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Nedel W, Strogulski NR, Kopczynski A, Portela LV. Assessment of mitochondrial function and its prognostic role in sepsis: a literature review. Intensive Care Med Exp 2024; 12:107. [PMID: 39585590 PMCID: PMC11589057 DOI: 10.1186/s40635-024-00694-9] [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: 08/01/2024] [Accepted: 11/08/2024] [Indexed: 11/26/2024] Open
Abstract
Sepsis is characterized by a dysregulated and excessive systemic inflammatory response to infection, associated with vascular and metabolic abnormalities that ultimately lead to organ dysfunction. In immune cells, both non-oxidative and oxidative metabolic rates are closely linked to inflammatory responses. Mitochondria play a central role in supporting these cellular processes by utilizing metabolic substrates and synthesizing ATP through oxygen consumption. To meet fluctuating cellular demands, mitochondria must exhibit adaptive plasticity underlying bioenergetic capacity, biogenesis, fusion, and fission. Given their role as a hub for various cellular functions, mitochondrial alterations induced by sepsis may hold significant pathophysiological implications and impact on clinical outcomes. In patients, mitochondrial DNA concentration, protein expression levels, and bioenergetic profiles can be accessed via tissue biopsies or isolated peripheral blood cells. Clinically, monocytes and lymphocytes serve as promising matrices for evaluating mitochondrial function. These mononuclear cells are highly oxidative, mitochondria-rich, routinely monitored in blood, easy to collect and process, and show a clinical association with immune status. Hence, mitochondrial assessments in immune cells could serve as biomarkers for clinical recovery, immunometabolic status, and responsiveness to oxygen and vasopressor therapies in sepsis. These characteristics underscore mitochondrial parameters in both tissues and immune cells as practical tools for exploring underlying mechanisms and monitoring septic patients in intensive care settings. In this article, we examine pathophysiological aspects, key methods for measuring mitochondrial function, and prominent studies in this field.
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Affiliation(s)
- Wagner Nedel
- Intensive Care Unit, Grupo Hospitalar Conceição (GHC), Porto Alegre, Brazil.
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
- Unidade de Terapia Intensiva, Hospital Nossa Senhora da Conceição, Av Francisco Trein, 596-primeiro andar, Porto Alegre, RS, Brazil.
| | - Nathan Ryzewski Strogulski
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland
| | - Afonso Kopczynski
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Programa de Pós-Graduação Em Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Luis Valmor Portela
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Programa de Pós-Graduação Em Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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Shin HE, Jang JY, Jung H, Won CW, Kim M. MicroRNAs as commonly expressed biomarkers for sarcopenia and frailty: A systematic review. Exp Gerontol 2024; 197:112600. [PMID: 39349187 DOI: 10.1016/j.exger.2024.112600] [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: 06/17/2024] [Revised: 09/03/2024] [Accepted: 09/27/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND Coexistent sarcopenia and frailty is more strongly associated with adverse health outcomes than each condition alone. As the importance of coexistent sarcopenia and frailty increases, exploring their underlying mechanisms is warranted. Recently, noncoding ribonucleic acids (RNAs) have been suggested as potential biomarkers of sarcopenia and frailty. This systematic review aimed to summarize noncoding RNAs commonly expressed in sarcopenia and frailty, and to search the predicted target genes and biological pathways of them. METHODS We systematically searched the literatures on PubMed, Embase, Cochrane Library, Web of Science, and Scopus for literature published till November 15, 2023. A total of 7,202 literatures were initially retrieved. After de-duplication, 34 studies (26 sarcopenia-related and 8 frailty-related) were full-text reviewed, and 15 studies (11 sarcopenia-related and 4 frailty-related) were finally included. RESULTS miR-29a-3p, miR-29b-3p, and miR-328 were identified as commonly expressed in same direction in sarcopenia and frailty. These microRNAs (miRNAs), identified in the literature search using PubMed, modulate transforming growth factor-β signaling via extracellular matrix components and calcineurin/nuclear factor of activated T cells 3 signaling via sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a, which are involved in regulating skeletal muscle fibrosis and the growth of slow-twitch muscle fibers, respectively. miR-155-5p, miR-486, and miR-23a-3p were also commonly expressed in two conditions, although in different or conflicting directions. CONCLUSION In this systematic review, we highlight the potential of shared miRNAs that exhibit consistent expression patterns as biomarkers for the early diagnosis and progression assessment of both sarcopenia and frailty.
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Affiliation(s)
- Hyung Eun Shin
- Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA 30329, USA; Department of Health Sciences and Technology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae Young Jang
- Department of Biomedical Science and Technology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Heeeun Jung
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Chang Won Won
- Elderly Frailty Research Center, Department of Family Medicine, College of Medicine, Kyung Hee University, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
| | - Miji Kim
- Department of Health Sciences and Technology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
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Toghiani R, Azimian Zavareh V, Najafi H, Mirian M, Azarpira N, Abolmaali SS, Varshosaz J, Tamaddon AM. Hypoxia-preconditioned WJ-MSC spheroid-derived exosomes delivering miR-210 for renal cell restoration in hypoxia-reoxygenation injury. Stem Cell Res Ther 2024; 15:240. [PMID: 39080774 PMCID: PMC11289969 DOI: 10.1186/s13287-024-03845-7] [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: 04/09/2024] [Accepted: 07/11/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Recent advancements in mesenchymal stem cell (MSC) technology have paved the way for innovative treatment options for various diseases. These stem cells play a crucial role in tissue regeneration and repair, releasing local anti-inflammatory and healing signals. However, challenges such as homing issues and tumorigenicity have led to exploring MSC-exosomes as a promising alternative. MSC-exosomes have shown therapeutic potential in conditions like renal ischemia-reperfusion injury, but low production yields hinder their clinical use. METHODS To address this limitation, we examined hypoxic preconditioning of Wharton jelly-derived MSCs (WJ-MSCs) 3D-cultured in spheroids on isolated exosome yields and miR-21 expression. We then evaluated their capacity to load miR-210 into HEK-293 cells and mitigate ROS production, consequently enhancing their survival and migration under hypoxia-reoxygenation conditions. RESULTS MiR-210 overexpression was significantly induced by optimized culture and preconditioning conditions, which also improved the production yield of exosomes from grown MSCs. The exosomes enriched with miR-210 demonstrated a protective effect by improving survival, reducing apoptosis and ROS accumulation in damaged renal cells, and ultimately promoting cell migration. CONCLUSION The present study underscores the possibility of employing advanced techniques to maximize the therapeutic attributes of exosomes produced from WJ-MSC spheroid for improved recovery outcomes in ischemia-reperfusion injuries.
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Affiliation(s)
- Reyhaneh Toghiani
- Department of Pharmaceutical Nanotechnology, Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vajihe Azimian Zavareh
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Hanyieh Najafi
- Department of Pharmaceutical Nanotechnology, Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sadat Abolmaali
- Department of Pharmaceutical Nanotechnology, Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jaleh Varshosaz
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Mohammad Tamaddon
- Department of Pharmaceutical Nanotechnology, Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Meruvu S, Ding Z, Choudhury M. Mono-(2-ethylhexyl) phthalate induces trophoblast hypoxia and mitochondrial dysfunction through HIF-1α-miR-210-3p axis in HTR-8/SVneo cell line. Curr Res Toxicol 2024; 7:100188. [PMID: 39175913 PMCID: PMC11338994 DOI: 10.1016/j.crtox.2024.100188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/24/2024] Open
Abstract
The exposure to the ubiquitous phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) is connected to dysregulated trophoblast function and placenta health; however, the underlying mechanisms preluding this scenario remain to be elucidated. In this study, we explored the hypoxemic effects of MEHP on a human placental first-trimester trophoblast cell line (HTR-8/Svneo). MEHP-treated trophoblast cells displayed significantly increased levels of oxidative stress and hypoxia-inducible factor-1 alpha (HIF-1α) attributed by the induction of hypoxia. Further, HIF-1α exhibited higher DNA binding activity and upregulated gene expression of its downstream target vascular endothelial growth factor A (VEGFA). The hypoxia-induced microRNA miR-210-3p was also significantly increased upon MEHP treatment followed by disrupted mitochondrial ATP generation and membrane potential. This was identified to possibly be facilitated by lowered mitochondrial DNA copy number and inhibited expression of electron transport chain subunits, such as mitochondrial complex-IV. These results suggest potential adverse effects of MEHP exposure in a trophoblast cell line mediated by HIF-1α and the epigenetic modulator miR-210-3p. Chronic placental hypoxia and oxidative stress have long been implicated in the pathogenesis of pregnancy complications such as preeclampsia. As we've revealed genetic and epigenetic factors underscoring a potential mechanism induced by MEHP, this brings to light another significant implication of phthalate exposure on maternal and fetal health.
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Affiliation(s)
- Sunitha Meruvu
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, 1114 TAMU, College Station, TX 77843-0000, USA
| | - Zehuan Ding
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, 1114 TAMU, College Station, TX 77843-0000, USA
| | - Mahua Choudhury
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, 1114 TAMU, College Station, TX 77843-0000, USA
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Wang B, Xu Y, Huang Y, Shao S, Xu D, Zhang Y, Pang L, Nan Z, Ye Q, Wang Y, Wang W, Jin K, Yuan L. miR-210-5p Promotes Pulmonary Hypertension by Blocking ATP2A2. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07568-y. [PMID: 38656637 DOI: 10.1007/s10557-024-07568-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/26/2024] [Indexed: 04/26/2024]
Abstract
AIM Aberrant expression of ATPase sarcoplasmic/endoplasmic retic Ca2+ transporting 2 (ATP2A2) has attracted attention for its pathophysiologic role in pulmonary hypertension (PH). Several miRNAs, including miR-210-5p, have also been reported to be pathogenic factors in PH, but their exact mechanisms remain unknown. This study aimed to elucidate the potential mechanisms of miR-210-5p and ATP2A2 in MCT-induced PH. METHODS Eighteen Sprague-Dawley rats were randomly divided into two groups-monoclonal (MCT) group and control group-and then administered MCT (60 mg/kg) and saline, respectively. mPAP, PVR, RVHI, WT%, and WA% were significantly increased in PH rats after 3 weeks, confirming that the modeling of PH rats was successful. Subsequently, we determined the expression of ATP2A2 and miR-210-5p in lung tissues using WB and qRT-PCR methods. We established an in vitro model using BMP4 and TGF-β1 treatment of pulmonary artery smooth muscle cells (PASMCs) and examined the expression of ATP2A2 and miR-210-5p using the same method. To further elucidate the regulatory relationship between ATP2A2 and miR-210-5p, we altered the expression level of miR-210-5p and detected the corresponding changes in ATP2A2 levels. In addition, we demonstrated the relationship by dual luciferase experiments. Finally, the effect of silencing ATP2A2 could be confirmed by the level of cell membrane Ca2+ in PAMSCs. RESULTS Up-regulation of miR-210-5p and down-regulation of ATP2A2 were observed in the MCT group compared with the control group, which was confirmed in the in vitro model. In addition, elevated miR-210-5p expression decreased the level of ATP2A2 while increasing the proliferation of PASMCs, and the results of the dual luciferase assay further confirmed that ATP2A2 is a downstream target of miR-210-5p. Additionally, silencing ATP2A2 resulted in increased cytoplasmic Ca2+ levels in PAMSCs. CONCLUSION In MCT-induced PH, miR-210-5p promotes pulmonary vascular remodeling by inhibiting ATP2A2.
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Affiliation(s)
- Boxiang Wang
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yidin Xu
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yilun Huang
- Alberta Institute, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Siming Shao
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Dongshan Xu
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yiying Zhang
- Alberta Institute, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Lingxia Pang
- Functionality Experimental Teaching Center, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zhuofan Nan
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Qianxi Ye
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China
- Department of Cardiovascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, People's Republic of China
| | - Yang Wang
- Department of Pathophysiology, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Wantie Wang
- Department of Pathophysiology, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Keke Jin
- Department of Pathophysiology, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Linbo Yuan
- Department of Physiology, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China.
