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Cairoli V, Valle-Millares D, Ryan P, Dominguez L, Martín-Carbonero L, De los Santos I, De Matteo E, Ameigeiras B, De Sousa M, Briz V, Preciado MV, Fernández-Rodriguez A, Valva P. Extracellular vesicles derived microRNAs as non-invasive markers of liver fibrosis in chronically infected HCV patients: a pilot study. Noncoding RNA Res 2025; 12:132-140. [PMID: 40176849 PMCID: PMC11964596 DOI: 10.1016/j.ncrna.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 12/08/2024] [Accepted: 03/04/2025] [Indexed: 04/05/2025] Open
Abstract
Extracellular vesicles (EVs) are an increasingly promising tool for liquid biopsy in liver diseases. Hepatitis C Virus (HCV) infection, alone or together with Human Immunodeficiency Virus (HIV) infection significantly impacts on the microRNA (miRNA) EVs content resembling chronic hepatitis C (CHC) progression. The objective of the study was to delve into the intricate EVs-miRNA profiles in CHC patients with different liver fibrosis stages, aiming to pinpoint non-invasive markers capable of distinguishing significant fibrosis. Plasma EV-miRNAs from 50 CHC patients (HCV+ and HCV+/HIV+) stratified in no significant (F < 2) and significant (F ≥ 2) fibrosis, were massively sequenced. General linear models (GLM) were used to identify significantly differential expressed (SDE) miRNAs according to liver fibrosis stages (F ≥ 2 and F < 2). Dysregulated biological pathways were subsequently analyzed in silico for the following groups: i) all patients; ii) HCV+; and iii) HCV+/HIV+. Multiple-ordered logistic regression analysis was performed to develop a score to identify F ≥ 2 cases. The diagnostic potential of both the SDE miRNAs and the developed score was assessed using ROC curve analysis. With respect to all CHC patients, two SDE miRNAs (hsa-miR-122-5p and hsa-miR-92a-3p) were identified which regulate genes related to cytoskeleton organization. Regarding their diagnostic performance to discriminate F ≥ 2, both miRNAs individually demonstrated acceptable diagnostic values. However, their combined use in a new score enhanced their diagnostic performance (AUROC = 0.833). In the HCV+ subgroup, 8 SDE miRNAs (hsa-miR-122-5p, hsa-miR-320c, hsa-miR-3615, hsa-miR-320a-3p, hsa-miR-374b-5p, hsa-let-7a-3p, hsa-miR-199a-5p, hsa-miR-142-5p), which regulate macrophage activity and cell growth/death regulation, were recognized. Among them, hsa-miR-3615 displayed the highest diagnostic performance to discriminate F ≥ 2 (AUROC = 0.936). With respect to HCV+/HIV+, 18 SDE miRNAs (hsa-miR-4508, hsa-miR-122-5p, hsa-miR-451a, hsa-miR-1290, hsa-miR-1246, hsa-miR-107, hsa-miR-15b-5p, hsa-miR-194-5p, hsa-miR-22-5p, hsa-miR-20b-5p, hsa-miR-142-5p, hsa-miR-328-3p, hsa-miR-335-3p, hsa-miR-125a-5p, hsa-miR-423-3p, hsa-let-7d-3p, hsa-miR-128-3p, hsa-miR-10a-5p) were recognized that regulate RNA silencing processes. In this case, hsa-miR-423-3p and hsa-miR-128-3p showed outstanding diagnostic performances (AUROC > 0.900). Distinct EVs-miRNA profiles were identified in patients with varying liver fibrosis stages, both in the overall CHC cohort and within HCV+ and HCV+/HIV+ subgroups. These specific miRNA signatures would allow the elucidation of potential mechanisms involved in clinical evolution and identification of specific biomarkers of unfavorable progression, plausible to be used in a diagnostic panel. Furthermore, the developed score demonstrates the ability to discriminate within the CHC group those individuals with significant fibrosis regardless of their HIV infection status.
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Affiliation(s)
- Victoria Cairoli
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
| | - Daniel Valle-Millares
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Pablo Ryan
- Infectious Diseases Department, Internal Medicine Department HIV/Hepatitis, Infanta Leonor University Hospital, 28031, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Lourdes Dominguez
- HIV Unit, Internal Medicine Department, Research Institute of the Hospital 12 de Octubre (imas12), 28041, Madrid, Spain
| | - Luz Martín-Carbonero
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
- Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, IdiPAZ, 28046, Madrid, Spain
| | - Ignacio De los Santos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
- Infectious Diseases Unit, Internal Medicine Department, La Princesa University Hospital, 28006, Madrid, Spain
| | - Elena De Matteo
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
| | - Beatriz Ameigeiras
- Liver Unit, Ramos Mejía Hospital, C1221ADC CABA, Buenos Aires, Argentina
| | - Marcela De Sousa
- Liver Unit, Ramos Mejía Hospital, C1221ADC CABA, Buenos Aires, Argentina
| | - Verónica Briz
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
- Viral Hepatitis Reference and Research Laboratory, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28222, Madrid, Spain
| | - María V. Preciado
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
| | - Amanda Fernández-Rodriguez
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Majadahonda, 28222, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Pamela Valva
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
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Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [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: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
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Fu Y, Yang L, Liu L, Kong L, Sun H, Sun Y, Yin F, Yan G, Wang X. Rhein: An Updated Review Concerning Its Biological Activity, Pharmacokinetics, Structure Optimization, and Future Pharmaceutical Applications. Pharmaceuticals (Basel) 2024; 17:1665. [PMID: 39770507 PMCID: PMC11679290 DOI: 10.3390/ph17121665] [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: 11/20/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein's pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine.
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Affiliation(s)
- Yuqi Fu
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China; (L.Y.); (Y.S.)
| | - Lei Liu
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Ling Kong
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Hui Sun
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Ye Sun
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China; (L.Y.); (Y.S.)
| | - Fengting Yin
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Guangli Yan
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Xijun Wang
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China; (L.Y.); (Y.S.)
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Ronan G, Bahcecioglu G, Yang J, Zorlutuna P. Cardiac tissue-resident vesicles differentially modulate anti-fibrotic phenotype by age and sex through synergistic miRNA effects. Biomaterials 2024; 311:122671. [PMID: 38941684 PMCID: PMC11344275 DOI: 10.1016/j.biomaterials.2024.122671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/30/2024]
Abstract
Aging is a risk factor for cardiovascular disease, the leading cause of death worldwide. Cardiac fibrosis is a harmful result of repeated myocardial infarction that increases risk of morbidity and future injury. Interestingly, both rates and outcomes of cardiac fibrosis differ between young and aged individuals, as well as men and women. Here, for the first time, we identify and isolate matrix-bound extracellular vesicles from the left ventricles (LVs) of young or aged males and females in both human and murine models. These LV vesicles (LVVs) show differences in morphology and content between these four cohorts in both humans and mice. LVV effects on fibrosis were also investigated in vitro, and aged male LVVs were pro-fibrotic while other LVVs were anti-fibrotic. From these LVVs, we could identify therapeutic miRNAs to promote anti-fibrotic effects. Four miRNAs were identified and together, but not individually, demonstrated significant cardioprotective effects when transfected. This suggests that miRNA synergy can regulate cell response, not just individual miRNAs, and also indicates that biological agent-associated therapeutic effects may be recapitulated using non-immunologically active agents. Furthermore, that chronic changes in LVV miRNA content may be a major factor in sex- and age-dependent differences in clinical outcomes of cardiac fibrosis.
