 04/11/2023] [Indexed: 05/25/2023] Open
Abstract
The host innate immune system's defense against viral infections depends heavily on type I interferon (IFN-I) production. Research into the mechanisms of virus-host interactions is essential for developing novel antiviral therapies. In this study, we compared the effect of the five members of the microRNA-200 (miR-200) family on IFN-I production during viral infection and found that miR-200b-3p displayed the most pronounced regulatory effect. During viral infection, we discovered that the transcriptional level of microRNA-200b-3p (miR-200b-3p) increased with the infection of influenza virus (IAV) and vesicular stomatitis virus (VSV), and miR-200b-3p production was modulated by the activation of the ERK and p38 pathways. We identified cAMP response element binding protein (CREB) as a novel transcription factor that binds to the miR-200b-3p promoter. MiR-200b-3p reduces NF-κB and IRF3-mediated IFN-I production by targeting the 3' untranslated region (3' UTR) of TBK1 mRNA. Applying miR-200b-3p inhibitor enhances IFN-I production in IAV and VSV-infected mouse models, thus inhibiting viral replication and improving mouse survival ratio. Importantly, in addition to IAV and VSV, miR-200b-3p inhibitors exhibited potent antiviral effects against multiple pathogenic viruses threatening human health worldwide. Overall, our study suggests that miR-200b-3p might be a potential therapeutic target for broad-spectrum antiviral therapy. IMPORTANCE The innate immune response mediated by type I interferon (IFN-I) is essential for controlling viral replication. MicroRNAs (miRNAs) have been found to regulate the IFN signaling pathway. In this study, we describe a novel function of miRNA-200b-3p in negatively regulating IFN-I production during viral infection. miRNA-200b-3p was upregulated by the MAPK pathway activated by IAV and VSV infection. The binding of miRNA-200b-3p to the 3' UTR of TBK1 mRNA reduced IFN-I activation mediated by IRF3 and NF-κB. Application of miR-200b-3p inhibitors exhibited potent antiviral effects against multiple RNA and DNA viruses. These results provide fresh insight into understanding the impact of miRNAs on host-virus interactions and reveal a potential therapeutic target for common antiviral intervention.
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Affiliation(s)
- An Fang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yueming Yuan
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Baokuen Sui
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhihui Wang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yuan Zhang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Ming Zhou
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Huanchun Chen
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei Hongshan Laboratory, Wuhan, China
| | - Zhen F. Fu
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Ling Zhao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei Hongshan Laboratory, Wuhan, China
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25
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Shen H, Lane RA. Extracellular Vesicles From Primed Adipose-Derived Stem Cells Enhance Achilles Tendon Repair by Reducing Inflammation and Promoting Intrinsic Healing. Stem Cells 2023; 41:617-627. [PMID: 37085269 PMCID: PMC10267691 DOI: 10.1093/stmcls/sxad032] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 04/12/2023] [Indexed: 04/23/2023]
Abstract
Achilles tendon rupture is a common sports-related injury. Even with advanced clinical treatments, many patients suffer from long-term pain and functional deficits. These unsatisfactory outcomes result primarily from an imbalanced injury response with excessive inflammation and inadequate tendon regeneration. Prior studies showed that extracellular vesicles from inflammation-primed adipose-derived stem cells (iEVs) can attenuate early tendon inflammatory response to injury. It remains to be determined if iEVs can both reduce inflammation and promote regeneration in the later phases of tendon healing and the underlying mechanism. Therefore, this study investigated the mechanistic roles of iEVs in regulating tendon injury response using a mouse Achilles tendon injury and repair model in vivo and iEV-macrophage and iEV-tendon cell coculture models in vitro. Results showed that iEVs promoted tendon anti-inflammatory gene expression and reduced mononuclear cell accumulation to the injury site in the remodeling phase of healing. iEVs also increased collagen deposition in the injury center and promoted tendon structural recovery. Accordingly, mice treated with iEVs showed less peritendinous scar formation, much lower incidence of postoperative tendon gap or rupture, and faster functional recovery compared to untreated mice. Further in vitro studies revealed that iEVs both inhibited macrophage M1 polarization and increased tendon cell proliferation and collagen production. The iEV effects were partially mediated by miR-147-3p, which blocked the toll-like receptor 4/NF-κB signaling pathway that activated the M1 phenotype of macrophages. The combined results demonstrate that iEVs are a promising therapeutic agent that can enhance tendon repair by attenuating inflammation and promoting intrinsic healing.
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Affiliation(s)
- Hua Shen
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Ryan A Lane
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
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26
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Lan X, Yu R, Xu J, Jiang X. Exosomes from chondrocytes overexpressing miR-214-3p facilitate M2 macrophage polarization and angiogenesis to relieve Legg Calvé-Perthes disease. Cytokine 2023; 168:156233. [PMID: 37247447 DOI: 10.1016/j.cyto.2023.156233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/09/2023] [Accepted: 05/15/2023] [Indexed: 05/31/2023]
Abstract
OBJECTIVE Legg-Calvé-Perthes disease (LCPD) is a partial or total necrosis of femoral head bone caused by blood supply disorder and its etiology is not clear. Studies have revealed that microRNA-214-3p (miR-214-3p) plays a vital role in LCPD, however, its exact mechanism is still unclear. In this study, we investigated the potential role of chondrocytes-derived exosomes carrying miR-214-3p (exos-miR-214-3p) in the pathogenesis of LCPD. METHODS RT-qPCR was performed to evaluate miR-214-3p expression level in femoral head cartilage, serum and chondrocytes of patients with LCPD, as well as dexamethasone (DEX)-exposed TC28 cells. Effects of exos-miR-214-3p on the proliferation and apoptosis were verified via MTT assay, TUNEL staining and caspase3 activity assay. The M2 macrophage markers were assessed by flow cytometry, RT-qPCR and Western blot. Moreover, angiogenic effects of human umbilical vein endothelial cells (HUVECs) were tested using CCK-8 and tube formation assays. Bioinformatics prediction, luciferase assay and ChIP were applied to verify the association between ATF7, RUNX1 and miR-214-3p. RESULTS miR-214-3p was found to be decreased in patients with LCPD and DEX-treated TC28 cells, of which overexpression promoted cell proliferation and suppressed apoptosis. Mechanistically, exos-miR-214-3p facilitated M2 polarization by ATF7/TLR4 axis and HUVECs angiogenesis via RUNX1/VEGFA axis. CONCLUSION miR-214-3p alleviates LCPD by promoting M2 polarization of macrophages and angiogenesis.
