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Yun HW, Kim M, Shin DI, Kwon HJ, Park IS, Park DY, Min BH. Matrix-bound nanovesicles recapitulate tissue-specific angiogenic properties of parent extracellular matrix with distinct miRNA profiles. BIOMATERIALS ADVANCES 2025; 175:214338. [PMID: 40378642 DOI: 10.1016/j.bioadv.2025.214338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/23/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025]
Abstract
Decellularized extracellular matrix (dECM) exhibits tissue-specific pro- or anti-angiogenic effects. Previous studies have demonstrated that matrix-bound nanovesicles (MBVs) act as key bioactive components of dECM, replicating various biological functions such as anti-inflammatory and immunomodulatory effects. Building on this evidence, this study hypothesized that MBVs derived from cartilage and small intestinal submucosa (SIS) modulate angiogenesis through the selective packaging of miRNAs. Cartilage-derived MBVs (cMBVs) and SIS-derived MBVs (sMBVs) were isolated, characterized, and analyzed for their miRNA profiles using RNA sequencing and RT-qPCR validation. The interactions between MBVs and human umbilical vein endothelial cells (HUVECs) were assessed by examining proliferation, adhesion, migration, and tube formation in comparison to the parent ECM. Angiogenic modulation was further evaluated using a mouse Matrigel plug assay and a rabbit corneal neovascularization (NV) model. Our results demonstrated that anti-angiogenic miRNAs (e.g., miR-140-3p, miR-455-5p, and miR-148a-5p) were predominant in cMBVs, suppressing endothelial cell activity and angiogenesis, while pro-angiogenic miRNAs (e.g., miR-143-3p, miR-181a, and miR-21-5p) were prevalent in sMBVs, enhancing vessel formation. In vivo, cMBVs significantly inhibited vascular invasion and neovessel formation, whereas sMBVs promoted angiogenesis in both models. These findings confirm that MBVs reflect the tissue-specific angiogenic regulatory functions of their parent ECM, and highlight their potential as therapeutic tools for targeted modulation of angiogenesis in regenerative medicine and tissue engineering.
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Affiliation(s)
- Hee-Woong Yun
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea; Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - Mijin Kim
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Dong Il Shin
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Hyeon Jae Kwon
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - In-Su Park
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - Do Young Park
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea; Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - Byoung-Hyun Min
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea; Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
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Eirin A, Siddiqi S, Hughes AG, Jiang Y, Zhu XY, Kazeminia S, Lu B, Xing L, Lu B, Tang H, Xue A, Lerman A, Textor SC, Lerman LO. Renovascular Disease and Mitochondrial Dysfunction in Human Mesenchymal Stem Cells. J Am Soc Nephrol 2024; 35:1507-1519. [PMID: 39012704 PMCID: PMC11543019 DOI: 10.1681/asn.0000000000000440] [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: 08/31/2023] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
Key Points Renovascular disease impairs the capacity of human adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic murine kidneys. miR-378h modulated the capacity of renovascular disease adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic kidneys in vivo . Background Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue–derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. Methods MSCs were harvested from subcutaneous abdominal fat of patients with renovascular disease and healthy volunteers (n =3 each), characterized and subsequently injected (5×105/200 μ l) into mice 2 weeks after renal artery stenosis or sham surgery (n =6/group). Two weeks later, mice underwent imaging and tissue studies. MSCs from healthy volunteers and in those with renovascular disease were also characterized by mRNA/microRNA (miRNA) sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in vitro before and after miRNA modulation and in vivo in additional renal artery stenosis mice administered with MSCs from renovascular disease pretreated with miR-378h mimic (n =5) or inhibitor (n =4). Results MSCs engrafted in stenotic mouse kidneys. Healthy volunteer MSCs (but not renovascular disease MSCs) decreased BP, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease MSCs versus healthy volunteer MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. Conclusions Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_08_21_ASN0000000000000440.mp3
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Affiliation(s)
- Alfonso Eirin
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
| | - Sarosh Siddiqi
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Autumn G. Hughes
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Yamei Jiang
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Sara Kazeminia
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Bo Lu
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Li Xing
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Brandon Lu
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Hui Tang
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Ailing Xue
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
| | - Stephen C. Textor
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
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Dussault S, Desjarlais M, Raguema N, Boilard E, Chemtob S, Rivard A. Selective Enrichment of Angiomirs in Extracellular Vesicles Released from Ischemic Skeletal Muscles: Potential Role in Angiogenesis and Neovascularization. Cells 2024; 13:1243. [PMID: 39120274 PMCID: PMC11312235 DOI: 10.3390/cells13151243] [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: 05/24/2024] [Revised: 07/17/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
MicroRNAs (miRs) regulate physiological and pathological processes, including ischemia-induced angiogenesis and neovascularization. They can be transferred between cells by extracellular vesicles (EVs). However, the specific miRs that are packaged in EVs released from skeletal muscles, and how this process is modulated by ischemia, remain to be determined. We used a mouse model of hindlimb ischemia and next generation sequencing (NGS) to perform a complete profiling of miR expression and determine the effect of ischemia in skeletal muscles, and in EVs of different sizes (microvesicles (MVs) and exosomes) released from these muscles. Ischemia significantly modulated miR expression in whole muscles and EVs, increasing the levels of several miRs that can have pro-angiogenic effects (angiomiRs). We found that specific angiomiRs are selectively enriched in MVs and/or exosomes in response to ischemia. In silico approaches indicate that these miRs modulate pathways that play key roles in angiogenesis and neovascularization, including HIF1/VEGF signaling, regulation of actin cytoskeleton and focal adhesion, NOTCH, PI3K/AKT, RAS/MAPK, JAK/STAT, TGFb/SMAD signaling and the NO/cGMP/PKG pathway. Thus, we show for the first time that angiomiRs are selectively enriched in MVs and exosomes released from ischemic muscles. These angiomiRs could be targeted in order to improve the angiogenic function of EVs for potential novel therapeutic applications in patients with severe ischemic vascular diseases.
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Affiliation(s)
- Sylvie Dussault
- Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM) Research Center, Montréal, QC H2X 0A9, Canada; (S.D.); (N.R.)
| | - Michel Desjarlais
- Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC H3T 1C5, Canada; (M.D.); (S.C.)
| | - Nozha Raguema
- Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM) Research Center, Montréal, QC H2X 0A9, Canada; (S.D.); (N.R.)
| | - Eric Boilard
- Department of Infectious Diseases and Immunity, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec City, QC G1V 0A6, Canada;
| | - Sylvain Chemtob
- Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC H3T 1C5, Canada; (M.D.); (S.C.)
| | - Alain Rivard
- Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM) Research Center, Montréal, QC H2X 0A9, Canada; (S.D.); (N.R.)
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Wu M, Wang X, Shuai J, Deng L, Lu H, Zhou Y, Wu M. Identification of key miRNAs in unilateral mastication-induced disruption of cartilage homeostasis. Oral Dis 2024; 30:551-561. [PMID: 36648372 DOI: 10.1111/odi.14504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 11/12/2022] [Accepted: 01/09/2023] [Indexed: 01/18/2023]
Abstract
OBJECTIVE The present study identified potentially pivotal miRNAs contributing to chondrogenic differentiation in temporomandibular joint suffering abnormal stress. MATERIALS AND METHODS Sprague-Dawley rats were randomly divided into control and experimental unilateral mastication (EUM) group. Bone micro-structure parameters was detected by micro-CT, and FGF-1 and MMP-1 expression was examined by immunohistochemistry. Differentially expressed miRNAs of bilateral condyle cartilage were screened via miRNA microarray at 4- and 8-week EUM, then further verified using quantitative reverse-transcription PCR. Over-expression of five differentially expressed miRNAs in chondrocytes was triggered by transfecting miRNA mimics. The expression of MMP-13, Col-II, OPN, and Runx2 was verified by western blotting. RESULTS Expressions of FGF-1 and MMP-1 in right condyles gradually increased from 2 to 6 weeks after EUM. A total of 20 differentially expressed miRNAs were regulated by EUM, which related to cell proliferation, invasion, and osteoblast differentiation pathways. The over-expression of miR-148a-3p and miR-1-3p led to down-regulation of Col-II, while MMP-13 and Runx2 were up-regulated by induction of hypotrophic differentiation or IL-1β stimulation. These findings suggested that miR-148a-3p and miR-1-3p promote chondrogenic differentiation. CONCLUSIONS Several pivotal miRNAs were found to be related to chondrogenic differentiation, which provides novel insight into pathogenic mechanisms of cartilage homeostasis.
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Affiliation(s)
- Mengjie Wu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Xuebin Wang
- College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Jing Shuai
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Liquan Deng
- School of Stomatology, Zhejiang Chinese Medical University, Hangzhou, China
| | - Haiping Lu
- School of Stomatology, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yiqun Zhou
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Mengrui Wu
- College of Life Sciences, Zhejiang University, Hangzhou, China
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Pengjie Y, Rong J, Pengfei N. miR-378a-5p exerts tumor-suppressive effects on esophageal squamous cell carcinoma after neoadjuvant immunotherapy by downregulating APOC1/CEP55. Sci Rep 2024; 14:305. [PMID: 38172247 PMCID: PMC10764758 DOI: 10.1038/s41598-023-50938-z] [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: 06/10/2023] [Accepted: 12/28/2023] [Indexed: 01/05/2024] Open
Abstract
Genetic assessment of tumors following neoadjuvant immunotherapy helps identifying targets that mediate anti-tumor immunity. In this study, we explored dysregulated RNAs in esophageal squamous cell carcinoma samples after neoadjuvant immunotherapy using deep sequencing and high-throughput screening. We identified 584 differentially expressed messenger RNAs (mRNAs), 67 differentially expressed microRNAs (miRNAs), and 1,047 differentially expressed long non-coding RNAs (lncRNAs) using differential expression analysis. Competing endogenous RNAs closely related to esophageal squamous cell carcinoma were selected via a combined Pearson's correlation test and weighted correlation network analysis. After validation using survival analysis and dry-lab and wet-lab-based studies, we identified the I-miR-378-5p-APOC1/CEP55 as a critical pathway for esophageal squamous cell carcinoma progression after neoadjuvant immunotherapy. Tumor immune infiltration analysis showed that APOC1 and CEP55 expression is associated with immune regulatory pathways and the function of multiple infiltrating immune cells. We investigated the mechanism of esophageal squamous carcinoma progression after neoadjuvant immunotherapy from the perspective of the mRNA-miRNA-lncRNA network. Furthermore, we identified accurate novel therapeutic targets and prognostic biomarkers, introduced novel perspectives to immunotherapy studies, and laid the foundation for the clinical treatment of patients with esophageal squamous carcinoma.
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Affiliation(s)
- Yang Pengjie
- Inner Mongolia Medical University, Jinshan Development Zone, Hohhot, 010110, Inner Mongolia Autonomous Region, China
- Thoracic Surgery Department, Peking University Cancer Hospital Inner Mongolia Hospital (Cancer Hospital Affiliated to Inner Mongolia Medical University), Hohhot, 010110, Inner Mongolia Autonomous Region, China
| | - Jia Rong
- Inner Mongolia Medical University, Jinshan Development Zone, Hohhot, 010110, Inner Mongolia Autonomous Region, China
| | - Ning Pengfei
- Inner Mongolia Medical University, Jinshan Development Zone, Hohhot, 010110, Inner Mongolia Autonomous Region, China.
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Pultar M, Oesterreicher J, Hartmann J, Weigl M, Diendorfer A, Schimek K, Schädl B, Heuser T, Brandstetter M, Grillari J, Sykacek P, Hackl M, Holnthoner W. Analysis of extracellular vesicle microRNA profiles reveals distinct blood and lymphatic endothelial cell origins. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e134. [PMID: 38938681 PMCID: PMC11080916 DOI: 10.1002/jex2.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 11/22/2023] [Accepted: 12/22/2023] [Indexed: 06/29/2024]
Abstract
Extracellular vesicles (EVs) are crucial mediators of cell-to-cell communication in physiological and pathological conditions. Specifically, EVs released from the vasculature into blood were found to be quantitatively and qualitatively different in diseases compared to healthy states. However, our understanding of EVs derived from the lymphatic system is still scarce. In this study, we compared the mRNA and microRNA (miRNA) expression in blood vascular (BEC) and lymphatic (LEC) endothelial cells. After characterization of the EVs by fluorescence-triggered flow cytometry, nanoparticle tracking analysis and cryo-transmission electron microscopy (cryo-TEM) we utilized small RNA-sequencing to characterize miRNA signatures in the EVs and identify cell-type specific miRNAs in BEC and LEC. We found miRNAs specifically enriched in BEC and LEC on the cellular as well as the extracellular vesicle level. Our data provide a solid basis for further functional in vitro and in vivo studies addressing the role of EVs in the blood and lymphatic vasculature.
