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Wei X, He Y, Yu Y, Tang S, Liu R, Guo J, Jiang Q, Zhi X, Wang X, Meng D. The Multifaceted Roles of BACH1 in Disease: Implications for Biological Functions and Therapeutic Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412850. [PMID: 39887888 PMCID: PMC11905017 DOI: 10.1002/advs.202412850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/22/2024] [Indexed: 02/01/2025]
Abstract
BTB domain and CNC homolog 1 (BACH1) belongs to the family of basic leucine zipper proteins and is expressed in most mammalian tissues. It can regulate its own expression and play a role in transcriptionally activating or inhibiting downstream target genes. It has a crucial role in various biological processes, such as oxidative stress, cell cycle, heme homeostasis, and immune regulation. Recent research highlights BACH1's significant regulatory roles in a series of conditions, including stem cell pluripotency maintenance and differentiation, growth, senescence, and apoptosis. BACH1 is closely associated with cardiovascular diseases and contributes to angiogenesis, atherosclerosis, restenosis, pathological cardiac hypertrophy, myocardial infarction, and ischemia/reperfusion (I/R) injury. BACH1 promotes tumor cell proliferation and metastasis by altering tumor metabolism and the epithelial-mesenchymal transition phenotype. Moreover, BACH1 appears to show an adverse role in diseases such as neurodegenerative diseases, gastrointestinal disorders, leukemia, pulmonary fibrosis, and skin diseases. Inhibiting BACH1 may be beneficial for treating these diseases. This review summarizes the role of BACH1 and its regulatory mechanism in different cell types and diseases, proposing that precise targeted intervention of BACH1 may provide new strategies for human disease prevention and treatment.
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Affiliation(s)
- Xiangxiang Wei
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Yunquan He
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Yueyang Yu
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Sichong Tang
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Ruiwen Liu
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Jieyu Guo
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Qingjun Jiang
- Department of Vascular & Endovascular SurgeryChangzheng HospitalNaval Medical UniversityShanghai200003China
| | - Xiuling Zhi
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Xinhong Wang
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
| | - Dan Meng
- Department of Physiology and PathophysiologySchool of Basic Medical SciencesDepartment of RheumatologyZhongshan HospitalZhongshan Hospital Immunotherapy Translational Research CenterFudan UniversityShanghai200032China
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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Hwang JS, Song HB, Lee G, Jeong S, Ma DJ. Extracellular Vesicles Derived from Adipose-Derived Mesenchymal Stem Cells Alleviate Apoptosis and Oxidative Stress of Retinal Pigment Epithelial Cells Through Activation of Nrf2 Signaling Pathway. J Ocul Pharmacol Ther 2024; 40:688-701. [PMID: 39451126 DOI: 10.1089/jop.2024.0064] [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] [Indexed: 10/26/2024] Open
Abstract
Purpose: To examine the potential protective effects of adipose-derived mesenchymal stem cell-derived extracellular vesicles (ASC-EVs) on ARPE-19 cells exposed to hydrogen peroxide (H2O2) stress and to evaluate their ability to delay retinal degeneration in Royal College of Surgeons (RCS) rats. Methods: ARPE-19 cells were pre-treated with ASC-EVs for 24 h, followed by exposure to 200 μM H2O2 for an additional 24 h. RCS rats received an intravitreal injection of phosphate-buffered saline in one eye and ASC-EVs in the other eye. Results: ASC-EV pretreatment significantly protected against H2O2 in the Cell Counting Kit-8 assay and was also effective in the lactate dehydrogenase-release assay. It notably reduced early apoptosis (Annexin V-fluorescein isothiocyanate/propidium iodide assay) and late apoptosis (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay), while significantly decreasing intracellular reactive oxygen species, glutathione levels, and superoxide dismutase activity. NFE2L2, HMOX1, and NQO1 mRNA levels, along with Nrf2, HO-1, and NQO1 protein levels, were significantly elevated with ASC-EV pretreatment. Compared with ARPE-19-derived EVs, 11 miRNAs were upregulated and 34 were downregulated in ASC-EVs. In RCS rats, intravitreal injections of ASC-EVs led to significant preservation of the outer nuclear layer and photoreceptor segments, along with increased nuclear Nrf2 expression and elevated HO-1 and NQO1 levels in the inner retina. Eyes that received intravitreal injections of ASC-EVs demonstrated significantly preserved electroretinography a- and b-wave amplitudes at 1 week post-injection, though this effect faded by 2 weeks. Conclusions: ASC-EVs mitigated apoptosis and oxidative stress in ARPE-19 cells subjected to H2O2 exposure and temporarily slowed retinal degeneration in RCS rats via Nrf2 pathway activation by miRNAs.
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Affiliation(s)
- Jin Sun Hwang
- Department of Ophthalmology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul, Republic of Korea
| | - Hyun Beom Song
- Department of Tropical Medicine and Parasitology and Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Geonhui Lee
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Sangmoo Jeong
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Dae Joong Ma
- Department of Ophthalmology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul, Republic of Korea
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Lee EJ, Jeong M, Lee H, Je MA, Park K, Lee DG, Xuan X, Kim S, Park S, Kim J. MiR-122, miR-133a, and miR-206 as potential biomarkers for post-mortem interval estimation. Genes Genomics 2024; 46:1175-1182. [PMID: 39207675 DOI: 10.1007/s13258-024-01559-x] [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: 06/18/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUD Accurate estimation of post-mortem interval (PMI) is crucial in forensic investigations. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that remain relatively stable within the cell nucleus despite post-mortem changes. OBJECTIVE We assessed three target genes (miR-122, miR-133a, and miR-206) for PMI estimation using 72 healthy adult male BALB/c mice exposed to two different temperatures (4 and 21℃) at nine different time points over 10 days. METHODS Initially, the stability of the two reference genes (RNU6B and 5 srRNA) was evaluated using gene stability analysis tools (Delta Ct, Best Keeper, and Genorm) to select the optimal reference gene. RNU6B was found to be the most stable endogenous control. Subsequently, the expression patterns of miR-122, miR-133a, and miR-206 were analyzed within a 10-day PMI period using the heart, skeletal muscle, liver, and brain tissues. RESULTS At 4℃, miR-122 levels significantly decreased on days 8 and 10 in all tissues, with only the liver showing significant changes at 21℃. MiR-133a decreased over time in the heart, muscles, and brain, showing a dramatic decrease on days 8 and 10 in the heart and muscles at both temperatures. Although miR-206 levels decreased over time in muscles and liver at 4 ℃, these increased in the brain at 21 ℃, with no expression changes in other organs. CONCLUSION In summary, miR-122, miR-133a, and miR-206 are potential PMI markers in heart and skeletal muscle tissues.
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Affiliation(s)
- Eun Ju Lee
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Department of Research and Development, Korea Mycobacterium Resource Center (KMRC), The Korean Institute of Tuberculosis, Osong, 28158, Republic of Korea
| | - Mingyoung Jeong
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Haneul Lee
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Min-A Je
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Kwangmin Park
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Dong Geon Lee
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Xianglan Xuan
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Sunghyun Kim
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Sunyoung Park
- School of Mechanical Engineering, Yonsei University, Seoul, 03772, Republic of Korea.
| | - Jungho Kim
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea.
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea.
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea.
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Zhang X, Wang T, Fan X, Wang M, Duan Z, He F, Wang HH, Li Z. Development of a Modular miRNA-Responsive Biosensor for Organ-Specific Evaluation of Liver Injury. BIOSENSORS 2024; 14:450. [PMID: 39329825 PMCID: PMC11430419 DOI: 10.3390/bios14090450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/01/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024]
Abstract
MicroRNAs (miRNAs) are increasingly being considered essential diagnostic biomarkers and therapeutic targets for multiple diseases. In recent years, researchers have emphasized the need to develop probes that can harness extracellular miRNAs as input signals for disease diagnostics. In this study, we introduce a novel miRNA-responsive biosensor (miR-RBS) designed to achieve highly sensitive and specific detection of miRNAs, with a particular focus on targeted organ-specific visualization. The miR-RBS employs a Y-structured triple-stranded DNA probe (Y-TSDP) that exhibits a fluorescence-quenched state under normal physiological conditions. The probe switches to an activated state with fluorescence signals in the presence of high miRNA concentrations, enabling rapid and accurate disease reporting. Moreover, the miR-RBS probe had a modular design, with a fluorescence-labeled strand equipped with a functional module that facilitates specific binding to organs that express high levels of the target receptors. This allowed the customization of miRNA detection and cell targeting using aptameric anchors. In a drug-induced liver injury model, the results demonstrate that the miR-RBS probe effectively visualized miR-122 levels, suggesting it has good potential for disease diagnosis and organ-specific imaging. Together, this innovative biosensor provides a versatile tool for the early detection and monitoring of diseases through miRNA-based biomarkers.