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Affiliation(s)
- Xia Lan
- Department of Orthopaedics, the First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Ronghui Yu
- Department of Orthopaedics, the First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Jianyun Xu
- Department of Orthopaedics, the First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Xiaohua Jiang
- Department of Orthopaedics, the First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, PR China.
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27
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Mohammadi AH, Karimian M, Mirzaei H, Milajerdi A. Epigenetic modifications and obsessive-compulsive disorder: what do we know? Brain Struct Funct 2023:10.1007/s00429-023-02649-4. [PMID: 37204485 DOI: 10.1007/s00429-023-02649-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/21/2023] [Indexed: 05/20/2023]
Abstract
Obsessive-Compulsive Disorder (OCD) is a chronic, severe disabling neuropsychiatric disorder whose pathophysiology is not yet well defined. Generally, the symptom onset occurs during pre-adult life and affects subjects in different life aspects, including professional and social relationships. Although robust evidence indicates the presence of genetic factors in the etiopathology of OCD, the entirely mechanisms are not totally clarified. Thus, the possible interactions between genes and environmental risk factors mediated by epigenetic mechanisms should be sought. Therefore, we provide a review of genetic and epigenetic mechanisms related to OCD with a deep focus on the regulation of critical genes of the central nervous system seeking possible potential biomarkers.
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Affiliation(s)
- Amir Hossein Mohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Mohammad Karimian
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Milajerdi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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28
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Takimoto Y, Chu PS, Nakamoto N, Hagihara Y, Mikami Y, Miyamoto K, Morikawa R, Teratani T, Taniki N, Fujimori S, Suzuki T, Koda Y, Ishihara R, Ichikawa M, Honda A, Kanai T. Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience 2023; 26:106220. [PMID: 36876136 PMCID: PMC9982274 DOI: 10.1016/j.isci.2023.106220] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 08/25/2022] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.
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Affiliation(s)
- Yoichi Takimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuya Hagihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kentaro Miyamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Sota Fujimori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Rino Ishihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Ibaraki 300-0395, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Sprenkle NT, Serezani CH, Pua HH. MicroRNAs in Macrophages: Regulators of Activation and Function. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:359-368. [PMID: 36724439 PMCID: PMC10316964 DOI: 10.4049/jimmunol.2200467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/13/2022] [Indexed: 02/03/2023]
Abstract
Macrophages are sentinels of the innate immune system that maintain tissue homeostasis and contribute to inflammatory responses. Their broad scope of action depends on both functional heterogeneity and plasticity. Small noncoding RNAs called microRNAs (miRNAs) contribute to macrophage function as post-transcriptional inhibitors of target gene networks. Genetic and pharmacologic studies have uncovered genes regulated by miRNAs that control macrophage cellular programming and macrophage-driven pathology. miRNAs control proinflammatory M1-like activation, immunoregulatory M2-like macrophage activation, and emerging macrophage functions in metabolic disease and innate immune memory. Understanding the gene networks regulated by individual miRNAs enhances our understanding of the spectrum of macrophage function at steady state and during responses to injury or pathogen invasion, with the potential to develop miRNA-based therapies. This review aims to consolidate past and current studies investigating the complexity of the miRNA interactome to provide the reader with a mechanistic view of how miRNAs shape macrophage behavior.
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Affiliation(s)
| | - C Henrique Serezani
- Department of Pathology, Microbiology, and Immunology
- Department of Medicine, Division of Infectious Diseases
- Vanderbilt Center for Immunobiology, Nashville, Tennessee 37232, USA
- Vandebilt Institute of Infection, Immunology and Inflammation; Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
| | - Heather H Pua
- Department of Pathology, Microbiology, and Immunology
- Vanderbilt Center for Immunobiology, Nashville, Tennessee 37232, USA
- Vandebilt Institute of Infection, Immunology and Inflammation; Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
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30
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Shen H, Lane RA. Extracellular Vesicles from Inflammation-Primed Adipose-Derived Stem Cells Enhance Achilles Tendon Repair by Reducing Inflammation and Promoting Intrinsic Healing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.31.526532. [PMID: 36778262 PMCID: PMC9915600 DOI: 10.1101/2023.01.31.526532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Achilles tendon rupture is a common sports-related tendon injury. Even with advanced clinical treatments, many patients suffer from long-term pain and reduced function. These unsatisfactory outcomes result primarily from an imbalanced injury response with excessive inflammation and inadequate regeneration. Prior studies showed that extracellular vesicles from inflammation-primed adipose-derived stem cells (iEVs) can attenuate inflammation in the early phase of tendon healing. However, the effect of iEVs on tendon inflammation and regeneration in the later phases of tendon healing and the underlying mechanism remain to be determined. Accordingly, this study investigated the mechanistic roles of iEVs in regulating tendon response to injury using a mouse Achilles tendon injury and repair model in vivo and iEV-macrophage and iEV-tendon cell co-culture models in vitro. Results showed that iEVs promoted tendon anti-inflammatory gene expression and reduced mononuclear cell infiltration in the remodeling phase of tendon healing. iEVs also increased injury site collagen deposition and promoted tendon structural recovery. As such, mice treated with iEVs showed less peritendinous scar formation, much lower incidence of postoperative tendon gap or rupture, and faster functional recovery compared to untreated mice. Further in vitro study revealed that iEVs both inhibited macrophage inflammatory response and increased tendon cell proliferation and collagen production. The iEV effects were partially mediated by miR-147-3p, which blocks the toll-like receptor 4/NF-κB signaling pathway that activates macrophage M1 polarization. The combined results demonstrated that iEVs are a promising therapeutic agent, which can enhance tendon repair by attenuating inflammation and promoting intrinsic healing. Significance statement Using a clinically relevant mouse Achilles tendon injury and repair model, this study revealed that iEVs, a biological product generated from inflammation-primed adipose-derived stem cells, can directly target both macrophages and tendon cells and enhance tendon structural and functional recovery by limiting inflammation and promoting intrinsic healing. Results further identified miR-147-3p as one of the active components of iEVs that modulate macrophage inflammatory response by inhibiting toll-like receptor 4/NF-κB signaling pathway. These promising findings paved the road toward clinical application of iEVs in the treatment of tendon injury and other related disorders.