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Hasani F, Masrour M, Jazi K, Ahmadi P, Hosseini SS, Lu VM, Alborzi A. MicroRNA as a potential diagnostic and prognostic biomarker in brain gliomas: a systematic review and meta-analysis. Front Neurol 2024; 15:1357321. [PMID: 38487328 PMCID: PMC10937740 DOI: 10.3389/fneur.2024.1357321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 02/12/2024] [Indexed: 03/17/2024] Open
Abstract
Introduction Brain neoplasms and central nervous system (CNS) disorders, particularly gliomas, have shown a notable increase in incidence over the last three decades, posing significant diagnostic and therapeutic challenges. MicroRNAs (miRNAs) have emerged as promising biomarkers due to their regulatory role in gene expression, offering potential enhancements in glioma diagnosis and prognosis. Methods This systematic review and meta-analysis, adhering to PRISMA guidelines, included 25 studies for diagnostic accuracy and 99 for prognostic analysis, published until August 27th, 2023. Studies were identified through comprehensive searches of PubMed, Web of Science, and Scopus databases. Inclusion criteria encompassed peer-reviewed original research providing sensitivity, specificity, and area under the curve (AUC) for miRNAs in glioma diagnosis, as well as survival outcomes with hazard ratios (HRs) or mean survival. Results and discussion Meta-analysis demonstrated miRNAs' high diagnostic accuracy, with a pooled sensitivity of 0.821 (95% CI: 0.781-0.855) and specificity of 0.831 (95% CI: 0.792-0.865), yielding an AUC of 0.893. Subgroup analysis by specimen type revealed consistent accuracy across blood, cerebrospinal fluid (CSF), and tissue samples. Our results also showed miRNAs can be potential prognostic biomarkers. miRNAs showed significant associations with overall survival (OS) (pooled HR: 2.0221; 95% CI: 1.8497-2.2105), progression-free survival (PFS) (pooled HR: 2.4248; 95% CI: 1.8888-3.1128), and disease-free survival (DFS) (pooled HR: 1.8973; 95% CI: 1.1637-3.0933) in tissue specimens. These findings underscore miRNAs' potential as valuable biomarkers for improving glioma diagnosis and prognosis, offering insights for enhancing clinical decision-making and patient outcomes.
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Affiliation(s)
- Fatemeh Hasani
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Gastroenterology and Hepatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mahdi Masrour
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kimia Jazi
- Clinical Research and Development Center, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Payam Ahmadi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saba sadat Hosseini
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Gastroenterology and Hepatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Victor M. Lu
- Department of Neurosurgery, University of Miami, Miami, FL, United States
| | - Amirmohammad Alborzi
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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Chellini F, Tani A, Parigi M, Palmieri F, Garella R, Zecchi-Orlandini S, Squecco R, Sassoli C. HIF-1α/MMP-9 Axis Is Required in the Early Phases of Skeletal Myoblast Differentiation under Normoxia Condition In Vitro. Cells 2023; 12:2851. [PMID: 38132171 PMCID: PMC10742321 DOI: 10.3390/cells12242851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Hypoxia-inducible factor (HIF)-1α represents an oxygen-sensitive subunit of HIF transcriptional factor, which is usually degraded in normoxia and stabilized in hypoxia to regulate several target gene expressions. Nevertheless, in the skeletal muscle satellite stem cells (SCs), an oxygen level-independent regulation of HIF-1α has been observed. Although HIF-1α has been highlighted as a SC function regulator, its spatio-temporal expression and role during myogenic progression remain controversial. Herein, using biomolecular, biochemical, morphological and electrophysiological analyses, we analyzed HIF-1α expression, localization and role in differentiating murine C2C12 myoblasts and SCs under normoxia. In addition, we evaluated the role of matrix metalloproteinase (MMP)-9 as an HIF-1α effector, considering that MMP-9 is involved in myogenesis and is an HIF-1α target in different cell types. HIF-1α expression increased after 24/48 h of differentiating culture and tended to decline after 72 h/5 days. Committed and proliferating mononuclear myoblasts exhibited nuclear HIF-1α expression. Differently, the more differentiated elongated and parallel-aligned cells, which are likely ready to fuse with each other, show a mainly cytoplasmic localization of the factor. Multinucleated myotubes displayed both nuclear and cytoplasmic HIF-1α expression. The MMP-9 and MyoD (myogenic activation marker) expression synchronized with that of HIF-1α, increasing after 24 h of differentiation. By means of silencing HIF-1α and MMP-9 by short-interfering RNA and MMP-9 pharmacological inhibition, this study unraveled MMP-9's role as an HIF-1α downstream effector and the fact that the HIF-1α/MMP-9 axis is essential in morpho-functional cell myogenic commitment.
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Affiliation(s)
- Flaminia Chellini
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Imaging Platform, University of Florence, 50134 Florence, Italy; (F.C.); (A.T.); (M.P.); (S.Z.-O.)
| | - Alessia Tani
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Imaging Platform, University of Florence, 50134 Florence, Italy; (F.C.); (A.T.); (M.P.); (S.Z.-O.)
| | - Martina Parigi
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Imaging Platform, University of Florence, 50134 Florence, Italy; (F.C.); (A.T.); (M.P.); (S.Z.-O.)
| | - Francesco Palmieri
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, 50134 Florence, Italy; (F.P.); (R.G.)
| | - Rachele Garella
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, 50134 Florence, Italy; (F.P.); (R.G.)
| | - Sandra Zecchi-Orlandini
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Imaging Platform, University of Florence, 50134 Florence, Italy; (F.C.); (A.T.); (M.P.); (S.Z.-O.)
| | - Roberta Squecco
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, 50134 Florence, Italy; (F.P.); (R.G.)
| | - Chiara Sassoli
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Imaging Platform, University of Florence, 50134 Florence, Italy; (F.C.); (A.T.); (M.P.); (S.Z.-O.)
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Koopmans PJ, Ismaeel A, Goljanek-Whysall K, Murach KA. The roles of miRNAs in adult skeletal muscle satellite cells. Free Radic Biol Med 2023; 209:228-238. [PMID: 37879420 PMCID: PMC10911817 DOI: 10.1016/j.freeradbiomed.2023.10.403] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/16/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
Satellite cells are bona fide muscle stem cells that are indispensable for successful post-natal muscle growth and regeneration after severe injury. These cells also participate in adult muscle adaptation in several capacities. MicroRNAs (miRNAs) are post-transcriptional regulators of mRNA that are implicated in several aspects of stem cell function. There is evidence to suggest that miRNAs affect satellite cell behavior in vivo during development and myogenic progenitor behavior in vitro, but the role of miRNAs in adult skeletal muscle satellite cells is less studied. In this review, we provide evidence for how miRNAs control satellite cell function with emphasis on satellite cells of adult skeletal muscle in vivo. We first outline how miRNAs are indispensable for satellite cell viability and control the phases of myogenesis. Next, we discuss the interplay between miRNAs and myogenic cell redox status, senescence, and communication to other muscle-resident cells during muscle adaptation. Results from recent satellite cell miRNA profiling studies are also summarized. In vitro experiments in primary myogenic cells and cell lines have been invaluable for exploring the influence of miRNAs, but we identify a need for novel genetic tools to further interrogate how miRNAs control satellite cell behavior in adult skeletal muscle in vivo.
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Affiliation(s)
- Pieter Jan Koopmans
- Exercise Science Research Center, Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, 72701, USA; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, 72701, USA
| | - Ahmed Ismaeel
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, 40506, USA
| | - Katarzyna Goljanek-Whysall
- School of Medicine, College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland
| | - Kevin A Murach
- Exercise Science Research Center, Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, 72701, USA; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, 72701, USA.
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Nedel W, Deutschendorf C, Portela LVC. Sepsis-induced mitochondrial dysfunction: A narrative review. World J Crit Care Med 2023; 12:139-152. [PMID: 37397587 PMCID: PMC10308342 DOI: 10.5492/wjccm.v12.i3.139] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/08/2023] [Accepted: 04/14/2023] [Indexed: 06/08/2023] Open
Abstract
Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction. Mitochondrial function has been shown to be severely impaired during the early phase of critical illness, with a reduction in biogenesis, increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%. Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays, particularly in peripheral mononuclear cells. Isolation of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection, sample processing, and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear cells. Studies have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic patients. However, few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical outcomes. An improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic targets. These features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care settings. The evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients, especially those with sepsis. In this article, we explore the pathophysiological aspects, main methods of measurement, and the main studies in this field.
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Affiliation(s)
- Wagner Nedel
- Intensive Care Unit, Grupo Hospitalar Conceição, Porto Alegre 91350200, Brazil
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Brazil
- Brazilian Research in Intensive Care Network-BRICNet, São Paulo 04039-002, Brazil
| | - Caroline Deutschendorf
- Infection Control Committee, Hospital de Clínicas de Porto Alegre, Porto Alegre 90410-000, Brazil
| | - Luis Valmor Cruz Portela
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Brazil
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Baig MS, Deepanshu, Prakash P, Alam P, Krishnan A. In silico analysis reveals hypoxia-induced miR-210-3p specifically targets SARS-CoV-2 RNA. J Biomol Struct Dyn 2023; 41:12305-12327. [PMID: 36752331 DOI: 10.1080/07391102.2023.2175255] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/01/2023] [Indexed: 02/09/2023]
Abstract
Human coronaviruses (HCoVs) until the emergence of SARS in 2003 were associated with mild cold and upper respiratory tract infections. The ongoing pandemic caused by SARS-CoV-2 has enhanced the potential for infection and transmission as compared to other known members of this family. MicroRNAs (miRNA) are 21-25 nucleotides long non-coding RNA that bind to 3' UTR of genes and regulate almost every aspect of cellular function. Several human miRNAs have been known to target viral genomes, mostly to downregulate their expression and sometimes to upregulate also. In some cases, host miRNAs could be sequestered by the viral genome to create a condition for favourable virus existence. The ongoing SARS CoV-2 pandemic is unique based on its transmissibility and severity and we hypothesised that there could be a unique mechanism for its pathogenesis. In this study, we exploited in silico approach to identify human respiratory system-specific miRNAs targeting the viral genome of three highly pathogenic HCoVs (SARS-CoV-2 Wuhan strain, SARS-CoV, and MERS-CoV) and three low pathogenic HCoVs (OC43, NL63, and HKU1). We identified ten common microRNAs that target all HCoVs studied here. In addition, we identified unique miRNAs which targeted specifically one particular HCoV. miR-210-3p was the single unique lung-specific miRNA, which was found to target the NSP3, NSP4, and NSP13 genes of SARS-CoV-2. Further miR-210-NSP3, miR-210-NSP4, and miR-210-NSP13 SARS-CoV-2 duplexes were docked with the hAGO2 protein (PDB ID 4F3T) which showed Z-score values of -1.9, -1.7, and -1.6, respectively. The role of miR-210-3p as master hypoxia regulator and inflammation regulation may be important for SARS-CoV-2 pathogenesis. Overall, this analysis advocates that miR-210-3p be investigated experimentally in SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Deepanshu
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| | - Prem Prakash
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| | - Pravej Alam
- Department of Biology, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Anuja Krishnan
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
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11
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Wang Y, Lu J, Liu Y. Skeletal Muscle Regeneration in Cardiotoxin-Induced Muscle Injury Models. Int J Mol Sci 2022; 23:ijms232113380. [PMID: 36362166 PMCID: PMC9657523 DOI: 10.3390/ijms232113380] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and regeneration of muscle. Therefore, this article reviews knowledge on the mechanisms of skeletal muscle regeneration after cardiotoxin-induced injury. The process of regeneration is similar in different mouse strains and is inhibited by aging, obesity, and diabetes. Exercise, microcurrent electrical neuromuscular stimulation, and mechanical loading improve regeneration. The mechanisms of regeneration are complex and strain-dependent, and changes in functional proteins involved in the processes of necrotic fiber debris clearance, M1 to M2 macrophage conversion, SC activation, myoblast proliferation, differentiation and fusion, and fibrosis and calcification influence the final outcome of the regenerative activity.