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Affiliation(s)
- Xinxin Zhang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Tingting Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Xiangqing Fan
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Meixia Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Zhixi Duan
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Department of Trauma Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- FuRong Laboratory, Changsha 410078, China
| | - Fang He
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Hong-Hui Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Zhihong Li
- Department of Trauma Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- FuRong Laboratory, Changsha 410078, China
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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Belot A, Puy H, Hamza I, Bonkovsky HL. Update on heme biosynthesis, tissue-specific regulation, heme transport, relation to iron metabolism and cellular energy. Liver Int 2024; 44:2235-2250. [PMID: 38888238 PMCID: PMC11625177 DOI: 10.1111/liv.15965] [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: 02/12/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 06/20/2024]
Abstract
Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a prosthetic group for oxygen-carrying proteins and enzymes involved in oxidation/reduction and electron transport reactions. Heme is essential for the function of numerous hemoproteins and has numerous other roles in the biochemistry of life. In mammals, heme is synthesised from glycine, succinyl-CoA, and ferrous iron in a series of eight steps. The first and normally rate-controlling step is catalysed by 5-aminolevulinate synthase (ALAS), which has two forms: ALAS1 is the housekeeping form with highly variable expression, depending upon the supply of the end-product heme, which acts to repress its activity; ALAS2 is the erythroid form, which is regulated chiefly by the adequacy of iron for erythroid haemoglobin synthesis. Abnormalities in the several enzymes of the heme synthetic pathway, most of which are inherited partial enzyme deficiencies, give rise to rare diseases called porphyrias. The existence and role of heme importers and exporters in mammals have been debated. Recent evidence established the presence of heme transporters. Such transporters are important for the transfer of heme from mitochondria, where the penultimate and ultimate steps of heme synthesis occur, and for the transfer of heme from cytoplasm to other cellular organelles. Several chaperones of heme and iron are known and important for cell health. Heme and iron, although promoters of oxidative stress and potentially toxic, are essential cofactors for cellular energy production and oxygenation.
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Affiliation(s)
- Audrey Belot
- Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Herve Puy
- Centre Français des Porphyries, Assistance Publique-Hôpitaux de Paris (APHP), Université de Paris Cité, INSERM U1149, Paris, France
| | - Iqbal Hamza
- Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA
| | - Herbert L. Bonkovsky
- Section on Gastroenterology & Hepatology, Department of Medicine, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, USA
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Zhou Y, Zhang X, Baker JS, Davison GW, Yan X. Redox signaling and skeletal muscle adaptation during aerobic exercise. iScience 2024; 27:109643. [PMID: 38650987 PMCID: PMC11033207 DOI: 10.1016/j.isci.2024.109643] [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] [Indexed: 04/25/2024] Open
Abstract
Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.
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Affiliation(s)
- Yingsong Zhou
- Faculty of Sports Science, Ningbo University, Ningbo, China
| | - Xuan Zhang
- School of Wealth Management, Ningbo University of Finance and Economics, Ningbo, China
| | - Julien S. Baker
- Centre for Health and Exercise Science Research, Hong Kong Baptist University, Kowloon Tong 999077, Hong Kong
| | - Gareth W. Davison
- Sport and Exercise Sciences Research Institute, Ulster University, Belfast BT15 IED, UK
| | - Xiaojun Yan
- School of Marine Sciences, Ningbo University, Ningbo, China
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Kimura M, Kothari S, Gohir W, Camargo JF, Husain S. MicroRNAs in infectious diseases: potential diagnostic biomarkers and therapeutic targets. Clin Microbiol Rev 2023; 36:e0001523. [PMID: 37909789 PMCID: PMC10732047 DOI: 10.1128/cmr.00015-23] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023] Open
Abstract
MicroRNAs (miRNAs) are conserved, short, non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They have been implicated in the pathogenesis of cancer and neurological, cardiovascular, and autoimmune diseases. Several recent studies have suggested that miRNAs are key players in regulating the differentiation, maturation, and activation of immune cells, thereby influencing the host immune response to infection. The resultant upregulation or downregulation of miRNAs from infection influences the protein expression of genes responsible for the immune response and can determine the risk of disease progression. Recently, miRNAs have been explored as diagnostic biomarkers and therapeutic targets in various infectious diseases. This review summarizes our current understanding of the role of miRNAs during viral, fungal, bacterial, and parasitic infections from a clinical perspective, including critical functional mechanisms and implications for their potential use as biomarkers and therapeutic targets.
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Affiliation(s)
- Muneyoshi Kimura
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sagar Kothari
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Wajiha Gohir
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Jose F. Camargo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shahid Husain
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
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Pérez-Carrillo L, Giménez-Escamilla I, García-Manzanares M, Triviño JC, Feijóo-Bandín S, Aragón-Herrera A, Lago F, Martínez-Dolz L, Portolés M, Tarazón E, Roselló-Lletí E. Altered MicroRNA Maturation in Ischemic Hearts: Implication of Hypoxia on XPO5 and DICER1 Dysregulation and RedoximiR State. Antioxidants (Basel) 2023; 12:1337. [PMID: 37507877 PMCID: PMC10376795 DOI: 10.3390/antiox12071337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
Ischemic cardiomyopathy (ICM) is associated with abnormal microRNA expression levels that involve an altered gene expression profile. However, little is known about the underlying causes of microRNA disruption in ICM and whether microRNA maturation is compromised. Therefore, we focused on microRNA maturation defects analysis and the implication of the microRNA biogenesis pathway and redox-sensitive microRNAs (redoximiRs). Transcriptomic changes were investigated via ncRNA-seq (ICM, n = 22; controls, n = 8) and mRNA-seq (ICM, n = 13; control, n = 10). The effect of hypoxia on the biogenesis of microRNAs was evaluated in the AC16 cell line. ICM patients showed a reduction in microRNA maturation compared to control (4.30 ± 0.94 au vs. 5.34 ± 1.07 au, p ˂ 0.05), accompanied by a deregulation of the microRNA biogenesis pathway: a decrease in pre-microRNA export (XPO5, FC = -1.38, p ˂ 0.05) and cytoplasmic processing (DICER, FC = -1.32, p ˂ 0.01). Both processes were regulated by hypoxia in AC16 cells (XPO5, FC = -1.65; DICER1, FC = -1.55; p ˂ 0.01; Exportin-5, FC = -1.81; Dicer, FC = -1.15; p ˂ 0.05). Patients displayed deregulation of several redoximiRs, highlighting miR-122-5p (FC = -2.41, p ˂ 0.001), which maintained a good correlation with the ejection fraction (r = 0.681, p ˂ 0.01). We evidenced a decrease in microRNA maturation mainly linked to a decrease in XPO5-mediated pre-microRNA export and DICER1-mediated processing, together with a general effect of hypoxia through deregulation of biogenesis pathway and the redoximiRs.
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Affiliation(s)
- Lorena Pérez-Carrillo
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Isaac Giménez-Escamilla
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - María García-Manzanares
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Medicine and Animal Surgery, Veterinary School, CEU Cardenal Herrera University, C/Lluís Vives, 1, 46115 Alfara del Patriarca, Spain
| | | | - Sandra Feijóo-Bandín
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Tr.ª da Choupana, 15706 Santiago de Compostela, Spain
| | - Alana Aragón-Herrera
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Tr.ª da Choupana, 15706 Santiago de Compostela, Spain
| | - Francisca Lago
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Tr.ª da Choupana, 15706 Santiago de Compostela, Spain
| | - Luis Martínez-Dolz
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Heart Failure and Transplantation Unit, Cardiology Department, University and Polytechnic La Fe Hospital, Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Manuel Portolés
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Estefanía Tarazón
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Esther Roselló-Lletí
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
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10
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Song Q, Mao X, Jing M, Fu Y, Yan W. Pathophysiological role of BACH transcription factors in digestive system diseases. Front Physiol 2023; 14:1121353. [PMID: 37228820 PMCID: PMC10203417 DOI: 10.3389/fphys.2023.1121353] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
BTB and CNC homologous (BACH) proteins, including BACH1 and BACH2, are transcription factors that are widely expressed in human tissues. BACH proteins form heterodimers with small musculoaponeurotic fibrosarcoma (MAF) proteins to suppress the transcription of target genes. Furthermore, BACH1 promotes the transcription of target genes. BACH proteins regulate physiological processes, such as the differentiation of B cells and T cells, mitochondrial function, and heme homeostasis as well as pathogenesis related to inflammation, oxidative-stress damage caused by drugs, toxicants, or infections; autoimmunity disorders; and cancer angiogenesis, epithelial-mesenchymal transition, chemotherapy resistance, progression, and metabolism. In this review, we discuss the function of BACH proteins in the digestive system, including the liver, gallbladder, esophagus, stomach, small and large intestines, and pancreas. BACH proteins directly target genes or indirectly regulate downstream molecules to promote or inhibit biological phenomena such as inflammation, tumor angiogenesis, and epithelial-mesenchymal transition. BACH proteins are also regulated by proteins, miRNAs, LncRNAs, labile iron, and positive and negative feedback. Additionally, we summarize a list of regulators targeting these proteins. Our review provides a reference for future studies on targeted drugs in digestive diseases.
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Affiliation(s)
- Qianben Song
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xin Mao
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengjia Jing
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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11
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Günay N, Taheri S, Memiş M, Yilmaz Şükranli Z, Şahin T, Demiryürek Ş, Ekici Günay N, Aslan YE, Demiryürek AT. Male- and female-specific microRNA expression patterns in a mouse model of methanol poisoning. Food Chem Toxicol 2023; 174:113666. [PMID: 36780935 DOI: 10.1016/j.fct.2023.113666] [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: 12/06/2022] [Revised: 01/29/2023] [Accepted: 02/09/2023] [Indexed: 02/13/2023]
Abstract
The aims of this study were to determine the miRNAs involved in the methanol poisoning, and identify the male- and female-specific miRNA expression patterns in mice. Methanol was applied orally at the doses of 4 g/kg and 8 g/kg to induce mild and severe methanol poisoning in Balb/c mice. miRNA expression levels were detected at 3 different time periods (30, 60, and 180 min) following methanol exposure. miRNA expression profiles were determined using the high-throughput Fluidigm BioMark real-time PCR. We observed that serum miR-206 expression in male mice and miR-6357 expression in female mice could be an indicator of methanol poisoning. miR-9-3p downregulation and miR-1187 upregulation could be important for liver tissue. miR-3106-5p and miR-133a-5p upregulations and miR-122-3p downregulation could be poison biomarkers for ocular tissue in male mice. However, miR-194-5p downregulation could be a biomarker for ocular tissue in female mice. miR-122-5p and miR-124-3p downregulations and miR-499a-5p upregulation appeared to be important for kidney tissue in male mice. miR-543 and miR-6342 upregulations could be potential candidate biomarkers for kidney tissue in female mice. Our study is the first to report that differential miRNA expressions are involved in blood and tissues in male and female mice after methanol treatment.