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Affiliation(s)
- George Ronan
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN, 46556, USA; Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Gokhan Bahcecioglu
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, 46556, USA
| | - Jun Yang
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Pinar Zorlutuna
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN, 46556, USA; Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, 46556, USA; Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA.
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Ismail M, Fadul MM, Taha R, Siddig O, Elhafiz M, Yousef BA, Jiang Z, Zhang L, Sun L. Dynamic role of exosomal long non-coding RNA in liver diseases: pathogenesis and diagnostic aspects. Hepatol Int 2024; 18:1715-1730. [PMID: 39306594 DOI: 10.1007/s12072-024-10722-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/15/2024] [Indexed: 12/11/2024]
Abstract
BACKGROUND Liver disease has emerged as a significant health concern, characterized by high rates of morbidity and mortality. Circulating exosomes have garnered attention as important mediators of intercellular communication, harboring protein and stable mRNAs, microRNAs, and long non-coding RNAs (lncRNA). This review highlights the involvement of exosomal lncRNA in the pathogenesis and diagnosis of various liver diseases. Notably, exosomal lncRNAs exhibit therapeutic potential as targets for conditions including hepatic carcinoma, hepatic fibrosis, and hepatic viral infections. METHOD An online screening process was employed to identify studies investigating the association between exosomal lncRNA and various liver diseases. RESULT Our study revealed a diverse array of lncRNAs carried by exosomes, including H19, Linc-ROR, VLDLR, MALAT1, DANCR, HEIH, ENSG00000248932.1, ENST00000457302.2, ZSCAN16-AS1, and others, exhibiting varied levels across different liver diseases compared to normal liver tissue. These exosomal-derived lncRNAs are increasingly recognized as pivotal biomarkers for diagnosing and prognosticating liver diseases, supported by emerging evidence. However, the precise mechanisms underlying the involvement of certain exosomal lncRNAs remain incompletely understood. Furthermore, the combined analysis of serum exosomes using ENSG00000258332.1, LINC00635, and serum AFP may serve as novel and valuable biomarker for HCC. Clinically, exosomal ATB expression is upregulated in HCC, while exosomal HEIH and RP11-513I15.6 have shown potential for distinguishing HCC related to HCV infection. CONCLUSION The lack of reliable biomarkers for liver diseases, coupled with the high specificity and sensitivity of exosomal lncRNA and its non-invasive detection, promotes exploring their role in pathogenesis and biomarker for diagnosis, prognosis, and response to treatment liver diseases.
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Affiliation(s)
- Mohammed Ismail
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Department of Pharmacology, Faculty of Medicine and Health Science, Dongola University, Dongola, Sudan
| | - Missaa M Fadul
- Department of Pharmacology, Faculty of Medicine and Health Science, Dongola University, Dongola, Sudan
| | - Reham Taha
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Orwa Siddig
- Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Muhanad Elhafiz
- Department of Pharmacology, Faculty of Pharmacy, Omdurman Islamic University, Khartoum, Sudan
| | - Bashir A Yousef
- Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan
| | - Zhenzhou Jiang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
- Centre for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Lixin Sun
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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Ciebiera M, Kociuba J, Ali M, Madueke-Laveaux OS, Yang Q, Bączkowska M, Włodarczyk M, Żeber-Lubecka N, Zarychta E, Corachán A, Alkhrait S, Somayeh V, Malasevskaia I, Łoziński T, Laudański P, Spaczynski R, Jakiel G, Al-Hendy A. Uterine fibroids: current research on novel drug targets and innovative therapeutic strategies. Expert Opin Ther Targets 2024; 28:669-687. [PMID: 39136530 DOI: 10.1080/14728222.2024.2390094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 08/05/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy. AREAS COVERED This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy. EXPERT OPINION While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.
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Affiliation(s)
- Michal Ciebiera
- Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, Warsaw, Poland
- Warsaw Institute of Women's Health, Warsaw, Poland
- Development and Research Center of Non-Invasive Therapies, Pro-Familia Hospital, Rzeszow, Poland
| | - Jakub Kociuba
- Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, Warsaw, Poland
- Warsaw Institute of Women's Health, Warsaw, Poland
| | - Mohamed Ali
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | | | - Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | - Monika Bączkowska
- Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, Warsaw, Poland
| | - Marta Włodarczyk
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Natalia Żeber-Lubecka
- Department of Gastroenterology, Hepatology and Clinical Oncology, Center of Postgraduate Medical Education, Warsaw, Poland
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Elżbieta Zarychta
- Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, Warsaw, Poland
| | - Ana Corachán
- Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
| | - Samar Alkhrait
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | - Vafaei Somayeh
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | | | - Tomasz Łoziński
- Development and Research Center of Non-Invasive Therapies, Pro-Familia Hospital, Rzeszow, Poland
- Department of Obstetrics and Gynecology, Pro-Familia Hospital, Rzeszow, Poland
- Department of Gynecology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Piotr Laudański
- Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland
- Women's Health Research Institute, Calisia University, Kalisz, Poland
- OVIklinika Infertility Center, Warsaw, Poland
| | - Robert Spaczynski
- Center for Gynecology, Obstetrics and Infertility Treatment, Poznan, Poland
- Collegium Medicum, University of Zielona Gora, Zielona Gora, Poland
| | - Grzegorz Jakiel
- First Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, Warsaw, Poland
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
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Li D, Yang W, Pang J, Yu G. Differential DNA methylation landscape of miRNAs genes in mice liver fibrosis. Mol Biol Rep 2024; 51:475. [PMID: 38553662 DOI: 10.1007/s11033-024-09416-6] [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: 10/30/2023] [Accepted: 03/05/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Patients with chronic liver disease were found nearly all to have liver fibrosis, which is characterized by excess accumulation of extracellular matrix (ECM) proteins. While ECM accumulation can prevent liver infection and injury, it can destroy normal liver function and architecture. miRNA's own regulation was involved in DNA methylation change. The purpose of this study is to detect DNA methylation landscape of miRNAs genes in mice liver fibrosis tissues. METHODS Male mice (10-12 weeks) were injected CCl4 from abdominal cavity to induced liver fibrosis. 850 K BeadChips were used to examine DNA methylation change in whole genome. The methylation change of 16 CpG dinucleotides located in promoter regions of 4 miRNA genes were detected by bisulfite sequencing polymerase chain reaction (BSP) to verify chip data accuracy, and these 4 miRNA genes' expressions were detected by RT-qPCR methods. RESULTS There are 769 differential methylation sites (DMS) in total between fibrotic liver tissue and normal mice liver tissue, which were related with 148 different miRNA genes. Chips array data were confirmed by bisulfite sequencing polymerase chain reaction (R = 0.953; P < 0.01). GO analysis of the target genes of 2 miRNA revealed that protein binding, cytoplasm and chromatin binding activity were commonly enriched; KEGG pathway enrichment analysis displayed that TGF-beta signaling pathway was commonly enriched. CONCLUSION The DNA of 148 miRNA genes was found to have methylation change in liver fibrosis tissue. These discoveries in miRNA genes are beneficial to future miRNA function research in liver fibrosis.