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Affiliation(s)
- Marianne Pultar
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- TAmiRNA GmbHViennaAustria
| | - Johannes Oesterreicher
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | | | - Moritz Weigl
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- TAmiRNA GmbHViennaAustria
| | | | - Katharina Schimek
- Technische Universität Berlin, Medical BiotechnologyBerlinGermany
- TissUse GmbHBerlinGermany
| | - Barbara Schädl
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- University Clinic of DentistryMedical University of ViennaViennaAustria
| | - Thomas Heuser
- Vienna Biocenter Core Facilities GmbH, EM FacilityViennaAustria
| | | | - Johannes Grillari
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- Department of Biotechnology, Institute of Molecular BiotechnologyUniversity of Natural Resources and Life SciencesViennaAustria
| | - Peter Sykacek
- Department of Biotechnology, Institute of Computational BiologyUniversity of Natural Resources and Life SciencesViennaAustria
| | | | - Wolfgang Holnthoner
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
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Magri F, Napoli L, Ripolone M, Ciscato P, Moggio M, Corti S, Comi GP, Sciacco M, Zanotti S. The Profiling of 179 miRNA Expression in Serum from Limb Girdle Muscular Dystrophy Patients and Healthy Controls. Int J Mol Sci 2023; 24:17402. [PMID: 38139231 PMCID: PMC10743601 DOI: 10.3390/ijms242417402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Limb girdle muscular dystrophies (LGMDs) are a group of genetically inherited neuromuscular diseases with a very variable clinical presentation and overlapping traits. Over the last few years there has been an increasing interest in the use of non-invasive circulating biomarkers to monitor disease progression and to evaluate the efficacy of therapeutic approaches. Our aim was to identify the miRNA signature with potential value for LGMD patient screening and stratification. Using miRCURY LNA miRNA qPCR Serum/Plasma Panel, we analyzed 179 miRNAs from 16 patients, divided in four pools based on their genetic diagnosis, and from healthy controls. The miRNAs analysis showed a total of 107 dysregulated miRNAs in LGMD patients when compared to the healthy controls. After filtering via skeletal tissue expression and gene/pathways target analysis, the number of dysregulated miRNAs drastically reduced. Six selected miRNAs-let-7f-5p (in LGMDR1), miR-20a-5p (in LGMDR2), miR-130b-5p, miR-378a-5p (both in LGMDR3), miR-376c-3p and miR-382-5p (both in LGMDR4)-whose expression was significantly lower compared to controls in the different LGMD pools, were further investigated. The bioinformatic analysis of the target genes in each selected miRNA revealed ECM-receptor interaction and TGF-beta signaling as the most involved pathways. The correlation analysis showed a good correlation of let-7f-5p with fibrosis and with the cross sectional area of type I and type II fibers, while miR-130b-5p showed a good correlation with the age of onset of the disease. The receiver operating characteristic curves showed how single miRNAs were able to discriminate a specific group of LGMD patients and how the combination of six miRNAs was able to discriminate LGMD patients from controls.
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Affiliation(s)
- Francesca Magri
- Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Laura Napoli
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
| | - Michela Ripolone
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
| | - Patrizia Ciscato
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
| | - Maurizio Moggio
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
| | - Stefania Corti
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
- Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy
| | - Giacomo Pietro Comi
- Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy
| | - Monica Sciacco
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
| | - Simona Zanotti
- Neuromuscular and Rare Disease Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (M.M.)
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Yamaguchi A, Maeshige N, Noguchi H, Yan J, Ma X, Uemura M, Su D, Kondo H, Sarosiek K, Fujino H. Pulsed ultrasound promotes secretion of anti-inflammatory extracellular vesicles from skeletal myotubes via elevation of intracellular calcium level. eLife 2023; 12:RP89512. [PMID: 38054662 PMCID: PMC10699803 DOI: 10.7554/elife.89512] [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] [Indexed: 12/07/2023] Open
Abstract
The regulation of inflammatory responses is an important intervention in biological function and macrophages play an essential role during inflammation. Skeletal muscle is the largest organ in the human body and releases various factors which mediate anti-inflammatory/immune modulatory effects. Recently, the roles of extracellular vesicles (EVs) from a large variety of cells are reported. In particular, EVs released from skeletal muscle are attracting attention due to their therapeutic effects on dysfunctional organs and tissues. Also, ultrasound (US) promotes release of EVs from skeletal muscle. In this study, we investigated the output parameters and mechanisms of US-induced EV release enhancement and the potential of US-treated skeletal muscle-derived EVs in the regulation of inflammatory responses in macrophages. High-intensity US (3.0 W/cm2) irradiation increased EV secretion from C2C12 murine muscle cells via elevating intracellular Ca2+ level without negative effects. Moreover, US-induced EVs suppressed expression levels of pro-inflammatory factors in macrophages. miRNA sequencing analysis revealed that miR-206-3p and miR-378a-3p were especially abundant in skeletal myotube-derived EVs. In this study we demonstrated that high-intensity US promotes the release of anti-inflammatory EVs from skeletal myotubes and exert anti-inflammatory effects on macrophages.
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Affiliation(s)
- Atomu Yamaguchi
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Noriaki Maeshige
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Hikari Noguchi
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Jiawei Yan
- School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China
| | - Xiaoqi Ma
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Mikiko Uemura
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Hiroyo Kondo
- Department of Health and Nutrition , Shubun University, Ichinomiya, Japan
| | - Kristopher Sarosiek
- John B. Little Center for Radiation Sciences, Harvard University T.H. Chan School of Public Health, Boston, United States
| | - Hidemi Fujino
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
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9
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Florczyk-Soluch U, Polak K, Sabo R, Martyniak A, Stępniewski J, Dulak J. Compromised diabetic heart function is not affected by miR-378a upregulation upon hyperglycemia. Pharmacol Rep 2023; 75:1556-1570. [PMID: 37851320 PMCID: PMC10661816 DOI: 10.1007/s43440-023-00535-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 10/19/2023]
Abstract
BACKGROUND Cardiac-abundant microRNA-378a (miR-378a) is associated with postnatal repression of insulin-like growth factor 1 receptor (IGF-1R) controlling physiological hypertrophy and survival pathways. IGF-1/IGF-1R axis has been proposed as a therapeutic candidate against the pathophysiological progress of diabetic cardiomyopathy (DCM). We ask whether hyperglycemia-driven changes in miR-378a expression could mediate DCM progression. METHODS Diabetes mellitus was induced by streptozotocin (STZ) (55 mg/kg i.p. for 5 days) in male C57BL/6 wild type (miR-378a+/+) and miR-378a knockout (miR-378a-/-) mice. As a parallel human model, we harnessed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM miR378a+/+ vs. hiPSC-CM miR378a-/-) subjected to high glucose (HG) treatment. RESULTS We reported miR-378a upregulation in cardiac diabetic milieu arising upon STZ administration to wild-type mice and in HG-treated hiPSC-CMs. Pro-hypertrophic IGF-1R/ERK1/2 pathway and hypertrophic marker expression were activated in miR-378a deficiency and upon STZ/HG treatment of miR-378a+/+ specimens in vivo and in vitro suggesting miR-378a-independent hyperglycemia-promoted hypertrophy. A synergistic upregulation of IGF-1R signaling in diabetic conditions was detected in miR-378a-/- hiPSC-CMs, but not in miR-378a-/- hearts that showed attenuation of this pathway, pointing to the involvement of compensatory mechanisms in the absence of miR-378a. Although STZ administration did not cause pro-inflammatory or pro-fibrotic effects that were detected in miR-378a-/- mice, the compromised diabetic heart function observed in vivo by high-resolution ultrasound imaging upon STZ treatment was not affected by miR-378a presence. CONCLUSIONS Overall, data underline the role of miR-378a in maintaining basal cardiac structural integrity while pointing to miR-378a-independent hyperglycemia-driven cardiac hypertrophy and associated dysfunction.
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Affiliation(s)
- Urszula Florczyk-Soluch
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
| | - Katarzyna Polak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Reece Sabo
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Alicja Martyniak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Jacek Stępniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
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10
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Jusic A, Junuzovic I, Hujdurovic A, Zhang L, Vausort M, Devaux Y. A Machine Learning Model Based on microRNAs for the Diagnosis of Essential Hypertension. Noncoding RNA 2023; 9:64. [PMID: 37987360 PMCID: PMC10660456 DOI: 10.3390/ncrna9060064] [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: 09/14/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/22/2023] Open
Abstract
INTRODUCTION Hypertension is a major and modifiable risk factor for cardiovascular diseases. Essential, primary, or idiopathic hypertension accounts for 90-95% of all cases. Identifying novel biomarkers specific to essential hypertension may help in understanding pathophysiological pathways and developing personalized treatments. We tested whether the integration of circulating microRNAs (miRNAs) and clinical risk factors via machine learning modeling may provide useful information and novel tools for essential hypertension diagnosis and management. MATERIALS AND METHODS In total, 174 participants were enrolled in the present observational case-control study, among which, there were 89 patients with essential hypertension and 85 controls. A discovery phase was conducted using small RNA sequencing in whole blood samples obtained from age- and sex-matched hypertension patients (n = 30) and controls (n = 30). A validation phase using RT-qPCR involved the remaining 114 participants. For machine learning, 170 participants with complete data were used to generate and evaluate the classification model. RESULTS Small RNA sequencing identified seven miRNAs downregulated in hypertensive patients as compared with controls in the discovery group, of which six were confirmed with RT-qPCR. In the validation group, miR-210-3p/361-3p/362-5p/378a-5p/501-5p were also downregulated in hypertensive patients. A machine learning support vector machine (SVM) model including clinical risk factors (sex, BMI, alcohol use, current smoker, and hypertension family history), miR-361-3p, and miR-501-5p was able to classify hypertension patients in a test dataset with an AUC of 0.90, a balanced accuracy of 0.87, a sensitivity of 0.83, and a specificity of 0.91. While five miRNAs exhibited substantial downregulation in hypertension patients, only miR-361-3p and miR-501-5p, alongside clinical risk factors, were consistently chosen in at least eight out of ten sub-training sets within the SVM model. CONCLUSIONS This study highlights the potential significance of miRNA-based biomarkers in deepening our understanding of hypertension's pathophysiology and in personalizing treatment strategies. The strong performance of the SVM model highlights its potential as a valuable asset for diagnosing and managing essential hypertension. The model remains to be extensively validated in independent patient cohorts before evaluating its added value in a clinical setting.
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Affiliation(s)
- Amela Jusic
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
- HAYA Therapeutics SA, Route De La Corniche 6, SuperLab Suisse—Batiment Serine, 1066 Epalinges, Switzerland
| | - Inela Junuzovic
- Department of Internal Medicine, Medical Center “Plava Medical Group”, Mihajla i Živka Crnogorčevića do br. 10, 75000 Tuzla, Bosnia and Herzegovina
| | - Ahmed Hujdurovic
- Department of Internal Medicine, Medical Center “Plava Medical Group”, Mihajla i Živka Crnogorčevića do br. 10, 75000 Tuzla, Bosnia and Herzegovina
| | - Lu Zhang
- Bioinformatics Platform, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
| | - Mélanie Vausort
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
| | - Yvan Devaux
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
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11
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Qu Y, Xue S, Zheng Y, Du Y, Zhang G, Huang L, Li H, Li H. Upregulated miR‑378a‑3p expression suppresses energy metabolism and promotes apoptosis by targeting a GLUT‑1/ALDOA/PKM2 axis in esophageal carcinoma. Oncol Lett 2023; 26:421. [PMID: 37664650 PMCID: PMC10472027 DOI: 10.3892/ol.2023.14007] [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: 08/24/2022] [Accepted: 07/10/2023] [Indexed: 09/05/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy of the digestive system with increasing incidence and mortality rates. The biological roles of microRNA (miR)-378a-3p in tumor cells remain contested, and the mechanisms underlying the functions, energy metabolism, and cell survival mechanisms in ESCC cells are yet to be fully elucidated. In the present study, miR-378a-3p overexpression and negative control plasmids were transfected into ECA-109 cells using electroporation. Western blotting was used to detect the relative expression of proteins, and flow cytometry was used to detect cell apoptosis. Subsequently, ELISA assays were performed to determine enzyme activity, and an ATP detection kit was used to measure ATP content. Dual-luciferase reporter assays were performed to identify the target genes of miR-378a-3p. The results of the present study demonstrated that miR-378a-3p inhibited the gene expression and enzyme activities of glucose transporter protein 1 (GLUT-1), Aldolase A (ALDOA), and pyruvate kinase M2 (PKM2), all of which are involved in the glycolytic pathway of cells. Energy metabolism was suppressed by miR-378a-3p by reducing ATP content, and this downregulated the expression of Bcl-2 and Survivin. Moreover, increased miR-378a-3p expression promoted cell apoptosis in the early stages by increasing the expression levels and the activity of Bad and Caspase-3, while inhibiting the expression levels of Bcl-2 and Survivin. The results of the present study also demonstrated that GLUT-1/ALDOA/PKM2 were target genes of miR-378a-3p. Notably, miR-378a-3p blocked energy production and promoted the apoptosis of tumor cells via the downregulation of glycolytic enzyme expression and by reducing the mitochondrial membrane potential in ESCC. Bad, Caspase-3, Survivin, and Bcl-2 may be associated with blocking energy production and promoting apoptosis via miR-378a-3p in ESCC cells.
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Affiliation(s)
- Yuan Qu
- Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Shan Xue
- Medical Research Center, Yuebei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
| | - Yujian Zheng
- Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Yajing Du
- Medical Research Center, Yuebei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
| | - Guoping Zhang
- Tumor Department, Yuebei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
| | - Liting Huang
- Medical Research Center, Yuebei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
| | - Hui Li
- Central Laboratory of Xinjiang Medical University, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Huiwu Li
- Medical Research Center, Yuebei People's Hospital, Shantou University, Shaoguan, Guangdong 512025, P.R. China
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12
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Busnelli M, Manzini S, Colombo A, Franchi E, Chiara M, Zaffaroni G, Horner D, Chiesa G. Effect of diet and genotype on the miRNome of mice with altered lipoprotein metabolism. iScience 2023; 26:107615. [PMID: 37664585 PMCID: PMC10474470 DOI: 10.1016/j.isci.2023.107615] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/14/2023] [Accepted: 08/09/2023] [Indexed: 09/05/2023] Open
Abstract
The molecular mechanism by which lipid/lipoprotein biosynthesis is regulated in mammals involves a very large number of genes that are subject to multiple levels of regulation. miRNAs are recognized contributors to lipid homeostasis at the post-transcriptional level, although the elucidation of their role is made difficult by the multiplicity of their targets and the ability of more miRNAs to affect the same mRNAs. In this study, an evaluation of how miRNA expression varies in organs playing a key role in lipid/lipoprotein metabolism was conducted in control mice and in two mouse models carrying genetic ablations which differently affect low-density lipoprotein metabolism. Mice were fed a lipid-poor standard diet and a diet enriched in cholesterol and saturated fat. The results obtained showed that there are no miRNAs whose expression constantly vary with dietary or genetic changes. Furthermore, it appears that diet, more than genotype, impacts on organ-specific miRNA expression profiles.