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Affiliation(s)
- Nurullah Günay
- Department of Emergency Medicine, Faculty of Medicine, Erciyes University, Kayseri, 38039, Turkey.
| | - Serpil Taheri
- Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, 38280, Turkey; Erciyes University, Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, 38280, Turkey
| | - Mehmet Memiş
- Erciyes University, Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, 38280, Turkey; Erciyes University, Gevher Nesibe Genome and Stem Cell Institute, Department of Medical Biology and Genetics, Kayseri, 38280, Turkey
| | - Zeynep Yilmaz Şükranli
- Erciyes University, Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, 38280, Turkey
| | - Taner Şahin
- Kayseri City Hospital, Clinics of Emergency Medicine, Kayseri, 38080, Turkey
| | - Şeniz Demiryürek
- Department of Physiology, Faculty of Medicine, Gaziantep University, Gaziantep, 27310, Turkey
| | - Nahide Ekici Günay
- Kayseri City Hospital, Clinics of Medical Biochemistry, Kayseri, 38080, Turkey
| | - Yusuf Ertugrul Aslan
- Department of Emergency Medicine, Faculty of Medicine, Erciyes University, Kayseri, 38039, Turkey
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12
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Megahed F, Tabll A, Atta S, Ragheb A, Smolic R, Petrovic A, Smolic M. MicroRNAs: Small Molecules with Significant Functions, Particularly in the Context of Viral Hepatitis B and C Infection. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:173. [PMID: 36676797 PMCID: PMC9862007 DOI: 10.3390/medicina59010173] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023]
Abstract
A MicroRNA (miRNA) is defined as a small molecule of non-coding RNA (ncRNA). Its molecular size is about 20 nucleotides (nt), and it acts on gene expression's regulation at the post-transcription level through binding to the 3'untranslated regions (UTR), coding sequences, or 5'UTR of the target messenger RNAs (mRNAs), which leads to the suppression or degradation of the mRNA. In recent years, a huge evolution has identified the origin and function of miRNAs, focusing on their important effects in research and clinical applications. For example, microRNAs are key players in HCV infection and have important host cellular factors required for HCV replication and cell growth. Altered expression of miRNAs affects the pathogenicity associated with HCV infection through regulating different signaling pathways that control HCV/immunity interactions, proliferation, and cell death. On the other hand, circulating miRNAs can be used as novel biomarkers and diagnostic tools for HCV pathogenesis and early therapeutic response. Moreover, microRNAs (miRNA) have been involved in hepatitis B virus (HBV) gene expression and advanced antiviral discovery. They regulate HBV/HCV replication and pathogenesis with different pathways involving facilitation, inhibition, activation of the immune system (innate and adaptive), and epigenetic modifications. In this short review, we will discuss how microRNAs can be used as prognostic, diagnostic, and therapeutic tools, especially for chronic hepatitis viruses (HBV and HCV), as well as how they could be used as new biomarkers during infection and advanced treatment.
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Affiliation(s)
- Fayed Megahed
- Nucleic Acid Research Department, Genetic Engineering and Biotechnological Research Institute (GEBRI), City for Scientific Researches and Technological Applications (SRTA-City), Alexandria 21934, Egypt
| | - Ashraf Tabll
- Microbial Biotechnology Department, National Research Centre, Giza 12622, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Shimaa Atta
- Department of Immunology, Theodor Bilharz Research Institute, Cairo 12411, Egypt
| | - Ameera Ragheb
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
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13
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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14
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Hassuna NA, Gamil AN, Mahmoud MS, Mohamed WK, Khairy R. Circulating microRNAs as predictors of response to sofosbuvir + daclatasvir + ribavirin in in HCV genotype-4 Egyptian patients. BMC Gastroenterol 2022; 22:499. [PMID: 36463118 PMCID: PMC9719120 DOI: 10.1186/s12876-022-02485-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 08/09/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection, the aim of the current study was to evaluate the potential use of serum miRNAs as biomarkers for diagnosis, prognosis, and prediction of responses to direct acting antivirals (sofosbuvir + daclatasvir + ribavirin) in HCV-4 patients. METHODS The serum expression profiles of four liver-associated miRNAs (miRNA-122, 155, 196 and 29) were assessed in 160 HCV-4 patients and 50 healthy controls using real-time PCR prior to therapy. RESULTS miR-122 and miR-155 showed upregulation in HCV-4 patients compared to healthy controls while miR-196 and miR-29 showed downregulation in HCV-4 patients. ROC curve analyses revealed that the four-studied miRNAs could be valuable biomarkers for predicting response to DAAs with AUC 0.973 for miR-122, 0.878 for miR-155, 0.808 for miR-29 and 0.874 for miR-196 respectively. Univariate logistic regression analysis revealed that miR-196 level is positive predictor for SVR, whereas miR-122,155 levels are negative predictors of response. Multivariate logistic regression analysis revealed that miR-196 is the most significant in predicting response to treatment (p value = 0.011). CONCLUSION To the best of our knowledge, the current study provided the first clinical evidence of the potential use of circulating miRNAs (miR; 122, 155, 196 and 29) as biomarkers of CHC in HCV-4 patients receiving the new DAA regimen (SOF/DAV + RIB), which is a strong motivator for further studies.
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Affiliation(s)
- Noha Anwar Hassuna
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Aya Nabil Gamil
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Mahmoud Shokry Mahmoud
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Wafaa Khairy Mohamed
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Rasha Khairy
- grid.411806.a0000 0000 8999 4945Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
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15
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Priyadarshini G, Rajappa M. Predictive markers in chronic kidney disease. Clin Chim Acta 2022; 535:180-186. [PMID: 35995274 DOI: 10.1016/j.cca.2022.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022]
Abstract
Chronic kidney disease (CKD) is defined by gradual deterioration of the renal parenchyma and decline of functioning nephrons. CKD is now recognized as a distinct risk factor for cardiovascular disease (CVD). This risk rises in tandem with the decline in kidney function and peaks at the end-stage. It is important to identify individuals with CKD who are at a higher risk of advancing to end-stage renal disease (ESRD) and the beginning of CVD. This will enhance the clinical benefits and so that evidence-based therapy may be started at the initial stages for those individuals. A promising biomarker must represent tissue damage, and be easy to detect using non-invasive methods. Current CKD progression indicators have difficulties in reaching this aim. Hence this review presents an update on markers studied in the last decade, which help in the prediction of CKD progression such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid-binding protein, cystatin-C, asymmetric dimethylarginine, symmetric dimethylarginine, endotrophin, methylglyoxal, sclerostin, uric acid, and miRNA-196a. Additional research is needed to determine the predictive usefulness of these indicators in clinical samples for disease development. Their utility as surrogate markers need to be explored further for the early identification of CKD progression.
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Affiliation(s)
- G Priyadarshini
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Medha Rajappa
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
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16
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Roles of microRNAs in Hepatitis C Virus Replication and Pathogenesis. Viruses 2022; 14:v14081776. [PMID: 36016398 PMCID: PMC9413378 DOI: 10.3390/v14081776] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/11/2022] [Accepted: 08/13/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is associated with the development of chronic liver diseases, e.g., fibrosis, cirrhosis, even hepatocellular carcinoma, and/or extra-hepatic diseases such as diabetes. As an obligatory intracellular pathogen, HCV absolutely relies on host cells to propagate and is able to modulate host cellular factors in favor of its replication. Indeed, lots of cellular factors, including microRNAs (miRNAs), have been identified to be dysregulated during HCV infection. MiRNAs are small noncoding RNAs that regulate protein synthesis of their targeting mRNAs at the post-transcriptional level, usually by suppressing their target gene expression. The miRNAs dysregulated during HCV infection could directly or indirectly modulate HCV replication and/or induce liver diseases. Regulatory mechanisms of various miRNAs in HCV replication and pathogenesis have been characterized. Some dysregulated miRNAs have been considered as the biomarkers for the detection of HCV infection and/or HCV-related diseases. In this review, we intend to briefly summarize the identified miRNAs functioning at HCV replication and pathogenesis, focusing on the recent developments.
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17
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Mir M, Mir R, Alghamdi MA, Alsayed B, Elfaki I, Al Bshabshe A, Farooq R, Alhujaily M, Alharthi M, Alamri MM, Al‑Shahrani A. Differential impact of the angiotensin‑converting enzyme‑2 (ACE2 rs4343 G>A) and miR‑196a2 rs11614913 C>T gene alterations in COVID‑19 disease severity and mortality. Exp Ther Med 2022; 23:418. [PMID: 35601073 PMCID: PMC9117950 DOI: 10.3892/etm.2022.11345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
The recent coronavirus outbreak from Wuhan China in late 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in a global pandemic of coronavirus-19 disease (COVID-19). Understating the underlying mechanism of the pathogenesis of coronavirus infection is important not only because it will help in accurate diagnosis and treatment of the infection but also in the production of effective vaccines. The infection begins when SARS-CoV-2 enters the cells through binding of its envelope glycoprotein to angiotensin-converting enzyme2 (ACE2). Gene variations of ACE2 and microRNA (miR)-196 are associated with viral infection and other diseases. The present study investigated the association of the ACE2 rs4343 G>A and miR-196a2 rs11614913 C>T gene polymorphisms with severity and mortality of COVID-19 using amplification refractory mutation system PCR in 117 COVID-19 patients and 103 healthy controls from three regions of Saudi Arabia. The results showed that ACE2 rs4343 GA genotype was associated with severity of COVID-19 (OR=2.10, P-value 0.0028) and ACE2 rs4343 GA was associated with increased mortality with OR=3.44, P-value 0.0028. A strong correlation between the ACE2 rs4343 G>A genotype distribution among COVID-19 patients was reported with respect to their comorbid conditions including sex (P<0.023), coronary artery disease (P<0.0001), oxygen saturation <60 mm Hg (P<0.0009) and antiviral therapy (0.003). The results also showed that the CT genotype and T allele of the miR-196a2 rs11614913 C>T were associated with decreased risk to COVID-19 with OR=0.76, P=0.006 and OR=0.54, P=0.005, respectively. These results need to be validated with future molecular genetic studies in a larger sample size and different populations.