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Affiliation(s)
- Deming Li
- State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, Overseas Expertise Introduction Center for Discipline Innovation of Pulmonary Fibrosis (111 Project), College of Life Science, Henan Normal University, Xinxiang, Henan, China
| | - Wentong Yang
- State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, Overseas Expertise Introduction Center for Discipline Innovation of Pulmonary Fibrosis (111 Project), College of Life Science, Henan Normal University, Xinxiang, Henan, China
| | - Jiaojiao Pang
- State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, Overseas Expertise Introduction Center for Discipline Innovation of Pulmonary Fibrosis (111 Project), College of Life Science, Henan Normal University, Xinxiang, Henan, China
| | - Guoying Yu
- State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, Overseas Expertise Introduction Center for Discipline Innovation of Pulmonary Fibrosis (111 Project), College of Life Science, Henan Normal University, Xinxiang, Henan, China.
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Bagheri M, Khansarinejad B, Mondanizadeh M, Azimi M, Alavi S. MiRNAs related in signaling pathways of women's reproductive diseases: an overview. Mol Biol Rep 2024; 51:414. [PMID: 38472662 DOI: 10.1007/s11033-024-09357-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 02/15/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND One of the main health issues that can affect women's health is reproductive diseases, such as polycystic ovary syndrome (PCOS), endometriosis (EMs), uterine leiomyomas (ULs), and ovarian cancer (OC). Although these diseases are very common, we do not have a complete understanding of their underlying cellular and molecular mechanisms. It is important to mention that the majority of patients are diagnosed with these diseases at later stages because of the absence of early diagnostic techniques and dependable molecular indicators. Hence, it is crucial to discover novel and non-invasive biomarkers that have prognostic, diagnostic and therapeutic capabilities. MiRNAs, also known as microRNAs, are small non-coding RNAs that play a crucial role in regulating gene expression at the post-transcriptional level. They are short in length, typically consisting of around 22 nucleotides, and are highly conserved across species. Numerous studies have shown that miRNAs are expressed differently in various diseases and can act as either oncogenes or tumor suppressors. METHODS The author conducted a comprehensive review of all the pertinent papers available in web of science, PubMed, Google Scholar, and Scopus databases. RESULTS We achieved three goals: providing readers with better information, enhancing search results, and making peer review easier. CONCLUSIONS This review focuses on the investigation of miRNAs and their involvement in various reproductive disorders in women, including their molecular targets. Additionally, it explores the role of miRNAs in the development and progression of these disorders.
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Affiliation(s)
- Malihe Bagheri
- Department of Biotechnology and Molecular Medicine, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Behzad Khansarinejad
- Department of Microbiology and Immunology, Arak University of Medical Sciences, Arak, Iran
| | - Mahdieh Mondanizadeh
- Department of Biotechnology and Molecular Medicine, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Mohadeseh Azimi
- Department of Biochemistry and Genetics, Arak University of Medical Sciences, Arak, Iran
| | - Shima Alavi
- Department of Obstetrics and Gynecology, Ghods Hospital, Arak, Iran
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9
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Wang Y, Chen S, Bao S, Yao L, Wen Z, Xu L, Chen X, Guo S, Pang H, Zhou Y, Zhou P. Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis. Front Immunol 2024; 15:1338922. [PMID: 38426100 PMCID: PMC10902513 DOI: 10.3389/fimmu.2024.1338922] [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: 11/16/2023] [Accepted: 02/02/2024] [Indexed: 03/02/2024] Open
Abstract
This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on the transition from acute radiation damage to a chronic fibrotic state. It reviewed the cellular and molecular responses of the skin to radiation, highlighting the role of myofibroblasts and the significant impact of Transforming Growth Factor-beta (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The review delves into the epigenetic regulation of fibrotic gene expression, the contribution of extracellular matrix proteins to the fibrotic microenvironment, and the regulation of the immune system in the context of fibrosis. Additionally, it discusses the potential of biomaterials and artificial intelligence in medical research to advance the understanding and treatment of radiation-induced skin fibrosis, suggesting future directions involving bioinformatics and personalized therapeutic strategies to enhance patient quality of life.
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Affiliation(s)
- Yiren Wang
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Shouying Chen
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Shuilan Bao
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Li Yao
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Zhongjian Wen
- School of Nursing, Southwest Medical University, Luzhou, China
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Lixia Xu
- School of Nursing, Southwest Medical University, Luzhou, China
| | - Xiaoman Chen
- School of Nursing, Southwest Medical University, Luzhou, China
| | - Shengmin Guo
- Department of Nursing, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Haowen Pang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yun Zhou
- School of Medical Information and Engineering, Southwest Medical University, Luzhou, China
| | - Ping Zhou
- Wound Healing Basic Research and Clinical Application Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
- Department of Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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10
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Wang L, Zhao W, Xia C, Ma S, Li Z, Wang N, Ding L, Wang Y, Cheng L, Liu H, Yang J, Li Y, Rosas I, Yu G. TRIOBP modulates β-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis. Cell Mol Life Sci 2023; 81:13. [PMID: 38157020 PMCID: PMC10756874 DOI: 10.1007/s00018-023-05080-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/17/2023] [Accepted: 12/05/2023] [Indexed: 01/03/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial-mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of β-catenin. We concluded that the miR-29b‒TRIOBP-TRIO-β-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.
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Affiliation(s)
- Lan Wang
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Wenyu Zhao
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Cong Xia
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Shuaichen Ma
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Zhongzheng Li
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Ningdan Wang
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Linke Ding
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Yaxuan Wang
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Lianhui Cheng
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Huibing Liu
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Juntang Yang
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Yajun Li
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China
| | - Ivan Rosas
- Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Guoying Yu
- State Key Laboratory of Cell Differentiation and Regulation; Henan International Joint Laboratory of Pulmonary Fibrosis; Henan Center for Outstanding Overseas Scientists of Organ Fibrosis; College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China.
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11
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Liu L, Guo J, Pang XL, Shang WJ, Wang ZG, Wang JX, Yang XL, Feng GW. Exploration of the mechanism of NORAD activation of TGF-β1/Smad3 through miR-136-5p and promotion of tacrolimus-induced renal fibrosis. Ren Fail 2023; 45:2147083. [PMID: 36748746 PMCID: PMC9930837 DOI: 10.1080/0886022x.2022.2147083] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Tacrolimus is a potent immunosuppressant, but has various side effects, with nephrotoxicity being the most common. Renal fibrosis is an important process of tacrolimus nephrotoxicity. Therefore, it is important to identify the factors that contribute to renal fibrosis after tacrolimus nephrotoxicity, and control its development. METHODS The present study aims to determine whether tacrolimus may speed up the course of renal fibrosis by upregulating noncoding RNA activated by DNA damage (NORAD) to compete with miR-136-5p, and activating the TGF-β1/Smad3 pathway. Furthermore, in vivo rat models and in vitro cell models were established. Then, the expression levels of NORAD and miR-136-5p were determined by RT-qPCR, while the expression of the TGF-β1/Smad3 pathway was determined by western blot and RT-qPCR. In order to investigate the interaction between NORAD and miR-136-5p, as well as miR-136-5p and SYK, two luciferase reporters were employed. The renal fibrosis of mice was observed using Masson and PAS staining. The expression of inflammatory factors IL-1, IL-6, MCP-1 and TNF-α was detected by ELISA. RESULTS In the in vitro experiments, NORAD was upregulated, while miR-136-5p was downregulated after tacrolimus induction. The expression of the TGF-β1/Smad3 pathway correspondingly changed after the induction by tacrolimus. In the in vivo experiments, the expression of NORAD and miR-136-5p, and the trend for renal fibrosis were consistent with the results in the in vitro experiments. Furthermore, the inflammatory factors correspondingly changed with the severity of renal fibrosis. Moreover, the expression trend of the TGF-β1/Smad3 pathway in tacrolimus-induced rats was consistent with that in the in vitro experiments. CONCLUSION Through in vitro and in vivo experiments, the present study was able to successfully prove that tacrolimus upregulates NORAD to compete with miR-136-5p, resulting in a decrease in miR-136-5p expression, which in turn activates the TGF-β1/smad3 pathway, and finally induces the aggravation of renal fibrosis.