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Affiliation(s)
- Marco Busnelli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy
| | - Stefano Manzini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy
| | - Alice Colombo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy
| | - Elsa Franchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy
| | - Matteo Chiara
- Department of Biosciences, Università degli Studi di Milano, Milano, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Gaia Zaffaroni
- Institute for Globally Distributed Open Research and Education, Gothenburg, Sweden
| | - David Horner
- Department of Biosciences, Università degli Studi di Milano, Milano, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Giulia Chiesa
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy
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13
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Mucha O, Podkalicka P, Żukowska M, Pośpiech E, Dulak J, Łoboda A. miR-378 influences muscle satellite cells and enhances adipogenic potential of fibro-adipogenic progenitors but does not affect muscle regeneration in the glycerol-induced injury model. Sci Rep 2023; 13:13434. [PMID: 37596327 PMCID: PMC10439181 DOI: 10.1038/s41598-023-40729-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: 04/07/2023] [Accepted: 08/16/2023] [Indexed: 08/20/2023] Open
Abstract
Skeletal muscle regeneration relies on the reciprocal interaction between many types of cells. Regenerative capacity may be altered in different disorders. In our study, we investigated whether the deletion of miR-378a (miR-378) affects muscle regeneration. We subjected 6-week-old wild-type (WT) and miR-378 knockout (miR-378-/-) animals to the glycerol-induced muscle injury and performed analyses in various time-points. In miR-378-/- animals, an elevated abundance of muscle satellite cells (mSCs) on day 3 was found. Furthermore, fibro-adipogenic progenitors (FAPs) isolated from the muscle of miR-378-/- mice exhibited enhanced adipogenic potential. At the same time, lack of miR-378 did not affect inflammation, fibrosis, adipose tissue deposition, centrally nucleated fiber count, muscle fiber size, FAP abundance, and muscle contractility at any time point analyzed. To conclude, our study revealed that miR-378 deletion influences the abundance of mSCs and the adipogenic potential of FAPs, but does not affect overall regeneration upon acute, glycerol-induced muscle injury.
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Affiliation(s)
- Olga Mucha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Monika Żukowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Ewelina Pośpiech
- Malopolska Centre of Biotechnology in Krakow, 30-387, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland.
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14
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Wade H, Pan K, Duan Q, Kaluzny S, Pandey E, Fatumoju L, Saraswathi V, Wu R, Harris EN, Su Q. Akkermansia muciniphila and its membrane protein ameliorates intestinal inflammatory stress and promotes epithelial wound healing via CREBH and miR-143/145. J Biomed Sci 2023; 30:38. [PMID: 37287024 PMCID: PMC10249216 DOI: 10.1186/s12929-023-00935-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 05/30/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND The intestinal epithelial barrier is the interface for interaction between gut microbiota and host metabolic systems. Akkermansia muciniphila (A. muciniphila) is a key player in the colonic microbiota that resides in the mucus layer, whose abundance is selectively decreased in the faecal microbiota of inflammatory bowel disease (IBD) patients. This study aims to investigate the regulatory mechanism among A. muciniphila, a transcription factor cAMP-responsive element-binding protein H (CREBH), and microRNA-143/145 (miR-143/145) in intestinal inflammatory stress, gut barrier integrity and epithelial regeneration. METHODS A novel mouse model with increased colonization of A muciniphila in the intestine of CREBH knockout mice, an epithelial wound healing assay and several molecular biological techniques were applied in this study. Results were analysed using a homoscedastic 2-tailed t-test. RESULTS Increased colonization of A. muciniphila in mouse gut enhanced expression of intestinal CREBH, which was associated with the mitigation of intestinal endoplasmic reticulum (ER) stress, gut barrier leakage and blood endotoxemia induced by dextran sulfate sodium (DSS). Genetic depletion of CREBH (CREBH-KO) significantly inhibited the expression of tight junction proteins that are associated with gut barrier integrity, including Claudin5 and Claudin8, but upregulated Claudin2, a tight junction protein that enhances gut permeability, resulting in intestinal hyperpermeability and inflammation. Upregulation of CREBH by A. muciniphila further coupled with miR-143/145 promoted intestinal epithelial cell (IEC) regeneration and wound repair via insulin-like growth factor (IGF) and IGFBP5 signalling. Moreover, the gene expressing an outer membrane protein of A. muciniphila, Amuc_1100, was cloned into a mammalian cell-expression vector and successfully expressed in porcine and human IECs. Expression of Amuc_1100 in IECs could recapitulate the health beneficial effect of A. muciniphila on the gut by activating CREBH, inhibiting ER stress and enhancing the expression of genes involved in gut barrier integrity and IEC's regeneration. CONCLUSIONS This study uncovers a novel mechanism that links A. muciniphila and its membrane protein with host CREBH, IGF signalling and miRNAs in mitigating intestinal inflammatory stress-gut barrier permeability and promoting intestinal wound healing. This novel finding may lend support to the development of therapeutic approaches for IBD by manipulating the interaction between host genes, gut bacteria and its bioactive components.
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Affiliation(s)
- Henry Wade
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK
| | - Kaichao Pan
- Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA
| | - Qihua Duan
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK
| | - Szczepan Kaluzny
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK
| | - Ekta Pandey
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA
| | - Linda Fatumoju
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA
| | | | - Rongxue Wu
- Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA
| | - Qiaozhu Su
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK.
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15
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de Pedro MÁ, Pulido M, Álvarez V, Marinaro F, Marchena AM, Sánchez-Margallo FM, Casado JG, López E. Menstrual blood-derived stromal cells: insights into their secretome in acute hypoxia conditions. Mol Med 2023; 29:48. [PMID: 37016307 PMCID: PMC10074862 DOI: 10.1186/s10020-023-00646-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/23/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND Despite constant advances in regenerative medicine, the closure of chronic wounds is still challenging. Therapeutic approaches using locally administered MSCs have been considered a promising option. However, the viability of these cells is seriously threatened by acute hypoxic stress linked to wound healing. In this work, we aimed to study the tolerance of Menstrual blood-derived stromal cells (MenSCs) to acute hypoxia and their therapeutic paracrine effect. METHODS Isolated MenSCs were phenotypically characterized and evaluated in terms of proliferation, viability, and gene expression, under acute hypoxia (AH) compared with conventional cultured condition or normoxia (N). A step further, the secretome of MenSCs under acute hypoxia was analyzed with respect to their miRNAs content and by in vitro functional assays. For the analysis of differences between the two groups, Student's t-test was performed and one-way ANOVA and Tukey's multiple comparisons test for multiple groups were used. RESULTS Our results revealed that the viability of MenSCs was not affected under acute hypoxia, although proliferation rate slowed down. Gene analysis revealed 5 up-regulated (BNIP3, ANGPTL4, IL6, IL1B, and PDK1) and 4 down-regulated genes (IDO1, HMOX1, ANGPTL2, and HGF) in AH compared to N. Global gene expression analysis revealed a decrease in the gene ontology functions of migration and wound response with respect to the normoxic condition. In contrast, functions such as angiogenesis were enriched under the AH condition. Regarding the secretome analysis, two miRNAs involved in angiogenic processes (hsa-miR-148a-3p and hsa-miR-378a-3p), were significantly up-expressed when compared to the normoxic condition, being MYC gene, the unique target of both. Functional assays on HUVECs revealed a potential pro-angiogenic capacity of MenSCs cultured in both oxygen conditions (N and AH) based on the wound closure and tube formation results of their released paracrine factors. However, when compared to normoxia, the paracrine factors of MenSCs under acute hypoxia slightly reduced the proliferation, migration, and in vitro wound closure of HUVECs. CONCLUSIONS MenSC exhibited a good survival capacity under acute hypoxic conditions as well as beneficial properties applicable in the field of tissue regeneration through their secretome, which makes them a potential cell source for wound healing interventions.
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Affiliation(s)
- María Ángeles de Pedro
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain
- RICORS-TERAV Network, ISCIII, 28029, Madrid, Spain
| | - María Pulido
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain
| | - Verónica Álvarez
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain
| | - Federica Marinaro
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain
| | - Ana María Marchena
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain
| | - Francisco Miguel Sánchez-Margallo
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain.
- RICORS-TERAV Network, ISCIII, 28029, Madrid, Spain.
| | - Javier G Casado
- RICORS-TERAV Network, ISCIII, 28029, Madrid, Spain
- Immunology Unit, University of Extremadura, 10003, Cáceres, Spain
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003, Cáceres, Spain
| | - Esther López
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, 10071, Cáceres, Spain
- RICORS-TERAV Network, ISCIII, 28029, Madrid, Spain
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16
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Westholm E, Edlund A, Karagiannopoulos A, Wendt A, Eliasson L. Interleukin-4 reduces insulin secretion in human islets from healthy but not type-2 diabetic donors. Biochem Biophys Res Commun 2023; 649:87-92. [PMID: 36758483 DOI: 10.1016/j.bbrc.2023.01.092] [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: 01/13/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023]
Abstract
Type 2 diabetes (T2D) is associated with low-grade inflammation. Here we investigate if the anti-inflammatory cytokine interleukin-4 (IL-4) affects glucose-stimulated insulin secretion (GSIS) in human islets from non-diabetic (ND) and type-2 diabetic (T2D) donors. We first confirmed that GSIS is reduced in islets from T2D donors. Treatment with IL-4 for 48 h had no further effect on GSIS in these islets but significantly reduced secretion in ND islets. Acute treatment with IL-4 for 1 h had no effect on GSIS in ND islets which led us to suspect that IL-4 affects a slow cellular mechanism such as gene transcription. IL-4 has been reported to regulate miR-378a-3p and, indeed, we found that this microRNA was increased with IL-4 treatment. However, overexpression of miR-378a-3p in the human beta cell line EndoC-βH1 did not affect GSIS. MiR-378a-3p is transcribed from the same gene as peroxisome proliferator-activated receptor gamma co-activator 1 beta (PCG-1β) and we found that IL-4 treatment showed a clear tendency to increased gene expression of PCG-1β. PCG-1β is a co-activator of peroxisome proliferator-activated receptor gamma (PPARγ) and, the gene expression of PPARγ was also increased with IL-4 treatment. Our data suggests that the protective role of IL-4 on beta cell survival comes at the cost of lowered insulin secretion, presumably involving the PPARγ-pathway.
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Affiliation(s)
- Efraim Westholm
- Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Anna Edlund
- Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Alexandros Karagiannopoulos
- Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Anna Wendt
- Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Lena Eliasson
- Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
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Bu S, Joseph JJ, Nguyen HC, Ehsan M, Rasheed B, Singh A, Qadura M, Frisbee JC, Singh KK. MicroRNA miR-378-3p is a novel regulator of endothelial autophagy and function. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2023; 3:100027. [PMID: 39803361 PMCID: PMC11708318 DOI: 10.1016/j.jmccpl.2022.100027] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 01/16/2025]
Abstract
Autophagy is a highly conserved cellular process in which cytoplasmic materials are internalized into an autophagosome that later fuses with a lysosome for their degradation and recycling. MicroRNAs (miRNAs) are integral regulators in various cellular processes including autophagy and endothelial function. Accordingly, we hypothesize that miRNA, miR-378-3p, is an essential regulator of endothelial autophagy and endothelial function. MiR-378-3p expression was measured following inhibition and activation of autophagy in endothelial cells. A gain- or loss-of function approach was employed to either overexpress or inhibit the expression of miR-378-3p, respectively, in cultured endothelial cells, and markers of autophagy and indices of endothelial function, such as proliferation, migration and tube forming potential were measured. Inhibition and activation of autophagy up- and down-regulated the expression of miR-378-3p, respectively. Furthermore, miR-378a-3p overexpression was associated with impaired autophagy indicated by a reduced LC3-II/LC3-I ratio, and endothelial function indicated by increased proliferation associated with reduced p21 expression, reduced angiogenic potential and increased migration, which were associated with reduced expression of endothelial nitric oxide synthase (eNOS), an essential regulator of endothelial function. Accordingly, miR-378a-3p inhibition was associated with reduced cell proliferation, migration and increased eNOS in endothelial cells. Apoptosis was not affected in cells transfected with antagomir. Using in silico approach, Protein Disulfide Isomerase Family A Member 4 (PDIA-4) was identified and confirmed as a target of miR-378-3p. PDIA-4 expression was significantly reduced or enhanced in miR-378-3p-overexpressing or -silenced endothelial cells, respectively. Our findings show an inverse relationship between miR-378-3p and endothelial autophagy and function, providing a novel insight about the epigenetic regulation of these processes.