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Affiliation(s)
- Mohammad Mir
- Department of Basic Medical Sciences (Biochemistry), College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Rashid Mir
- Prince Fahd Bin Sultan Research chair, Department of MLT, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Mushabab Ayed Alghamdi
- Department of Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Badr Alsayed
- Department of Internal Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Imadeldin Elfaki
- Department of Biochemistry, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Ali Al Bshabshe
- Department of Internal Medicine/Critical Care, College of Medicine King Khalid University, Abha 61421, Saudi Arabia
| | - Rabia Farooq
- Department of Basic Medical Sciences (Biochemistry), College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Muhanad Alhujaily
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
| | - Muffarah Alharthi
- Department of Family Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mohannad Mohammad Alamri
- Department of Family Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Abdullah Al‑Shahrani
- Department of Family Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
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18
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Inhibiting BTB domain and CNC homolog 1 (Bach1) as an alternative to increase Nrf2 activation in chronic diseases. Biochim Biophys Acta Gen Subj 2022; 1866:130129. [DOI: 10.1016/j.bbagen.2022.130129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/25/2022] [Accepted: 03/09/2022] [Indexed: 12/15/2022]
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19
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Roy S, Ganguly N, Banerjee S. Exploring clinical implications and role of non-coding RNAs in lung carcinogenesis. Mol Biol Rep 2022; 49:6871-6883. [PMID: 35076850 DOI: 10.1007/s11033-022-07159-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/18/2022] [Indexed: 12/12/2022]
Abstract
Lung cancer is the utmost familiar category of cancer with greatest fatality rate worldwide and several regulatory mechanisms exercise cellular control on critical oncogenic trails implicated in lung associated carcinogenesis. The non-coding RNAs (ncRNAs) are shown to play a variety of regulatory roles, including stimulating cell proliferation, inhibiting programmed cell death, enhancing cancer cell metastatic ability and acquiring resistance to drugs. Furthermore, ncRNAs exhibit tissue-specific expression as well as great stability in bodily fluids. As a consequence, they are strong contenders for cancer based theragnostics. microRNA (miRNA) alters gene expression primarily by either degrading or interfering with the translation of targeted mRNA and long non-coding RNAs (lncRNAs) can influence gene expression by targeting transcriptional activators or repressors, RNA polymers and even DNA-duplex. lncRNAs are typically found to be dysregulated in lung cancer and hence targeting ncRNAs could be a viable strategy for developing potential therapies as well as for overcoming chemoresistance in lung cancer. The purpose of this review is to elucidate the role of ncRNAs, revisiting the recent studies in lung cancer.
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Affiliation(s)
- Swagata Roy
- School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632 014, India
| | - Neeldeep Ganguly
- School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632 014, India
| | - Satarupa Banerjee
- School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632 014, India.
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20
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Circulating miRNAs and tissue iron overload in transfusion-dependent β-thalassemia major: novel predictors and follow-up guide. Ann Hematol 2021; 100:2909-2917. [PMID: 34432101 DOI: 10.1007/s00277-021-04639-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/18/2021] [Indexed: 11/27/2022]
Abstract
Tissue iron overload is a life-threatening scenario in children with transfusion-dependent β-thalassemia major, miRNAs that are involved in iron hemostasis could serve as therapeutic targets for control of iron overload. We aimed to find out the association between three iron-related miRNAs "miR-let-7d, miR-122, and miR-200b" and excess iron in tissues, in transfusion-dependent β-thalassemia major patients. Circulating miRNA expressions are measured in peripheral blood (PB) samples using qPCR of transfusion-dependent (TDT) β-thalassemia patients (n = 140) and normalized to non-transfusion-dependent (NTDT) β-thalassemia (n = 45). Results revealed that plasma expression levels of miR-let-7d and miR-200b were significantly downregulated in TDT patients; however, miR-122 was upregulated. In terms of tissue iron load, aberrant expression of miRNAs was significantly associated with increased-iron accumulation in hepatic and cardiac tissues. We concluded that circulating miRNAs are strong candidates that associate iron hemostasis in transfusion-dependent β-thalassemia major patients. And by extension, targeting miR-let-7d, miR-122, and miR-200 might serve as novel sensitive, specific and non-invasive predictor biomarkers for cellular damage under condition of tissue iron excess.
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21
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Bastami M, Masotti A, Saadatian Z, Daraei A, Farjam M, Ghanbariasad A, Vahed SZ, Eyvazi S, Mansoori Y, Nariman-Saleh-Fam Z. Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications. Exp Mol Pathol 2021; 122:104664. [PMID: 34166682 DOI: 10.1016/j.yexmp.2021.104664] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/26/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.
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Affiliation(s)
- Milad Bastami
- Non-communicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Andrea Masotti
- Research Laboratories, Bambino Gesù Children's Hospital-IRCCS, Rome 00146, Italy
| | - Zahra Saadatian
- Department of Genetics, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Abdolreza Daraei
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mojtaba Farjam
- Non-communicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Ali Ghanbariasad
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Shirin Eyvazi
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Yaser Mansoori
- Non-communicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran; Medical Genetics Department, Fasa University of Medical Sciences, Fasa, Iran.
| | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Tian C, Gao L, Zucker IH. Regulation of Nrf2 signaling pathway in heart failure: Role of extracellular vesicles and non-coding RNAs. Free Radic Biol Med 2021; 167:218-231. [PMID: 33741451 PMCID: PMC8096694 DOI: 10.1016/j.freeradbiomed.2021.03.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/26/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022]
Abstract
The balance between pro- and antioxidant molecules has been established as an important driving force in the pathogenesis of cardiovascular disease. Chronic heart failure is associated with oxidative stress in the myocardium and globally. Redox balance in the heart and brain is controlled, in part, by antioxidant proteins regulated by the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which is reduced in the heart failure state. Nrf2 can, in turn, be regulated by a variety of mechanisms including circulating microRNAs (miRNAs) encapsulated in extracellular vesicles (EVs) derived from multiple cell types in the heart. Here, we review the role of the Nrf2 and antioxidant enzyme signaling pathway in mediating redox balance in the myocardium and the brain in the heart failure state. This review focuses on Nrf2 and antioxidant protein regulation in the heart and brain by miRNA-enriched EVs in the setting of heart failure. We discuss EV-mediated intra- and inter-organ communications especially, communication between the heart and brain via an EV pathway that mediates cardiac function and sympatho-excitation in heart failure. Importantly, we speculate how engineered EVs with specific miRNAs or antagomirs may be used in a therapeutic manner in heart failure.
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Affiliation(s)
- Changhai Tian
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Lie Gao
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198-5850, USA.
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Sun X, Zhu H, Cao R, Zhang J, Wang X. BACH1 is transcriptionally inhibited by TET1 in hepatocellular carcinoma in a microRNA-34a-dependent manner to regulate autophagy and inflammation. Pharmacol Res 2021; 169:105611. [PMID: 33878446 DOI: 10.1016/j.phrs.2021.105611] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/22/2021] [Accepted: 04/09/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the main contributors to cancer-associated deaths globally, is characterized by high invasiveness. Herein, we studied the molecular mechanisms underlying ten-eleven translocation 1 (TET1)-mediated autophagy in HCC. Following data mining using GSE101728, GSE14520 and GSE138178, TET1 was screened out, and the differential expression of TET1 was verified by bioinformatics analysis. TET1, one of the prognostic markers in HCC, was poorly expressed in HCC. Through functional experiments, we determined that upregulation of TET1 inhibited the proliferation, migration, invasion, tumorigenesis, metastasis and inflammatory factors of HCC cells, and promoted cell autophagy and apoptosis. Mechanistically, TET1 activated miR-34a by demethylating miR-34a. BTB domain and CNC homology 1 (BACH1) was identified as the target gene of miR-34a. Notably, Downregulation of miR-34a increased cellular inflammatory factors and decreased autophagy in the presence of TET1, while declines in BACH1 suppressed cellular inflammatory factors and enhanced autophagy in the presence of miR-34a inhibitor. BACH1 negatively regulated the p53 pathway. In conclusion, TET1 is a tumor suppressor in the progression of HCC by regulating the miR-34a/BACH1/p53 axis, and may contribute to the improvement of HCC prognosis and therapy.
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Affiliation(s)
- Xuehu Sun
- Department of Emergency Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui, PR China
| | - Hongmei Zhu
- Department of Emergency Surgery, the First Affiliated Hospital of Anhui Medical University, High-tech Hospital District, Hefei 230088, Anhui, PR China
| | - Rongge Cao
- Department of Emergency Surgery, the First Affiliated Hospital of University of Science and Technology of China, Hefei 230000, Anhui, PR China
| | - Jianlin Zhang
- Department of Emergency Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui, PR China
| | - Xingyu Wang
- Department of Emergency Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui, PR China.