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31
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Hu YJ, Song GY, Zhang F, Zhang N, Wang F, Wang JL, Wang X, Wang TY, Li YF, Yan YD, Dou WT, Cheng CY, Xu P. Activation of long-non-coding RNA NEAT1 sponging microRNA-147 inhibits radiation damage by targeting PDPK1 in troxerutin radioprotection. iScience 2023; 26:105932. [PMID: 36698722 PMCID: PMC9868541 DOI: 10.1016/j.isci.2023.105932] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 11/26/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
A better understanding of the molecular mechanism involving the lncRNA-miRNA-mRNA network underlying radiation damage can be beneficial for radioprotection. This study was designed to investigate the potential role of lncRNA NEAT1, miR-147 and Phosphoinositide Dependent Protein Kinase 1 (PDPK1) interaction in radioprotection by troxerutin (TRT). We first demonstrated that NEAT1 sponged miR-147, and PDPK1 mRNA was the primary target of miR-147. In the cells, the NEAT1 and PDPK1 levels were downregulated after the radiation but increased after the treatment with TRT. The miR-147 level was significantly induced by radiation and inhibited by TRT. NEAT1 negatively regulated the expression of miR-147, whereas miR-47 targeted PDPK1 to downregulate its expression. In radioprotection, TRT effectively upregulated NEAT1 to inhibit miR-147 and to upregulate PDPK1. We concluded that TRT could promote radioprotection by stimulating NEAT1 to upregulate PDPK1 expression by suppressing miR-147. NEAT1 could be a critical therapeutic target of radiation damage.
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Affiliation(s)
- Yong-jian Hu
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Gui-yuan Song
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China,School of Public Health, Weifang Medical University, Weifang, Shandong 261000, China,Radiology Laboratory, Central Laboratory, Rizhao People’s Hospital, Rizhao, Shandong 276800, China
| | - Fan Zhang
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Nan Zhang
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China
| | - Fei Wang
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China
| | - Jing-long Wang
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China
| | - Xia Wang
- College of Medical Laboratory, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Tao-yang Wang
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Yu-feng Li
- Radiology Laboratory, Central Laboratory, Rizhao People’s Hospital, Rizhao, Shandong 276800, China
| | - Yi-di Yan
- Basic Medical School, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Wen-tao Dou
- Basic Medical School, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Chen-yi Cheng
- Basic Medical School, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Ping Xu
- School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong 277160, China,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan 453003, China,Corresponding author
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32
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Zheng SS, Wu YF, Zhang BH, Huang C, Xue TC. A novel myeloid cell marker genes related signature can indicate immune infiltration and predict prognosis of hepatocellular carcinoma: Integrated analysis of bulk and single-cell RNA sequencing. Front Mol Biosci 2023; 10:1118377. [PMID: 36959981 PMCID: PMC10027926 DOI: 10.3389/fmolb.2023.1118377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/27/2023] [Indexed: 03/09/2023] Open
Abstract
Myeloid cells are physiologically related to innate immunity and inflammation. Tumor-associated myeloid cells gained increasing interest because of their critical roles in tumor progression and anticancer immune responses in human malignancies. However, the associations between tumor-associated myeloid cell-related genes and hepatocellular carcinoma have yet to be revealed. Here, through the integrating analysis of bulk and single-cell RNA (scRNA) sequencing of public HCC samples, we developed a gene signature to investigate the role of HCC-specific myeloid signature genes in HCC patients. We firstly defined 317 myeloid cell marker genes through analyzing scRNA data of HCC from the GEO dataset. After selecting the differentially expressed genes, eleven genes were also proved prognostic. Then we built a gene signature from the TCGA cohort and verified further with the ICGC dataset by applying the LASSO Cox method. An eight genes signature (FABP5, C15orf48, PABPC1, TUBA1B, AKR1C3, NQO1, AKR1B10, SPP1) was achieved finally. Patients in the high risk group correlated with higher tumor stages and poor survival than those in the low-risk group. The risk score was proved to be an independent risk factor for prognosis. The high risk group had higher infiltrations of dendritic cells, macrophages and Tregs. And the APC co-inhibition, T cell co-inhibition pathways were also activated. Besides, the risk score positively correlated with multidrug resistance proteins. In conclusion, our myeloid cell marker genes related signature can predict patients' survival and may also indicate the levels of immune infiltration and drug resistance.
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Affiliation(s)
- Su-Su Zheng
- Department of Hepatic Oncology, Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China
| | - Yan-Fang Wu
- Department of Hepatic Oncology, Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China
| | - Bo-Heng Zhang
- Department of Hepatic Oncology, Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
- Center for Evidence-based Medicine, Shanghai Medical School, Fudan University, Shanghai, China
| | - Cheng Huang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- *Correspondence: Cheng Huang, ; Tong-Chun Xue,
| | - Tong-Chun Xue
- The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, China
- *Correspondence: Cheng Huang, ; Tong-Chun Xue,
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Lin S, Wang Q, Huang X, Feng J, Wang Y, Shao T, Deng X, Cao Y, Chen X, Zhou M, Zhao C. Wounds under diabetic milieu: The role of immune cellar components and signaling pathways. Biomed Pharmacother 2023; 157:114052. [PMID: 36462313 DOI: 10.1016/j.biopha.2022.114052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/19/2022] [Accepted: 11/25/2022] [Indexed: 12/05/2022] Open
Abstract
A major challenge in the field of diabetic wound healing is to confirm the body's intrinsic mechanism that could sense the immune system damage promptly and protect the wound from non-healing. Accumulating literature indicates that macrophage, a contributor to prolonged inflammation occurring at the wound site, might play such a role in hindering wound healing. Likewise, other immune cell dysfunctions, such as persistent neutrophils and T cell infection, may also lead to persistent oxidative stress and inflammatory reaction during diabetic wound healing. In this article, we discuss recent advances in the immune cellular components in wounds under the diabetic milieu, and the role of key signaling mechanisms that compromise the function of immune cells leading to persistent wound non-healing.