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Affiliation(s)
- Shuhan Bu
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Jameela J. Joseph
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Hien C. Nguyen
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Mehroz Ehsan
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Berk Rasheed
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Aman Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Mohammad Qadura
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Jefferson C. Frisbee
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
| | - Krishna K. Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
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Yamaguchi A, Maeshige N, Yan J, Ma X, Uemura M, Matsuda M, Nishimura Y, Hasunuma T, Kondo H, Fujino H, Yuan ZM. Skeletal myotube-derived extracellular vesicles enhance itaconate production and attenuate inflammatory responses of macrophages. Front Immunol 2023; 14:1099799. [PMID: 36936950 PMCID: PMC10018131 DOI: 10.3389/fimmu.2023.1099799] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 02/09/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction Macrophages play an important role in the innate immunity. While macrophage inflammation is necessary for biological defense, it must be appropriately controlled. Extracellular vesicles (EVs) are small vesicles released from all types of cells and play a central role in intercellular communication. Skeletal muscle has been suggested to release anti-inflammatory factors, but the effect of myotube-derived EVs on macrophages is unknown. As an anti-inflammatory mechanism of macrophages, the immune responsive gene 1 (IRG1)-itaconate pathway is essential. In this study, we show that skeletal muscle-derived EVs suppress macrophage inflammatory responses, upregulating the IRG1-itaconate pathway. Methods C2C12 myoblasts were differentiated into myotubes and EVs were extracted by ultracentrifugation. Skeletal myotube-derived EVs were administered to mouse bone marrow-derived macrophages, then lipopolysaccharide (LPS) stimulation was performed and inflammatory cytokine expression was measured by RT-qPCR. Metabolite abundance in macrophages after addition of EVs was measured by CE/MS, and IRG1 expression was measured by RT-PCR. Furthermore, RNA-seq analysis was performed on macrophages after EV treatment. Results EVs attenuated the expression of LPS-induced pro-inflammatory factors in macrophages. Itaconate abundance and IRG1 expression were significantly increased in the EV-treated group. RNA-seq analysis revealed activation of the PI3K-Akt and JAK-STAT pathways in macrophages after EV treatment. The most abundant miRNA in myotube EVs was miR-206-3p, followed by miR-378a-3p, miR-30d-5p, and miR-21a-5p. Discussion Skeletal myotube EVs are supposed to increase the production of itaconate via upregulation of IRG1 expression and exhibited an anti-inflammatory effect in macrophages. This anti-inflammatory effect was suggested to involve the PI3K-Akt and JAK-STAT pathways. The miRNA profiles within EVs implied that miR-206-3p, miR-378a-3p, miR-30d-5p, and miR-21a-5p may be responsible for the anti-inflammatory effects of the EVs. In summary, in this study we showed that myotube-derived EVs prevent macrophage inflammatory responses by activating the IRG1-itaconate pathway.
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Affiliation(s)
- Atomu Yamaguchi
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Noriaki Maeshige
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
- *Correspondence: Noriaki Maeshige, ; Hidemi Fujino,
| | - Jiawei Yan
- School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China
| | - Xiaoqi Ma
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Mikiko Uemura
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Mami Matsuda
- Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan
| | - Yuya Nishimura
- Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan
| | - Tomohisa Hasunuma
- Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan
- Engineering Biology Research Center, Kobe University, Kobe, Japan
| | - Hiroyo Kondo
- Department of Food Science and Nutrition, Nagoya Women’s University, Nagoya, Japan
| | - Hidemi Fujino
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
- *Correspondence: Noriaki Maeshige, ; Hidemi Fujino,
| | - Zhi-Min Yuan
- Department of Environmental Health, Harvard University T.H Chan School of Public Health, Boston, MA, United States
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Brown C, Mantzaris M, Nicolaou E, Karanasiou G, Papageorgiou E, Curigliano G, Cardinale D, Filippatos G, Memos N, Naka KK, Papakostantinou A, Vogazianos P, Ioulianou E, Shammas C, Constantinidou A, Tozzi F, Fotiadis DI, Antoniades A. A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research. CARDIO-ONCOLOGY 2022; 8:16. [PMID: 36071532 PMCID: PMC9450324 DOI: 10.1186/s40959-022-00142-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/02/2022] [Indexed: 12/01/2022]
Abstract
Breast cancer patients are at a particularly high risk of cardiotoxicity from chemotherapy having a detrimental effect on quality-of-life parameters and increasing the risk of mortality. Prognostic biomarkers would allow the management of therapies to mitigate the risks of cardiotoxicity in vulnerable patients and a key potential candidate for such biomarkers are microRNAs (miRNA). miRNAs are post-transcriptional regulators of gene expression which can also be released into the circulatory system and have been associated with the progression of many chronic diseases including many types of cancer. In this review, the evidence for the potential application of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity (CIC) in breast cancer patientsis evaluated and a simple meta-analysis is performed to confirm the replication status of each reported miRNA. Further selection of miRNAs is performed by reviewing the reported associations of each miRNA with other cardiovascular conditions. Based on this research, the most representative panels targeting specific chemotherapy agents and treatment regimens are suggested, that contain several informative miRNAs, including both general markers of cardiac damage as well as those for the specific cancer treatments.
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20
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Fletcher D, Brown E, Javadala J, Uysal‐Onganer P, Guinn B. microRNA expression in acute myeloid leukaemia: New targets for therapy? EJHAEM 2022; 3:596-608. [PMID: 36051053 PMCID: PMC9421970 DOI: 10.1002/jha2.441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/27/2022] [Accepted: 03/31/2022] [Indexed: 11/09/2022]
Abstract
Recent studies have shown that short non-coding RNAs, known as microRNAs (miRNAs) and their dysregulation, are implicated in the pathogenesis of acute myeloid leukaemia (AML). This is due to their role in the control of gene expression in a variety of molecular pathways. Therapies involving miRNA suppression and replacement have been developed. The normalisation of expression and the subsequent impact on AML cells have been investigated for some miRNAs, demonstrating their potential to act as therapeutic targets. Focussing on miRs with therapeutic potential, we have reviewed those that have a significant impact on the aberrant biological processes associated with AML, and crucially, impact leukaemic stem cell survival. We describe six miRNAs in preclinical trials (miR-21, miR-29b, miR-126, miR-181a, miR-223 and miR-196b) and two miRNAs that are in clinical trials (miR-29 and miR-155). However none have been used to treat AML patients and greater efforts are needed to develop miRNA therapies that could benefit AML patients in the future.
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Affiliation(s)
| | - Elliott Brown
- Department of Biomedical SciencesUniversity of HullHull, UK
| | | | - Pinar Uysal‐Onganer
- Cancer Research GroupSchool of Life SciencesUniversity of WestminsterLondonUK
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21
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Phu TA, Ng M, Vu NK, Bouchareychas L, Raffai RL. IL-4 polarized human macrophage exosomes control cardiometabolic inflammation and diabetes in obesity. Mol Ther 2022; 30:2274-2297. [PMID: 35292359 PMCID: PMC9171286 DOI: 10.1016/j.ymthe.2022.03.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/25/2022] [Accepted: 03/10/2022] [Indexed: 11/25/2022] Open
Abstract
Cardiometabolic disease is an increasing cause of morbidity and death in society. While M1-like macrophages contribute to metabolic inflammation and insulin resistance, those polarized to an M2-like phenotype exert protective properties. Building on our observations reporting M2-like macrophage exosomes in atherosclerosis control, we tested whether they could serve to control inflammation in the liver and adipose tissue of obese mice. In thinking of clinical translation, we studied human THP-1 macrophages exposed to interleukin (IL)-4 as a source of exosomes (THP1-IL4-exo). Our findings show that THP1-IL4-exo polarized primary macrophages to an anti-inflammatory phenotype and reprogramed their energy metabolism by increasing levels of microRNA-21/99a/146b/378a (miR-21/99a/146b/378a) while reducing miR-33. This increased lipophagy, mitochondrial activity, and oxidative phosphorylation (OXPHOS). THP1-IL4-exo exerted a similar regulation of these miRs in cultured 3T3-L1 adipocytes. This enhanced insulin-dependent glucose uptake through increased peroxisome proliferator activated receptor gamma (PPARγ)-driven expression of GLUT4. It also increased levels of UCP1 and OXPHOS activity, which promoted lipophagy, mitochondrial activity, and beiging of 3T3-L1 adipocytes. Intraperitoneal infusions of THP1-IL4-exo into obese wild-type and Ldlr-/- mice fed a Western high-fat diet reduced hematopoiesis and myelopoiesis, and favorably reprogramed inflammatory signaling and metabolism in circulating Ly6Chi monocytes. This also reduced leukocyte numbers and inflammatory activity in the circulation, aorta, adipose tissue, and the liver. Such treatments reduced hepatic steatosis and increased the beiging of white adipose tissue as revealed by increased UCP1 expression and OXPHOS activity that normalized blood insulin levels and improved glucose tolerance. Our findings support THP1-IL4-exo as a therapeutic approach to control cardiometabolic disease and diabetes in obesity.
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Affiliation(s)
- Tuan Anh Phu
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Martin Ng
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Ngan K Vu
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Laura Bouchareychas
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Robert L Raffai
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA; Department of Surgery, Division of Endovascular and Vascular Surgery, University of California, San Francisco, CA 94143, USA.
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22
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Hatmal MM, Al-Hatamleh MAI, Olaimat AN, Alshaer W, Hasan H, Albakri KA, Alkhafaji E, Issa NN, Al-Holy MA, Abderrahman SM, Abdallah AM, Mohamud R. Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects. Biomedicines 2022; 10:1219. [PMID: 35740242 PMCID: PMC9219990 DOI: 10.3390/biomedicines10061219] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/15/2022] [Accepted: 05/17/2022] [Indexed: 02/07/2023] Open
Abstract
Infants who are exclusively breastfed in the first six months of age receive adequate nutrients, achieving optimal immune protection and growth. In addition to the known nutritional components of human breast milk (HBM), i.e., water, carbohydrates, fats and proteins, it is also a rich source of microRNAs, which impact epigenetic mechanisms. This comprehensive work presents an up-to-date overview of the immunomodulatory constituents of HBM, highlighting its content of circulating microRNAs. The epigenetic effects of HBM are discussed, especially those regulated by miRNAs. HBM contains more than 1400 microRNAs. The majority of these microRNAs originate from the lactating gland and are based on the remodeling of cells in the gland during breastfeeding. These miRNAs can affect epigenetic patterns by several mechanisms, including DNA methylation, histone modifications and RNA regulation, which could ultimately result in alterations in gene expressions. Therefore, the unique microRNA profile of HBM, including exosomal microRNAs, is implicated in the regulation of the genes responsible for a variety of immunological and physiological functions, such as FTO, INS, IGF1, NRF2, GLUT1 and FOXP3 genes. Hence, studying the HBM miRNA composition is important for improving the nutritional approaches for pregnancy and infant's early life and preventing diseases that could occur in the future. Interestingly, the composition of miRNAs in HBM is affected by multiple factors, including diet, environmental and genetic factors.
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Affiliation(s)
- Ma’mon M. Hatmal
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Mohammad A. I. Al-Hatamleh
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia;
| | - Amin N. Olaimat
- Department of Clinical Nutrition and Dietetics, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan; (A.N.O.); (M.A.A.-H.)
| | - Walhan Alshaer
- Cell Therapy Center (CTC), The University of Jordan, Amman 11942, Jordan;
| | - Hanan Hasan
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan;
| | - Khaled A. Albakri
- Faculty of Medicine, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Enas Alkhafaji
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan;
| | - Nada N. Issa
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Murad A. Al-Holy
- Department of Clinical Nutrition and Dietetics, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan; (A.N.O.); (M.A.A.-H.)
| | - Salim M. Abderrahman
- Department of Biology and Biotechnology, Faculty of Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Atiyeh M. Abdallah
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar;
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia;
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23
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Tuerxun N, Wang J, Qin YT, Zhao F, Wang H, Qu JH, Uddin MN, Hao JP. Identification of key genes and miRNA-mRNA regulatory networks associated with bone marrow immune microenvironment regulations in multiple myeloma by integrative bioinformatics analysis. Hematology 2022; 27:506-517. [PMID: 35536760 DOI: 10.1080/16078454.2022.2068873] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The deregulation of microRNAs (miRNAs) and genes in the bone marrow microenvironment have been involved with the pathogenesis of multiple myeloma (MM). However, the exploration of miRNA-mRNA regulatory networks in MM remains lacking. We used GSE125363, GSE125361, GSE47552, GSE2658, GSE136324, GSE16558, and GSE13591 datasets for this bioinformatics study. We identified 156 downregulated and 13 upregulated differentially expressed miRNAs (DEmiRs) in MM. The DEmiRs are associated with the enrichment of pathways mainly involved with cancers, cellular signaling, and immune regulations. We identified 112 hub genes associated with five significant clusters in MM. Moreover, we identified 9 upregulated hub genes (such as IGF1, RPS28, UBA52, CDKN1A, and CDKN2A) and 52 downregulated hub genes (such as TP53, PCNA, BRCA1, CCNB1, and MSH2) in MM that is targeted by DEmiRs. The expression of DEmiRs targeted two hub genes (CDKN2A and TP53) are correlated with the survival prognosis of MM patients. Furthermore, the expression level of CDKN2A is correlated with immune signatures, including CD4+ Regulatory T cells, T cell exhaustion, MHC Class I, immune checkpoint genes, macrophages, neutrophils, and TH2 cells in the TME of MM. Finally, we revealed the consistently deregulated expression level of key gene CDKN2A and its co-regulatory DEmiRs, including hsa-mir-192, hsa-mir-10b, hsa-mir-492, and hsa-mir-24 in the independent cohorts of MM. Identifying key genes and miRNA-mRNA regulatory networks may provide new molecular insights into the tumor immune microenvironment in MM.