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12
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Hu XQ, Song R, Dasgupta C, Romero M, Juarez R, Hanson J, Blood AB, Wilson SM, Zhang L. MicroRNA-210-mediated mitochondrial reactive oxygen species confer hypoxia-induced suppression of spontaneous transient outward currents in ovine uterine arteries. Br J Pharmacol 2022; 179:4640-4654. [PMID: 35776536 PMCID: PMC9474621 DOI: 10.1111/bph.15914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 05/26/2022] [Accepted: 06/22/2022] [Indexed: 12/05/2022] Open
Abstract
Background and Purpose Hypoxia during pregnancy is associated with increased uterine vascular resistance and elevated blood pressure both in women and female sheep. A previous study demonstrated a causal role of microRNA‐210 (miR‐210) in gestational hypoxia‐induced suppression of Ca2+ sparks/spontaneous transient outward currents (STOCs) in ovine uterine arteries, but the underlying mechanisms remain undetermined. We tested the hypothesis that miR‐210 perturbs mitochondrial metabolism and increases mitochondrial reactive oxygen species (mtROS) that confer hypoxia‐induced suppression of STOCs in uterine arteries. Experimental Approach Resistance‐sized uterine arteries were isolated from near‐term pregnant sheep and were treated ex vivo in normoxia and hypoxia (10.5% O2) for 48 h. Key Results Hypoxia increased mtROS and suppressed mitochondrial respiration in uterine arteries, which were also produced by miR‐210 mimic to normoxic arteries and blocked by antagomir miR‐210‐LNA in hypoxic arteries. Hypoxia or miR‐210 mimic inhibited Ca2+ sparks/STOCs and increased uterine arterial myogenic tone, which were inhibited by the mitochondria‐targeted antioxidant MitoQ. Hypoxia and miR‐210 down‐regulated iron–sulfur cluster scaffold protein (ISCU) in uterine arteries and knockdown of ISCU via siRNAs suppressed mitochondrial respiration, increased mtROS, and inhibited STOCs. In addition, blockade of mitochondrial electron transport chain with antimycin and rotenone inhibited large‐conductance Ca2+‐activated K+ channels, decreased STOCs and increased uterine arterial myogenic tone. Conclusion and Implications This study demonstrates a novel mechanistic role for the miR‐210‐ISCU‐mtROS axis in inhibiting Ca2+ sparks/STOCs in the maladaptation of uterine arteries and provides new insights into the understanding of mitochondrial perturbations in the pathogenesis of pregnancy complications resulted from hypoxia.
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Affiliation(s)
- Xiang-Qun Hu
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Rui Song
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Chiranjib Dasgupta
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Monica Romero
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Rucha Juarez
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Jenna Hanson
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Arlin B Blood
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Sean M Wilson
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Lubo Zhang
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
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13
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Genetic regulation and variation of expression of miRNA and mRNA transcripts in fetal muscle tissue in the context of sex, dam and variable fetal weight. Biol Sex Differ 2022; 13:24. [PMID: 35550009 PMCID: PMC9103043 DOI: 10.1186/s13293-022-00433-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/25/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Impaired skeletal muscle growth in utero can result in reduced birth weight and pathogenesis of intrauterine growth restriction. Fetal and placental growth is influenced by many factors including genetic, epigenetic and environmental factors. In fact, the sex and genotype of the fetus itself, as well as the mother providing it with a suitable environment, influence the growth of the fetus. Hence, our goal was to decipher and elucidate the molecular pathways of developmental processes mediated by miRNAs and mRNAs in fetal muscle tissue in the context of sex, dam, and fetal weight. Therefore, we analyse the variation of miRNA and mRNA expression in relation to these factors. In addition, the coincidence of genetic regulation of these mRNAs and miRNAs, as revealed by expression quantitative trait loci (eQTL) analyses, with sex-, mother- and weight-associated expression was investigated. METHODS A three-generation pig F2 population (n = 118) based on reciprocal crossing of German Landrace (DL) and Pietrain (Pi) was used. Genotype information and transcriptomic data (mRNA and miRNA) from longissimus dorsi muscle (LDM) of pig fetuses sampled at 63 days post-conception (dpc) were used for eQTL analyses. RESULTS The transcript abundances of 13, 853, and 275 probe-sets were influenced by sex, dam and fetal weight at 63 dpc, respectively (FDR < 5%). Most of significant transcripts affected by sex were located on the sex chromosomes including KDM6A and ANOS1 or autosomes including ANKS1B, LOC100155138 and miR-153. The fetal muscle transcripts associated with fetal weight indicated clearer metabolic directions than maternally influenced fetal muscle transcripts. Moreover, coincidence of genetic regulation (eQTL) and variation in transcript abundance due to sex, dam and fetal weight were identified. CONCLUSIONS Integrating information on eQTL, sex-, dam- and weight-associated differential expression and QTL for fetal weight allowed us to identify molecular pathways and shed light on the basic biological processes associated with differential muscle development in males and females, with implications for adaptive fetal programming.
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14
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Zaccagnini G, Greco S, Voellenkle C, Gaetano C, Martelli F. miR-210 hypoxamiR in Angiogenesis and Diabetes. Antioxid Redox Signal 2022; 36:685-706. [PMID: 34521246 DOI: 10.1089/ars.2021.0200] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: microRNA-210 (miR-210) is the master hypoxia-inducible miRNA (hypoxamiR) since it has been found to be significantly upregulated under hypoxia in a wide range of cell types. Recent advances: Gene ontology analysis of its targets indicates that miR-210 modulates several aspects of cellular response to hypoxia. Due to its high pleiotropy, miR-210 not only plays a protective role by fine-tuning mitochondrial metabolism and inhibiting red-ox imbalance and apoptosis, but it can also promote cell proliferation, differentiation, and migration, substantially contributing to angiogenesis. Critical issues: As most miRNAs, modulating different gene pathways, also miR-210 can potentially lead to different and even opposite effects, depending on the physio-pathological contexts in which it acts. Future direction: The use of miRNAs as therapeutics is a fast growing field. This review aimed at highlighting the role of miR-210 in angiogenesis in the context of ischemic cardiovascular diseases and diabetes in order to clarify the molecular mechanisms underpinning miR-210 action. Particular attention will be dedicated to experimentally validated miR-210 direct targets involved in cellular processes related to angiogenesis and diabetes mellitus, such as mitochondrial metabolism, redox balance, apoptosis, migration, and adhesion. Antioxid. Redox Signal. 36, 685-706.
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Affiliation(s)
- Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Simona Greco
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Christine Voellenkle
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Carlo Gaetano
- Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
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15
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Sacco A, Martelli F, Pal A, Saraceno C, Benussi L, Ghidoni R, Rongioletti M, Squitti R. Regulatory miRNAs in Cardiovascular and Alzheimer's Disease: A Focus on Copper. Int J Mol Sci 2022; 23:3327. [PMID: 35328747 PMCID: PMC8948703 DOI: 10.3390/ijms23063327] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 11/16/2022] Open
Abstract
Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs' functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer's disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs.
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Affiliation(s)
- Anna Sacco
- Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy;
| | - Amit Pal
- Department of Biochemistry, AIIMS, Kalyani 741245, India;
| | - Claudia Saraceno
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (L.B.); (R.G.)
| | - Luisa Benussi
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (L.B.); (R.G.)
| | - Roberta Ghidoni
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (L.B.); (R.G.)
| | - Mauro Rongioletti
- Department of Laboratory Medicine, Research and Development Division, San Giovanni Calibita Fatebenefratelli Hospital, Isola Tiberina, 00186 Rome, Italy;
| | - Rosanna Squitti
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (L.B.); (R.G.)
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16
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Islam SU, Ahmed MB, Sonn JK, Jin EJ, Lee YS. PRP4 Induces Epithelial–Mesenchymal Transition and Drug Resistance in Colon Cancer Cells via Activation of p53. Int J Mol Sci 2022; 23:ijms23063092. [PMID: 35328513 PMCID: PMC8955441 DOI: 10.3390/ijms23063092] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pre-mRNA processing factor 4B (PRP4) promotes pre-mRNA splicing and signal transduction. Recent studies have shown that PRP4 modulates the assembly of actin cytoskeleton in cancer cells and induces epithelial–mesenchymal transition (EMT) and drug resistance. PRP4 displays kinase domain-like cyclin-dependent kinases and mitogen-activated protein kinases, making it capable of phosphorylating p53 and other target proteins. In the current study, we report that PRP4 induces drug resistance and EMT via direct binding to the p53 protein, inducing its phosphorylation. Moreover, PRP4 overexpression activates the transcription of miR-210 in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, which activates p53. The involvement of miR-210 in the activation of p53 was confirmed by utilizing si-miR210. si-miR210 blocked the PRP4-activated cell survival pathways and reversed the PRP4-induced EMT phenotype. Moreover, we used deferoxamine as a hypoxia-mimetic agent, and si-HIF to silence HIF-1α. This procedure demonstrated that PRP4-induced EMT and drug resistance emerged in response to consecutive activation of HIF-1α, miR-210, and p53 by PRP4 overexpression. Collectively, our findings suggest that the PRP4 contributes to EMT and drug resistance induction via direct interactions with p53 and actions that promote upregulation of HIF-1α and miR-210. We conclude that PRP4 is an essential factor promoting cancer development and progression. Specific PRP4 inhibition could benefit patients with colon cancer.
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Affiliation(s)
- Salman Ul Islam
- Department of Pharmacy, Cecos University, Hayatabad, Peshawar 25000, Pakistan;
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Muhammad Bilal Ahmed
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Jong-Kyung Sonn
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Eun-Jung Jin
- Department of Biological Science, College of Natural Science, Wonkwang University, Iksan 54538, Korea
- Correspondence: (E.-J.J.); (Y.-S.L.); Tel.: +82-63-8500-6197(E.-J.J.); +82-53-950-6353 (Y.-S.L.); Fax: +82-53-943-2762 (E.-J.J.)
| | - Young-Sup Lee
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
- Correspondence: (E.-J.J.); (Y.-S.L.); Tel.: +82-63-8500-6197(E.-J.J.); +82-53-950-6353 (Y.-S.L.); Fax: +82-53-943-2762 (E.-J.J.)
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17
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Erman A, Hawkins LJ, Storey KB. MicroRNA, mRNA and protein responses to dehydration in skeletal muscle of the African-clawed frog, Xenopus laevis. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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18
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Tributyrin, a Butyrate Pro-Drug, Primes Satellite Cells for Differentiation by Altering the Epigenetic Landscape. Cells 2021; 10:cells10123475. [PMID: 34943981 PMCID: PMC8700657 DOI: 10.3390/cells10123475] [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: 10/13/2021] [Revised: 11/29/2021] [Accepted: 12/07/2021] [Indexed: 01/07/2023] Open
Abstract
Satellite cells (SC) are a population of muscle resident stem cells that are responsible for postnatal muscle growth and repair. With investigation into the genomic regulation of SC fate, the role of the epigenome in governing SC myogenesis is becoming clearer. Histone deacetylase (HDAC) inhibitors have been demonstrated to be effective at enhancing the myogenic program of SC, but their role in altering the epigenetic landscape of SC remains undetermined. Our objective was to determine how an HDAC inhibitor, butyrate, promotes myogenic differentiation. SC from tributyrin treated neonatal piglets showed a decrease relative to SC from control animals in the expression of enhance of zeste homologue-2 (EZH2), a chromatin modifier, ex vivo. Chromatin Immunoprecipitation-Sequencing (ChIP-Seq) analysis of SC isolated from tributyrin treated pigs showed a global reduction of the tri-methylation of lysine 27 of histone H3 (H3K27me3) repressive chromatin mark. To determine if reductions in EZH2 was the primary mechanism through which butyrate affects SC behavior, SC were transfected with siRNA targeting EZH2, treated with 0.5 mM butyrate, or both. Treatment with butyrate reduced paired-box-7 (Pax7) and myogenic differentiation-1 (MyoD) gene expression, while siRNA caused reductions in EZH2 had no effect on their expression. EZH2 depletion did result in an increase in differentiating SC, but not in myotube hypertrophy. These results indicate that while EZH2 reduction may force myogenic differentiation, butyrate may operate through a parallel mechanism to enhance the myogenic program.