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Affiliation(s)
- Siyuan Lin
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China; Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qixue Wang
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China; Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaoting Huang
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Jiawei Feng
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yuqing Wang
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Tengteng Shao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Xiaofei Deng
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yemin Cao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Xinghua Chen
- Jinshan Hospital Affiliated to Fudan University, Shanghai, China.
| | - Mingmei Zhou
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China; Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Cheng Zhao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
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Wang J, Li G, Lin M, Lin S, Wu L. microRNA-338-3p suppresses lipopolysaccharide-induced inflammatory response in HK-2 cells. BMC Mol Cell Biol 2022; 23:60. [PMID: 36564725 PMCID: PMC9789656 DOI: 10.1186/s12860-022-00455-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/25/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Inflammation is the most common cause of kidney damage, and inflammatory responses in a number of diseases are mediated by microRNA-338-3p (miR-338-3p). However, there are only a few reports which described the regulation of miR-338-3p in human proximal tubular cells. The goal of this study was to see how miR-338-3p affected lipopolysaccharide (LPS)-caused inflammatory response in HK-2 cells. METHODS LPS was used to construct an inflammatory model in HK-2 cells. miR-338-3p mimic was used to increase the levels of miR-338-3p in HK-2 cells. MTT, JC-1 staining, and apoptosis assays were used to detect cell viability, mitochondrial membrane potential (MMP), and apoptosis, respectively. The production of inflammatory factors and the levels of p38, p65, phospho-p65, phospho-p38, Bax, Bcl-2, cleaved caspase-9, and cleaved caspase-3 were investigated using real-time polymerase chain reaction, western blotting, or enzyme-linked immunosorbent assay. RESULTS The levels of miR-338-3p were significantly lower in serum from patients with sepsis-induced kidney injury compared to the serum from healthy volunteers (P < 0.05). LPS reduced the level of miR-338-3p in HK-2 cells (P < 0.05). HK-2 cell viability, mitochondrial membrane potential, and Bcl-2 mRNA and protein levels were decreased by LPS (all P < 0.05). Apoptosis, the mRNA and protein levels of inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) and Bax, and the levels of cleaved caspase-9 and caspase-3 were increased by LPS (all P < 0.05). Raising the level of miR-338-3p mitigated these effects of LPS (all P < 0.05). CONCLUSION LPS-induced inflammation in HK-2 cells is reduced by miR-338-3p.
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Affiliation(s)
- Jing Wang
- Department of nosocomial infection management, Fujian Maternity and Child Health Hospital, Fujian Fuzhou, 350001 China
| | - Guokai Li
- Department of nosocomial infection management, Fujian Maternity and Child Health Hospital, Fujian Fuzhou, 350001 China
| | - Min Lin
- Pediatric intensive care unit, Fujian Maternity and Child Health Hospital, Fujian Fuzhou, 350001 China
| | - Sheng Lin
- Department of pediatrics, Fujian Maternity and Child Health Hospital, No. 18 Daoshan Road, Gulou District, Fujian Fuzhou, 350001 China
| | - Ling Wu
- Department of pediatrics, Fujian Maternity and Child Health Hospital, No. 18 Daoshan Road, Gulou District, Fujian Fuzhou, 350001 China
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35
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Xie Y, Chen H, Qu P, Qiao X, Guo L, Liu L. Novel insight on the role of Macrophages in atherosclerosis: Focus on polarization, apoptosis and efferocytosis. Int Immunopharmacol 2022; 113:109260. [DOI: 10.1016/j.intimp.2022.109260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/13/2022] [Indexed: 11/05/2022]
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36
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Zou Y, Meng JX, Wei XY, Gu XY, Chen C, Geng HL, Yang LH, Zhang XX, Cao HW. CircRNA and miRNA expression analysis in livers of mice with Toxoplasma gondii infection. Front Cell Infect Microbiol 2022; 12:1037586. [PMID: 36389171 PMCID: PMC9646959 DOI: 10.3389/fcimb.2022.1037586] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/07/2022] [Indexed: 11/23/2022] Open
Abstract
Toxoplasmosis is an important zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii). However, the functions of circRNAs and miRNAs in response to T. gondii infection in the livers of mice at acute and chronic stages remain unknown. Here, high-throughput RNA sequencing was performed for detecting the expression of circRNAs and miRNAs in livers of mice infected with 20 T. gondii cysts at the acute and chronic stages, in order to understand the potential molecular mechanisms underlying hepatic toxoplasmosis. Overall, 265 and 97 differentially expressed (DE) circRNAs were found in livers at the acute and chronic infection stages in comparison with controls, respectively. In addition, 171 and 77 DEmiRNAs were found in livers at the acute and chronic infection stages, respectively. Functional annotation showed that some immunity-related Gene ontology terms, such as “positive regulation of cytokine production”, “regulation of T cell activation”, and “immune receptor activity”, were enriched at the two infection stages. Moreover, the pathways “Valine, leucine, and isoleucine degradation”, “Fatty acid metabolism”, and “Glycine, serine, and threonine metabolism” were involved in liver disease. Remarkably, DEcircRNA 6:124519352|124575359 was significantly correlated with DEmiRNAs mmu-miR-146a-5p and mmu-miR-150-5p in the network that was associated with liver immunity and pathogenesis of disease. This study revealed that the expression profiling of circRNAs in the livers was changed after T. gondii infection, and improved our understanding of the transcriptomic landscape of hepatic toxoplasmosis in mice.