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Affiliation(s)
- Lei Liu
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Guo
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin-lu Pang
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wen-jun Shang
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhi-gang Wang
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jun-xiang Wang
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | | | - Gui-wen Feng
- Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,CONTACT Guiwen Feng Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
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12
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Wang Z, Spitz R, Vezina C, Hou J, Bjorling DE. Lack of expression of miR-29a/b1 impairs bladder function in male mice. Dis Model Mech 2023; 16:dmm050054. [PMID: 37283037 PMCID: PMC10259841 DOI: 10.1242/dmm.050054] [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: 12/23/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Lower urinary tract symptoms (LUTS) refer to various urological diseases, and incomplete bladder emptying is common among affected patients. The etiology of LUTS is largely unknown, and investigations of LUTS suggest that bladder fibrosis contributes to pathogenesis of LUTS. MicroRNAs (miRNAs) are short (∼22 nucleotides), non-coding RNAs that repress target gene expression by a combination of mRNA degradation and translation inhibition. The miR-29 family is best known for its anti-fibrotic role in various organs. miR-29 was decreased in bladders of patients with outlet obstruction and a rat model of bladder outlet obstruction, suggesting that miR-29 may contribute to impaired bladder function subsequent to tissue fibrosis. We characterized bladder function in male mice lacking expression of Mir29a and Mir29b-1 (miR-29a/b1). Lack of miR-29a/b1 resulted in severe urinary retention, increased voiding duration and reduced flow rate, and these mice failed to void or voided irregularly during anesthetized cytometry. Collagens and elastin were increased in bladders of mice lacking miR-29a/b1. These findings reveal an important role for miR-29 in bladder homeostasis and suggest the therapeutic potential of miR-29 to improve symptoms in patients with LUTS.
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Affiliation(s)
- Zunyi Wang
- Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Robert Spitz
- Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Chad Vezina
- The O'Brien Center for Urologic Research, University of Wisconsin-Madison, Madison, WI 53706, USA
- Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Jianghui Hou
- Division of Nephrology, Washington University School of Medicine, St Louis, MO 63110, USA
| | - Dale E. Bjorling
- Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
- The O'Brien Center for Urologic Research, University of Wisconsin-Madison, Madison, WI 53706, USA
- Urology, University of Wisconsin-Madison, Madison, WI 53706, USA
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13
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Ullah A, Rehman IU, Ommer K, Ahmed N, Odenthal M, Yu X, Ahmad J, Nadeem T, Ali Q, Ahmad B. Circulating miRNA-192 and miR-29a as Disease Progression Biomarkers in Hepatitis C Patients with a Prevalence of HCV Genotype 3. Genes (Basel) 2023; 14:genes14051056. [PMID: 37239415 DOI: 10.3390/genes14051056] [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: 02/08/2023] [Revised: 05/02/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
MicroRNAs miR-29a and miR-192 are involved in inflammatory and fibrotic processes of chronic liver disease, and circulating miR-29a is suggested to diagnose fibrosis progression due to hepatitis C virus (HCV) infection. This study aimed to evaluate the expression profile of circulating miR-192 and 29a in a patient cohort with a high frequency of HCV genotype-3. A total of 222 HCV blood samples were collected and serum were separated. Patients were classified into mild, moderate, and severe liver injury based on their Child-Turcotte-Pugh CTP score. RNA was isolated from the serum and used for quantitative real-time PCR. The HCV genotype-3 (62%) was the predominant HCV genotype. In HCV patients, the serum miR-192 and miR-29a levels were significantly upregulated in comparison to healthy controls (p = 0.0017 and p = 0.0001, respectively). The progression rate of miR-192 and 29a in the patient group with mild was highly upregulated compared to patients with moderate and severe hepatitis infection. The ROC curve of miR-192 and miR-29a of moderate liver disease had a significant diagnostic performance compared to the other HCV-infected groups. The increase in miR-29a and miR-192 serum levels was even slightly higher in patients with HCV genotype-3 than in non-genotype-3 patients. In conclusion, serum miR-192 and miR-29a levels significantly increased during the progression of chronic HCV infection. The marked upregulation in patients with HCV genotype-3 suggests them as potential biomarkers for hepatic disease, independently of the HCV genotype.
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Affiliation(s)
- Amin Ullah
- Department of Health and Biological Sciences, Abasyn University, Peshawar 25000, Pakistan
- Institute for Pathology, University of Cologne, 50923 Cologne, Germany
| | - Irshad Ur Rehman
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar 25000, Pakistan
| | - Katharina Ommer
- Institute of Transfusion Medicine, University of Cologne, 50923 Cologne, Germany
| | - Nadeem Ahmed
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore 54000, Pakistan
| | | | - Xiaojie Yu
- Institute for Pathology, University of Cologne, 50923 Cologne, Germany
| | - Jamshaid Ahmad
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar 25000, Pakistan
| | - Tariq Nadeem
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore 54000, Pakistan
| | - Qurban Ali
- Department of Plant Breeding and Genetics, University of the Punjab, Lahore 54000, Pakistan
| | - Bashir Ahmad
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar 25000, Pakistan
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14
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Li QY, Gong T, Huang YK, Kang L, Warner CA, Xie H, Chen LM, Duan XQ. Role of noncoding RNAs in liver fibrosis. World J Gastroenterol 2023; 29:1446-1459. [PMID: 36998425 PMCID: PMC10044853 DOI: 10.3748/wjg.v29.i9.1446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/27/2022] [Accepted: 02/27/2023] [Indexed: 03/07/2023] Open
Abstract
Liver fibrosis is a wound-healing response following chronic liver injury caused by hepatitis virus infection, obesity, or excessive alcohol. It is a dynamic and reversible process characterized by the activation of hepatic stellate cells and excess accumulation of extracellular matrix. Advanced fibrosis could lead to cirrhosis and even liver cancer, which has become a significant health burden worldwide. Many studies have revealed that noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, are involved in the pathogenesis and development of liver fibrosis by regulating signaling pathways including transforming growth factor-β pathway, phosphatidylinositol 3-kinase/protein kinase B pathway, and Wnt/β-catenin pathway. NcRNAs in serum or exosomes have been reported to tentatively applied in the diagnosis and staging of liver fibrosis and combined with elastography to improve the accuracy of diagnosis. NcRNAs mimics, ncRNAs in mesenchymal stem cell-derived exosomes, and lipid nanoparticles-encapsulated ncRNAs have become promising therapeutic approaches for the treatment of liver fibrosis. In this review, we update the latest knowledge on ncRNAs in the pathogenesis and progression of liver fibrosis, and discuss the potentials and challenges to use these ncRNAs for diagnosis, staging and treatment of liver fibrosis. All these will help us to develop a comprehensive understanding of the role of ncRNAs in liver fibrosis.