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19
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Rahmati M, Ferns GA, Mobarra N. The lower expression of circulating miR-210 and elevated serum levels of HIF-1α in ischemic stroke; Possible markers for diagnosis and disease prediction. J Clin Lab Anal 2021; 35:e24073. [PMID: 34708885 PMCID: PMC8649366 DOI: 10.1002/jcla.24073] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/25/2021] [Accepted: 10/08/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Stroke, either due to ischemia or hemorrhage, causes acute neurological damages to the brain. There is shortage of reliable biomarkers for ischemic stroke (IS), and we therefore investigated the serum concentrations of microRNA-210 (miR-210) and hypoxia inducible factor-1α (HIF-1α), as possible diagnostic and/or prognostic markers for IS. METHODS Serum samples were acquired from 52 IS patients and their healthy counterparts at five time points: upon admission, 24 and 48 h after admission, upon discharge and 3 months later. Serum levels of miR-210 and HIF-1α were respectively analyzed using real time RT-PCR and ELISA. Diagnostic and prognostic accuracy tests were performed to assess the value of suggested biomarkers. RESULTS IS patients demonstrated higher levels of serum HIF-1α and lower miR-210 in comparison to the healthy subjects. MiR-210 was suggested to be a weak diagnostic biomarker at the time of admission (AUC = 0.61; p = 0.05), while HIF-1α was an acceptable diagnostic marker for IS (AUC = 0.73; p < 0.0001). The higher expression of miR-210 and lower levels of HIF-1α were associated with better survivals in IS patients. CONCLUSIONS Serum miR-210 is a weak diagnostic marker of IS. Serum HIF-1α is a better biomarker in diagnosing IS patients but further work in larger groups, including those with hemorrhagic stroke is necessary to confirm its diagnostic utility. Similarly, the prognostic potentiality of miR-210 and HIF-1α was acceptable but needs bigger sample size and longer follow-up to be statistically confirmed.
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Affiliation(s)
- Mina Rahmati
- Department of BiochemistryMetabolic Disorders Research CenterFaculty of MedicineGolestan University of Medical SciencesGorganIran
| | - Gordon A. Ferns
- Brighton and Sussex Medical SchoolDivision of Medical EducationBrightonUK
| | - Naser Mobarra
- Department of Clinical BiochemistrySchool of MedicineMashhad University of Medical SciencesMashhadIran
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20
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Kashfi K, Kannikal J, Nath N. Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO. Cells 2021; 10:3194. [PMID: 34831416 PMCID: PMC8624911 DOI: 10.3390/cells10113194] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/09/2021] [Accepted: 11/14/2021] [Indexed: 12/15/2022] Open
Abstract
Nitric oxide and its production by iNOS is an established mechanism critical to tumor promotion or suppression. Macrophages have important roles in immunity, development, and progression of cancer and have a controversial role in pro- and antitumoral effects. The tumor microenvironment consists of tumor-associated macrophages (TAM), among other cell types that influence the fate of the growing tumor. Depending on the microenvironment and various cues, macrophages polarize into a continuum represented by the M1-like pro-inflammatory phenotype or the anti-inflammatory M2-like phenotype; these two are predominant, while there are subsets and intermediates. Manipulating their plasticity through programming or reprogramming of M2-like to M1-like phenotypes presents the opportunity to maximize tumoricidal defenses. The dual role of iNOS-derived NO also influences TAM activity by repolarization to tumoricidal M1-type phenotype. Regulatory pathways and immunomodulation achieve this through miRNA that may inhibit the immunosuppressive tumor microenvironment. This review summarizes the classical physiology of macrophages and polarization, iNOS activities, and evidence towards TAM reprogramming with current information in glioblastoma and melanoma models, and the immunomodulatory and therapeutic options using iNOS or NO-dependent strategies.
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Affiliation(s)
- Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10016, USA
| | - Jasmine Kannikal
- Department of Biological and Chemical Sciences, College of Arts and Sciences, New York Institute of Technology, New York, NY 10023, USA;
| | - Niharika Nath
- Department of Biological and Chemical Sciences, College of Arts and Sciences, New York Institute of Technology, New York, NY 10023, USA;
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21
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Li Z, Wang S, Gong C, Hu Y, Liu J, Wang W, Chen Y, Liao Q, He B, Huang Y, Luo Q, Zhao Y, Xiao Y. Effects of Environmental and Pathological Hypoxia on Male Fertility. Front Cell Dev Biol 2021; 9:725933. [PMID: 34589489 PMCID: PMC8473802 DOI: 10.3389/fcell.2021.725933] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/23/2021] [Indexed: 12/28/2022] Open
Abstract
Male infertility is a widespread health problem affecting approximately 6%-8% of the male population, and hypoxia may be a causative factor. In mammals, two types of hypoxia are known, including environmental and pathological hypoxia. Studies looking at the effects of hypoxia on male infertility have linked both types of hypoxia to poor sperm quality and pregnancy outcomes. Hypoxia damages testicular seminiferous tubule directly, leading to the disorder of seminiferous epithelium and shedding of spermatogenic cells. Hypoxia can also disrupt the balance between oxidative phosphorylation and glycolysis of spermatogenic cells, resulting in impaired self-renewal and differentiation of spermatogonia, and failure of meiosis. In addition, hypoxia disrupts the secretion of reproductive hormones, causing spermatogenic arrest and erectile dysfunction. The possible mechanisms involved in hypoxia on male reproductive toxicity mainly include excessive ROS mediated oxidative stress, HIF-1α mediated germ cell apoptosis and proliferation inhibition, systematic inflammation and epigenetic changes. In this review, we discuss the correlations between hypoxia and male infertility based on epidemiological, clinical and animal studies and enumerate the hypoxic factors causing male infertility in detail. Demonstration of the causal association between hypoxia and male infertility will provide more options for the treatment of male infertility.
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Affiliation(s)
- Zhibin Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.,Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chunli Gong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yiyang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jiao Liu
- Department of Endoscope, The General Hospital of Shenyang Military Region, Liaoning, China
| | - Wei Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yang Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiushi Liao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bing He
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.,Department of Laboratory Medicine, General Hospital of Northern Theater Command, Shenyang, China
| | - Yu Huang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yongbing Zhao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yufeng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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Ali A, Murani E, Hadlich F, Liu X, Wimmers K, Ponsuksili S. In Utero Fetal Weight in Pigs Is Regulated by microRNAs and Their Target Genes. Genes (Basel) 2021; 12:genes12081264. [PMID: 34440438 PMCID: PMC8393551 DOI: 10.3390/genes12081264] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/17/2022] Open
Abstract
Impaired skeletal muscle growth in utero can result in reduced birth weight and poor carcass quality in pigs. Recently, we showed the role of microRNAs (miRNAs) and their target genes in prenatal skeletal muscle development and pathogenesis of intrauterine growth restriction (IUGR). In this study, we performed an integrative miRNA-mRNA transcriptomic analysis in longissimus dorsi muscle (LDM) of pig fetuses at 63 days post conception (dpc) to identify miRNAs and genes correlated to fetal weight. We found 13 miRNAs in LDM significantly correlated to fetal weight, including miR-140, miR-186, miR-101, miR-15, miR-24, miR-29, miR-449, miR-27, miR-142, miR-99, miR-181, miR-199, and miR-210. The expression of these miRNAs decreased with an increase in fetal weight. We also identified 1315 genes significantly correlated to fetal weight at 63 dpc, of which 135 genes were negatively correlated as well as identified as potential targets of the above-listed 13 miRNAs. These miRNAs and their target genes enriched pathways and biological processes important for fetal growth, development, and metabolism. These results indicate that the transcriptomic profile of skeletal muscle can be used to predict fetal weight, and miRNAs correlated to fetal weight can serve as potential biomarkers of prenatal fetal health and growth.
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Affiliation(s)
- Asghar Ali
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (A.A.); (E.M.); (F.H.); (X.L.); (K.W.)
| | - Eduard Murani
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (A.A.); (E.M.); (F.H.); (X.L.); (K.W.)
| | - Frieder Hadlich
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (A.A.); (E.M.); (F.H.); (X.L.); (K.W.)
| | - Xuan Liu
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (A.A.); (E.M.); (F.H.); (X.L.); (K.W.)
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (A.A.); (E.M.); (F.H.); (X.L.); (K.W.)
- Faculty of Agricultural and Environmental Sciences, University Rostock, 18059 Rostock, Germany
| | - Siriluck Ponsuksili
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (A.A.); (E.M.); (F.H.); (X.L.); (K.W.)
- Correspondence: ; Tel.: +49-38208-68703; Fax: +49-38208-68702
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23
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Pichu S, Vimalraj S, Viswanathan V. Impact of microRNA-210 on wound healing among the patients with diabetic foot ulcer. PLoS One 2021; 16:e0254921. [PMID: 34293021 PMCID: PMC8297780 DOI: 10.1371/journal.pone.0254921] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 07/06/2021] [Indexed: 12/26/2022] Open
Abstract
Aim Diabetic foot ulcer (DFU) is a major concern in diabetes and its control requires in-depth molecular investigation. The present study aimed to screen the expression of microRNA-210 (miR-210) and its association in hypoxic pathway in DFU patients. Methods The study consists of 3 groups of circulation samples (50 in each group of: healthy volunteers, T2DM and T2DM with DFU) and 2 groups of tissue samples (10 in each group of: control and T2DM with DFU). Expression of miR-210 and hypoxia inducible factor-1 alpha (HIF-1α), and its responsive genes such as VEGF, TNF-α, IL-6, BCl2, Bax and Caspase 3 were analyzed by RT-PCR, Western blot and ELISA analyses. Results The HIF-1α expression decreased in DFU patients with increased miR-210 expression in both circulation and tissue biopsies. The circulatory IL-6 and inflammatory gene TNF-α expression was increased in DFU compared to healthy controls and T2DM subjects. Further, we found there was no alteration in the angiogenic marker, VEGF expression. In comparison, anti-apoptotic BCl2 was decreased and Bax and Caspase 3 was increased in DFU tissues relative to control. Conclusions The study showed that there was an inverse relationship between miR-210 and HIF-1α expression in patients with DFU, indicating that miR-210 may regulate the expression of the hypoxic gene.
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Affiliation(s)
- Sivakamasundari Pichu
- AU-KBC Research Center, Anna University MIT campus, Chromepet, Chennai, India
- * E-mail:
| | - Selvaraj Vimalraj
- Centre for Biotechnology, Anna University, Chennai, India
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
| | - Vijay Viswanathan
- Department of Genetics and Molecular Biology, Prof M. Viswanathan Diabetes Research Centre, MV Hospital for Diabetes, Royapuram, Chennai, India
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24
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Mytidou C, Koutsoulidou A, Katsioloudi A, Prokopi M, Kapnisis K, Michailidou K, Anayiotos A, Phylactou LA. Muscle-derived exosomes encapsulate myomiRs and are involved in local skeletal muscle tissue communication. FASEB J 2021; 35:e21279. [PMID: 33484211 DOI: 10.1096/fj.201902468rr] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/02/2020] [Accepted: 12/01/2020] [Indexed: 12/23/2022]
Abstract
Exosomes are extracellular vesicles that are released from most cell types encapsulating specific molecular cargo. Exosomes serve as mediators of cell-to-cell and tissue-to-tissue communications under normal and pathological conditions. It has been shown that exosomes carrying muscle-specific miRNAs, myomiRs, are secreted from skeletal muscle cells in vitro and are elevated in the blood of muscle disease patients. The aim of this study was to investigate the secretion of exosomes encapsulating the four myomiRs from skeletal muscle tissues and to assess their role in inter-tissue communication between neighboring skeletal muscles in vivo. We demonstrate, for the first time, that isolated, intact skeletal muscle tissues secrete exosomes encapsulating the four myomiRs, miR-1, miR-133a, miR-133b, and miR-206. Notably, we show that the sorting of the four myomiRs within exosomes varies between skeletal muscles of different muscle fiber-type composition. miR-133a and miR-133b downregulation in TA muscles caused a reduction of their levels in neighboring skeletal muscles and in serum exosomes. In conclusion, our results reveal that skeletal muscle-derived exosomes encapsulate the four myomiRs, some of which enter the blood, while a portion is used for the local communication between proximal muscle tissues. These findings provide important evidence regarding novel pathways implicated in skeletal muscle function.