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Affiliation(s)
- Yang Zou
- School of Pharmacy, Yancheng Teachers University, Yancheng, China
- College of Life Sciences, Changchun Sci-Tech University, Changchun, China
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jin-Xin Meng
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Xin-Yu Wei
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Xiao-Yi Gu
- School of Pharmacy, Yancheng Teachers University, Yancheng, China
| | - Chao Chen
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Hong-Li Geng
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Li-Hua Yang
- College of Life Sciences, Changchun Sci-Tech University, Changchun, China
- *Correspondence: Li-Hua Yang, ; Xiao-Xuan Zhang, ; Hong-Wei Cao,
| | - Xiao-Xuan Zhang
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
- *Correspondence: Li-Hua Yang, ; Xiao-Xuan Zhang, ; Hong-Wei Cao,
| | - Hong-Wei Cao
- School of Pharmacy, Yancheng Teachers University, Yancheng, China
- *Correspondence: Li-Hua Yang, ; Xiao-Xuan Zhang, ; Hong-Wei Cao,
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37
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Yao J, Cai L, Chen Y, Zhang J, Zhuang W, Liang J, Li H. Exosomes: mediators regulating the phenotypic transition of vascular smooth muscle cells in atherosclerosis. Cell Commun Signal 2022; 20:153. [PMID: 36221105 PMCID: PMC9555104 DOI: 10.1186/s12964-022-00949-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/31/2022] [Indexed: 11/10/2022] Open
Abstract
Cardiovascular disease is one of the leading causes of human mortality worldwide, mainly due to atherosclerosis (AS), and the phenotypic transition of vascular smooth muscle cells (VSMCs) is a key event in the development of AS. Exosomes contain a variety of specific nucleic acids and proteins that mediate intercellular communication. The role of exosomes in AS has attracted attention. This review uses the VSMC phenotypic transition in AS as the entry point, introduces the effect of exosomes on AS from different perspectives, and discusses the status quo, deficiencies, and potential future directions in this field to provide new ideas for clinical research and treatment of AS. Video Abstract.
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Affiliation(s)
- Jiali Yao
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Linqian Cai
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yingrui Chen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jie Zhang
- Department of Neurology, Afliated Hospital of Yangzhou University, Yangzhou, 225001, China
| | - Wenwen Zhuang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jingyan Liang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China.,Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Hongliang Li
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .,Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
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38
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Sufianov A, Begliarzade S, Kudriashov V, Nafikova R, Ilyasova T, Liang Y. Role of miRNAs in vascular development. Noncoding RNA Res 2022; 8:1-7. [PMID: 36262425 PMCID: PMC9552023 DOI: 10.1016/j.ncrna.2022.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/27/2022] Open
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Decoding microRNA drivers in Atherosclerosis. Biosci Rep 2022; 42:231479. [PMID: 35758143 PMCID: PMC9289798 DOI: 10.1042/bsr20212355] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/17/2022] [Accepted: 06/26/2022] [Indexed: 11/17/2022] Open
Abstract
An estimated 97% of the human genome consists of non-protein-coding sequences. As our understanding of genome regulation improves, this has led to the characterization of a diverse array of non-coding RNAs (ncRNA). Among these, micro-RNAs (miRNAs) belong to the short ncRNA class (22–25 nucleotides in length), with approximately 2500 miRNA genes encoded within the human genome. From a therapeutic perspective, there is interest in exploiting miRNA as biomarkers of disease progression and response to treatments, as well as miRNA mimics/repressors as novel medicines. miRNA have emerged as an important class of RNA master regulators with important roles identified in the pathogenesis of atherosclerotic cardiovascular disease. Atherosclerosis is characterized by a chronic inflammatory build-up, driven largely by low-density lipoprotein cholesterol accumulation within the artery wall and vascular injury, including endothelial dysfunction, leukocyte recruitment and vascular remodelling. Conventional therapy focuses on lifestyle interventions, blood pressure-lowering medications, high-intensity statin therapy and antiplatelet agents. However, a significant proportion of patients remain at increased risk of cardiovascular disease. This continued cardiovascular risk is referred to as residual risk. Hence, a new drug class targeting atherosclerosis could synergise with existing therapies to optimise outcomes. Here, we review our current understanding of the role of ncRNA, with a focus on miRNA, in the development and progression of atherosclerosis, highlighting novel biological mechanisms and therapeutic avenues.
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Gierlikowski W, Gierlikowska B. MicroRNAs as Regulators of Phagocytosis. Cells 2022; 11:cells11091380. [PMID: 35563685 PMCID: PMC9106007 DOI: 10.3390/cells11091380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/11/2022] [Accepted: 04/17/2022] [Indexed: 12/10/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression and thus act as important regulators of cellular phenotype and function. As their expression may be dysregulated in numerous diseases, they are of interest as biomarkers. What is more, attempts of modulation of some microRNAs for therapeutic reasons have been undertaken. In this review, we discuss the current knowledge regarding the influence of microRNAs on phagocytosis, which may be exerted on different levels, such as through macrophages polarization, phagosome maturation, reactive oxygen species production and cytokines synthesis. This phenomenon plays an important role in numerous pathological conditions.
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Affiliation(s)
- Wojciech Gierlikowski
- Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
- Correspondence:
| | - Barbara Gierlikowska
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Żwirki i Wigury 63a, 02-091 Warsaw, Poland;
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TLR4 activation inhibits the proliferation and osteogenic differentiation of skeletal muscle stem cells by downregulating LGI1. J Physiol Biochem 2022; 78:667-678. [PMID: 35294724 DOI: 10.1007/s13105-022-00888-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 03/03/2022] [Indexed: 10/18/2022]
Abstract
Skeletal muscle stem cells (SMSCs) are vital to the growth, maintenance, and repair of the muscles; emerging evidence has indicated that Toll-like receptor 4 (TLR4) can potentially regulate muscle regeneration. In present study, in vitro and in vivo experiments were performed to explore the correlation of TLR4 with leucine-rich glioma-inactivated 1 (LGI1) as well as their effects on the proliferation and osteogenesis potential of SMSCs. In order to examine the regulatory mechanisms of TLR4 and LGI1 in SMSCs, the obtained cells were treated with lipopolysaccharide (LPS, used as an activator of TLR4) of different concentration at different time points as well as the siRNA against LGI1. Subsequently, a series of detection was undertaken in order to measure the proliferation and differentiation potential of SMSCs, which involved detection of the related factors, cell activity, and the sphere-forming capability. Following LPS treatment, the increased TLR4 expression and reduced LGI1 expression were observed. Consequently, we also discovered that Erk signaling pathway was inactivated and cell proliferation and osteogenesis capabilities declined, presented by the downregulation of related factors such as cyclin B1 and runt-related transcription factor 2. Moreover, the cell activity and sphere-formation performance of SMSCs were also declined. These results were also validated in rats with cecal ligation and perforation-induced rat models with sepsis. In conclusion, the present study reveals a regulatory mechanism in SMSCs whereby LGI1 expression is reduced by TLR4, thus impeding cell proliferation and osteogenesis, highlighting TLR4 as a potential therapeutic target against many diseases related to SMSCs.