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Affiliation(s)
- Niluopaer Tuerxun
- Department of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Jie Wang
- Department of Pharmacy, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yu-Ting Qin
- Department of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Fang Zhao
- Department of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Huan Wang
- Department of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Jian-Hua Qu
- Department of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Md Nazim Uddin
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jian-Ping Hao
- Department of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
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24
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Louro AF, Paiva MA, Oliveira MR, Kasper KA, Alves PM, Gomes‐Alves P, Serra M. Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell-Cardiomyocyte Differentiation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2104296. [PMID: 35322574 PMCID: PMC9130911 DOI: 10.1002/advs.202104296] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/05/2022] [Indexed: 05/17/2023]
Abstract
Extracellular vesicles (EV) are an attractive therapy to boost cardiac regeneration. Nevertheless, identification of native EV and corresponding cell platform(s) suitable for therapeutic application, is still a challenge. Here, EV are isolated from key stages of the human induced pluripotent stem cell-cardiomyocyte (hiPSC-CM) differentiation and maturation, i.e., from hiPSC (hiPSC-EV), cardiac progenitors, immature and mature cardiomyocytes, with the aim of identifying a promising cell biofactory for EV production, and pinpoint the genetic signatures of bioactive EV. EV secreted by hiPSC and cardiac derivatives show a typical size distribution profile and the expression of specific EV markers. Bioactivity assays show increased tube formation and migration in HUVEC treated with hiPSC-EV compared to EV from committed cell populations. hiPSC-EV also significantly increase cell cycle activity of hiPSC-CM. Global miRNA expression profiles, obtained by small RNA-seq analysis, corroborate an EV-miRNA pattern indicative of stem cell to cardiomyocyte specification, confirming that hiPSC-EV are enriched in pluripotency-associated miRNA with higher in vitro pro-angiogenic and pro-proliferative properties. In particular, a stemness maintenance miRNA cluster upregulated in hiPSC-EV targets the PTEN/PI3K/AKT pathway, involved in cell proliferation and survival. Overall, the findings validate hiPSC as cell biofactories for EV production for cardiac regenerative applications.
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Affiliation(s)
- Ana F. Louro
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
| | - Marta A. Paiva
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
| | - Marta R. Oliveira
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
| | - Katharina A. Kasper
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
| | - Paula M. Alves
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
| | - Patrícia Gomes‐Alves
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
| | - Margarida Serra
- iBETInstituto de Biologia Experimental e TecnológicaApartado 12Oeiras2781‐901Portugal
- ITQB‐NOVAInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de LisboaAv. da RepúblicaOeiras2780‐157Portugal
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25
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Piechowska A, Kruszniewska-Rajs C, Kimsa-Dudek M, Kołomańska M, Strzałka-Mrozik B, Gola J, Głuszek S. The role of miR-370 and miR-138 in the regulation of BMP2 suppressor gene expression in colorectal cancer: preliminary studies. J Cancer Res Clin Oncol 2022; 148:1569-1582. [PMID: 35292840 DOI: 10.1007/s00432-022-03977-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/06/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Colorectal cancer (CRC) is the fourth-most common cancer worldwide and the second most common cancer cause of death in the world. The components of the TGFβ-signalling pathway, which are often affected by miRNAs, are involved in the regulation of apoptosis and cell cycle. Therefore, in the current study, the expression of BMP2 gene in CRC tissues at different clinical stages compared to the non-tumour tissues has been assessed. Moreover, the plasma BMP2 protein concentration in the same group of CRC patients has been validated. Due to the constant necessity to conduct further research of the correlation between specific miRNAs and mRNAs in CRC, in silico analysis has been performed to select miRNAs that regulate BMP2 mRNA. METHODS The cDNA samples from tumor and non-tumor tissue were used in a qPCR reaction to determine the mRNA expression of the BMP2 gene and the expression of selected miRNAs. The concentration of BMP2 protein in plasma samples was also measured. RESULTS It was indicated that BMP2 was downregulated in CRC tissue. Moreover, miR-370 and miR-138 expression showed an upward trend. Decreased BMP2 with accompanied increasing miR-370 and miR-138 expression was relevant to the malignant clinicopathological features of CRC and consequently poor patient prognosis. CONCLUSION Our data suggest that miR-370 with its clear expression in plasma samples may be a potential diagnostic marker to determine the severity of the disease in patients at a later stage of colorectal cancer.
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Affiliation(s)
- Agnieszka Piechowska
- Department of Surgical Medicine With the Laboratory of Medical Genetics, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Celina Kruszniewska-Rajs
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kimsa-Dudek
- Department of Nutrigenomics and Bromatology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kołomańska
- Department of Anatomy, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Barbara Strzałka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland.
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Stanisław Głuszek
- Department of Surgical Medicine With the Laboratory of Medical Genetics, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland.,Department of Clinic General Oncological and Endocrinological Surgery, Regional Hospital, Kielce, Poland
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26
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Podkalicka P, Mucha O, Kaziród K, Szade K, Stępniewski J, Ivanishchuk L, Hirao H, Pośpiech E, Józkowicz A, Kupiec-Weglinski JW, Dulak J, Łoboda A. miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy. Sci Rep 2022; 12:3945. [PMID: 35273230 PMCID: PMC8913680 DOI: 10.1038/s41598-022-07868-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/22/2022] [Indexed: 02/08/2023] Open
Abstract
Although Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder. We propose that microRNA-378a (miR-378) alters carbohydrate and lipid metabolism in dystrophic mdx mice. In our study, we utilized double knockout animals which lacked both dystrophin and miR-378 (mdx/miR-378-/-). RNA sequencing of the liver identified 561 and 194 differentially expressed genes that distinguished mdx versus wild-type (WT) and mdx/miR-378-/- versus mdx counterparts, respectively. Bioinformatics analysis predicted, among others, carbohydrate metabolism disorder in dystrophic mice, as functionally proven by impaired glucose tolerance and insulin sensitivity. The lack of miR-378 in mdx animals mitigated those effects with a faster glucose clearance in a glucose tolerance test (GTT) and normalization of liver glycogen levels. The absence of miR-378 also restored the expression of genes regulating lipid homeostasis, such as Acly, Fasn, Gpam, Pnpla3, and Scd1. In conclusion, we report for the first time that miR-378 loss results in increased systemic metabolism of mdx mice. Together with our previous finding, demonstrating alleviation of the muscle-related symptoms of DMD, we propose that the inhibition of miR-378 may represent a new strategy to attenuate the multifaceted symptoms of DMD.
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Affiliation(s)
- Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Olga Mucha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Katarzyna Kaziród
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Krzysztof Szade
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Jacek Stępniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Liudmyla Ivanishchuk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Hirofumi Hirao
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Ewelina Pośpiech
- Malopolska Centre of Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland
| | - Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387, Kraków, Poland.
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Xia P, Pasquali L, Gao C, Srivastava A, Khera N, Freisenhausen JC, Luo L, Rosén E, van Lierop A, Homey B, Pivarcsi A, Sonkoly E. miR-378a regulates keratinocyte responsiveness to IL-17A in psoriasis. Br J Dermatol 2022; 187:211-222. [PMID: 35257359 PMCID: PMC9545829 DOI: 10.1111/bjd.21232] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/15/2022] [Accepted: 02/28/2022] [Indexed: 12/04/2022]
Abstract
Background Psoriasis is an immune‐mediated inflammatory skin disease, in which an interplay between infiltrating immune cells and keratinocytes sustains chronic skin inflammation. Interleukin (IL)‐17A is a key inflammatory cytokine in psoriasis and its main cellular targets are keratinocytes. Objectives To explore the role of miR‐378a in psoriasis. Methods Keratinocytes obtained from psoriatic skin and healthy epidermis were separated by magnetic sorting, and the expression of miR‐378a was analysed by quantitative polymerase chain reaction. The regulation and function of miR‐378a was studied using primary human keratinocytes. The expression of miR‐378a was modulated by synthetic mimics, and nuclear factor kappa B (NF‐κB) activity and transcriptomic changes were studied. Synthetic miR‐378a was delivered to mouse skin in conjunction with induction of psoriasiform skin inflammation by imiquimod. Results We show that miR‐378a is induced by IL‐17A in keratinocytes through NF‐κB, C/EBP‐β and IκBζ and that it is overexpressed in psoriatic epidermis. In cultured keratinocytes, ectopic expression of miR‐378a resulted in the nuclear translocation of p65 and enhanced NF‐κB‐driven promoter activity even in the absence of inflammatory stimuli. Moreover, miR‐378a potentiated the effect of IL‐17A on NF‐κB nuclear translocation and downstream activation of the NF‐κB pathway. Finally, injection of miR‐378a into mouse skin augmented psoriasis‐like skin inflammation with increased epidermal proliferation and induction of inflammatory mediators. Mechanistically, miR‐378a acts as a suppressor of NFKBIA/IκBζ, an important negative regulator of the NF‐κB pathway in keratinocytes. Conclusions Collectively, our findings identify miR‐378a as an amplifier of IL‐17A‐induced NF‐κB signalling in keratinocytes and suggest that increased miR‐378a levels contribute to the amplification of IL‐17A‐driven skin inflammation in psoriasis.
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Affiliation(s)
- Ping Xia
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.,Dermatology Unit, Wuhan No.1 Hospital, Wuhan, China
| | - Lorenzo Pasquali
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden
| | - Chenying Gao
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.,Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
| | - Ankit Srivastava
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.,Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.,The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA
| | - Nupur Khera
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden
| | - Jan Cedric Freisenhausen
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden
| | - Longlong Luo
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden
| | - Einar Rosén
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Anke van Lierop
- Department of Dermatology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Bernhard Homey
- Department of Dermatology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Andor Pivarcsi
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Biochemistry and Microbiology (IMBIM), Uppsala University, Uppsala, Sweden
| | - Enikö Sonkoly
- Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Valacchi G, Pambianchi E, Coco S, Pulliero A, Izzotti A. MicroRNA Alterations Induced in Human Skin by Diesel Fumes, Ozone, and UV Radiation. J Pers Med 2022; 12:176. [PMID: 35207665 PMCID: PMC8880698 DOI: 10.3390/jpm12020176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/17/2022] Open
Abstract
Epigenetic alterations are a driving force of the carcinogenesis process. MicroRNAs play a role in silencing mutated oncogenes, thus defending the cell against the adverse consequences of genotoxic damages induced by environmental pollutants. These processes have been well investigated in lungs; however, although skin is directly exposed to a great variety of environmental pollutants, more research is needed to better understand the effect on cutaneous tissue. Therefore, we investigated microRNA alteration in human skin biopsies exposed to diesel fumes, ozone, and UV light for over 24 h of exposure. UV and ozone-induced microRNA alteration right after exposure, while the peak of their deregulations induced by diesel fumes was reached only at the end of the 24 h. Diesel fumes mainly altered microRNAs involved in the carcinogenesis process, ozone in apoptosis, and UV in DNA repair. Accordingly, each tested pollutant induced a specific pattern of microRNA alteration in skin related to the intrinsic mechanisms activated by the specific pollutant. These alterations, over a short time basis, reflect adaptive events aimed at defending the tissue against damages. Conversely, whenever environmental exposure lasts for a long time, the irreversible alteration of the microRNA machinery results in epigenetic damage contributing to the pathogenesis of inflammation, dysplasia, and cancer induced by environmental pollutants.
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Affiliation(s)
- Giuseppe Valacchi
- Animal Science Department, Plants for Human Health Institute, North Carolina State University, Research Campus Kannapolis, Kannapolis, NC 28081, USA; (G.V.); (E.P.)
- Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
- Department of Food and Nutrition, Kyung Hee University, Seoul 130-701, Korea
| | - Erika Pambianchi
- Animal Science Department, Plants for Human Health Institute, North Carolina State University, Research Campus Kannapolis, Kannapolis, NC 28081, USA; (G.V.); (E.P.)
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | | | - Alberto Izzotti
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy
- UOC Mutagenesis and Cancer Prevention, IRCCS San Martino Hospital, 16132 Genova, Italy
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Yang Q, Chan P. Skeletal Muscle Metabolic Alternation Develops Sarcopenia. Aging Dis 2022; 13:801-814. [PMID: 35656108 PMCID: PMC9116905 DOI: 10.14336/ad.2021.1107] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/28/2021] [Indexed: 11/23/2022] Open
Abstract
Sarcopenia is a new type of senile syndrome with progressive skeletal muscle mass loss with age, accompanied by decreased muscle strength and/or muscle function. Sarcopenia poses a serious threat to the health of the elderly and increases the burden of family and society. The underlying pathophysiological mechanisms of sarcopenia are still unclear. Recent studies have shown that changes of skeletal muscle metabolism are the risk factors for sarcopenia. Furthermore, the importance of the skeletal muscle metabolic microenvironment in regulating satellite cells (SCs) is gaining significant attention. Skeletal muscle metabolism has intrinsic relationship with the regulation of skeletal muscle mass and regeneration. This review is to discuss recent findings regarding skeletal muscle metabolic alternation and the development of sarcopenia, hoping to contribute better understanding and treatment of sarcopenia.
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Affiliation(s)
- Qiumei Yang
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China.
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.
| | - Piu Chan
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China.
- Clinical Center for Parkinson’s Disease, Capital Medical University, Beijing Institute of Geriatrics, Beijing, China.
- Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.