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Affiliation(s)
- Chrystalla Mytidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | | | - Marianna Prokopi
- Theramir Ltd, Limassol, Cyprus.,Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus.,Department of Research and Development, German Oncology Center, Limassol, Cyprus
| | - Konstantinos Kapnisis
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus
| | - Kyriaki Michailidou
- The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,Biostatistics Unit, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Andreas Anayiotos
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
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25
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Pircher T, Wackerhage H, Aszodi A, Kammerlander C, Böcker W, Saller MM. Hypoxic Signaling in Skeletal Muscle Maintenance and Regeneration: A Systematic Review. Front Physiol 2021; 12:684899. [PMID: 34248671 PMCID: PMC8260947 DOI: 10.3389/fphys.2021.684899] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/26/2021] [Indexed: 12/26/2022] Open
Abstract
In skeletal muscle tissue, oxygen (O2) plays a pivotal role in both metabolism and the regulation of several intercellular pathways, which can modify proliferation, differentiation and survival of cells within the myogenic lineage. The concentration of oxygen in muscle tissue is reduced during embryogenesis and pathological conditions. Myogenic progenitor cells, namely satellite cells, are necessary for muscular regeneration in adults and are localized in a hypoxic microenvironment under the basal lamina, suggesting that the O2 level could affect their function. This review presents the effects of reduced oxygen levels (hypoxia) on satellite cell survival, myoblast regeneration and differentiation in vertebrates. Further investigations and understanding of the pathways involved in adult muscle regeneration during hypoxic conditions are maybe clinically relevant to seek for novel drug treatments for patients with severe muscle damage. We especially outlined the effect of hypoxia-inducible factor 1-alpha (HIF1A), the most studied transcriptional regulator of cellular and developmental response to hypoxia, whose investigation has recently been awarded with the Nobel price.
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Affiliation(s)
- Tamara Pircher
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital, Munich, Germany
| | - Henning Wackerhage
- Faculty of Sport and Health Sciences, Technical University of Munich, Munich, Germany
| | - Attila Aszodi
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital, Munich, Germany
| | - Christian Kammerlander
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital, Munich, Germany
| | - Wolfgang Böcker
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital, Munich, Germany
| | - Maximilian Michael Saller
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital, Munich, Germany
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26
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Ali A, Murani E, Hadlich F, Liu X, Wimmers K, Ponsuksili S. Prenatal Skeletal Muscle Transcriptome Analysis Reveals Novel MicroRNA-mRNA Networks Associated with Intrauterine Growth Restriction in Pigs. Cells 2021; 10:cells10051007. [PMID: 33923344 PMCID: PMC8145024 DOI: 10.3390/cells10051007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Intrauterine growth restriction (IUGR) occurs in 15–20% of pig neonates and poses huge economic losses to the pig industry. IUGR piglets have reduced skeletal muscle growth, which may persist after birth. Prenatal muscle growth is regulated by complex molecular pathways that are not well understood. MicroRNAs (miRNAs) have emerged as the main regulators of vital pathways and biological processes in the body. This study was designed to identify miRNA–mRNA networks regulating prenatal skeletal muscle development in pigs. We performed an integrative miRNA–mRNA transcriptomic analysis in longissimus dorsi muscle from IUGR fetuses and appropriate for gestational age (AGA) fetuses at 63 days post conception. Our data showed that 47 miRNAs and 3257 mRNAs were significantly upregulated, and six miRNAs and 477 mRNAs were significantly downregulated in IUGR compared to AGA fetuses. Moreover, 47 upregulated miRNAs were negatively correlated and can potentially target 326 downregulated genes, whereas six downregulated miRNAs were negatively correlated and can potentially target 1291 upregulated genes. These miRNA–mRNA networks showed enrichment in biological processes and pathways critical for fetal growth, development, and metabolism. The miRNA–mRNA networks identified in this study can potentially serve as indicators of prenatal fetal growth and development as well as postnatal carcass quality.
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Affiliation(s)
- Asghar Ali
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Eduard Murani
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Frieder Hadlich
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Xuan Liu
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
- Faculty of Agricultural and Environmental Sciences, University Rostock, 18059 Rostock, Germany
| | - Siriluck Ponsuksili
- Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
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27
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Codenotti S, Marampon F, Triggiani L, Bonù ML, Magrini SM, Ceccaroli P, Guescini M, Gastaldello S, Tombolini V, Poliani PL, Asperti M, Poli M, Monti E, Fanzani A. Caveolin-1 promotes radioresistance in rhabdomyosarcoma through increased oxidative stress protection and DNA repair. Cancer Lett 2021; 505:1-12. [PMID: 33610729 DOI: 10.1016/j.canlet.2021.02.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 02/01/2021] [Accepted: 02/03/2021] [Indexed: 10/22/2022]
Abstract
The aim of this work was to investigate whether Caveolin-1 (Cav-1), a membrane scaffolding protein widely implicated in cancer, may play a role in radiation response in rhabdomyosarcoma (RMS), a pediatric soft tissue tumor. For this purpose, we employed human RD cells in which Cav-1 expression was stably increased via gene transfection. After radiation treatment, we observed that Cav-1 limited cell cycle arrest in the G2/M phase and enhanced resistance to cell senescence and apoptosis via reduction of p21Cip1/Waf1, p16INK4a and Caspase-3 cleavage. After radiotherapy, Cav-1-mediated cell radioresistance was characterized by low accumulation of H2AX foci, as confirmed by Comet assay, marked neutralization of reactive oxygen species (ROS) and enhanced DNA repair via activation of ATM, Ku70/80 complex and DNA-PK. We found that Cav-1-overexpressing RD cells, already under basal conditions, had higher glutathione (GSH) content and greater catalase expression, which conferred protection against acute treatment with hydrogen peroxide. Furthermore, pre-treatment of Cav-1-overexpressing cells with PP2 or LY294002 compounds restored the sensitivity to radiation treatment, indicating a role for Src-kinases and Akt pathways in Cav-1-mediated radioresistance. These findings were confirmed using radioresistant RD and RH30 lines generated by hypofractionated radiotherapy protocol, which showed marked increase of Cav-1, catalase and Akt, and sensitivity to PP2 and LY294002 treatment. In conclusion, these data suggest that concerted activity of Cav-1 and catalase, in cooperation with activation of Src-kinase and Akt pathways, may represent a network of vital mechanisms that allow irradiated RMS cells to evade cell death induced by oxidative stress and DNA damage.
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Affiliation(s)
- Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Francesco Marampon
- Department of Pediatrics, "Sapienza" University of Rome, Rome, Italy; Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy
| | - Luca Triggiani
- Radiation Oncology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - Marco Lorenzo Bonù
- Radiation Oncology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - Stefano Maria Magrini
- Radiation Oncology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - Paola Ceccaroli
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Michele Guescini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Stefano Gastaldello
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Precision Medicine Research Center, School of Pharmacy, Binzhou Medical University, Laishan District, Guanhai Road 346, Yantai, Shandong Province, 264003 China
| | - Vincenzo Tombolini
- Department of Pediatrics, "Sapienza" University of Rome, Rome, Italy; Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy
| | - Pietro Luigi Poliani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Michela Asperti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Eugenio Monti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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28
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TAKAI Y, WATANABE T, SANO T. Elevated level of microRNA-210 at the initiation of muscular regeneration in acetic acid-induced non-ischemic skeletal muscular injury in mice. J Toxicol Pathol 2021; 35:183-192. [PMID: 35516838 PMCID: PMC9018401 DOI: 10.1293/tox.2021-0061] [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: 09/15/2021] [Accepted: 11/29/2021] [Indexed: 11/29/2022] Open
Abstract
The alteration in microRNA-210 level, a hypoxia-inducible microRNA, is not well known in
non-ischemic tissue injury. In this study, we characterized the histopathological time
course of acetic acid-induced skeletal muscle injury as a non-ischemic tissue injury model
and investigated the expression of microRNA-210, hypoxia-inducible factor 1α, and growth
factors using quantitative polymerase chain reaction analysis. After a single
intramuscular dose of 3% (v/v) acetic acid to C57BL/6J mice, focal coagulative necrosis of
muscle fibers was noted from 3 h after dosing and infiltration of F4/80 and Galectin-3
positive M2 macrophage was noted at 1 d after dosing. Muscular regeneration was initiated
from 3 d, when M2 macrophage infiltration was most prominent, till 14 d after dosing.
Hif1α and Hgf expression increased from 3 h onwards,
and microRNA-210 level increased after 3 d after the treatment. However, no clear
elevation in the levels of Igf1 or Vegf was observed.
The infiltrative macrophages and regenerative muscle fibers were positive for
hypoxia-inducible factor 1α, microRNA-210, and hepatocyte growth factor as assessed by
immunohistochemistry or in situ hybridization. In this study, dominant
infiltration of M2 macrophages at muscular necrosis and subsequent regeneration after a
single intramuscular injection of acetic acid in mice were observed. The increase in hif1α
level was observed just after the muscular injury in this non-ischemic tissue injury
model, and the elevation in microRNA-210 level was noted at the initiation of tissue
regeneration, indicating its effects on tissue protection and repair.
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Affiliation(s)
- Yuichi TAKAI
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Takeshi WATANABE
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Tomoya SANO
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
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29
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Takai Y, Nishimura S, Kandori H, Watanabe T. Histopathological significance of microRNA-210 expression in acute peripheral ischemia in a murine femoral artery ligation model. J Toxicol Pathol 2020; 33:211-217. [PMID: 33239839 PMCID: PMC7677622 DOI: 10.1293/tox.2020-0023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 04/27/2020] [Indexed: 12/22/2022] Open
Abstract
Under hypoxic conditions, microRNA-210 is upregulated and plays multiple physiological
roles including in cell growth arrest, stem cell survival, repression of mitochondrial
respiration, angiogenesis, and arrest of DNA repair. In this study, we investigated the
histopathological expression of microRNA-210 under hypoxic conditions using a femoral
artery ligation model established in C57BL/6J mice to determine the pathological
significance of microRNA-210. Following femoral artery ligation, ischemia was represented
by decreased blood flow compared to the control, in which a sham operation was performed.
On histopathology, degeneration/necrosis of the muscle fibers, inflammatory cell
infiltration, and regeneration of the muscle fibers were sequentially observed from 3 h to
3 d after ligation of the artery. The degree of these effects was more severe in the area
in which type I muscular fibers are dominant. The histological expression of
hypoxia-inducible factor 1α, a well-known biomarker of hypoxia, and microRNA-210 was
observed in a few necrotic muscle fibers, macrophages, and myoblasts, a distribution
consistent with the histopathological lesions, and their signal increased over time. The
expression of microRNA-210 in macrophages and myoblasts under ischemia might be indicative
of a significant role in the recovery from ischemic lesions. In addition, the in
situ hybridization of microRNA-210 could potentially be used for the detection
of hypoxia as a histological marker in addition to the immunohistochemistry of
hypoxia-inducible factor 1α.