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Chu AJ, Williams JM. Astrocytic MicroRNA in Ageing, Inflammation, and Neurodegenerative Disease. Front Physiol 2022; 12:826697. [PMID: 35222067 PMCID: PMC8867065 DOI: 10.3389/fphys.2021.826697] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 12/27/2021] [Indexed: 12/13/2022] Open
Abstract
Astrocytes actively regulate numerous cell types both within and outside of the central nervous system in health and disease. Indeed, astrocyte morphology, gene expression and function, alongside the content of astrocyte-derived extracellular vesicles (ADEVs), is significantly altered by ageing, inflammatory processes and in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Here, we review the relevant emerging literature focussed on perturbation in expression of microRNA (miRNA), small non-coding RNAs that potently regulate gene expression. Synthesis of this literature shows that ageing-related processes, neurodegenerative disease-associated mutations or peptides and cytokines induce dysregulated expression of miRNA in astrocytes and in some cases can lead to selective incorporation of miRNA into ADEVs. Analysis of the miRNA targets shows that the resulting downstream consequences of alterations to levels of miRNA include release of cytokines, chronic activation of the immune response, increased apoptosis, and compromised cellular functioning of both astrocytes and ADEV-ingesting cells. We conclude that perturbation of these functions likely exacerbates mechanisms leading to neuropathology and ultimately contributes to the cognitive or motor symptoms of neurodegenerative diseases. This field requires comprehensive miRNA expression profiling of both astrocytes and ADEVs to fully understand the effect of perturbed astrocytic miRNA expression in ageing and neurodegenerative disease.
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Mirna M, Paar V, Topf A, Kraus T, Sotlar K, Aigner A, Ewe A, Watzinger S, Podesser BK, Hackl M, Pistulli R, Hoppe UC, Kiss A, Lichtenauer M. A new player in the game: treatment with antagomiR-21a-5p significantly attenuates histological and echocardiographic effects of experimental autoimmune myocarditis. Cardiovasc Res 2022; 118:556-572. [PMID: 33483746 DOI: 10.1093/cvr/cvab015] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/09/2021] [Indexed: 12/16/2022] Open
Abstract
AIMS Myocarditis is associated with formidable symptoms and increased risk of adverse outcomes. Current approaches mostly rely on symptomatic treatments, warranting novel concepts for clinical practice. The aim of this study was to investigate the microRNA (miRNA) expression profile of Balb/c mice with experimental autoimmune myocarditis (EAM), choose a representative miRNA to antagonize after review of available literature and test its effects on myocardial inflammation in vitro and in vivo. METHODS AND RESULTS Phase 1: EAM was induced in 12 male Balb/c mice, 10 animals served as controls. After sacrifice, next-generation sequencing (NGS) of the miRNA expression profile was performed. Based on these results, H9C2 cells and human ventricular cardiac fibroblasts exposed to lipopolysaccharide (LPS) were treated with the selected candidate antagomiR-21a-5p. Phase 2: EAM was induced in 48 animals. Thereof, 24 animals were either treated with antagomiR-21a-5p or negative control oligonucleotide in a nanoparticle formulation. Transthoracic echocardiography (TTE) was performed on Days 0, 7, 14, and 21. Histopathological examination was performed after sacrifice. Phase 1: EAM resulted in a significant up-regulation of 27 miRNAs, including miR-21a-5p (log2FC: 2.23, adj. P = 0.0026). Transfection with antagomiR-21a-5p resulted in a significant reduction of TNFα, IL-6, and collagen I in vitro. Phase 2: Treatment with antagomiR-21a-5p, formulated in polymeric nanoparticles for systemic injection, significantly attenuated myocardial inflammation (P = 0.001) and fibrosis (P = 0.013), as well as myocardial 'hypertrophy' on TTE. CONCLUSIONS Silencing of miR-21a-5p results in a significant reduction of the expression of pro-inflammatory cytokines in vitro, as well as a significant attenuation of inflammation, fibrosis and echocardiographic effects of EAM in vivo.
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Affiliation(s)
- Moritz Mirna
- Department of Cardiology, University Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Vera Paar
- Department of Cardiology, University Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Albert Topf
- Department of Cardiology, University Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Theo Kraus
- University Institute of Pathology, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Karl Sotlar
- University Institute of Pathology, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Achim Aigner
- Rudolf-Boehm-Institut for Pharmacology und Toxicology, Clinical Pharmacology, University of Leipzig, Faculty of Medicine, Haertelstraße 16-18, 04107 Leipzig, Germany
| | - Alexander Ewe
- Rudolf-Boehm-Institut for Pharmacology und Toxicology, Clinical Pharmacology, University of Leipzig, Faculty of Medicine, Haertelstraße 16-18, 04107 Leipzig, Germany
| | - Simon Watzinger
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research, Medical University of Vienna, Waehringerguertel 18-20, 1090 Vienna, Austria
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research, Medical University of Vienna, Waehringerguertel 18-20, 1090 Vienna, Austria
| | | | - Rudin Pistulli
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Muenster, Albert-Schweitzer-Strasse 33, 48149 Muenster, Germany
| | - Uta C Hoppe
- Department of Cardiology, University Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research at Center for Biomedical Research, Medical University of Vienna, Waehringerguertel 18-20, 1090 Vienna, Austria
| | - Michael Lichtenauer
- Department of Cardiology, University Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria
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Characterization of agapornis fischeri interferon gamma and its activity against beak and feather disease virus. Virus Res 2022; 308:198647. [PMID: 34838936 DOI: 10.1016/j.virusres.2021.198647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 11/24/2022]
Abstract
This study sought to clone and sequence the interferon-γ (IFN-γ) gene of the Fischer's lovebird parrot (Agapornis fischeri). Raw264.7 cells treated with the expressed IFN-γ protein exhibited an upregulation in inducible nitric oxide synthase protein expression and nitric oxide (NO) production coupled with increases in phagocytosis and pinocytosis, as well as an induction of interferon-stimulated genes through the activation of the NF-κB factor, all of which are indicators of the innate immune responses of the activated macrophages. Similar to the IFN-γ protein of other species, the NO production activity of the parrot IFN-γ protein decreased by 80% after exposure at 60 °C for 4 min. Additionally, only half of the NO production activity of the parrot IFN-γ protein remained upon exposure to HCl for 30 min. These findings suggested that the parrot IFN-γ protein was heat-labile and sensitive to acidic conditions. Therefore, all of these effects contributed to the blockage of the uptake of BFDV virus-like particles (VLPs) by cells, the nuclear entry of the Cap protein of BFDV VLPs, and the clearance of the virus from BFDV-infected parrots by the IFN-γ protein of Agapornis fischeri. This study is the first to describe the cloning of the IFN-γ gene of Agapornis fischeri and characterize the anti-beak and feather disease virus activity of the IFN-γ protein of Agapornis fischeri.