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MicroRNA Interference in Hepatic Host-Pathogen Interactions. Int J Mol Sci 2021; 22:ijms22073554. [PMID: 33808062 PMCID: PMC8036276 DOI: 10.3390/ijms22073554] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/14/2022] Open
Abstract
The liver is well recognized as a non-immunological visceral organ that is involved in various metabolic activities, nutrient storage, and detoxification. Recently, many studies have demonstrated that resident immune cells in the liver drive various immunological reactions by means of several molecular modulators. Understanding the mechanistic details of interactions between hepatic host immune cells, including Kupffer cells and lymphocytes, and various hepatic pathogens, especially viruses, bacteria, and parasites, is necessary. MicroRNAs (miRNAs), over 2600 of which have been discovered, are small, endogenous, interfering, noncoding RNAs that are predicted to regulate more than 15,000 genes by degrading specific messenger RNAs. Several recent studies have demonstrated that some miRNAs are associated with the immune response to pathogens in the liver. However, the details of the underlying mechanisms of miRNA interference in hepatic host-pathogen interactions still remain elusive. In this review, we summarize the relationship between the immunological interactions of various pathogens and hepatic resident immune cells, as well as the role of miRNAs in the maintenance of liver immunity against pathogens.
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25
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Shafaati M, Jamalidoust M, Kargar M, Arefian E, Kafilzadeh F. Downregulation of hepatitis C virus replication by miR-196a using lentiviral vectors. Microbiol Immunol 2021; 65:161-170. [PMID: 33470443 DOI: 10.1111/1348-0421.12875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/25/2020] [Accepted: 01/08/2021] [Indexed: 11/29/2022]
Abstract
Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis and hepatocellular carcinoma. Cellular microRNAs (miRNAs) directly modulate the viral infectivity and indirectly through targeting virus-related host factors. They play an essential role in the progression of different stages of HCV infection. The roles of miR-196 family in HCV infection and hepatocellular carcinoma progression remain poorly understood. Using ViTa databases, miR-196a as a high-score miRNA targeting the NS5 A region of HCV genome was selected. Using dual luciferase assay and an established cell-cultured HCV (HCVcc) system, the effect of miR-196a on HCV genome was assessed. In silico analysis demonstrated the significant role of miR-196a in the downregulation of HCV replication. Using dual luciferase assay, the liver-specific miR-196a and NS5 A gene binding was confirmed. To assess the experimental role of miR-196a, an HCVcc system was established in the Huh 7.5 cell lines. The HCV-RNA 1b derived from an infected patient was transfected into Huh 7.5 cells containing miR-196a lentiviral vectors (Huh 7.5/miR-196a), mocks (Huh 7.5/mock vector), and naïve Huh 7.5 cells. The rate of reduction of the HCV genome replication was assessed using relative real-time PCR assay. These results represent miR-196a overexpression and its roles in regulating HCV genome replication. However, miR-196a may inhibit HCV replication and accelerate the early stages of apoptosis. Overexpression of miR-196a in Huh 7.5 replicon cell is a potential new strategy to prevent hepatitis C infection. The results of this study suggest that miR-196a directly downregulates HCV replication and may serve as a new antiviral therapy.
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Affiliation(s)
- Maryam Shafaati
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | - Marzieh Jamalidoust
- Department of Virology, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Kargar
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Farshid Kafilzadeh
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
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26
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Sanada Y, Tan SJO, Adachi N, Miyaki S. Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis. Antioxidants (Basel) 2021; 10:antiox10030419. [PMID: 33803317 PMCID: PMC8001640 DOI: 10.3390/antiox10030419] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/19/2021] [Accepted: 03/02/2021] [Indexed: 12/17/2022] Open
Abstract
Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity.
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Affiliation(s)
- Yohei Sanada
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 7348551, Japan;
- Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 7348551, Japan; (S.J.O.T.); (N.A.)
| | - Sho Joseph Ozaki Tan
- Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 7348551, Japan; (S.J.O.T.); (N.A.)
| | - Nobuo Adachi
- Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 7348551, Japan; (S.J.O.T.); (N.A.)
| | - Shigeru Miyaki
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 7348551, Japan;
- Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 7348551, Japan; (S.J.O.T.); (N.A.)
- Correspondence: ; Tel.: +81-82-257-5231
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Expression profiling of miRNA-196a biomarker in naïve hepatitis C virus-infected and Sofosbuvir plus Daclatasvir-treated patients. Arch Microbiol 2021; 203:2365-2371. [PMID: 33660021 DOI: 10.1007/s00203-021-02233-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 12/31/2020] [Accepted: 02/11/2021] [Indexed: 10/22/2022]
Abstract
Micro-RNA (miRNA) is a short stretch of nucleotides that can regulate many genes associated with the various stages of the hepatitis C virus (HCV) life cycle and disease progression. This study evaluates the expression profiling of miRNA-196a in naïve HCV-infected, and Sofosbuvir plus Daclatasvir-treated patients. MiRNA-196a can inhibit HCV replication by silencing the HCV NS5A protein or downregulating the human BACH-I mRNA. The expression level of miRNA-196a was determined by quantitative reverse transcription PCR (RT-qPCR) using the whole RNA extracted from the recruited participant's serum. Results showed a 0.83-fold decrease in the miRNA-196a level in naïve HCV-infected than controls. On the contrary, an increase in the expression level by 0.06-fold was observed in Sofosbuvir plus Daclatasvir-treated patients. A negative but significant correlation was recorded between the HCV-RNA load and miRNA-196a expression level in the naïve-infected patients. Serum miRNA-196a ROC curve analysis revealed an area under the curve of 0.8278 (95% CI 0.7033-0.9524, p < 0.0001) with 82.05% sensitivity and 76.19% specificity in discriminating the healthy controls from the HCV-infected samples. In conclusion, our study explored the comparative expression levels of miRNA-196a in HCV-infected and Sofosbuvir plus Daclatasvir patients. Further studies are needed to examine the possible role of miR-196a as a therapeutic agent for treating HCV-infected patients.
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28
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Heme Oxgenase-1, a Cardinal Modulator of Regulated Cell Death and Inflammation. Cells 2021; 10:cells10030515. [PMID: 33671004 PMCID: PMC7997353 DOI: 10.3390/cells10030515] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/18/2021] [Accepted: 02/22/2021] [Indexed: 12/12/2022] Open
Abstract
Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron. The inducible form of the enzyme, heme oxygenase-1 (HO-1), exerts a central role in cellular protection. The substrate, heme, is a potent pro-oxidant that can accelerate inflammatory injury and promote cell death. HO-1 has been implicated as a key mediator of inflammatory cell and tissue injury, as validated in preclinical models of acute lung injury and sepsis. A large body of work has also implicated HO-1 as a cytoprotective molecule against various forms of cell death, including necrosis, apoptosis and newly recognized regulated cell death (RCD) programs such as necroptosis, pyroptosis, and ferroptosis. While the antiapoptotic potential of HO-1 and its reaction product CO in apoptosis regulation has been extensively characterized, relatively fewer studies have explored the regulatory role of HO-1 in other forms of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). HO-1 may provide anti-inflammatory protection in necroptosis or pyroptosis. In contrast, in ferroptosis, HO-1 may play a pro-death role via enhancing iron release. HO-1 has also been implicated in co-regulation of autophagy, a cellular homeostatic program for catabolic recycling of proteins and organelles. While autophagy is primarily associated with cell survival, its occurrence can coincide with RCD programs. This review will summarize the roles of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease.
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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30
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Chiang S, Huang MLH, Park KC, Richardson DR. Antioxidant defense mechanisms and its dysfunctional regulation in the mitochondrial disease, Friedreich's ataxia. Free Radic Biol Med 2020; 159:177-188. [PMID: 32739593 DOI: 10.1016/j.freeradbiomed.2020.07.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
Abstract
Redox stress is associated with the pathogenesis of a wide variety of disease states. This can be amplified potentially through redox active iron deposits in oxidatively active organelles such as the mitochondrion. There are a number of disease states, including Friedreich's ataxia (FA) and sideroblastic anemia, where iron metabolism is dysregulated and leads to mitochondrial iron accumulation. Considering FA, which is due to the decreased expression of the mitochondrial protein, frataxin, this iron accumulation does not occur within protective storage proteins such as mitochondrial ferritin. Instead, it forms unbound biomineral aggregates composed of high spin iron(III), phosphorous and sulfur, which probably contributes to the observed redox stress. There is also a dysregulated response to the ensuing redox assault, as the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation. The dysfunctional response of Nrf2 in FA is due to multiple mechanisms including: (1) up-regulation of Keap1 that is involved in Nrf2 degradation; (2) activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling; and (3) inhibited nuclear translocation of Nrf2. More recently, increased microRNA (miRNA) 144 expression has been demonstrated to down-regulate Nrf2 in several disease states, including an animal model of FA. Other miRNAs have also demonstrated to be dysregulated upon frataxin depletion in vivo in humans and animal models of FA. Collectively, frataxin depletion results in multiple, complex responses that lead to detrimental redox effects that could contribute to the mechanisms involved in the pathogenesis of FA.
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Affiliation(s)
- S Chiang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - M L H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - K C Park
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - D R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Centre for Cancer Cell Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, 4111, Australia.