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Affiliation(s)
- Qing-Yuan Li
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Tao Gong
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yi-Ke Huang
- Center for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052, Sichuan Province, China
| | - Lan Kang
- Center for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052, Sichuan Province, China
| | - Charlotte A Warner
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - He Xie
- Department of Clinical Laboratory, The Hospital of Xidian Group, Xi’an 710077, Shaanxi Province, China
| | - Li-Min Chen
- Center for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052, Sichuan Province, China
- Department of Clinical Laboratory, The Hospital of Xidian Group, Xi’an 710077, Shaanxi Province, China
| | - Xiao-Qiong Duan
- Center for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu 610052, Sichuan Province, China
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15
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Mukherjee AG, Wanjari UR, Gopalakrishnan AV, Katturajan R, Kannampuzha S, Murali R, Namachivayam A, Ganesan R, Renu K, Dey A, Vellingiri B, Prince SE. Exploring the Regulatory Role of ncRNA in NAFLD: A Particular Focus on PPARs. Cells 2022; 11:3959. [PMID: 36552725 PMCID: PMC9777112 DOI: 10.3390/cells11243959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven to play a significant role in the pathogenesis of virtually all acute and chronic liver disorders. Recent studies demonstrated the medical applications of miRNA in various phases of hepatic pathology. PPARs play a major role in regulating many signaling pathways involved in various metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, encompassing a spectrum spanning from mild steatosis to severe non-alcoholic steatohepatitis (NASH). PPARs were found to be one of the major regulators in the progression of NAFLD. There is no recognized treatment for NAFLD, even though numerous clinical trials are now underway. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC), and its frequency increases as obesity and diabetes become more prevalent. Reprogramming anti-diabetic and anti-obesity drugs is an effective therapy option for NAFLD and NASH. Several studies have also focused on the role of ncRNAs in the pathophysiology of NAFLD. The regulatory effects of these ncRNAs make them a primary target for treatments and as early biomarkers. In this study, the main focus will be to understand the regulation of PPARs through ncRNAs and their role in NAFLD.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Ramkumar Katturajan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Arunraj Namachivayam
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Republic of Korea
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata 700073, West Bengal, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda 151401, Punjab, India
| | - Sabina Evan Prince
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
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16
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Elliot S, Catanuto P, Pereira-simon S, Xia X, Shahzeidi S, Roberts E, Ludlow J, Hamdan S, Daunert S, Parra J, Stone R, Pastar I, Tomic-Canic M, Glassberg MK. Urine-derived exosomes from individuals with IPF carry pro-fibrotic cargo. eLife 2022; 11:e79543. [PMID: 36454035 PMCID: PMC9714968 DOI: 10.7554/elife.79543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 10/31/2022] [Indexed: 12/03/2022] Open
Abstract
Background MicroRNAs (miRNA) and other components contained in extracellular vesicles may reflect the presence of a disease. Lung tissue, sputum, and sera of individuals with idiopathic pulmonary fibrosis (IPF) show alterations in miRNA expression. We designed this study to test whether urine and/or tissue derived exosomal miRNAs from individuals with IPF carry cargo that can promote fibrosis. Methods Exosomes were isolated from urine (U-IPFexo), lung tissue myofibroblasts (MF-IPFexo), serum from individuals with IPF (n=16) and age/sex-matched controls without lung disease (n=10). We analyzed microRNA expression of isolated exosomes and their in vivo bio-distribution. We investigated the effect on ex vivo skin wound healing and in in vivo mouse lung models. Results U-IPFexo or MF-IPFexo expressed miR-let-7d, miR-29a-5p, miR-181b-3p and miR-199a-3p consistent with previous reports of miRNA expression obtained from lung tissue/sera from patients with IPF. In vivo bio-distribution experiments detected bioluminescent exosomes in the lung of normal C57Bl6 mice within 5 min after intravenous infusion, followed by distribution to other organs irrespective of exosome source. Exosomes labeled with gold nanoparticles and imaged by transmission electron microscopy were visualized in alveolar epithelial type I and type II cells. Treatment of human and mouse lung punches obtained from control, non-fibrotic lungs with either U-IPFexo or MF-IPFexo produced a fibrotic phenotype. A fibrotic phenotype was also induced in a human ex vivo skin model and in in vivo lung models. Conclusions Our results provide evidence of a systemic feature of IPF whereby exosomes contain pro-fibrotic miRNAs when obtained from a fibrotic source and interfere with response to tissue injury as measured in skin and lung models. Funding This work was supported in part by Lester and Sue Smith Foundation and The Samrick Family Foundation and NIH grants R21 AG060338 (SE and MKG), U01 DK119085 (IP, RS, MTC).
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Affiliation(s)
- Sharon Elliot
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of MedicineMiamiUnited States
| | - Paola Catanuto
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of MedicineMiamiUnited States
| | - Simone Pereira-simon
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of MedicineMiamiUnited States
| | - Xiaomei Xia
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of MiamiMiamiUnited States
| | | | - Evan Roberts
- Cancer Modeling Shared Resource Sylvester Comprehensive Cancer Center, University of MiamiMiamiUnited States
| | | | - Suzana Hamdan
- Department of Biochemistry and Molecular Biology, University of Miami, Miller School of MedicineMiamiUnited States
- Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami Miller School of MedicineMiamiUnited States
| | - Sylvia Daunert
- Department of Biochemistry and Molecular Biology, University of Miami, Miller School of MedicineMiamiUnited States
- Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami Miller School of MedicineMiamiUnited States
- Miami Clinical and Translational Science Institute, University of Miami Miller School of MedicineMiamiUnited States
| | - Jennifer Parra
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of MiamiMiamiUnited States
| | - Rivka Stone
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of MiamiMiamiUnited States
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of MiamiMiamiUnited States
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of MiamiMiamiUnited States
| | - Marilyn K Glassberg
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of MedicineMiamiUnited States
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of MiamiMiamiUnited States
- Department of Medicine, Stritch School of Medicine, Loyola University ChicagoChicagoUnited States
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Enge AM, Sprenger H, Braeuning A, Hessel-Pras S. Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells. Foods 2022; 11:foods11040532. [PMID: 35206009 PMCID: PMC8871147 DOI: 10.3390/foods11040532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/04/2022] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepatoma cell line HepaRG. The major mode of action of PAs is DNA- and protein-adduct formation. Beyond that, nuclear receptor activation has only been observed for one receptor and two PAs, yielding the possibility that other cellular mediators are involved in PA-mediated toxicity. Here, the mode of action of Senecionine (Sc), a prominent and ubiquitous representative of hepatotoxic PAs, was investigated by analyzing 7 hepatic microRNAs (miRNAs) in HepaRG cells. Ultimately, 11 target genes that were predicted with Ingenuity Pathway Analysis software (IPA) were found to be significantly downregulated, while their assigned miRNAs showed significant upregulation of gene expression. According to IPA, these targets are positively correlated with apoptosis and cellular death and are involved in diseases such as hepatocellular carcinoma. Subsequent antagomiR-inhibition analysis revealed a significant correlation between PA-induced miRNA-4434 induction and P21-Activated Kinase-1 (PAK1) downregulation. PAK1 downregulation is usually associated with cell cycle arrest, suggesting a new function of Sc-mediated toxicity in human liver cells.