- Correspondence should be addressed to: Dr. Piu Chan, Department of Neurobiology, Xuanwu Hospital of Capital Medical University, 45 Changchun Road, Beijing 100053, China. .
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30
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Peng J, Shi S, Yu J, Liu J, Wei H, Song H, Wang S, Li Z, He S, Li L, Zhang H, Yan Z, Zhao R, Liu Y, Liu Y, Li J, Zhang R, Wang W. miR-378d suppresses malignant phenotype of ESCC cells through AKT signaling. Cancer Cell Int 2021; 21:702. [PMID: 34937563 PMCID: PMC8697470 DOI: 10.1186/s12935-021-02403-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/08/2021] [Indexed: 01/12/2023] Open
Abstract
Background Post-resistance progress in paclitaxel (PTX) treatment remains a major challenge in tumor treatment. A high dose of PTX was used for cell lines to analyze the changes in molecular expression. The miR-378d was sharply reduced in surviving cells, but the role of miR-378d in Esophageal squamous cell carcinoma (ESCC) remained unclear. Methods We analyzed the relationship between miR-378d expression and the clinicopathological features of ESCC. We constructed miR-378d silent expression cell lines to study phenotypes and molecular mechanisms. Results The miR-378d expression was associated with good prognosis in patients with ESCC. miR-378d inhibition promoted chemo-resistance, monoclonal formation, EMT, migration, invasion, stemness, and metastasis of ESCC cells. miR-378d can target downregulated AKT1. Conclusions Therefore, miR-378d expression is a good prognostic factor of patients with ESCC and regulates the malignant phenotype of tumor cells through AKT. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02403-y.
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31
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Quaglio AEV, Santaella FJ, Rodrigues MAM, Sassaki LY, Di Stasi LC. MicroRNAs expression influence in ulcerative colitis and Crohn's disease: A pilot study for the identification of diagnostic biomarkers. World J Gastroenterol 2021; 27:7801-7812. [PMID: 34963743 PMCID: PMC8661377 DOI: 10.3748/wjg.v27.i45.7801] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/14/2021] [Accepted: 11/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) comprises two distinct diseases, Crohn's disease (CD) and ulcerative colitis (UC), both of which are chronic, relapsing inflammatory disorders of the gastrointestinal tract with a mostly unknown etiology. The incidence and prevalence of IBD are continually increasing, indicating the need for further studies to investigate the genetic determinants of these diseases. Since microRNAs (miRNAs) regulate protein translation via complementary binding to mRNA, discovering differentially expressed miRNAs (DE) in UC or CD patients could be important for diagnostic biomarker identification, assisting in the appropriate disease differentiation progressing the understanding of IBD pathogenesis. AIM To determine the miRNA expression profile in UC and CD patients and the potential pathophysiological contributions of differentially expressed miRNA. METHODS A total of 20 formalin-fixed paraffin-embedded colonic samples were collected from the Pathology Department of Botucatu Medical School at São Paulo State University (Unesp). The diagnosis of UC or CD was based on clinical, endoscopic, radiologic, and histological criteria and confirmed by histopathological analysis at the time of selection. The TaqMan™ Array Human MicroRNA A+B Cards Set v3.0 (Applied Biosystems™) platform was used to analyze 754 miRNAs. Targets of DE-miRNAs were predicted using miRNA Data Integration Portal (mirDIP) and the miRNA Target Interaction database (MiRTarBase). All statistical analyses were conducted using GraphPad Prism software. Parametric and nonparametric data were analyzed using t-tests and Mann-Whitney U tests, respectively. RESULTS The results showed that of the 754 miRNAs that were initially evaluated, 643 miRNAs were found to be expressed in at least five of the patients who were diagnosed with either CD or UC; the remaining 111 miRNAs were not considered to be expressed in these patients. The expression levels of 28 miRNAs were significantly different between the CD and UC patients (P ≤ 0.05); 13 miRNAs demonstrated a fold-change in expression level greater than 1. Five miRNAs with a downregulated expression were selected for enrichment analysis. The miRNAs whose expression levels were significantly lower in UC patients than in CD patients were enriched in certain signaling pathways that were mostly correlated with cancer-related processes and respective biomarkers. CONCLUSION MiRNAs could be used to differentiate UC from CD, and differently expressed miRNAs could help explain the distinct pathophysiology of each disease.
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Affiliation(s)
- Ana Elisa Valencise Quaglio
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTec), Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| | - Felipe Jose Santaella
- Department of Pathology, Botucatu Medical School, Sao Paulo State University (Unesp), Botucatu 18618-687, São Paulo, Brazil
| | | | - Ligia Yukie Sassaki
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University (Unesp), Botucatu 18618-687, São Paulo, Brazil
| | - Luiz Claudio Di Stasi
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTec), Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
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32
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Visconti VV, Centofanti F, Fittipaldi S, Macrì E, Novelli G, Botta A. Epigenetics of Myotonic Dystrophies: A Minireview. Int J Mol Sci 2021; 22:ijms222212594. [PMID: 34830473 PMCID: PMC8623789 DOI: 10.3390/ijms222212594] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/19/2021] [Accepted: 11/20/2021] [Indexed: 12/14/2022] Open
Abstract
Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an in trans toxic RNA mechanism, triggered by untranslated CTG and CCTG repeat expansions in the DMPK and CNBP genes for DM1 and DM2, respectively. Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of both diseases. In this review, we discuss the available information on epigenetic mechanisms that could contribute to the DMs outcome and progression. Changes in DNA cytosine methylation, chromatin remodeling and expression of regulatory noncoding RNAs are described, with the intent of depicting an epigenetic signature of DMs. Epigenetic biomarkers have a strong potential for clinical application since they could be used as targets for therapeutic interventions avoiding changes in DNA sequences. Moreover, understanding their clinical significance may serve as a diagnostic indicator in genetic counselling in order to improve genotype–phenotype correlations in DM patients.
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Affiliation(s)
- Virginia Veronica Visconti
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (F.C.); (S.F.); (E.M.); (G.N.)
| | - Federica Centofanti
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (F.C.); (S.F.); (E.M.); (G.N.)
| | - Simona Fittipaldi
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (F.C.); (S.F.); (E.M.); (G.N.)
| | - Elisa Macrì
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (F.C.); (S.F.); (E.M.); (G.N.)
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (F.C.); (S.F.); (E.M.); (G.N.)
- IRCCS (Institute for Treatment and Research) Neuromed, 86077 Pozzilli, Italy
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | - Annalisa Botta
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (V.V.V.); (F.C.); (S.F.); (E.M.); (G.N.)
- Correspondence: ; Tel.: +39-6-7259-6078
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Qu Q, Sun JY, Zhang ZY, Su Y, Li SS, Li F, Wang RX. Hub microRNAs and genes in the development of atrial fibrillation identified by weighted gene co-expression network analysis. BMC Med Genomics 2021; 14:271. [PMID: 34781940 PMCID: PMC8591905 DOI: 10.1186/s12920-021-01124-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 11/08/2021] [Indexed: 01/17/2023] Open
Abstract
Co-expression network may contribute to better understanding molecular interaction patterns underlying cellular processes. To explore microRNAs (miRNAs) expression patterns correlated with AF, we performed weighted gene co-expression network analysis (WGCNA) based on the dataset GSE28954. Thereafter, we predicted target genes using experimentally verified databases (ENOCRI, miRTarBase, and Tarbase), and overlapped genes with differentially expressed genes (DEGs) from GSE79768 were identified as key genes. Integrated analysis of association between hub miRNAs and key genes was conducted to screen hub genes. In general, we identified 3 differentially expressed miRNAs (DEMs) and 320 DEGs, predominantly enriched in inflammation-related functional items. Two significant modules (red and blue) and hub miRNAs (hsa-miR-146b-5p and hsa-miR-378a-5p), which highly correlated with AF-related phenotype, were detected by WGCNA. By overlapping the DEGs and predicted target genes, 38 genes were screened out. Finally, 9 genes (i.e. ATP13A3, BMP2, CXCL1, GABPA, LIF, MAP3K8, NPY1R, S100A12, SLC16A2) located at the core region in the miRNA-gene interaction network were identified as hub genes. In conclusion, our study identified 2 hub miRNAs and 9 hub genes, which may improve the understanding of molecular mechanisms and help to reveal potential therapeutic targets against AF.
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Affiliation(s)
- Qiang Qu
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China.,Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jin-Yu Sun
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China.,Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhen-Ye Zhang
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China
| | - Yue Su
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China.,Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shan-Shan Li
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China
| | - Feng Li
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China
| | - Ru-Xing Wang
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, China.
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Li X, Gao Z, Ma ML, Li L, Guo S. Identification of serum miR-378 and miR-575 as diagnostic indicators and predicting surgical prognosis in human epilepsy. J Med Biochem 2021; 41:184-190. [PMID: 35510204 PMCID: PMC9010044 DOI: 10.5937/jomb0-32988] [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: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 11/15/2022] Open
Abstract
Background Epilepsy (EP) is a common neurological disorder which is characterized by excessive abnormal synchronization of neuronal discharges in the brain due to chronic recurrent seizures of multiple etiologies. Variety of microRNAs have been associated with the occurrence and development of EP. This study aimed to determine the aberrant expression of miR-378 and miR-575 in EP patients to validate their potential to distinguish EP from healthy patients. Methods RT-qPCR was used to determine the expressions of miR-378 and miR-575 from serum specimens of 106 EP and 103 control individuals. Clinical indicators between EP patients and controls were assessed. Based on surgical outcome, EP patients were further divided into Engel I-IV EP. The potentials of miR-378 and miR-575 in discriminating EP from healthy participants and predicting surgical prognosis were calculated by receiver operating characteristic (ROC) analysis. Results We found the miR-378 and miR-575 were significantly declined (P<0.001) in Engel I-II and III-IV EP patients with no difference in clinical parameters compared. Moreover, miR-378 and miR-575 displayed high sensitivity, specificity, and accuracy in distinguishing EP patients and predicting surgical outcomes. Moreover, after surgical treatment, miR-378 and miR-575 levels were increased compared with those at admission, suggesting their potentials in treatment response. Conclusions miR-378 and miR-575 could be utilized as novel and non-invasive serum biomarkers in discriminating EP from healthy controls and predicting surgical outcome, shedding new insights on epileptogenesis and EP treatment.
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Affiliation(s)
- Xiuxiu Li
- Linyi Central Hospital, Department of Neurology, Linyi City, Shandong Province, China
| | - Zhiqing Gao
- Linyi Central Hospital, Department of Neurology, Linyi City, Shandong Province, China
| | - Mei Ling Ma
- Linyi Central Hospital, Department of Neurology, Linyi City, Shandong Province, China
| | - Li Li
- Linyi Central Hospital, Department of Neurology, Linyi City, Shandong Province, China
| | - Shifeng Guo
- Linyi Central Hospital, Department of Neurology, Linyi City, Shandong Province, China
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35
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Abdelaleem OO, Fouad NA, Shaker OG, Ahmed TI, Abdelghaffar NK, Eid HM, Mohamed AA, Elebiary AM, Mohamed MM, Mahmoud RH. Serum miR-224, miR-760, miR-483-5p, miR-378 and miR-375 as potential novel biomarkers in rheumatoid arthritis. Int J Clin Pract 2021; 75:e14651. [PMID: 34310809 DOI: 10.1111/ijcp.14651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/21/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which affects various tissues and organs mainly joints. Serum microRNAs are considered a new class of non-coding RNA which plays a vital role in pathogenesis of RA. METHODS The current study was conducted on 80 RA patients and 80 healthy participants. Serum expression levels of miR-224, miR-760, miR-483-5p, miR-378 and miR-375 were evaluated via real-time quantitative polymerase chain reaction (PCR). RESULTS Significant upregulation of miR-224, miR-760, miR-483-5p, miR-378 and miR-375 was reported in the present study with respect to the control group (P = .031, P = .017, P = .026, P = .036 and P = .05, respectively). Furthermore, significant positive correlation between the abovementioned microRNAs with DAS28 score (P < .001, each) was demonstrated. CONCLUSION Early detection of RA could be achieved through evaluation of serum expression of miR-224, miR-760, miR-483-5p, miR-378 and miR-375 which also may be used as targets for treatment of patients with RA.
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Affiliation(s)
- Omayma O Abdelaleem
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Nermeen A Fouad
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Olfat G Shaker
- Department of Biochemistry and molecular biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Tarek I Ahmed
- Department of Internal medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Noha K Abdelghaffar
- Department of clinical pathology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Hanaa M Eid
- Department of Medical microbiology and immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Abdelrahmaan A Mohamed
- Department of Medical microbiology and immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Ahmed Magdy Elebiary
- Department of Medical physiology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Mohamed M Mohamed
- Department of Internal medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rania H Mahmoud
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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Wang X, Liu H, Zhang Q, Zhang X, Qin Y, Zhu G, Dang J, Wang F, Yang X, Fan R. LINC00514 promotes lipogenesis and tumor progression in esophageal squamous cell carcinoma by sponging miR‑378a‑5p to enhance SPHK1 expression. Int J Oncol 2021; 59:86. [PMID: 34533201 PMCID: PMC8460062 DOI: 10.3892/ijo.2021.5266] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence has demonstrated that long non‑coding RNAs serve pivotal roles in tumor development, progression, metastasis and metabolism. However, to the best of our knowledge, the roles and molecular mechanisms of long intergenic nonprotein‑coding RNA 00514 (LINC00514) in esophageal squamous cell carcinoma (ESCC) remain unknown. The present study found that LINC00514 and sphingosine kinase 1 (SPHK1) were both upregulated in ESCC tissues and cells, and their high expression levels were closely associated with Tumor‑Node‑Metastasis stage, lymph node metastasis and poor prognosis of patients with ESCC. Functionally, knockdown of LINC00514 inhibited cell proliferation and invasion, and led to the downregulation of lipogenesis‑related proteins, including SPHK1, fatty acid synthase, acetyl‑coenzyme (Co)A carboxylase α and stearoyl‑CoA desaturase 1, whereas LINC00514 overexpression promoted cell proliferation and invasion in ESCC KYSE150 and KYSE30 cells, and upregulated expression of lipogenesis‑related proteins. Mechanistically, LINC00514 functioned as a competing endogenous RNA by sponging microRNA (miR)‑378a‑5p, resulting in the upregulation of SPHK1, which was accompanied by the activation of lipogenesis‑related pathways, to promote ESCC cell proliferation and invasion. Taken together, these findings suggest that LINC00514 may participate in ESCC lipogenesis, and targeting the LINC00514/miR‑378a‑5p/SPHK1 signaling axis may be a novel and promising therapeutic strategy for management of patients with ESCC.