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Trung NT, Lien TT, Sang VV, Hoan NX, Manh ND, Thau NS, Quyen DT, Hien TTT, Hoan PQ, Bang MH, Velavan TP, Song LH. Circulating miR-147b as a diagnostic marker for patients with bacterial sepsis and septic shock. PLoS One 2021; 16:e0261228. [PMID: 34914790 PMCID: PMC8675720 DOI: 10.1371/journal.pone.0261228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 11/24/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Early diagnosis, precise antimicrobial treatment and subsequent patient stratification can improve sepsis outcomes. Circulating biomarkers such as plasma microRNAs (miRNAs) have proven to be surrogates for diagnosis, severity and case management of infections. The expression of four selected miRNAs (miR-146-3p, miR-147b, miR-155 and miR-223) was validated for their prognostic and diagnostic potential in a clinically defined cohort of patients with sepsis and septic shock. METHODS The expression of plasma miRNAs was quantified by quantitative PCR (qPCR) in patients with bacterial sepsis (n = 78), in patients with septic shock (n = 52) and in patients with dengue haemorrhagic fever (DHF; n = 69) and in healthy controls (n = 82). RESULTS The expression of studied miRNA was significantly increased in patients with bacterial sepsis and septic shock. The plasma miR-147b was able to differentiate bacterial sepsis from non-sepsis and septic shock (AUC = 0.77 and 0.8, respectively, p≤ 0.05), while the combination of plasma miR-147b and procalcitonin (PCT) predicted septic shock (AUC = 0.86, p≤ 0.05). CONCLUSIONS The plasma miR-147b may be an useful biomarker independently or in combination with PCT to support clinical diagnosis of sepsis and equally prognosis of patients with septic shock.
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Affiliation(s)
- Ngo Tat Trung
- Centre for Genetics Consultation and Cancer Screening, Hanoi, Vietnam
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Molecular Biology, Hanoi, Vietnam
- * E-mail: (LHS); (NTT)
| | - Tran Thi Lien
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
| | - Vu Viet Sang
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Molecular Biology, Hanoi, Vietnam
| | - Nguyen Dang Manh
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
| | - Nguyen Sy Thau
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
| | - Dao Thanh Quyen
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Molecular Biology, Hanoi, Vietnam
| | | | | | - Mai Hong Bang
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Gastroenterology, Hanoi, Vietnam
| | - Thirumalaisamy P. Velavan
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Le Huu Song
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
- * E-mail: (LHS); (NTT)
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Clayton SA, Daley KK, MacDonald L, Fernandez-Vizarra E, Bottegoni G, O’Neil JD, Major T, Griffin D, Zhuang Q, Adewoye AB, Woolcock K, Jones SW, Goodyear C, Elmesmari A, Filer A, Tennant DA, Alivernini S, Buckley CD, Pitceathly RDS, Kurowska-Stolarska M, Clark AR. Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48. SCIENCE ADVANCES 2021; 7:eabl5182. [PMID: 34878835 PMCID: PMC8654286 DOI: 10.1126/sciadv.abl5182] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/18/2021] [Indexed: 05/10/2023]
Abstract
Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.
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Affiliation(s)
- Sally A. Clayton
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Kalbinder K. Daley
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Lucy MacDonald
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | | | - Giovanni Bottegoni
- Dipartimento di Scienze Biomolecolari, University of Urbino, Urbino, Italy
- School of Pharmacy, Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
| | - John D. O’Neil
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Triin Major
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Daniel Griffin
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Qinqin Zhuang
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Adeolu B. Adewoye
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Kieran Woolcock
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Simon W. Jones
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Carl Goodyear
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Aziza Elmesmari
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Andrew Filer
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Daniel A. Tennant
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Stefano Alivernini
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Christopher D. Buckley
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Robert D. S. Pitceathly
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
| | - Mariola Kurowska-Stolarska
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Andrew R. Clark
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle, Oxford, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
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Yang B, Wang D, Liu M, Wu X, Yin J, Zhu G. Host cells with transient overexpression of MDR1 as a novel in vitro model for evaluating on-target effect for activity against the epicellular Cryptosporidium parasite. J Antimicrob Chemother 2021; 77:124-134. [PMID: 34648615 DOI: 10.1093/jac/dkab369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/08/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES To rapidly generate host cells with resistance to multiple compounds for differentiating drug action on parasite target or the host cell target (i.e. on-target or off-target effect) against the zoonotic enteric parasite Cryptosporidium parvum. METHODS Transient overexpression of a multidrug resistance protein 1 (MDR1) gene in host cells (HCT-8 cell line) was explored to increase drug tolerance of the host cells to selected anti-cryptosporidial leads. In vitro cytotoxicity and anti-cryptosporidial efficacy of selected compounds were evaluated on the parasite grown in WT parental and transiently transfected HCT-8 cells. The approach was based on the theory that, for an epicellular parasite receiving consistent exposure to compounds in culture medium, overexpressing MDR1 in HCT-8 cells would increase drug tolerance of host cells to selected compounds but would not affect the anti-cryptosporidial efficacy if the compounds acted solely on the parasite target and the drug action on host cell target played no role on the antiparasitic efficacy. RESULTS Six known anti-cryptosporidial leads were tested. Transient overexpression of MDR1 increased drug tolerance of HCT-8 cells on paclitaxel, doxorubicin HCl and vincristine sulphate (2.11- to 2.27-fold increase), but not on cyclosporin A, daunorubicin HCl and nitazoxanide. Increased drug tolerance in host cells had no effect on antiparasitic efficacy of paclitaxel, but affected that of doxorubicin HCl. CONCLUSIONS Data confirmed that, at efficacious concentrations, paclitaxel acted mainly on the parasite target, while doxorubicin might act on both parasite and host cell targets. This model can be employed for studying the action of additional anti-cryptosporidial leads, and adapted to studying drug action in other epicellular pathogens. The limitation of the model is that the anti-cryptosporidial leads/hits need to be MDR1 substrates.