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18
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Abstract
Uterine fibroids (leiomyomas) are present in >75% of women and can cause serious morbidity. They are by far the leading cause of hysterectomy. Fibroids are a complex mixture of cells that include fibroblasts and smooth muscle cells. Rich in extracellular matrix, they typically arise through somatic mutations, most commonly MED12. Their lack of growth inhibition and their ability to have facets of malignancy yet be histologically and biologically benign provide opportunities to explore basic processes. To date, the mechanisms responsible for growth and development of leiomyomas are an enigma. This review provides an overview of current understanding and future directions for clinical and basic research of fibroids.
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Affiliation(s)
- Elizabeth A. Stewart
- 1Division of Reproductive Endocrinology and Infertility, Mayo Clinic, Rochester, Minnesota,2Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota,3Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota,4Department of Surgery, Mayo Clinic, Rochester, Minnesota,5Women’s Health Research Center, Mayo Clinic, Rochester, Minnesota
| | - Romana A. Nowak
- 6Department of Animal Sciences, University of Illinois, Urbana, Illinois,7Institute for Genomic Biology, University of Illinois, Urbana, Illinois
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19
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Thibonnier M, Ghosh S, Blanchard A. Effects of a short-term cold exposure on circulating microRNAs and metabolic parameters in healthy adult subjects. J Cell Mol Med 2021; 26:548-562. [PMID: 34921497 PMCID: PMC8743656 DOI: 10.1111/jcmm.17121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 11/19/2021] [Accepted: 11/29/2021] [Indexed: 11/28/2022] Open
Abstract
This discovery study investigated in healthy subjects whether a short‐term cold exposure may alter circulating microRNAs and metabolic parameters and if co‐expression networks between these factors could be identified. This open randomized crossover (cold vs no cold exposure) study with blind end‐ point evaluation was conducted at 1 center with 10 healthy adult male volunteers. Wearing a cooling vest perfused at 14°C for 2 h reduced the local skin temperature without triggering shivering, increased norepinephrine and blood pressure while decreasing copeptin, C‐peptide and heart rate. Circulating microRNAs measured before and after wearing the cooling vest twice (4 time points) identified 196 mature microRNAs with excellent reproducibility over 72 h. Significant correlations of microRNA expression with copeptin, norepinephrine and C‐peptide were found. A co‐expression‐based microRNA‐microRNA network, as well as microRNA pairs displaying differential correlation as a function of temperature were also detected. This study demonstrates that circulating miRNAs are differentially expressed and coregulated upon cold exposure in humans, supporting their use as predictive and dynamic biomarkers of cardio‐metabolic disorders.
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Affiliation(s)
| | - Sujoy Ghosh
- Duke-NUS Medical School, Singapore City, Singapore.,Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Anne Blanchard
- Clinical Investigation Center, Hôpital Européen Georges Pompidou, Paris, France
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20
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Fan Y, Zhao X, Ma J, Yang L. LncRNA GAS5 Competitively Combined With miR-21 Regulates PTEN and Influences EMT of Peritoneal Mesothelial Cells via Wnt/β-Catenin Signaling Pathway. Front Physiol 2021; 12:654951. [PMID: 34526907 PMCID: PMC8435904 DOI: 10.3389/fphys.2021.654951] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022] Open
Abstract
Objective Epithelial-mesenchymal transition (EMT) is an important factor leading to peritoneal fibrosis (PF) in end-stage renal disease (ESRD) patients. The current research aimed to evaluate the effect of long non-coding RNA growth arrest-specific 5 (lncRNA GAS5) in human peritoneal mesothelial cells (HPMCs) EMT and explore the potential molecular mechanisms. Materials and Methods HPMCs were cultured under control conditions or with high glucose (HG). The cells were then treated with lncRNA GAS5, lncRNA GAS5 siRNA, with or without miR-21 inhibitor and PTEN transfection. Expression of lncRNA GAS5, miR-21, α-SMA, Vimentin, E-cadherin, phosphatase and tensin homolog deleted on chromosome ten (PTEN), Wnt3a, and β-catenin were measured by real time PCR and Western blotting. Bioinformatics analyses were used to test the specific binding sites between the 3' UTR of the PTEN gene, miR-21, and lncRNA GAS5. Rescue experiments were performed to confirm the lncRNA GAS5/miR-21/PTEN axis in HPMC EMT. Results We found that HG-induced EMT decreased lncRNA GAS5 and that overexpression of lncRNA GAS5 can attenuate EMT in HPMCs. In addition, lncRNA GAS5 regulated HG-induced EMT through miR-21/PTEN. Cotransfection of miR-21 inhibitors remarkably increased PTEN expression and attenuated EMT in lncRNA GAS5 knockdown HPMCs. Moreover, rescue experiments showed that overexpression of PTEN attenuated the EMT effects of lncRNA GAS5 siRNA in HPMCs. We also confirmed that the Wnt/β-catenin pathway was stimulated in lncRNA GAS5/miR-21/PTEN-mediated EMT. Conclusion Our research showed that lncRNA GAS5 competitively combined with miR-21 to regulate PTEN expression and influence EMT of HPMCs via the Wnt/β-catenin signaling pathway. This study provides novel evidence that lncRNA GAS5 may be a potential therapeutic target for HPMC EMT.
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Affiliation(s)
- Yi Fan
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xingxu Zhao
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jianfei Ma
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lina Yang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
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21
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Momen-Heravi F, Catalano D, Talis A, Szabo G, Bala S. Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:155-167. [PMID: 34458001 PMCID: PMC8368790 DOI: 10.1016/j.omtn.2021.05.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.