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31
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Emilia M, Roman N, Barbara SM, Urszula M, Krzysztof Ł, Paweł O. Expression profile of Tripartite motif family (TRIM) in human fibroblasts (NHDF) infected with porcine endogenous retrovirus (PERV). Xenotransplantation 2020; 28:e12650. [PMID: 33037648 DOI: 10.1111/xen.12650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 08/31/2020] [Accepted: 09/07/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Understanding the interactions between the microRNA (miRNA) and mRNA of genes encoding restriction factors (RFs) can lead to the development of new antiretroviral strategies aimed at providing the resistance and reducing susceptibility of human cells to potential PERV infection. Among RFs TRIM family play an important role in shaping the immune response during various stages of infection. The aim of the study was to evaluate in vitro the transcriptional profile of TRIM family genes and identify complementary miRNAs in NHDF cells infected with PERVs and induced by gram negative lipopolysacharide (LPS). METHODS Human dermal fibroblasts cells were cultured in four separate conditions- 2 monocultures: control (N), treated with LPS (NL) and 2 co-cultures with porcine PK15 cells: without LPS (NP) and treated with LPS (NLP). Bacterial LPS was used in this study as an inducer of inflammation in NHDF cells. After extraction of DNA and RNA from cells PERV infection was confirmed in co-cultures by qPCR and RTqPCR. RNA extracts served as a matrix for HGU 133A 2.0 and miRNA 2.0 microarrays to evaluate the expression profile of the selected TRIM family genes and miRNAs adequately. TRIM 2, 14, 22, and 28 were selected for the validation of HGU 133A 2.0 results. Statistical analyses were performed with the use of REST© 2009 and Genespring GX 13.0. Transcriptome Analysis Console 4.0 program (Affymetrix) was used to identify miRNAs that differentiate the studied genes in all conditions. RESULTS Porcine endogenous retrovirus infection at DNA and RNA level was confirmed in NHDF cells in each of the tested groups (NP and NLP). Contamination was excluded in N and NL groups. Based on the analysis of HGU 133A 2.0 results 93 mRNA IDs of TRIM family genes differentiating analyzed conditions were selected P < .05. HGU 133A 2.0 mRNA fluorescence profile was confirmed with RTqPCR of TRIM2, TRIM14, TRIM22 and TRIM28 P < .05. TRIM14 down regulation was specific only in PERV monoinfection (group NP). In miRNA 2.0 microarray 346 miRNAs were identified as differentiating NHDF cells in all analyzed conditions, P < .05. According to the analysis with mirTAR platform and Microrna.org datatbase none of the selected miRNAs had the potential to regulate the selected genes of the TRIM family. CONCLUSION Porcine endogenous retrovirus infection of NHDF cells is accompanied by TRIM14 down regulation suggesting TRIM14 as a possible marker of retroviral infection. None of the selected miRNAs had statistically significant potential to regulate the expression of the selected TRIMs in any of the analyzed conditions.
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Affiliation(s)
- Morawiec Emilia
- Department of Microbiology, Faculty of Medicine in Zabrze, University of Technology in Katowice, Katowice, Poland.,Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland.,Gyncentrum, Laboratory of Molecular Biology and Virology, Katowice, Poland.,Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland
| | - Nowak Roman
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland.,Orthopaedic Clinical Unit No 5 Sosnowiec, Silesian Medical University Sosnowiec, Poland
| | - Strzałka-Mrozik Barbara
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland
| | - Mazurek Urszula
- Jozef Tyszkiewicz Higher School in Bielsko-Biała, Bielsko-Biała, Poland.,Karol Godula Upper Silesian Academy of Entrepreneurship Chorzów, Chorzów, Poland
| | - Łopata Krzysztof
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland.,HYDREX DIAGNOSTICS Sp. z o.o. Sp.k, Warszawa, Poland
| | - Olczyk Paweł
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland
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32
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Moradi M, Mozafari F, Hosseini S, Rafiee R, Ghasemi F. A concise review on impacts of microRNAs in biology and medicine of hepatitis C virus. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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33
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Zhu P, Qi T, Huang ZS, Li H, Wang B, Feng JX, Ma S, Xiao HJ, Tang YX, Liu W, Chen J. Proteomic analysis of oxidative stress response in human umbilical vein endothelial cells (HUVECs): role of heme oxygenase 1 (HMOX1) in hypoxanthine-induced oxidative stress in HUVECs. Transl Androl Urol 2020; 9:218-231. [PMID: 32420127 PMCID: PMC7215041 DOI: 10.21037/tau.2020.03.11] [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] [Indexed: 11/06/2022] Open
Abstract
Background Erectile dysfunction (ED) is a well-known complication of diabetes, affecting up to 75% of diabetic men. Although the etiology of diabetic ED is multifactorial, endothelial dysfunction is considered to be a pillar of its pathophysiology. Endothelial dysfunction is caused by the harmful effects of high glucose levels and increased oxidative stress on the endothelial cells that comprise the vascular endothelium. The aim of this study was to identify the proteomic changes caused by high glucose-induced oxidative stress and explore the role of heme oxygenase 1 (HMOX1) in it. Methods The cellular proteomic response to hypoxanthine-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) was analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) were analyzed through Network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Further validation assays was performed to validate the role of HMOX1. Results The results showed that 66 and 76 DEPs were markedly upregulated and downregulated, respectively, for HUVECs oxidative stress. Among these proteins, we verified eight dysregulated genes by quantitative reverse transcription PCR, including nucleolin (NCL), X-ray repair cross-complementing protein 6 (XRCC6), ubiquinol-cytochrome C reductase binding protein (UQCRB), non-POU domain containing octamer binding (NONO), heme oxygenase 1 (HMOX1), nucleobindin 1 (NUCB1), DEK, and chromatin target of prmt1 (CHTOP). Further, using overexpression and genetic knockdown approaches, we found that HMOX1 was critical for the oxidative stress response in HUVECs. Conclusions We found that HMOX1 was closely related to the oxidative stress response induced by hypoxanthine. To the best of our knowledge, this study is the first overview of the responses of HUVECs to oxidative stress. The findings will contribute to analyses of the detailed molecular mechanisms involved in the pathogenesis of endothelial dysfunction and related molecular mechanisms in ED patients.
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Affiliation(s)
- Pei Zhu
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Tao Qi
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zhan-Sen Huang
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Hao Li
- Department of Urology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Bo Wang
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jia-Xin Feng
- Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Shuai Ma
- Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Heng-Jun Xiao
- Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Yu-Xin Tang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Wei Liu
- Guangdong Provincial Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Jun Chen
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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Onishi M, Ochiya T, Tanaka Y. MicroRNA and liver cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3:385-400. [PMID: 35582451 PMCID: PMC8992476 DOI: 10.20517/cdr.2019.110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/28/2020] [Accepted: 02/28/2020] [Indexed: 11/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. HCC is characterized by a poor prognosis and an ever increasing number of scientific studies aim to find new diagnostic, prognostic, and therapeutic targets. MicroRNAs (miRNAs), small non-coding RNAs that regulate the gene expression in many processes, have been shown to play a crucial role in regulating hepatocellular carcinoma. miRNAs may act as oncogenic miRNAs and tumor suppressor miRNAs and regulate cancer cell proliferation, invasion, and metastasis by being differently upregulated or downregulated and targeting the genes related with carcinogenesis. miRNAs secreted from cancer cells are found circulating in the blood, presenting an opportunity for their use as disease-related biomarkers. Moreover, extracellular vesicle-derived miRNAs are known to reflect the cell of origin and function and may provide effective biomarkers for predicting diagnosis and prognosis and new therapeutic target in HCC. In this article, we describe the most recent findings regarding the molecular mechanisms and gene regulation of microRNA in HCC, as well as their application in diagnosis/prognosis and treatment.
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Affiliation(s)
- Masaya Onishi
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Yasuhito Tanaka
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
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Non-Coding RNAs in Lung Tumor Initiation and Progression. Int J Mol Sci 2020; 21:ijms21082774. [PMID: 32316322 PMCID: PMC7215285 DOI: 10.3390/ijms21082774] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022] Open
Abstract
Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize hallmarks involved in lung cancer initiation and progression. For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors. Hallmarks involved in lung cancer progression include metastasis and drug tolerance and resistance. The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response.
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36
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DUAN L, YIN X, MENG H, FANG X, MIN J, WANG F. [Progress on epigenetic regulation of iron homeostasis]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020; 49:58-70. [PMID: 32621410 PMCID: PMC8800797 DOI: 10.3785/j.issn.1008-9292.2020.02.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.
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Hasham K, Ahmed N, Zeshan B. Circulating microRNAs in oncogenic viral infections: potential diagnostic biomarkers. SN APPLIED SCIENCES 2020. [DOI: 10.1007/s42452-020-2251-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Wang S, Luan J, Lv X. Inhibition of Endoplasmic Reticulum Stress Attenuated Ethanol-Induced Exosomal miR-122 and Acute Liver Injury in Mice. Alcohol Alcohol 2020; 54:465-471. [PMID: 31361816 DOI: 10.1093/alcalc/agz058] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 07/19/2019] [Indexed: 12/19/2022] Open
Abstract
AIMS In acute alcoholic liver injury, alcohol can directly or indirectly induce endoplasmic reticulum stress (ERS) to participate in liver injury, and it is found that the expression of serum exosomal miR-122 is significantly affected. Therefore, the present study investigated the effects of endoplasmic reticulum stress inhibition on the expression of serum exosomal miR-122 and acute liver injury. METHODS The acute alcoholic liver injury models were established by the intragastric administration of ethanol (5 g/kg) in ICR mice. Intervention group received 4-phenylbutyric acid (PBA, endoplasmic reticulum stress inhibitor; 75 mg/kg and 150 mg/kg, intraperitoneal) 12 and 24 hours before intragastric administration. Mice treated with saline were used as controls. RESULTS The ethanol treated mice exhibited significantly elevated hepatosomatic index (liver weight/body weight) and alanine aminotransferase (ALT), compared with those in the control group (P < 0.05). The ERS inhibitor 4-phenylbutyric acid protected against ethanol induced acute liver injury and hepatocyte necrosis, and PBA 150 mg/kg significantly attenuated ethanol induced hepatic ER stress-related proteins (GRP78, pIRE1α and pIF2α) (P < 0.05). Moreover, PBA 150 mg/kg markedly alleviated ethanol induced elevation of hepatic and serum exosomal miR-122 and pri-miR-122 (P < 0.05). CONCLUSIONS These findings suggest that ER stress inhibitor PBA attenuated ethanol induced acute liver injury and serum exosomal miR-122, and provides a potential therapy strategy for acute alcoholic liver injury.