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Affiliation(s)
- Bo Yang
- Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Dongqiang Wang
- Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Mingxiao Liu
- Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Xiaodong Wu
- Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Jigang Yin
- Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Guan Zhu
- Key Laboratory of Zoonosis Research of the Ministry of Education, The Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun 130062, China
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Ahmad A. Epigenetic regulation of immunosuppressive tumor-associated macrophages through dysregulated microRNAs. Semin Cell Dev Biol 2021; 124:26-33. [PMID: 34556420 DOI: 10.1016/j.semcdb.2021.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/02/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023]
Abstract
Macrophages are immune cells that play different roles under different physiological conditions. They are present in all tissues where they primarily protect from bacteria and pathogens in addition to assisting in tissue repair. During tumor progression, macrophages can exert contrasting effects based on the M1 vs. M2 polarization. The M2 macrophages support tumor growth through mechanisms that help suppress immune responses and/or circumvent immune-surveillance. A number of such mechanisms such as production of IL-10 and arginase, and expression of PD-L1, V-domain Ig suppressor of T cell activation and B7 family molecule B7-H4 are now believed central to the immunosuppressive effects of tumor-associated macrophages (TAMs). Emerging data has identified epigenetic regulation of these immunosuppressive mechanisms by small non-coding RNAs, the microRNAs (miRNAs). This review discusses the available literature on the subject, including the exosomes mediated transfer of miRNAs between cancer cells and the macrophages within the tumor microenvironment. A number of miRNAs are now believed to be involved in TAMs' production of IL-10 and expression of PD-L1 while the information on such regulation of other immunosuppressive mechanisms is slowly emerging. A better understanding of epigenetic regulation of macrophages-mediated immunosuppressive effect can help identify novel targets for therapy and aid the design of future studies aimed at sensitizing tumors to immune responses.
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Affiliation(s)
- Aamir Ahmad
- Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
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Dong W, Gao W, Yan X, Sun Y, Xu T. microRNA-132 as a negative regulator in NF-κB signaling pathway via targeting IL-1β in miiuy croaker. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 122:104113. [PMID: 33979576 DOI: 10.1016/j.dci.2021.104113] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 06/12/2023]
Abstract
The innate immune system is the first line of defense against the invasion of pathogens. It can make a rapid immune response to the invading pathogenic microorganisms, thereby eliminating the invading pathogens and protecting the body from harm. microRNAs are a family of small non-coding ribonucleic acid molecules, which are important and multifunctional regulator of immune response. In this study, we studied the role of miR-132 as a key regulatory factor of IL-1β-mediated inflammation. The seed region of miR-132 can regulate gene expression by binding to the 3'UTR of IL-1β, and inhibit the expression of IL-1β at the post-transcriptional level. More importantly, miR-132 inhibits LPS-induced NF-κB signaling pathway by targeting IL-1β, thereby preventing excessive inflammatory response from causing autoimmune diseases. These results will help to better understand the complex regulatory mechanisms of teleost fishes.
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Affiliation(s)
- Wenjing Dong
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Wenya Gao
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Xiaolong Yan
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Yuena Sun
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai, China.
| | - Tianjun Xu
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai, China; National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China.
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50
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Miyoshi Y, Saika A, Nagatake T, Matsunaga A, Kunisawa J, Katakura Y, Yamasaki-Yashiki S. Mechanisms underlying enhanced IgA production in Peyer's patch cells by membrane vesicles derived from Lactobacillus sakei. Biosci Biotechnol Biochem 2021; 85:1536-1545. [PMID: 33885732 DOI: 10.1093/bbb/zbab065] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/05/2021] [Indexed: 12/20/2022]
Abstract
We analyzed the mechanisms underlying enhanced IgA production in the cells of Peyer's patch cells via membrane vesicles derived from Lactobacillus sakei subsp. sakei NBRC 15893. Depletion of CD11c+ cells from Peyer's patch cells suppressed the enhanced IgA production mediated by membrane vesicles. Meanwhile, the stimulation of bone-marrow-derived dendritic cells with membrane vesicles increased gene expression of inducible nitric oxide synthase, retinaldehyde dehydrogenase 2, and several inflammatory cytokines. The production of nitric oxide and interleukin (IL)-6 by membrane vesicle stimulation was induced via Toll-like receptor 2 on bone marrow-derived dendritic cells. Inhibition of inducible nitric oxide synthase and retinaldehyde dehydrogenase 2, as well as the neutralization of IL-6 in Peyer's patch cells, suppressed the enhanced IgA production by membrane vesicle stimulation. Hence, nitric oxide, retinoic acid, and IL-6 induced by membrane vesicles play crucial roles in the enhanced IgA production elicited by membrane vesicles in Peyer's patch cells.
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Affiliation(s)
- Yuki Miyoshi
- Chemistry, Materials and Bioengineering Major, Graduate School of Science and Engineering, Kansai University, Suita, Osaka, Japan.,Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Azusa Saika
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Takahiro Nagatake
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Ayu Matsunaga
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Department of Food and Life Science, School of Life and Environmental Science, Azabu University, Sagamihara, Kanagawa, Japan
| | - Jun Kunisawa
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Yoshio Katakura
- Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka, Japan
| | - Shino Yamasaki-Yashiki
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka, Japan
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