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Affiliation(s)
- Xin Wang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongtao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Qing Zhang
- Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Xueying Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yue Qin
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Guangzhao Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Jinghan Dang
- Department of Clinical Medicine, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Feng Wang
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xiangxiang Yang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ruitai Fan
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Giordani C, Silvestrini A, Giuliani A, Olivieri F, Rippo MR. MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence. Front Physiol 2021; 12:734976. [PMID: 34566699 PMCID: PMC8458936 DOI: 10.3389/fphys.2021.734976] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/12/2021] [Indexed: 01/12/2023] Open
Abstract
Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential "messengers" of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.
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Affiliation(s)
- Chiara Giordani
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Andrea Silvestrini
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
- Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
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Yang C, Gao C, Liu N, Zhu Y, Zhu X, Su X, Zhang Q, Wu Y, Zhang C, Liu A, Lin W, Tao L, Yang H, Lin J. The effect of traumatic brain injury on bone healing from a novel exosome centered perspective in a mice model. J Orthop Translat 2021; 30:70-81. [PMID: 34611516 PMCID: PMC8476897 DOI: 10.1016/j.jot.2021.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 09/12/2021] [Accepted: 09/13/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND In patients with traumatic brain injury (TBI) combined with long bone fracture, the fracture healing is always faster than that of patients with single fracture, which is characterized by more callus growth at the fracture site and even ectopic ossification. Exosomes are nanoscale membrane vesicles secreted by cells, which contain cell-specific proteins, miRNAs, and mRNAs. METHODS In this study, we used exosomes as the entry point to explore the mechanism of brain trauma promoting fracture healing. We established a model of tibia fracture with TBI in mice to observe the callus growth and expression of osteogenic factors at the fracture site. Blood samples of model mice were further collected, exosomes in plasma were extracted by ultra-centrifugation method, and then identified and acted on osteoblasts cultured in vitro. The effects of exosomes on osteoblast differentiation at the cell, protein and gene levels were investigated by Western Blot and q-PCR, respectively. Furthermore, miRNA sequencing of exosomes was performed to identify a pattern of miRNAs that were present at increased or decreased levels. RESULTS The results suggested that plasma exosomes after TBI had the ability to promote the proliferation and differentiation of osteoblasts, which might be due to the increased expression of osteoblast-related miRNA in exosomes. They were transmitted to the osteoblasts at the fracture site, so as to achieve the role of promoting osteogenic differentiation. CONCLUSION The TBI-derived exosomes may have potential applications for promoting fracture healing in future. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE Plasma exosomes early after TBI have the ability to promote osteoblast proliferation and differentiation. The mechanism may be achieved by miRNA in exosomes. Plasma exosomes may be used as breakthrough clinical treatment for delayed or non-union fractures.
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Affiliation(s)
- Chengyuan Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Cheng Gao
- Department of Forensic Medicine, Soochow University, Suzhou, China
| | - Naicheng Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yitong Zhu
- Suzhou Key Laboratory for Medical Biotechnology, Suzhou Vocational Health College, Suzhou, China
| | - Xu Zhu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xinlin Su
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qin Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanglin Wu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chenhui Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ang Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weifeng Lin
- Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Luyang Tao
- Department of Forensic Medicine, Soochow University, Suzhou, China
| | - Huilin Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jun Lin
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Circulating microRNAs Signature for Predicting Response to GLP1-RA Therapy in Type 2 Diabetic Patients: A Pilot Study. Int J Mol Sci 2021; 22:ijms22179454. [PMID: 34502360 PMCID: PMC8431190 DOI: 10.3390/ijms22179454] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/27/2021] [Accepted: 08/27/2021] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes (T2D) represents one of the major health issues of this century. Despite the availability of an increasing number of anti-hyperglycemic drugs, a significant proportion of patients are inadequately controlled, thus highlighting the need for novel biomarkers to guide treatment selection. MicroRNAs (miRNAs) are small non-coding RNAs, proposed as useful diagnostic/prognostic markers. The aim of our study was to identify a miRNA signature occurring in responders to glucagon-like peptide 1 receptor agonists (GLP1-RA) therapy. We investigated the expression profile of eight T2D-associated circulating miRNAs in 26 prospectively evaluated diabetic patients in whom GLP1-RA was added to metformin. As expected, GLP1-RA treatment induced significant reductions of HbA1c and body weight, both after 6 and 12 months of therapy. Of note, baseline expression levels of the selected miRNAs revealed two distinct patient clusters: “high expressing” and “low expressing”. Interestingly, a significantly higher percentage of patients in the high expression group reached the glycemic target after 12 months of treatment. Our findings suggest that the evaluation of miRNA expression could be used to predict the likelihood of an early treatment response to GLP1-RA and to select patients in whom to start such treatment, paving the way to a personalized medicine approach.
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Wehbe Z, Kreydiyyeh S. Cow's milk may be delivering potentially harmful undetected cargoes to humans. Is it time to reconsider dairy recommendations? Nutr Rev 2021; 80:874-888. [PMID: 34338770 DOI: 10.1093/nutrit/nuab046] [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] [Indexed: 11/13/2022] Open
Abstract
Mammalian evolution has shaped milk into a species-specific vehicle for post-natal development, continuing what began within the mother's womb. Increased consumption of the mother's breast milk is associated with the most adequate metabolic programming and lowers the incidence of the diseases of civilization during adulthood. An abundance of short sequences of RNA, known as microRNA, exists in mammalian breast milk, enclosed within robust small extracellular vesicles known as exosomes. These microRNAs can epigenetically regulate over 60% of human genes. When cow's milk is consumed by humans, the bovine exosomes are transported through the gastrointestinal tract, detected intact in the blood stream, and taken up by target cells, where they alter protein expression. The aim of this review was to highlight the role of dairy exosomes and microRNA, and of the type of dairy product consumed, in human diseases. Given that microRNAs are involved in a vast array of physiological processes and associated with several diseases, perhaps caution should be practiced with regard to human consumption of dairy, particularly for individuals within developmentally critical time frames, such as pregnant and lactating mothers, and young children.
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Affiliation(s)
- Zena Wehbe
- Z. Wehbe and S. Kreydiyyeh are with the Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
| | - Sawsan Kreydiyyeh
- Z. Wehbe and S. Kreydiyyeh are with the Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
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Martyniak A, Andrysiak K, Motais B, Coste S, Podkalicka P, Ferdek P, Stępniewski J, Dulak J. Generation of microRNA-378a-deficient hiPSC as a novel tool to study its role in human cardiomyocytes. J Mol Cell Cardiol 2021; 160:128-141. [PMID: 34329686 DOI: 10.1016/j.yjmcc.2021.07.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 06/29/2021] [Accepted: 07/23/2021] [Indexed: 12/17/2022]
Abstract
microRNA-378a (miR-378a) is one of the most highly expressed microRNAs in the heart. However, its role in the human cardiac tissue has not been fully understood. It was observed that miR-378a protects cardiomyocytes from hypertrophic growth by regulation of IGF1R and the expression of downstream kinases. Increased levels of miR-378a were reported in the serum of Duchenne muscular dystrophy (DMD) patients and female carriers of DMD gene-associated mutations with developed cardiomyopathy. In order to shed more light on the role of miR-378a in human cardiomyocytes and its potential involvement in DMD-related cardiomyopathy, we generated two human induced pluripotent stem cell (hiPSC) models; one with deletion of miR-378a and the second one with deletion of DMD exon 50 leading to the DMD phenotype. Our results indicate that lack of miR-378a does not influence the pluripotency of hiPSC and their ability to differentiate into cardiomyocytes (hiPSC-CM). miR-378a-deficient hiPSC-CM exhibited, however, significantly bigger size compared to the isogenic control cells, indicating the role of this miRNA in the hypertrophic growth of human cardiomyocytes. In accordance, the level of NFATc3, phosphoAKT, phosphoERK and ERK was higher in these cells compared to the control counterparts. A similar effect was achieved by silencing miR-378a with antagomirs. Of note, the percentage of cells with nuclear localization of NFATc3 was higher in miR-378a-deficient hiPSC-CM. Analysis of electrophysiological properties and Ca2+ oscillations revealed the decrease in the spike slope velocity and lower frequency of calcium spikes in miR-378a-deficient hiPSC-CM. Interestingly, the level of miR-378a increased gradually during cardiac differentiation of hiPSC. Of note, it was low until day 15 in differentiating DMD-deficient hiPSC-CM and then rose to a similar level as in the isogenic control counterparts. In summary, our findings confirmed the utility of hiPSC-based models for deciphering the role of miR-378a in the control and diseased human cardiomyocytes.
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Affiliation(s)
- Alicja Martyniak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Kalina Andrysiak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Benjamin Motais
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Solène Coste
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Paweł Ferdek
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Jacek Stępniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
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Ding L, Wang M, Qin S, Xu L. The Roles of MicroRNAs in Tendon Healing and Regeneration. Front Cell Dev Biol 2021; 9:687117. [PMID: 34277629 PMCID: PMC8283311 DOI: 10.3389/fcell.2021.687117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/11/2021] [Indexed: 01/20/2023] Open
Abstract
Tendons connect the muscle abdomen of skeletal muscles to the bone, which transmits the force generated by the muscle abdomen contraction and pulls the bone into motion. Tendon injury is a common clinical condition occurring in certain populations, such as repeated tendon strains in athletes. And it can lead to substantial pain and loss of motor function, in severe cases, significant disability. Tendon healing and regeneration have attracted growing interests. Some treatments including growth factors, stem cell therapies and rehabilitation programs have been tried to improve tendon healing. However, the basic cellular biology and pathology of tendons are still not fully understood, and the management of tendon injury remains a considerable challenge. Regulating gene expression at post-transcriptional level, microRNA (miRNA) has been increasingly recognized as essential regulators in the biological processes of tendon healing and regeneration. A wide range of miRNAs in tendon injury have been shown to play vital roles in maintaining and regulating its physiological function, as well as regulating the tenogenic differentiation potential of stem cells. In this review, we show the summary of the latest information on the role of miRNAs in tendon healing and regeneration, and also discuss potentials for miRNA-directed diagnosis and therapy in tendon injuries and tendinopathy, which may provide new theoretical foundation for tenogenesis and tendon healing.
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Affiliation(s)
- Lingli Ding
- Lingnan Medical Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Min Wang
- Lingnan Medical Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shengnan Qin
- Department of Orthopaedics, Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, China
| | - Liangliang Xu
- Lingnan Medical Research Center, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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Florczyk-Soluch U, Polak K, Dulak J. The multifaceted view of heart problem in Duchenne muscular dystrophy. Cell Mol Life Sci 2021; 78:5447-5468. [PMID: 34091693 PMCID: PMC8257522 DOI: 10.1007/s00018-021-03862-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/29/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022]
Abstract
Dystrophin is a large protein serving as local scaffolding repetitively bridging cytoskeleton and the outside of striated muscle cell. As such dystrophin is a critical brick primarily in dystrophin-associated protein complex (DAGC) and in a larger submembranous unit, costamere. Accordingly, the lack of functional dystrophin laying at the root of Duchenne muscular dystrophy (DMD) drives sarcolemma instability. From this point on, the cascade inevitably leading to the death of myocyte begins. In cardiomyocytes, intracellular calcium overload and related mitochondrial-mediated cell death mainly contribute to myocardial dysfunction and dilation while other protein dysregulation and/or mislocalization may affect electrical conduction system and favor arrhythmogenesis. Although clinically DMD manifests as progressive muscle weakness and skeletal muscle symptoms define characteristic of DMD, it is the heart problem the biggest challenge that most often develop in the form of dilated cardiomyopathy (DCM). Current standards of treatment and recent progress in respiratory care, introduced in most settings in the 1990s, have improved quality of life and median life expectancy to 4th decade of patient's age. At the same time, cardiac causes of death related to DMD increases. Despite preventive and palliative cardiac treatments available, the prognoses remain poor. Direct therapeutic targeting of dystrophin deficiency is critical, however, hindered by the large size of the dystrophin cDNA and/or stochastic, often extensive genetic changes in DMD gene. The correlation between cardiac involvement and mutations affecting specific dystrophin isoforms, may provide a mutation-specific cardiac management and novel therapeutic approaches for patients with CM. Nonetheless, the successful cardiac treatment poses a big challenge and may require combined therapy to combat dystrophin deficiency and its after-effects (critical in DMD pathogenesis). This review locates the multifaceted heart problem in the course of DMD, balancing the insights into basic science, translational efforts and clinical manifestation of dystrophic heart disease.