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Affiliation(s)
- Sheng Wang
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Jiajie Luan
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
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Kim KH, Lee JI, Kim OH, Hong HE, Kwak BJ, Choi HJ, Ahn J, Lee TY, Lee SC, Kim SJ. Ameliorating liver fibrosis in an animal model using the secretome released from miR-122-transfected adipose-derived stem cells. World J Stem Cells 2019; 11:990-1004. [PMID: 31768225 PMCID: PMC6851007 DOI: 10.4252/wjsc.v11.i11.990] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 09/02/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome. AIM To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs). METHODS We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared. RESULTS MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome. CONCLUSION We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.
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Affiliation(s)
- Kee-Hwan Kim
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Jae Im Lee
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
| | - Ok-Hee Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Ha-Eun Hong
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Bong Jun Kwak
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Joseph Ahn
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Tae Yun Lee
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Sang Chul Lee
- Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 34943, South Korea
| | - Say-June Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea.
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Klieser E, Mayr C, Kiesslich T, Wissniowski T, Fazio PD, Neureiter D, Ocker M. The Crosstalk of miRNA and Oxidative Stress in the Liver: From Physiology to Pathology and Clinical Implications. Int J Mol Sci 2019; 20:5266. [PMID: 31652839 PMCID: PMC6862076 DOI: 10.3390/ijms20215266] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is the central metabolic organ of mammals. In humans, most diseases of the liver are primarily caused by an unhealthy lifestyle-high fat diet, drug and alcohol consumption- or due to infections and exposure to toxic substances like aflatoxin or other environmental factors. All these noxae cause changes in the metabolism of functional cells in the liver. In this literature review we focus on the changes at the miRNA level, the formation and impact of reactive oxygen species and the crosstalk between those factors. Both, miRNAs and oxidative stress are involved in the multifactorial development and progression of acute and chronic liver diseases, as well as in viral hepatitis and carcinogenesis, by influencing numerous signaling and metabolic pathways. Furthermore, expression patterns of miRNAs and antioxidants can be used for biomonitoring the course of disease and show potential to serve as possible therapeutic targets.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Till Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Matthias Ocker
- Translational Medicine Oncology, Bayer AG, 13353 Berlin, Germany.
- Department of Gastroenterology CBF, Charité University Medicine Berlin, 12200 Berlin, Germany.
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Huang PS, Wang CS, Yeh CT, Lin KH. Roles of Thyroid Hormone-Associated microRNAs Affecting Oxidative Stress in Human Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:E5220. [PMID: 31640265 PMCID: PMC6834183 DOI: 10.3390/ijms20205220] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress occurs as a result of imbalance between the generation of reactive oxygen species (ROS) and antioxidant genes in cells, causing damage to lipids, proteins, and DNA. Accumulating damage of cellular components can trigger various diseases, including metabolic syndrome and cancer. Over the past few years, the physiological significance of microRNAs (miRNA) in cancer has been a focus of comprehensive research. In view of the extensive level of miRNA interference in biological processes, the roles of miRNAs in oxidative stress and their relevance in physiological processes have recently become a subject of interest. In-depth research is underway to specifically address the direct or indirect relationships of oxidative stress-induced miRNAs in liver cancer and the potential involvement of the thyroid hormone in these processes. While studies on thyroid hormone in liver cancer are abundantly documented, no conclusive information on the potential relationships among thyroid hormone, specific miRNAs, and oxidative stress in liver cancer is available. In this review, we discuss the effects of thyroid hormone on oxidative stress-related miRNAs that potentially have a positive or negative impact on liver cancer. Additionally, supporting evidence from clinical and animal experiments is provided.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan.
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Chen WC, Wei CK, Lee JC. MicroRNA-let-7c suppresses hepatitis C virus replication by targeting Bach1 for induction of haem oxygenase-1 expression. J Viral Hepat 2019; 26:655-665. [PMID: 30706605 DOI: 10.1111/jvh.13072] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 12/17/2018] [Accepted: 01/05/2019] [Indexed: 12/26/2022]
Abstract
MicroRNAs are small noncoding RNAs that are central factors between hepatitis C virus (HCV) and host cellular factors for viral replication and liver disease progression, including liver fibrosis, cirrhosis and hepatocellular carcinoma. In the present study, we found that overexpressing miR-let-7c markedly reduced HCV replication because it induced haem oxygenase-1 (HO-1) expression by targeting HO-1 transcriptional repressor Bach1, ultimately leading to stimulating an antiviral interferon response and blockade of HCV viral protease activity. In contrast, the antiviral actions of miR-let-7c were attenuated by miR-let-7c inhibitor treatment, exogenously expressing Bach1 or suppressing HO-1 activity and expression. A proposed model indicates a key role for miR-let-7c targeting Bach1 to transactivate HO-1-mediated antiviral actions against HCV. miR-let-7c may serve as an attractive target for antiviral development.
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Affiliation(s)
- Wei-Chun Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Ku Wei
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jin-Ching Lee
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.,PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
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Guo Z, Sui L, Qi J, Sun Q, Xu Y, Zou N, Xie Y, Kong Y. miR-196b inhibits cell migration and invasion through targeting MAP3K1 in hydatidiform mole. Biomed Pharmacother 2019; 113:108760. [PMID: 30889489 DOI: 10.1016/j.biopha.2019.108760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 03/01/2019] [Accepted: 03/05/2019] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that are closely associated with carcinogenesis. Accumulating data indicate that miR-196b participates in the development of various types of cancers. However, the role of miR-196b in the formation of hydatidiform mole (HM) is still unclear. Our previous studies have demonstrated that miR-196b levels were decreased in JAR and BeWo cells and in HM tissue samples, as demonstrated by RT-PCR analysis. Furthermore, we discovered that overexpression of miR-196b in JAR and BeWo cells inhibited cellular proliferation, migration and invasion, as shown by Cell counting kit-8 (CCK-8) and transwell assays, respectively. Subsequently, we explored the interaction of miR-196b with its target gene in human choriocarcinoma cell lines. MAP3K1 is a target gene predicted by bioinformatic analysis that was previously shown to exhibit reduced expression levels following treatment with miR-196b in JAR and BeWo cells. We demonstrated that MAP3K1 was a direct target of miR-196b using the dual-luciferase reporter assay in Hela cells. In summary, the present study demonstrated that miR-196b suppressed proliferation, migration and invasion of human choriocarcinoma cells by inhibiting its transcriptional target MAP3K1. miR-196b and MAP3K1 may be considered potential targets for the clinical treatment of HM.
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Affiliation(s)
- Zhenzhen Guo
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Linlin Sui
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Jia Qi
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Qiannan Sun
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Yuefei Xu
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Na Zou
- Department of Pathology, Dalian Municipal Women and Children's Medical Center, Dalian 116044, Liaoning, China.
| | - Yunpeng Xie
- Dalian Med Univ, First Affiliated Hosp, Inst Cardiovasc Dis, Dept Cardiol, Dalian 116044116021, Liaoning, China.
| | - Ying Kong
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
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Watson SF, Knol LI, Witteveldt J, Macias S. Crosstalk Between Mammalian Antiviral Pathways. Noncoding RNA 2019; 5:E29. [PMID: 30909383 PMCID: PMC6468734 DOI: 10.3390/ncrna5010029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/19/2019] [Accepted: 03/20/2019] [Indexed: 12/15/2022] Open
Abstract
As part of their innate immune response against viral infections, mammals activate the expression of type I interferons to prevent viral replication and dissemination. An antiviral RNAi-based response can be also activated in mammals, suggesting that several mechanisms can co-occur in the same cell and that these pathways must interact to enable the best antiviral response. Here, we will review how the classical type I interferon response and the recently described antiviral RNAi pathways interact in mammalian cells. Specifically, we will uncover how the small RNA biogenesis pathway, composed by the nucleases Drosha and Dicer can act as direct antiviral factors, and how the type-I interferon response regulates the function of these. We will also describe how the factors involved in small RNA biogenesis and specific small RNAs impact the activation of the type I interferon response and antiviral activity. With this, we aim to expose the complex and intricate network of interactions between the different antiviral pathways in mammals.