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Affiliation(s)
- Yuichi Takai
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Ltd., 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Satoshi Nishimura
- Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Hitoshi Kandori
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Ltd., 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Takeshi Watanabe
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Ltd., 26-1 Muraoka-Higashi 2 Chome, Fujisawa, Kanagawa 251-8555, Japan
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30
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Hui X, Al-Ward H, Shaher F, Liu CY, Liu N. The Role of miR-210 in the Biological System: A Current Overview. Hum Hered 2020; 84:233-239. [PMID: 32906127 DOI: 10.1159/000509280] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 06/08/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19-23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms. SUMMARY miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. Key Message: miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.
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Affiliation(s)
- Xu Hui
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, China
| | - Hisham Al-Ward
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, China,
| | - Fahmi Shaher
- Department of Pathophysiology, Jiamusi University School of Basic Medical Sciences, Jiamusi, China
| | - Chun-Yang Liu
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, China
| | - Ning Liu
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, China
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31
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Nelson MC, O'Connell RM. MicroRNAs: At the Interface of Metabolic Pathways and Inflammatory Responses by Macrophages. Front Immunol 2020; 11:1797. [PMID: 32922393 PMCID: PMC7456828 DOI: 10.3389/fimmu.2020.01797] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
Macrophages are key cells of the innate immune system with functional roles in both homeostatic maintenance of self-tissues and inflammatory responses to external stimuli, including infectious agents. Recent advances in metabolic research have revealed that macrophage functions rely upon coordinated metabolic programs to regulate gene expression, inflammation, and other important cellular processes. Polarized macrophages adjust their use of nutrients such as glucose and amino acids to meet their changing metabolic needs, and this in turn supports the functions of the activated macrophage. Metabolic and inflammatory processes have been widely studied, and a crucial role for their regulation at the post-transcriptional level by microRNAs (miRNAs) has been identified. miRNAs govern many facets of macrophage biology, including direct targeting of metabolic regulators and inflammatory pathways. This review will integrate emerging data that support an interplay between miRNAs and metabolism during macrophage inflammatory responses, highlighting critical miRNAs and miRNA families. Additionally, we will address the implications of these networks for human disease and discuss emerging areas of research in this field.
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Affiliation(s)
- Morgan C Nelson
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States.,Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Ryan M O'Connell
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States.,Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
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32
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Preda MB, Lupan AM, Neculachi CA, Leti LI, Fenyo IM, Popescu S, Rusu EG, Marinescu CI, Simionescu M, Burlacu A. Evidence of mesenchymal stromal cell adaptation to local microenvironment following subcutaneous transplantation. J Cell Mol Med 2020; 24:10889-10897. [PMID: 32785979 PMCID: PMC7521285 DOI: 10.1111/jcmm.15717] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 12/13/2022] Open
Abstract
Subcutaneous transplantation of mesenchymal stromal cells (MSC) emerged as an alternative to intravenous administration because it avoids the pulmonary embolism and prolongs post-transplantation lifetime. The goal of this study was to investigate the mechanisms by which these cells could affect remote organs. To this aim, murine bone marrow-derived MSC were subcutaneously transplanted in different anatomical regions and the survival and behaviour have been followed. The results showed that upon subcutaneous transplantation in mice, MSC formed multicellular aggregates and did not migrate significantly from the site of injection. Our data suggest an important role of hypoxia-inducible signalling pathways in stimulating local angiogenesis and the ensuing modulation of the kinetics of circulating cytokines with putative protective effects at distant sites. These data expand the current understanding of cell behaviour after subcutaneous transplantation and contribute to the development of a non-invasive cell-based therapy for distant organ protection.
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Affiliation(s)
- Mihai Bogdan Preda
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | - Ana-Mihaela Lupan
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | | | - Livia Ioana Leti
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | - Ioana Madalina Fenyo
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | - Sinziana Popescu
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | - Evelyn Gabriela Rusu
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | | | - Maya Simionescu
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
| | - Alexandrina Burlacu
- Institute of Cellular Biology and Pathology 'Nicolae Simionescu', Bucharest, Romania
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Su X, Xiao D, Huang L, Li S, Ying J, Tong Y, Ye Q, Mu D, Qu Y. MicroRNA Alteration in Developing Rat Oligodendrocyte Precursor Cells Induced by Hypoxia-Ischemia. J Neuropathol Exp Neurol 2020; 78:900-909. [PMID: 31403686 DOI: 10.1093/jnen/nlz071] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
microRNAs (miRNAs) are involved in the pathogenesis of white matter injury (WMI). However, their roles in developing rat brains under hypoxia-ischemia (HI) insult remain unknown. Here, we examined the expression profiles of miRNAs in oligodendrocyte precursor cells using microarray analysis. We identified 162 miRNAs and only 6 were differentially regulated in HI compared with sham. Next, we used these 6 miRNAs and 525 extensively changed coding genes (fold change absolute: FC(abs) ≥2, p < 0.05) to establish the coexpression network, the result revealed that only 3 miRNAs (miR-142-3p, miR-466b-5p, and miR-146a-5p) have differentially expressed targeted mRNAs. RT-PCR analysis showed that the expression of the miRNAs was consistent with the microarray analysis. Further gene ontology and KEGG pathway analysis of the targets of these 3 miRNAs indicated that they were largely associated with neural activity. Furthermore, we found that 2 of the 3 miRNAs, miR-142-3p, and miR-466b-5p, have the same target gene, Capn6, an antiapoptotic gene that is tightly regulated in the pathogenesis of neurological diseases. Collectively, we have shown that a number of miRNAs change in oligodendrocyte precursor cells in response to HI insult in developing brains, and miR-142-3p/miR-466b-5p/Capn6 pathway might affect the pathogenesis of WMI, providing us new clues for the diagnosis and therapy for WMI.
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Affiliation(s)
- Xiaojuan Su
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Dongqiong Xiao
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Lingyi Huang
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Shiping Li
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Junjie Ying
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Yu Tong
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Qianghua Ye
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Dezhi Mu
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
| | - Yi Qu
- Department of Pediatrics, West China Second University Hospital.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education
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Ren L, Li Q, Hu X, Yang Q, Du M, Xing Y, Wang Y, Li J, Zhang L. A Novel Mechanism of bta-miR-210 in Bovine Early Intramuscular Adipogenesis. Genes (Basel) 2020; 11:genes11060601. [PMID: 32485948 PMCID: PMC7349823 DOI: 10.3390/genes11060601] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 02/04/2023] Open
Abstract
Intramuscular fat (IMF) is one of the major factors determining beef quality. IMF formation is influenced by multiple conditions including genetic background, age and nutrition. In our previous investigation, bta-miR-210 was found to be increased during adipogenesis using miRNA-seq. In this study, we validated the upregulation of bta-miR-210 in platelet-derived growth factor receptor α positive (PDGFRα+) progenitor cells during adipogenic differentiation in vitro. To investigate its role in adipogenesis, bta-miR-210 mimics were introduced into progenitor cells, which resulted in enhanced intracellular lipid accumulation. Accordingly, the expression of adipocyte-specific genes significantly increased in the bta-miR-210 mimic group compared to that in the negative control group (p < 0.01). Dual-luciferase reporter assays revealed that WISP2 is a target of bta-miR-210. WISP2 knockdown enhanced adipogenesis. In conclusion, bta-miR-210 positively regulates the adipogenesis of PDGFRα+ cells derived from bovine fetal muscle by targeting WISP2.
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Affiliation(s)
- Ling Ren
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
| | - Qian Li
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
| | - Xin Hu
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
- Molecular and Cellular Biology, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium
| | - Qiyuan Yang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Min Du
- Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA;
| | - Yishen Xing
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
| | - Yahui Wang
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
| | - Junya Li
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
| | - Lupei Zhang
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.R.); (Q.L.); (X.H.); (Y.X.); (Y.W.); (J.L.)
- Correspondence: ; Tel.: +86-1062-890-940
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Fetal Hypoxia Impacts on Proliferation and Differentiation of Sca-1 + Cardiac Progenitor Cells and Maturation of Cardiomyocytes: A Role of MicroRNA-210. Genes (Basel) 2020; 11:genes11030328. [PMID: 32244901 PMCID: PMC7140790 DOI: 10.3390/genes11030328] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/16/2020] [Accepted: 03/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hypoxia is one of the most frequent and severe stresses to an organism’s homeostatic mechanisms, and hypoxia during gestation has profound adverse effects on the heart development increasing the occurrence of congenital heart defects (CHDs). Cardiac progenitor cells (CPCs) are responsible for early heart development and the later occurrence of heart disease. However, the mechanism of how hypoxic stress affects CPC fate decisions and contributes to CHDs remains a topic of debate. Here we examined the effect of hypoxic stress on the regulations of CPC fate decisions and the potential mechanism. We found that experimental induction of hypoxic responses compromised CPC function by regulating CPC proliferation and differentiation and restraining cardiomyocyte maturation. In addition, echocardiography indicated that fetal hypoxia reduced interventricular septum thickness at diastole and the ejection time, but increased the heart rate, in mouse young adult offspring with a gender-related difference. Further study revealed that hypoxia upregulated microRNA-210 expression in Sca-1+ CPCs and impeded the cell differentiation. Blockage of microRNA-210 with LNA-anti-microRNA-210 significantly promoted differentiation of Sca-1+ CPCs into cardiomyocytes. Thus, the present findings provide clear evidence that hypoxia alters CPC fate decisions and reveal a novel mechanism of microRNA-210 in the hypoxic effect, raising the possibility of microRNA-210 as a potential therapeutic target for heart disease.
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Wang X, De Geyter C, Jia Z, Peng Y, Zhang H. HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition. Int J Oncol 2020; 56:1186-1198. [PMID: 32319576 PMCID: PMC7115742 DOI: 10.3892/ijo.2020.5002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 01/29/2020] [Indexed: 01/11/2023] Open
Abstract
As a transcription factor, SNAIL plays a crucial role in embryonic development and cancer progression by mediating epithelial‑mesenchymal transition (EMT); however, post‑translational modifications, such as ubiquitination, which control the degradation of SNAIL have been observed to affect its functional role in EMT. In a previous study by the authors, it was demonstrated that the HECT domain E3 ubiquitin ligase 1 (HECTD1) regulated the dynamic nature of adhesive structures. In the present study, HECTD1 was observed to interact with SNAIL and regulate its stability through ubiquitination, and the knockdown of HECTD1 increased the expression levels of SNAIL. HECTD1 was discovered to contain putative nuclear localization and export signals that facilitated its translocation between the cytoplasm and nucleus, a process regulated by epidermal growth factor (EGF). Treatment with leptomycin B resulted in the nuclear retention of HECTD1, which was associated with the loss of SNAIL expression. The knockdown of HECTD1 in HeLa cells increased cell migration and induced a mesenchymal phenotype, in addition to demonstrating sustained EGF signaling, which was observed through increased phosphorylated ERK expression levels. Under hypoxic conditions, HECTD1 expression levels were decreased by microRNA (miRNA or miR)‑210. Upon the observation of genetic abnormalities in the HECTD1 gene in cervical cancer specimens, it was observed that the decreased expression levels of HECTD1 were significantly associated with a poor patient survival. Thus, it was hypothesized that HECTD1 may regulate EMT through the hypoxia/hypoxia inducible factor 1α/miR‑210/HECTD1/SNAIL signaling pathway and the EGF/EGF receptor/HECTD1/ERK/SNAIL signaling pathway in cervical cancer. On the whole, the data of the present study indicated that HECTD1 serves as an E3 ubiquitin ligase to mediate the stability of SNAIL proteins.