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Affiliation(s)
- Fatemeh Momen-Heravi
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Austin Talis
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
- KASA BIO, 10405 Old Alabama Road Connector, Suite 201, Alpharetta, GA 30022, USA
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22
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Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T. Adrenomedullin Ameliorates Pulmonary Fibrosis by Regulating TGF-ß-Smads Signaling and Myofibroblast Differentiation. Endocrinology 2021; 162:bqab090. [PMID: 33955458 DOI: 10.1210/endocr/bqab090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Indexed: 11/19/2022]
Abstract
Pulmonary fibrosis is an irreversible, potentially fatal disease. Adrenomedullin (AM) is a multifunctional peptide whose activity is regulated by receptor activity-modifying protein 2 (RAMP2). In the present study, we used the bleomycin (BLM)-induced mouse pulmonary fibrosis model to investigate the pathophysiological significance of the AM-RAMP2 system in the lung. In heterozygous AM knockout mice (AM+/-), hydroxyproline content and Ashcroft scores reflecting the fibrosis severity were significantly higher than in wild-type mice (WT). During the acute phase after BLM administration, FACS analysis showed significant increases in eosinophil, monocyte, and neutrophil infiltration into the lungs of AM+/-. During the chronic phase, fibrosis-related molecules were upregulated in AM+/-. Notably, nearly identical changes were observed in RAMP2+/-. AM administration reduced fibrosis severity. In the lungs of BLM-administered AM+/-, the activation level of Smad3, a receptor-activated Smad, was higher than in WT. In addition, Smad7, an antagonistic Smad, was downregulated and microRNA-21, which targets Smad7, was upregulated compared to WT. Isolated AM+/- lung fibroblasts showed less proliferation and migration capacity than WT fibroblasts. Stimulation with TGF-β increased the numbers of α-SMA-positive myofibroblasts, which were more prominent among AM+/- cells. TGF-β-stimulated AM+/- myofibroblasts were larger and exhibited greater contractility and extracellular matrix production than WT cells. These cells were α-SMA (+), F-actin (+), and Ki-67(-) and appeared to be nonproliferating myofibroblasts (non-p-MyoFbs), which contribute to the severity of fibrosis. Our findings suggest that in addition to suppressing inflammation, the AM-RAMP2 system ameliorates pulmonary fibrosis by suppressing TGF-β-Smad3 signaling, microRNA-21 activity and differentiation into non-p-MyoFbs.
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Affiliation(s)
- Yangxuan Wei
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Shinji Kakihara
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yunlu Zhao
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Kohsuke Aruga
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Hideki Sanjo
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan
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Li C, Wang N, Rao P, Wang L, Lu D, Sun L. Role of the microRNA-29 family in myocardial fibrosis. J Physiol Biochem 2021; 77:365-376. [PMID: 34047925 DOI: 10.1007/s13105-021-00814-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 04/01/2021] [Indexed: 12/11/2022]
Abstract
Myocardial fibrosis (MF) is an inevitable pathological process in the terminal stage of many cardiovascular diseases, often leading to serious cardiac dysfunction and even death. Currently, microRNA-29 (miR-29) is thought to be a novel diagnostic and therapeutic target of MF. Understanding the underlying mechanisms of miR-29 that regulate MF will provide a new direction for MF therapy. In the present review, we concentrate on the underlying signaling pathway of miR-29 affecting MF and the crosstalk regulatory relationship among these pathways to illustrate the complex regulatory network of miR-29 in MF. Additionally, based on our mechanistic understanding, we summarize opportunities and challenges of miR-29-based MF diagnosis and therapy.
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Affiliation(s)
- Changyan Li
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Nan Wang
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Peng Rao
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Limeiting Wang
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Di Lu
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China.
| | - Lin Sun
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China.
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24
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Yang J, Xu C, Wu M, Wu Y, Jia X, Zhou C, Zhang X, Ge S, Li Z, Zhang L. MicroRNA-124 inhibits hepatic stellate cells inflammatory cytokines secretion by targeting IQGAP1 through NF-κB pathway. Int Immunopharmacol 2021; 95:107520. [PMID: 33743313 DOI: 10.1016/j.intimp.2021.107520] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 01/01/2023]
Abstract
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. To date, there was no direct approved antifibrotic therapy, and current treatment was mainly the removal of the causative factor. Recent studies demonstrated that aberrant expression of miR-124 was involved in the progression of various liver diseases including hepatocellular carcinoma (HCC). However, whether miR-124 could function as a transcriptional regulator in the inflammatory cytokines secretion of liver fibrosis remains unclear. In this study, we demonstrated that the expression of miR-124 was downregulated in liver fibrosis tissues and TNF-α-induced LX-2 cells, concomitant with the upregulated expression of IQGAP1, suggesting that miR-124 and IQGAP1 might be associated with the development of inflammation in liver fibrosis. Therefore, we demonstrated that the overexpression of miR-124 and knockdown of IQGAP1 could lead to the downregulation of TNF-α, IL-1β and IL-6. While knockdown of miR-124 or overexpression of IQGAP1 showed reversed results. Moreover, dual luciferase reporter assays demonstrated that miR-124 specifically targeted the 3'-UTR of IQGAP1, and thus inhibited the expression of IQGAP1. Mechanistically, we found that the expression changes of miR-124 and IQGAP1 could be involved in inhibition or activation of NF-κB signaling pathway in response to TNF-α. In conclusion, these results indicated that miR-124 plays a crucial role in TNF-α-induced LX-2 cells via regulating NF-κB signaling pathway.
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Affiliation(s)
- Junfa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Changqing Xu
- The Third People's Hospital of Hefei (Hefei Third Clinical College of Anhui Medical University), Hefei, Anhui Province, China
| | - Maomao Wu
- Department of Pharmacy, Anhui Chest Hospital, Hefei, Anhui Province, China
| | - Ying Wu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xiaodi Jia
- Fujian Normal University, Fuzhou 350007, China
| | - Chang Zhou
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Xianzheng Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Shenglin Ge
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
| | - Zeng Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China.
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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25
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MicroRNA-34a Promotes EMT and Liver Fibrosis in Primary Biliary Cholangitis by Regulating TGF- β1/smad Pathway. J Immunol Res 2021; 2021:6890423. [PMID: 33977112 PMCID: PMC8087466 DOI: 10.1155/2021/6890423] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 01/11/2021] [Accepted: 04/13/2021] [Indexed: 12/27/2022] Open
Abstract
Background and Aims Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease. We found microRNA-34a (miR-34a), as the downstream gene of p53, was overexpressed in some of fibrogenic diseases. In this study, we sought to explore whether miR-34a plays a role in the fibrosis of PBC. Methods The peripheral blood of PBC patients and controls was collected to analyze the level of miR-34a. Human intrahepatic biliary epithelial cells (HIBEC) were cultured. The expression of miR-34a was regulated by miR-34a mimics and inhibitor. The biomarkers of epithelium-mesenchymal transition (EMT), fibrogenesis, inflammation, and transforming growth factor- (TGF-) β1/smad pathway were analyzed. Results We found that miR-34a was overexpressed in the peripheral blood in PBC patients. In vitro, overexpressed miR-34a increased the EMT and fibrogenesis activity of HIBEC. Transforming growth factor-beta type 1 receptor (TβR1), TGF-β1, and p-smad2/3 were upregulated by miR-34a. Inflammatory factors such as IL-6 and IL-17 were also upregulated. Finally, we showed that miR-34a promoted EMT and liver fibrosis in PBC by targeting the TGF-β1/smad pathway antagonist transforming growth factor-beta-induced factor homeobox 2 (TGIF2). Conclusions Our findings show that miR-34a plays an important role in the EMT and fibrosis of PBC through the TGF-β1/smad pathway by targeting TGIF2. This study suggests that miR-34a may be a new marker of fibrogenesis in PBC. Inhibition of miR-34a may be a promising strategy in treating PBC and improving the prognosis of the disease.