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Affiliation(s)
- Samir F Watson
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
| | - Lisanne I Knol
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
| | - Jeroen Witteveldt
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
| | - Sara Macias
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
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45
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Musaddaq G, Shahzad N, Ashraf MA, Arshad MI. Circulating liver-specific microRNAs as noninvasive diagnostic biomarkers of hepatic diseases in human. Biomarkers 2019; 24:103-109. [PMID: 30252499 DOI: 10.1080/1354750x.2018.1528631] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 09/22/2018] [Indexed: 02/08/2023]
Abstract
CONTEXT Hepatitis is an endemic disease worldwide leading to chronic and debilitating cancers. The viral agents and hepatotoxic substances lead to damage of hepatocytes and release of damage associated molecules in circulation. The lack of timely and rapid diagnosis of hepatitis results in chronic disease. OBJECTIVE The present review aimed to describe regulation, release and functions of microRNAs (miR) during human liver pathology and insights into their promising use as noninvasive biomarkers of hepatitis. METHODS Comprehensive data were collected from PubMed, ScienceDirect and the Web of Science databases utilizing the keywords "biomarkers", "microRNAs" and "hepatic diseases". RESULTS The miRs are readily released in the body fluids and blood during HBV/HCV associated hepatitis as well as metabolic, alcoholic, drug induced and autoimmune hepatitis. The liver-specific microRNAs including miR-122, miR-130, miR-183, miR-196, miR-209 and miR-96 are potential indicators of liver injury (mainly via apoptosis, necrosis and necroptosis) or hepatitis with their varied expression during acute/fulminant, chronic, liver fibrosis/cirrhosis and hepato-cellular carcinoma. CONCLUSIONS The liver-specific miRs can be used as rapid and noninvasive biomarkers of hepatitis to discern different stages of hepatitis. Blocking or stimulating pathways associated with miR regulation in liver could unveil novel therapeutic strategies in the management of liver diseases. Clinical significance Liver specific microRNAs interact with cellular proteins and signaling molecules to regulate the expression of various genes controlling biological processes. The circulatory level of liver specific microRNAs is indicator of severity of HBV and HCV infections as well as prognostic and therapeutic candidates. The expression of liver specific microRNAs is strongly associated with infectious, drug-induced, hepatotoxic, nonalcoholic steatohepatitis and nonalcoholic fatty liver diseases.
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Affiliation(s)
- Ghulam Musaddaq
- a Institute of Microbiology, University of Agriculture , Faisalabad , Pakistan
| | - Naveed Shahzad
- b School of Biological Sciences (SBS), University of the Punjab , Lahore , Pakistan
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Fuschi P, Maimone B, Gaetano C, Martelli F. Noncoding RNAs in the Vascular System Response to Oxidative Stress. Antioxid Redox Signal 2019; 30:992-1010. [PMID: 28683564 DOI: 10.1089/ars.2017.7229] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Redox homeostasis plays a pivotal role in vascular cell function and its imbalance has a causal role in a variety of vascular diseases. Accordingly, the response of mammalian cells to redox cues requires precise transcriptional and post-transcriptional modulation of gene expression patterns. Recent Advances: Mounting evidence shows that nonprotein-coding RNAs (ncRNAs) are important for the functional regulation of most, if not all, cellular processes and tissues. Not surprisingly, a prominent role of ncRNAs has been identified also in the vascular system response to oxidative stress. CRITICAL ISSUES The highly heterogeneous family of ncRNAs has been divided into several groups. In this article we focus on two classes of regulatory ncRNAs: microRNAs and long ncRNAs (lncRNAs). Although knowledge in many circumstances, and especially for lncRNAs, is still fragmentary, ncRNAs are clinically interesting because of their diagnostic and therapeutic potential. We outline ncRNAs that are regulated by oxidative stress as well as ncRNAs that modulate reactive oxygen species production and scavenging. More importantly, we describe the role of these ncRNAs in vascular physiopathology and specifically in disease conditions wherein oxidative stress plays a crucial role, such as hypoxia and ischemia, ischemia reperfusion, inflammation, diabetes mellitus, and atherosclerosis. FUTURE DIRECTIONS The therapeutic potential of ncRNAs in vascular diseases and in redox homeostasis is discussed.
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Affiliation(s)
- Paola Fuschi
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Biagina Maimone
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Carlo Gaetano
- 2 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany
| | - Fabio Martelli
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
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Pockar S, Globocnik Petrovic M, Peterlin B, Vidovic Valentincic N. MiRNA as biomarker for uveitis - A systematic review of the literature. Gene 2019; 696:162-175. [PMID: 30763668 DOI: 10.1016/j.gene.2019.02.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/13/2019] [Accepted: 02/01/2019] [Indexed: 12/20/2022]
Abstract
AIM A systematic review of miRNA profiling studies in uveitis. METHODS Literature search strategy - Pubmed central central database, using miRNA/microRNA and intraocular inflammation/uveitis as keywords. RESULTS We found twenty publications regarding the experimental and clinical use of miRNA in uveitis, published between 2011 and 2018. CONCLUSION The publications regarding the role of miRNA in uveitis are very scarce, but provide some valuable information about the potential new mechanisms in uveitis. Some of the identified miRNAs in different uveitis entities could serve as a biomarker of intraocular inflammation. Possible candidate miRNAs could be let-7e, miRNA-1, miR-9-3, miR-20a-5p, miR-23a, mir-29a-3p, miR-140-5p, miR-143, miR-146a and miR-146a-5p, miR-155, miR-182 and miR-182-5p, miR-196a2, miR-205, miR-223-3p, miR-301a. MiR-146a, miR-146a-5p, miR-155, miR-182, miR-223-3p, have been found to be possibly associated with uveitis disease in both, human and animal species.
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Affiliation(s)
- Sasa Pockar
- Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Mojca Globocnik Petrovic
- Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Borut Peterlin
- Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Natasa Vidovic Valentincic
- Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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Sodroski C, Lowey B, Hertz L, Jake Liang T, Li Q. MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors. Virol Sin 2018; 34:197-210. [PMID: 30456659 PMCID: PMC6513812 DOI: 10.1007/s12250-018-0055-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 09/13/2018] [Indexed: 12/12/2022] Open
Abstract
Cellular microRNAs (miRNAs) have been shown to modulate HCV infection via directly acting on the viral genome or indirectly through targeting the virus-associated host factors. Recently we generated a comprehensive map of HCV–miRNA interactions through genome-wide miRNA functional screens and transcriptomics analyses. Many previously unappreciated cellular miRNAs were identified to be involved in HCV infection, including miR-135a, a human cancer-related miRNA. In the present study, we investigated the role of miR-135a in regulating HCV life cycle and showed that it preferentially enhances viral genome replication. Bioinformatics-based integrative analyses and subsequent functional assays revealed three antiviral host factors, including receptor interacting serine/threonine kinase 2 (RIPK2), myeloid differentiation primary response 88 (MYD88), and C-X-C motif chemokine ligand 12 (CXCL12), as bona fide targets of miR-135a. These genes have been shown to inhibit HCV infection at the RNA replication stage. Our data demonstrated that repression of key host restriction factors mediated the proviral effect of miR-135a on HCV propagation. In addition, miR-135a hepatic abundance is upregulated by HCV infection in both cultured hepatocytes and human liver, likely mediating a more favorable environment for viral replication and possibly contributing to HCV-induced liver malignancy. These results provide novel insights into HCV–host interactions and unveil molecular pathways linking miRNA biology to HCV pathogenesis.
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Affiliation(s)
- Catherine Sodroski
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, USA
| | - Brianna Lowey
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, USA
| | - Laura Hertz
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, USA
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, USA.
| | - Qisheng Li
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, USA.
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Zhan CY, Chen D, Luo JL, Shi YH, Zhang YP. Protective role of down-regulated microRNA-31 on intestinal barrier dysfunction through inhibition of NF-κB/HIF-1α pathway by binding to HMOX1 in rats with sepsis. Mol Med 2018; 24:55. [PMID: 30340459 PMCID: PMC6194748 DOI: 10.1186/s10020-018-0053-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023] Open
Abstract
Background Intestinal barrier dysfunction is a significant clinical problem, commonly developing in a variety of acute or chronic pathological conditions. Herein, we evaluate the effect of microRNA-31 (miR-31) on intestinal barrier dysfunction through NF-κB/HIF-1α pathway by targeting HMOX1 in rats with sepsis. Methods Male Sprague-Dawley rats were collected and divided into the sham group, and the cecum ligation and perforation group which was subdivided after CACO-2 cell transfection of different mimic, inhibitor, or siRNA. Levels of serum D-lactic acid, diamine oxidase and fluorescence isothiocyanate dextran, FITC-DX concentration, and bacterial translocation were detected. Superoxidedismutase (SOD) activity and malondialdehyde (MDA) content were evaluated using the colorimetric method and an automatic microplate reader, respectively. Additionally, the levels of tumor necrosis factor, interleukin (IL)-6, and IL-10 were tested using enzyme-linked immunosorbent assay. The expression of miR-31, HMOX1, NF-κB, HIF-1α, IκB, ZO-1 and Occludin were assessed by reverse transcription quantitative polymerase chain reaction and Western blot analysis. Results Inhibition of miR-31 decreased intestinal mucosal permeability and intestinal barrier function. The increased levels of miR-31 could cause oxidative damage and affect the expression of inflammatory factors in intestinal tissue of rats. HMOX1 was confirmed as a target gene of miR-31. MiR-31 affected intestinal mucosal permeability and intestinal barrier function, as well as oxidative damage and inflammation level by regulating HMOX1. Down-regulation of miR-31 inhibited NF-κB/HIF-1α pathway related genes by regulating HMOX1 expression. Furthermore, inhibition of miR-31 increased survival rates of rats. Conclusion Overall, the current study found that inhibition of miR-31 protects against intestinal barrier dysfunction through suppression of the NF-κB/HIF-1α pathway by targeting HMOX1 in rats with sepsis.
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Affiliation(s)
- Cheng-Ye Zhan
- Intensive Care Unit, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Road, Qiaokou District, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Di Chen
- Intensive Care Unit, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Road, Qiaokou District, Wuhan, 430030, Hubei Province, People's Republic of China.
| | - Jin-Long Luo
- Intensive Care Unit, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Road, Qiaokou District, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Ying-Hua Shi
- Intensive Care Unit, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Road, Qiaokou District, Wuhan, 430030, Hubei Province, People's Republic of China
| | - You-Ping Zhang
- Intensive Care Unit, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Road, Qiaokou District, Wuhan, 430030, Hubei Province, People's Republic of China
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