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Affiliation(s)
- Xinggang Wang
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
| | - Christian De Geyter
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
| | - Zanhui Jia
- Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Ya Peng
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
| | - Hong Zhang
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
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Karshovska E, Wei Y, Subramanian P, Mohibullah R, Geißler C, Baatsch I, Popal A, Corbalán Campos J, Exner N, Schober A. HIF-1α (Hypoxia-Inducible Factor-1α) Promotes Macrophage Necroptosis by Regulating miR-210 and miR-383. Arterioscler Thromb Vasc Biol 2020; 40:583-596. [PMID: 31996026 DOI: 10.1161/atvbaha.119.313290] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Inflammatory activation changes the mitochondrial function of macrophages from oxidative phosphorylation to reactive oxygen species production, which may promote necrotic core formation in atherosclerotic lesions. In hypoxic and cancer cells, HIF-1α (hypoxia-inducible factor) promotes oxygen-independent energy production by microRNAs. Therefore, we studied the role of HIF-1α in the regulation of macrophage energy metabolism in the context of atherosclerosis. Approach and Results: Myeloid cell-specific deletion of Hif1a reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis in apolipoprotein E-deficient mice. In inflammatory bone marrow-derived macrophages, deletion of Hif1a increased oxidative phosphorylation, ATP levels, and the expression of genes encoding mitochondrial proteins and reduced reactive oxygen species production and necroptosis. microRNA expression profiling showed that HIF-1α upregulates miR-210 and downregulates miR-383 levels in lesional macrophages and inflammatory bone marrow-derived macrophages. In contrast to miR-210, which inhibited oxidative phosphorylation and enhanced mitochondrial reactive oxygen species production, miR-383 increased ATP levels and inhibited necroptosis. The effect of miR-210 was due to targeting 2,4-dienoyl-CoA reductase, which is essential in the β oxidation of unsaturated fatty acids. miR-383 affected the DNA damage repair pathway in bone marrow-derived macrophages by targeting poly(ADP-ribose)-glycohydrolase (Parg), which reduced energy consumption and increased cell survival. Blocking the targeting of Parg by miR-383 prevented the protective effect of Hif1a deletion in macrophages on atherosclerosis and necrotic core formation in mice. CONCLUSIONS Our findings unveil a new mechanism by which activation of HIF-1α in inflammatory macrophages increases necroptosis through microRNA-mediated ATP depletion, thus increasing atherosclerosis by necrotic core formation.
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Affiliation(s)
- Ela Karshovska
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.).,DZHK, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (E.K., Y.W., A.S.)
| | - Yuanyuan Wei
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.).,DZHK, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (E.K., Y.W., A.S.)
| | - Pallavi Subramanian
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.)
| | - Rokia Mohibullah
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.)
| | - Claudia Geißler
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.)
| | - Isabelle Baatsch
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.)
| | - Aamoun Popal
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.)
| | - Judit Corbalán Campos
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.)
| | - Nicole Exner
- Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany (N.E.).,German Center for Neurodegenerative Diseases (DZNE), Munich, Germany (N.E.)
| | - Andreas Schober
- From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.).,DZHK, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (E.K., Y.W., A.S.)
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Zeng W, Lei Q, Ma J, Ju R. Effects of hypoxic-ischemic pre-treatment on microvesicles derived from endothelial progenitor cells. Exp Ther Med 2020; 19:2171-2178. [PMID: 32104281 PMCID: PMC7027331 DOI: 10.3892/etm.2020.8468] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 12/19/2019] [Indexed: 12/12/2022] Open
Abstract
Endothelial progenitor cells (EPCs) have protective roles in ischemic injury due to their ability to improve endothelial function and modulate angiogenesis. Microvesicles (MVs) are small membrane particles released by various cell types, including EPCs, which affect various target cells by transferring carried genetic information, including microRNAs (miRNAs/miRs). Depending on the stimuli and cell types, MVs exert different functions. In the present study, oxygen-glucose deprivation (OGD) was used to mimic ischemic-hypoxic (HI) insult, where the effects of HI insult on EPC-derived MVs (EPC-MVs) were subsequently investigated. OGD induced Ca2+ influx in EPCs and increased the release of EPC-MVs compared with normoxic conditions. In addition, MVs prepared from EPCs cultured under normoxic conditions or OGD conditions (OGD-EMVs) had the ability to stimulate the proliferation of EPCs. Furthermore, OGD-EMVs induced stronger effects on proliferation, which may be associated with the upregulation of miR-210 in EPC-MVs. In conclusion, the present results indicated that HI insult promoted the release of MVs from EPCs and upregulated miR-210 in MVs, leading to positive modulation of the proliferation of EPCs cultured under normoxic conditions.
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Affiliation(s)
- Wen Zeng
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, P.R. China
| | - Qiaoling Lei
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, P.R. China
| | - Jiao Ma
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, P.R. China
| | - Rong Ju
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, P.R. China
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Jin J, Bakker AD, Wu G, Klein-Nulend J, Jaspers RT. Physicochemical Niche Conditions and Mechanosensing by Osteocytes and Myocytes. Curr Osteoporos Rep 2019; 17:235-249. [PMID: 31428977 PMCID: PMC6817749 DOI: 10.1007/s11914-019-00522-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Bone and muscle mass increase in response to mechanical loading and biochemical cues. Bone-forming osteoblasts differentiate into early osteocytes which ultimately mature into late osteocytes encapsulated in stiff calcified matrix. Increased muscle mass originates from muscle stem cells (MuSCs) enclosed between their plasma membrane and basal lamina. Stem cell fate and function are strongly determined by physical and chemical properties of their microenvironment, i.e., the cell niche. RECENT FINDINGS The cellular niche is a three-dimensional structure consisting of extracellular matrix components, signaling molecules, and/or other cells. Via mechanical interaction with their niche, osteocytes and MuSCs are subjected to mechanical loads causing deformations of membrane, cytoskeleton, and/or nucleus, which elicit biochemical responses and secretion of signaling molecules into the niche. The latter may modulate metabolism, morphology, and mechanosensitivity of the secreting cells, or signal to neighboring cells and cells at a distance. Little is known about how mechanical loading of bone and muscle tissue affects osteocytes and MuSCs within their niches. This review provides an overview of physicochemical niche conditions of (early) osteocytes and MuSCs and how these are sensed and determine cell fate and function. Moreover, we discuss how state-of-the-art imaging techniques may enhance our understanding of these conditions and mechanisms.
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Affiliation(s)
- Jianfeng Jin
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | - Astrid D Bakker
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | - Gang Wu
- Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | - Jenneke Klein-Nulend
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | - Richard T Jaspers
- Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
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40
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Effect of Hypoxia-Induced MicroRNA-210 Expression on Cardiovascular Disease and the Underlying Mechanism. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4727283. [PMID: 31249644 PMCID: PMC6556335 DOI: 10.1155/2019/4727283] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/08/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
Cardiovascular diseases have high morbidity and mortality rates worldwide, and their treatment and prevention are challenging. MicroRNAs are a series of noncoding RNAs with highly conserved sequences and regulate gene expression by inhibiting mRNA transcription or degrading targeting proteins. MicroRNA-210 is significantly upregulated during hypoxia and plays a protective role by inhibiting apoptosis and regulating cell proliferation, differentiation, migration, mitochondrial metabolism, and angiogenesis in hypoxic cells. MicroRNA-210 expression is altered in cardiovascular diseases such as atherosclerosis, acute myocardial infarction, preeclampsia, aortic stenosis, and heart failure, and overexpression of microRNA-210 in some of these diseases exerts protective effects on target organs. Furthermore, chronically upregulated miR-210 potentially plays a marked pathogenic role in specific situations. This review primarily focuses on the upstream pathways, downstream targets, clinical progress in cardiovascular disease, and potential applications of microRNA-210.
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Severino P, D'Amato A, Netti L, Pucci M, Infusino F, Maestrini V, Mancone M, Fedele F. Myocardial Ischemia and Diabetes Mellitus: Role of Oxidative Stress in the Connection between Cardiac Metabolism and Coronary Blood Flow. J Diabetes Res 2019; 2019:9489826. [PMID: 31089475 PMCID: PMC6476021 DOI: 10.1155/2019/9489826] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/23/2019] [Accepted: 03/13/2019] [Indexed: 12/27/2022] Open
Abstract
Ischemic heart disease (IHD) has several risk factors, among which diabetes mellitus represents one of the most important. In diabetic patients, the pathophysiology of myocardial ischemia remains unclear yet: some have atherosclerotic plaque which obstructs coronary blood flow, others show myocardial ischemia due to coronary microvascular dysfunction in the absence of plaques in epicardial vessels. In the cross-talk between myocardial metabolism and coronary blood flow (CBF), ion channels have a main role, and, in diabetic patients, they are involved in the pathophysiology of IHD. The exposition to the different cardiovascular risk factors and the ischemic condition determine an imbalance of the redox state, defined as oxidative stress, which shows itself with oxidant accumulation and antioxidant deficiency. In particular, several products of myocardial metabolism, belonging to oxidative stress, may influence ion channel function, altering their capacity to modulate CBF, in response to myocardial metabolism, and predisposing to myocardial ischemia. For this reason, considering the role of oxidative and ion channels in the pathophysiology of myocardial ischemia, it is allowed to consider new therapeutic perspectives in the treatment of IHD.
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Affiliation(s)
- Paolo Severino
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Andrea D'Amato
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Lucrezia Netti
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Mariateresa Pucci
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Fabio Infusino
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Viviana Maestrini
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Massimo Mancone
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Francesco Fedele
- Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, 00161 Rome, Italy
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Fuschi P, Maimone B, Gaetano C, Martelli F. Noncoding RNAs in the Vascular System Response to Oxidative Stress. Antioxid Redox Signal 2019; 30:992-1010. [PMID: 28683564 DOI: 10.1089/ars.2017.7229] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Redox homeostasis plays a pivotal role in vascular cell function and its imbalance has a causal role in a variety of vascular diseases. Accordingly, the response of mammalian cells to redox cues requires precise transcriptional and post-transcriptional modulation of gene expression patterns. Recent Advances: Mounting evidence shows that nonprotein-coding RNAs (ncRNAs) are important for the functional regulation of most, if not all, cellular processes and tissues. Not surprisingly, a prominent role of ncRNAs has been identified also in the vascular system response to oxidative stress. CRITICAL ISSUES The highly heterogeneous family of ncRNAs has been divided into several groups. In this article we focus on two classes of regulatory ncRNAs: microRNAs and long ncRNAs (lncRNAs). Although knowledge in many circumstances, and especially for lncRNAs, is still fragmentary, ncRNAs are clinically interesting because of their diagnostic and therapeutic potential. We outline ncRNAs that are regulated by oxidative stress as well as ncRNAs that modulate reactive oxygen species production and scavenging. More importantly, we describe the role of these ncRNAs in vascular physiopathology and specifically in disease conditions wherein oxidative stress plays a crucial role, such as hypoxia and ischemia, ischemia reperfusion, inflammation, diabetes mellitus, and atherosclerosis. FUTURE DIRECTIONS The therapeutic potential of ncRNAs in vascular diseases and in redox homeostasis is discussed.
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Affiliation(s)
- Paola Fuschi
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Biagina Maimone
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Carlo Gaetano
- 2 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany
| | - Fabio Martelli
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
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Goradel NH, Mohammadi N, Haghi-Aminjan H, Farhood B, Negahdari B, Sahebkar A. Regulation of tumor angiogenesis by microRNAs: State of the art. J Cell Physiol 2019; 234:1099-1110. [PMID: 30070704 DOI: 10.1002/jcp.27051] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/25/2018] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs, miRs) are small (21-25 nucleotides) endogenous and noncoding RNAs involved in many cellular processes such as apoptosis, development, proliferation, and differentiation via binding to the 3'-untranslated region of the target mRNA and inhibiting its translation. Angiogenesis is a hallmark of cancer, which provides oxygen and nutrition for tumor growth while removing deposits and wastes from the tumor microenvironment. There are many angiogenesis stimulators, among which vascular endothelial growth factor (VEGF) is the most well known. VEGF has three tyrosine kinase receptors, which, following VEGF binding, initiate proliferation, invasion, migration, and angiogenesis of endothelial cells in the tumor environment. One of the tumor microenvironment conditions that induce angiogenesis through increasing VEGF and its receptors expression is hypoxia. Several miRNAs have been identified that affect different targets in the tumor angiogenesis pathway. Most of these miRNAs affect VEGF and its tyrosine kinase receptors expression downstream of the hypoxia-inducible Factor 1 (HIF-1). This review focuses on tumor angiogenesis regulation by miRNAs and the mechanism underlying this regulation.