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Affiliation(s)
- Urszula Florczyk-Soluch
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Katarzyna Polak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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Dong Z, Gu H, Guo Q, Liang S, Xue J, Yao F, Liu X, Li F, Liu H, Sun L, Zhao K. Profiling of Serum Exosome MiRNA Reveals the Potential of a MiRNA Panel as Diagnostic Biomarker for Alzheimer's Disease. Mol Neurobiol 2021; 58:3084-3094. [PMID: 33629272 DOI: 10.1007/s12035-021-02323-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 02/05/2021] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease in the older adults. Although much effort has been made in the analyses of diagnostic biomarkers, such as amyloid-β, tau, and neurofilament light chain, identifying peripheral blood-based biomarkers is in extremely urgent need for their minimal invasiveness and more convenience. Here we characterized the miRNA profile by RNA sequencing in human serum exosomes from AD patients and healthy controls (HC) to investigate its potential for AD diagnosis. Subsequently, Gene Ontology analysis and pathway analysis were performed for the targeted genes from the differentially expressed miRNAs. These basic functions were differentially enriched, including cell adhesion, regulation of transcription, and the ubiquitin system. Functional network analysis highlighted the pathways of proteoglycans in cancer, viral carcinogenesis, signaling pathways regulating pluripotency of stem cells, and cellular senescence in AD. A total of 24 miRNAs showed significantly differential expression between AD and HC with more than ± 2.0-fold change at p value < 0.05 and at least 50 reads for each sample. Logistic regression analysis established a model for AD prediction by serum exosomal miR-30b-5p, miR-22-3p, and miR-378a-3p. Sequencing results were validated using quantitative reverse transcription PCR. The data showed that miR-30b-5p, miR-22-3p, and miR-378a-3p were significantly deregulated in AD, with area under the curve (AUC) of 0.668, 0.637, and 0.718, respectively. The combination of the three miRs gained a better diagnostic capability with AUC of 0.880. This finding revealed a miR panel as potential biomarker in the peripheral blood to distinguish AD from HC.
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Affiliation(s)
- Zhiwu Dong
- Department of Laboratory Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 147 Jiankang Road, Jinshan District, Shanghai, 201599, People's Republic of China.
| | - Hongjun Gu
- Shanghai Jinshan Zhongren Aged Care Hospital, Shanghai, 201501, China
| | - Qiang Guo
- Department of Ultrasound Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 201599, China
| | - Shuang Liang
- Department of Laboratory Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 147 Jiankang Road, Jinshan District, Shanghai, 201599, People's Republic of China
| | - Jian Xue
- Shanghai Jinshan Zhongren Aged Care Hospital, Shanghai, 201501, China
| | - Feng Yao
- Shanghai Jinshan Zhongren Aged Care Hospital, Shanghai, 201501, China
| | - Xianglu Liu
- Department of Laboratory Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 147 Jiankang Road, Jinshan District, Shanghai, 201599, People's Republic of China
| | - Feifei Li
- Department of Laboratory Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 147 Jiankang Road, Jinshan District, Shanghai, 201599, People's Republic of China
| | - Huiling Liu
- Department of Laboratory Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 147 Jiankang Road, Jinshan District, Shanghai, 201599, People's Republic of China
| | - Li Sun
- Department of Laboratory Medicine, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 147 Jiankang Road, Jinshan District, Shanghai, 201599, People's Republic of China
| | - Kewen Zhao
- Department of Pathophysiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, People's Republic of China
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Fouda E, Elrazek Midan DA, Ellaban R, El-kousy S, Arafat E. The diagnostic and prognostic role of MiRNA 15b and MiRNA 378a in neonatal sepsis. Biochem Biophys Rep 2021; 26:100988. [PMID: 33817353 PMCID: PMC8010206 DOI: 10.1016/j.bbrep.2021.100988] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Sepsis is one of the major factors for both term and preterm babies with morbidity and mortality. On the basis of recent clinical trials, altered circulating micro-RNAs (miRNAs) may serve as possible biomarkers in sepsis for diagnosis and prognosis. The aim of this research is to assess the diagnostic and prognostic biomarkers of miRNA 15b and miRNA 378a for neonatal sepsis. SUBJECTS & METHODS This study was carried out 25 neonates with sepsis admitted to neonatal ICU of Menoufia University Hospital and 25 healthy controls from February 2019 to May 2020. The relative quantification (RQ) of miRNA-15b and miRNA-378a expression was assessed using real time PCR technique. Results: Our results demonstrated that patients with sepsis had significantly higher level of MiRNA-15b than the healthy volunteers. On the other hand, patients with sepsis had significantly lower level of MiRNA-378a than the healthy volunteers. The ROC curve showed that the serum MiRNA-15b was a significant discriminator of sepsis with a combined sensitivity and specificity of 76% and 88% with cutoff point of 3.24. In addition, serum MiRNA-378a was a significant discriminator of sepsis with a combined sensitivity and specificity of 60% and 88% with cutoff point of 0.361. The miRNA-15b expression significantly correlated positive with respiratory rate (r =0.415,p =0.039), WBCs (r = 0.408, p =0.043), and CRP (r =0.407, p=0.043). Likewise, miRNA-378a expression significantly correlated negative with respiratory rate (r =-0.415p =0.024), WBCs (r =- 0.442, p =0.027), and CRP (r =- 0.459, p=0.021). CONCLUSION Both MiRNA 15b and 378a are promising biomarker for neonatal sepsis.
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Affiliation(s)
- Eman Fouda
- Faculty of Science, Menoufia University, Egypt
| | | | - Rania Ellaban
- Diploma of Biochemistry, Faculty of Science, Menoufia University, Egypt
| | | | - Eman Arafat
- Faculty of Medicine, Menoufia University, Egypt
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Sileno S, Beji S, D'Agostino M, Carassiti A, Melillo G, Magenta A. microRNAs involved in psoriasis and cardiovascular diseases. VASCULAR BIOLOGY 2021; 3:R49-R68. [PMID: 34291190 PMCID: PMC8284950 DOI: 10.1530/vb-21-0007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022]
Abstract
Psoriasis is a chronic inflammatory disease involving the skin. Both genetic and environmental factors play a pathogenic role in psoriasis and contribute to the severity of the disease. Psoriasis, in fact, has been associated with different comorbidities such as diabetes, metabolic syndrome, gastrointestinal or kidney diseases, cardiovascular disease (CVD), and cerebrovascular diseases (CeVD). Indeed, life expectancy in severe psoriasis is reduced by up to 5 years due to CVD and CeVD. Moreover, patients with severe psoriasis have a higher prevalence of traditional cardiovascular (CV) risk factors, including dyslipidemia, diabetes, smoking, and hypertension. Further, systemic inflammation is associated with oxidative stress increase and induces endothelial damage and atherosclerosis progression. Different miRNA have been already described in psoriasis, both in the skin tissues and in the blood flow, to play a role in the progression of disease. In this review, we will summarize and discuss the most important miRNAs that play a role in psoriasis and are also linked to CVD.
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Affiliation(s)
- Sara Sileno
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Sara Beji
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Marco D'Agostino
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Alessandra Carassiti
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory Via Monti di Creta, Rome, Italy
| | - Guido Melillo
- Unit of Cardiology, IDI-IRCCS, Via Monti di Creta, Rome, Italy
| | - Alessandra Magenta
- Institute of Translational Pharmacology (IFT), National Research Council of Italy (CNR), Via Fosso del Cavaliere, Rome, Italy
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Khromova NV, Fedorov AV, Ma Y, Kondratov KA, Prikhodko SS, Ignatieva EV, Artemyeva MS, Anopova AD, Neimark AE, Kostareva AA, Babenko AY, Dmitrieva RI. Regulatory Action of Plasma from Patients with Obesity and Diabetes towards Muscle Cells Differentiation and Bioenergetics Revealed by the C2C12 Cell Model and MicroRNA Analysis. Biomolecules 2021; 11:769. [PMID: 34063883 PMCID: PMC8224077 DOI: 10.3390/biom11060769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 11/17/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are often combined and pathologically affect many tissues due to changes in circulating bioactive molecules. In this work, we evaluated the effect of blood plasma from obese (OB) patients or from obese patients comorbid with diabetes (OBD) on skeletal muscle function and metabolic state. We employed the mouse myoblasts C2C12 differentiation model to test the regulatory effect of plasma exposure at several levels: (1) cell morphology; (2) functional activity of mitochondria; (3) expression levels of several mitochondria regulators, i.e., Atgl, Pgc1b, and miR-378a-3p. Existing databases were used to computationally predict and analyze mir-378a-3p potential targets. We show that short-term exposure to OB or OBD patients' plasma is sufficient to affect C2C12 properties. In fact, the expression of genes that regulate skeletal muscle differentiation and growth was downregulated in both OB- and OBD-treated cells, maximal mitochondrial respiration rate was downregulated in the OBD group, while in the OB group, a metabolic switch to glycolysis was detected. These alterations correlated with a decrease in ATGL and Pgc1b expression in the OB group and with an increase of miR-378a-3p levels in the OBD group.
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Affiliation(s)
- Natalya V. Khromova
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Anton V. Fedorov
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Yi Ma
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Kirill A. Kondratov
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Stanislava S. Prikhodko
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Elena V. Ignatieva
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Marina S. Artemyeva
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Anna D. Anopova
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Aleksandr E. Neimark
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Anna A. Kostareva
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
- Center for Molecular Medicine, Department of Women’s and Children’s Health, Karolinska Institute, 17177 Stockholm, Sweden
| | - Alina Yu. Babenko
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
| | - Renata I. Dmitrieva
- National Almazov Medical Research Centre, Institute of Molecular Biology and Genetics, 197341 Saint-Petersburg, Russia; (A.V.F.); (Y.M.); (K.A.K.); (S.S.P.); (E.V.I.); (M.S.A.); (A.D.A.); (A.E.N.); (A.A.K.); (A.Y.B.); (R.I.D.)
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Chen W, Huang L, Liang J, Ye Y, He S, Niu J. RETRACTED: Hepatocellular carcinoma cells-derived exosomal microRNA-378b enhances hepatocellular carcinoma angiogenesis. Life Sci 2021; 273:119184. [PMID: 33577844 DOI: 10.1016/j.lfs.2021.119184] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 2D/G/H, 4C, 5F and 6D, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Wei Chen
- Department of Gastroenterology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 3420272, Hubei, China.
| | - Li Huang
- Neurology Department, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 3420272, Hubei, China
| | - Junhua Liang
- Department of Gastroenterology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 3420272, Hubei, China
| | - Yingjian Ye
- Department of Gastroenterology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 3420272, Hubei, China
| | - Shan He
- Department of Gastroenterology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 3420272, Hubei, China
| | - Junli Niu
- Department of Gastroenterology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 3420272, Hubei, China
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Liang Y, Wang M, Wang C, Liu Y, Naruse K, Takahashi K. The Mechanisms of the Development of Atherosclerosis in Prediabetes. Int J Mol Sci 2021; 22:ijms22084108. [PMID: 33921168 PMCID: PMC8071517 DOI: 10.3390/ijms22084108] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022] Open
Abstract
Lifestyle changes, such as overeating and underexercising, can increase the risk of prediabetes. Diabetes is one of the leading causes of atherosclerosis, and recently it became clear that the pathophysiology of atherosclerosis progresses even before the onset of diabetic symptoms. In addition to changes in platelets and leukocytes in the hyperglycemic state and damage to vascular endothelial cells, extracellular vesicles and microRNAs were found to be involved in the progression of prediabetes atherosclerosis. This review discusses the cellular and molecular mechanisms of these processes, with an intention to enable a comprehensive understanding of the pathophysiology of prediabetes and atherosclerosis.
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50
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Rovira-Llopis S, Díaz-Rúa R, Grau-del Valle C, Iannantuoni F, Abad-Jimenez Z, Bosch-Sierra N, Panadero-Romero J, Victor VM, Rocha M, Morillas C, Bañuls C. Characterization of Differentially Expressed Circulating miRNAs in Metabolically Healthy versus Unhealthy Obesity. Biomedicines 2021; 9:321. [PMID: 33801145 PMCID: PMC8004231 DOI: 10.3390/biomedicines9030321] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/30/2022] Open
Abstract
Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pathways were upregulated in the MUO group. Among these miRNAs, hsa-miR-6796-5p and hsa-miR-4697-3p, which regulate oxidative stress, showed significant correlations with glucose, triglycerides, HbA1c and HDLc. Our results provide evidence of a pattern of differentially expressed miRNAs in obesity according to MetS, and identify those related to insulin resistance and lipid metabolism pathways.
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Affiliation(s)
- Susana Rovira-Llopis
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
| | - Rubén Díaz-Rúa
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
| | - Carmen Grau-del Valle
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
| | - Francesca Iannantuoni
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
| | - Zaida Abad-Jimenez
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
| | - Neus Bosch-Sierra
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
| | | | - Víctor M. Victor
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
- CIBERehd-Department of Pharmacology and Physiology, University of Valencia, 46015 Valencia, Spain
- Department of Physiology, University of Valencia, 46015 Valencia, Spain
| | - Milagros Rocha
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
- CIBERehd-Department of Pharmacology and Physiology, University of Valencia, 46015 Valencia, Spain
| | - Carlos Morillas
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
- Department of Medicine, University of Valencia, 46015 Valencia, Spain
| | - Celia Bañuls
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (S.R.-L.); (R.D.-R.); (C.G.-d.V.); (F.I.); (Z.A.-J.); (N.B.-S.); (V.M.V.); (M.R.); (C.M.)
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