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MiR-15b and miR-16 suppress TGF-β1-induced proliferation and fibrogenesis by regulating LOXL1 in hepatic stellate cells. Life Sci 2021; 270:119144. [PMID: 33545201 DOI: 10.1016/j.lfs.2021.119144] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/19/2021] [Accepted: 01/27/2021] [Indexed: 12/13/2022]
Abstract
Activation of hepatic stellate cells (HSCs) is an important event during the progress of liver fibrosis. MicroRNA (miR)-15b and miR-16 have been found to be involved in activation of HSCs. However, the roles of miR-15b/16 in liver fibrosis remain unclear. The expression of miR-15b/16 was decreased in TGF-β1-stimulated LX-2 cells. Overexpression of miR-15b/16 in LX-2 cells suppressed TGF-β1-induced cell proliferation and the expression levels of tissue inhibitor of metalloproteinase type 1, collagen type I, and α-smooth muscle actin. The activation of Smad2/3 caused by TGF-β1 was repressed by miR-15b/16 overexpression. The two miRNAs directly bound to the 3'-UTR of lysyl oxidase-like 1 (LOXL1) and suppressed the LOXL1 expression. Furthermore, knockdown of LOXL1 attenuated miR-15b/16 downregulation-induced cell proliferation, fibrogenic response and phosphorylation of Smad2/3. Collectively, miR-15b/16 exhibited anti-fibrotic activity through regulation of Smad2/3 pathway.
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27
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Abu-Halima M, Meese E, Saleh MA, Keller A, Abdul-Khaliq H, Raedle-Hurst T. MicroRNA-29b/c-3p Indicate Advanced Liver Fibrosis/Cirrhosis in Univentricular Heart Patients With and Without Fontan Palliation. Front Cardiovasc Med 2021; 7:619083. [PMID: 33490119 PMCID: PMC7820747 DOI: 10.3389/fcvm.2020.619083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/14/2020] [Indexed: 12/22/2022] Open
Abstract
Aim: The present study aims to identify those microRNAs (miRNAs) in patients with univentricular heart (UVH) disease with and without Fontan palliation that may be associated with advanced liver fibrosis/cirrhosis. Materials and Methods: SurePrint™ 8 × 60K Human v21 miRNA arrays were used to determine the miRNA abundance profiles in the blood of 48 UVH patients with and without Fontan palliation and 32 matched healthy controls. The abundance levels of selected miRNAs have been validated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Results: According to microarray analysis, 50 miRNAs were found to be significantly abundant in UVH patients of which miR-29b-3p and miR-29c-3p were significantly related to the model of end-stage liver disease (MELD)-Albumin and albumin-bilirubin (ALBI) score representing advanced liver fibrosis/cirrhosis. Relative expression levels of both miRNAs were significantly higher in patients with a higher collapsibility index representing venous hepatic congestion, a higher MELD-Albumin or ALBI score and incomplete or no Fontan palliation. In the logistic regression analysis, a MELD-Albumin score ≥ 11 or ALBI score > -2.6 were best predicted by total bilirubin (OR 6.630, P = 0.016), albumin (OR 0.424, P = 0.026), and miR-29c-3p (OR 33.060, P = 0.047). After adjustment to the status of Fontan palliation, however, no statistical significance of these parameters was found thus underlining the importance of palliation status on progression of liver fibrosis/ cirrhosis in UVH patients. Conclusions: In UVH patients with and without Fontan palliation, miR-29b-3p and miR-29c-3p seem to be markers of advanced liver fibrosis/cirrhosis and thus may be used in the risk assessment of these patients.
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Affiliation(s)
- Masood Abu-Halima
- Institute of Human Genetics, Saarland University Medical Center, Homburg, Germany
- Department of Pediatric Cardiology, Saarland University Medical Center, Homburg, Germany
| | - Eckart Meese
- Institute of Human Genetics, Saarland University Medical Center, Homburg, Germany
| | - Mohamad Ali Saleh
- Department of Pediatric Cardiology, Saarland University Medical Center, Homburg, Germany
| | - Andreas Keller
- Center for Clinical Bioinformatics, Saarland University, Saarbruecken, Germany
| | - Hashim Abdul-Khaliq
- Department of Pediatric Cardiology, Saarland University Medical Center, Homburg, Germany
| | - Tanja Raedle-Hurst
- Department of Pediatric Cardiology, Saarland University Medical Center, Homburg, Germany
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MiR-3613-3p inhibits hypertrophic scar formation by down-regulating arginine and glutamate-rich 1. Mol Cell Biochem 2020; 476:1025-1036. [PMID: 33165823 DOI: 10.1007/s11010-020-03968-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022]
Abstract
Hypertrophic scar (HS) is a severe skin disorder characterized by excessive extracellular matrix production and abnormal function of fibroblasts. Recent studies have demonstrated that microRNAs (miRNAs) play critical roles in HS formation. This study aims to investigate the role of miR-3613-3p in the formation of HS. The mRNA and miRNA levels were measured by quantitative RT-PCR analysis. The protein levels were examined by Western blot assay. Cell proliferation was determined by Cell Counting Kit-8 assay. The Caspase-3 and Caspase-9 activities were measured using flow cytometry assay. Dual-luciferase activity reporter assay and mRNA-miRNA pulldown assay were conducted to validate the target of miR-3613-3p. miR-3613-3p was downregulated, while arginine and glutamate-rich 1 (ARGLU1) was upregulated in HS fibroblasts (HSFs) and tissues. Overexpression of miR-3613-3p or knockdown of ARGLU1 markedly inhibited the expression of extracellular matrix (ECM) production-associated proteins and promoted Caspase-3 and Caspase-9 activations in HSFs. ARGLU1 was further identified as a direct target of miR-3613-3p. Restoration of ARGLU1 abrogated the suppressive effect of miR-3613-3p on cell proliferation and ECM protein expression of HSFs. Our results demonstrated that miR-3613-3p inhibited HS formation via targeting ARGLU1, which may provide potential therapeutic targets for the management of HS.
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Abstract
PURPOSE OF REVIEW Uterine fibroids are the most common benign neoplasms of the female reproductive tract and one of the major public health concerns. Although most women with uterine fibroids are asymptomatic, over 30% of them will present with varying symptoms. This review focuses on the role of non-hormonal mediators and pathways in uterine fibroid biology. Furthermore, it provides data regarding the most recent findings in the field of compounds, which use those non-hormonal pathways in the medical therapy of uterine fibroids. RECENT FINDINGS Complex signaling pathway alterations are crucial for uterine fibroid development. The topic of the pathophysiology of uterine fibroids focuses mostly on steroids and other hormones. However, other very important pathways exist, and some of them are independent of hormones. Some of the most important pathways, which are non-hormonal, but in some cases still hormone-depended, include growth factors, cytokines and inflammation, Smad proteins, wingless type/β-catenin and others. SUMMARY Much more is known about hormonal than about non-hormonal signaling in uterine fibroids. Growth factors, early life exposure and inflammation are key factors in uterine fibroid biology. Numerous agents depend on those pathways and may find their place in the current and future therapy of uterine fibroids.
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Affiliation(s)
- Esra Cetin
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ayman Al-Hendy
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
- Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Michał Ciebiera
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
- Second Department of Obstetrics and Gynecology, the Center of Postgraduate Medical Education, Warsaw, Poland
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Khodayari N, Oshins R, Holliday LS, Clark V, Xiao Q, Marek G, Mehrad B, Brantly M. Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo. Cell Commun Signal 2020; 18:140. [PMID: 32887613 PMCID: PMC7487708 DOI: 10.1186/s12964-020-00648-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
Background Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic “gain-of-function” inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease. Methods EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. Results We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs. Conclusion AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease.
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