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Affiliation(s)
- Nasser H Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nejad Mohammadi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Haghi-Aminjan
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Skalis G, Katsi V, Miliou A, Georgiopoulos G, Papazachou O, Vamvakou G, Nihoyannopoulos P, Tousoulis D, Makris T. MicroRNAs in Preeclampsia. Microrna 2019; 8:28-35. [PMID: 30101723 DOI: 10.2174/2211536607666180813123303] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 05/22/2018] [Accepted: 07/27/2018] [Indexed: 11/22/2022]
Abstract
Preeclampsia (PE) continues to represent a worldwide problem and challenge for both clinicians and laboratory-based doctors. Despite many efforts, the knowledge acquired regarding its pathogenesis and pathophysiology does not allow us to treat it efficiently. It is not possible to arrest its progressive nature, and the available therapies are limited to symptomatic treatment. Furthermore, both the diagnosis and prognosis are frequently uncertain, whilst the ability to predict its occurrence is very limited. MicroRNAs are small non-coding RNAs discovered two decades ago, and present great interest given their ability to regulate almost every aspect of the cell function. A lot of evidence regarding the role of miRNAs in pre-eclampsia has been accumulated in the last 10 years. Differentially expressed miRNAs are characteristic of both mild and severe PE. In many cases they target signaling pathway-related genes that result in altered processes which are directly involved in PE. Immune system, angiogenesis and trophoblast proliferation and invasion, all fundamental aspects of placentation, are controlled in various degrees by miRNAs which are up- or downregulated. Finally, miRNAs represent a potential therapeutic target and a diagnostic tool.
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Affiliation(s)
- Georgios Skalis
- Department of Cardiology, Helena Venizelou Hospital, Athens, Greece
| | - Vasiliki Katsi
- Cardiology Department, Hippokration Hospital, National Health System, Athens, Greece
| | - Antigoni Miliou
- 1st Department of Cardiology, Hippokration Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | | | | | - Georgia Vamvakou
- Department of Cardiology, Helena Venizelou Hospital, Athens, Greece
| | - Petros Nihoyannopoulos
- 1st Department of Cardiology, Hippokration Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Tousoulis
- 1st Department of Cardiology, Hippokration Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | - Thomas Makris
- Department of Cardiology, Helena Venizelou Hospital, Athens, Greece
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Jia W, Liang D, Li N, Liu M, Dong Z, Li J, Dong X, Yue Y, Hu P, Yao J, Zhao Q. Zebrafish microRNA miR-210-5p inhibits primitive myelopoiesis by silencing foxj1b and slc3a2a mRNAs downstream of gata4/5/6 transcription factor genes. J Biol Chem 2018; 294:2732-2743. [PMID: 30593510 DOI: 10.1074/jbc.ra118.005079] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 12/22/2018] [Indexed: 12/21/2022] Open
Abstract
Zebrafish gata4/5/6 genes encode transcription factors that lie on the apex of the regulatory hierarchy in primitive myelopoiesis. However, little is known about the roles of microRNAs in gata4/5/6-regulated processes. Performing RNA-Seq deep sequencing analysis of the expression changes of microRNAs in gata4/5/6-knockdown embryos, we identified miR-210-5p as a regulator of zebrafish primitive myelopoiesis. Knocking down gata4/5/6 (generating gata5/6 morphants) significantly increased miR-210-5p expression, whereas gata4/5/6 overexpression greatly reduced its expression. Consistent with inhibited primitive myelopoiesis in the gata5/6 morphants, miR-210-5p overexpression repressed primitive myelopoiesis, indicated by reduced numbers of granulocytes and macrophages. Moreover, knocking out miR-210 partially rescued the defective primitive myelopoiesis in zebrafish gata4/5/6-knockdown embryos. Furthermore, we show that the restrictive role of miR-210-5p in zebrafish primitive myelopoiesis is due to impaired differentiation of hemangioblast into myeloid progenitor cells. By comparing the set of genes with reduced expression levels in the gata5/6 morphants to the predicted target genes of miR-210-5p, we found that foxj1b and slc3a2a, encoding a forkhead box transcription factor and a solute carrier family 3 protein, respectively, are two direct downstream targets of miR-210-5p that mediate its inhibitory roles in zebrafish primitive myelopoiesis. In summary, our results reveal that miR-210-5p has an important role in the genetic network controlling zebrafish primitive myelopoiesis.
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Affiliation(s)
- Wenshuang Jia
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Dong Liang
- the Department of Prenatal Diagnosis, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, and
| | - Nan Li
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Meijing Liu
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Zhangji Dong
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Jingyun Li
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Xiaohua Dong
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Yunyun Yue
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061
| | - Ping Hu
- the Department of Prenatal Diagnosis, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, and
| | - Jihua Yao
- the State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China
| | - Qingshun Zhao
- From the MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061,
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Ji W, Wang L, He S, Yan L, Li T, Wang J, Kong ANT, Yu S, Zhang Y. Effects of acute hypoxia exposure with different durations on activation of Nrf2-ARE pathway in mouse skeletal muscle. PLoS One 2018; 13:e0208474. [PMID: 30513114 PMCID: PMC6279028 DOI: 10.1371/journal.pone.0208474] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 11/16/2018] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Hypoxia training enhances the endurance capacity of athletes. This response may in part be attributed to the hypoxia-induced increase in antioxidant capacity in skeletal muscles. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor which regulates the expression of genes via binding to the antioxidant-response element (ARE) of these genes, plays a crucial role in stimulating the body's defense system and potentially responds to hypoxia. Meanwhile, hypoxia-inducible factor-1α (HIF-1α) is an important player in protecting cells from hypoxic stress. The purpose of this study was to investigate the effects of acute hypoxia exposure with different durations on the activation of Nrf2-ARE pathway and a possible regulatory role of HIF-1α in these responses. METHODS C57BL/6J mice were allocated into the non-hypoxia 0-hour, 6-hour, 24-hour, and 48-hour hypoxic exposure (11.2% oxygen) groups. The quadriceps femoris was collected immediately after hypoxia. Further, to investigate the possible role of HIF-1α, C2C12 myoblasts with HIF-1α knockdown by small interfering RNA (siRNA) and the inducible HIF-1α transgenic mice were employed. RESULTS The results showed that 48-hour hypoxia exposure up-regulated protein expression of Nrf2, Nrf2/ARE binding activity and the transcription of antioxidative genes containing ARE (Sod1 and others) in mouse skeletal muscle. Moreover, HIF-1α siRNA group of C2C12 myoblasts showed a remarkable inhibition of Nrf2 protein expression and nuclear accumulation in hypoxia exposure for 72 hours compared with that in siRNA-Control group of the cells. In addition, HIF-1α transgenic mice gave higher Nrf2 protein expression, Nrf2/ARE binding activity and expressions of Nrf2-mediated antioxidative genes in their skeletal muscle, compared with those in the wild-type mice. CONCLUSIONS The findings suggested that the acute hypoxia exposure could trigger the activation of Nrf2-ARE pathway, with longer duration associated with higher responses, and HIF-1α expression might be involved in promoting the Nrf2-mediated antioxidant responses in skeletal muscle.
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Affiliation(s)
- Weixiu Ji
- School of Sport Science, Beijing Sport University, Beijing, China
- Tianjin University of Sport, Tianjin, China
| | - Linjia Wang
- School of Sport Science, Beijing Sport University, Beijing, China
| | - Shiyi He
- School of Sport Science, Beijing Sport University, Beijing, China
| | - Lu Yan
- School of Sport Science, Beijing Sport University, Beijing, China
| | - Tieying Li
- School of Sport Science, Beijing Sport University, Beijing, China
| | - Jianxiong Wang
- Faculty of Health, Engineering, and Sciences, University of Southern Queensland, Toowoomba, Queensland, Australia
| | - Ah-Ng Tony Kong
- Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Camden, New Jersey, United States of America
| | - Siwang Yu
- Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Ying Zhang
- School of Sport Science, Beijing Sport University, Beijing, China
- * E-mail:
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Besnier M, Gasparino S, Vono R, Sangalli E, Facoetti A, Bollati V, Cantone L, Zaccagnini G, Maimone B, Fuschi P, Da Silva D, Schiavulli M, Aday S, Caputo M, Madeddu P, Emanueli C, Martelli F, Spinetti G. miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia. Mol Ther 2018; 26:1694-1705. [PMID: 29908843 DOI: 10.1016/j.ymthe.2018.06.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 06/05/2018] [Accepted: 06/05/2018] [Indexed: 12/28/2022] Open
Abstract
Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.
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Affiliation(s)
- Marie Besnier
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Stefano Gasparino
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Rosa Vono
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Elena Sangalli
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Amanda Facoetti
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy
| | - Valentina Bollati
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Laura Cantone
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Biagina Maimone
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Paola Fuschi
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Daniel Da Silva
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy
| | - Michele Schiavulli
- AORN Santobono Pausilipon, Transfusion Medicine and Bone Marrow Transplantation Unit-Regional Reference Center for Coagulation Disorders, Napoli, Italy
| | - Sezin Aday
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Massimo Caputo
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Paolo Madeddu
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK
| | - Costanza Emanueli
- Bristol Heart Institute, School of Clinical Science, University of Bristol, Bristol, UK; National Heart and Lung Institute, Imperial College London, London, UK
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato, Italy.
| | - Gaia Spinetti
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy.
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Archer‐Lahlou E, Lan C, Jagoe RT. Physiological culture conditions alter myotube morphology and responses to atrophy treatments: implications for in vitro research on muscle wasting. Physiol Rep 2018; 6:e13726. [PMID: 29932505 PMCID: PMC6014447 DOI: 10.14814/phy2.13726] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 05/09/2018] [Indexed: 01/05/2023] Open
Abstract
Standard in vitro myotube culture conditions are nonphysiological and there is increasing evidence that this may distort adaptations to both catabolic and anabolic stimuli and hamper preclinical research into mechanisms and treatments for muscle atrophy in cancer and other chronic diseases. We tested a new model of myotube culture which mimics more accurately the basal conditions for muscle tissue in patients with chronic disease, such as cancer. Myotubes derived from C2C12 myoblasts, cultured under the modified conditions were thinner, more numerous, with more uniform morphology and an increased proportion of mature myotubes. Furthermore, modified conditions led to increased expression of mir-210-3p, genes related to slow-twitch, oxidative phenotype and resistance to commonly used experimental atrophy-inducing treatments. However, treatment with a combination of drugs used in anti-cancer treatment (doxorubicin and dexamethasone) under the modified culture conditions did lead to myotube atrophy which was only partially prevented by co-administration of curcumin. The results underline the importance and potential advantages of using physiological conditions for in vivo experiments investigating mechanisms of muscle atrophy and especially for preclinical screening of therapies for cancer-related muscle wasting.
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Affiliation(s)
- Elodie Archer‐Lahlou
- Lady Davis Institute for Medical ResearchSegal Cancer CentreJewish General HospitalMcGill UniversityMontrealQuebecCanada
| | - Cathy Lan
- Lady Davis Institute for Medical ResearchSegal Cancer CentreJewish General HospitalMcGill UniversityMontrealQuebecCanada
| | - R. Thomas Jagoe
- Lady Davis Institute for Medical ResearchSegal Cancer CentreJewish General HospitalMcGill UniversityMontrealQuebecCanada
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Nizyaeva NV, Sukhacheva TV, Serov RA, Kulikova GV, Nagovitsyna MN, Kan NE, Tyutyunnik VL, Pavlovich SV, Poltavtseva RA, Yarotskaya EL, Shchegolev AI, Sukhikh GT. Ultrastructural and Immunohistochemical Features of Telocytes in Placental Villi in Preeclampsia. Sci Rep 2018; 8:3453. [PMID: 29472628 PMCID: PMC5823867 DOI: 10.1038/s41598-018-21492-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 02/06/2018] [Indexed: 11/09/2022] Open
Abstract
A new cell type, interstitial Cajal-like cell (ICLC), was recently described in different organs. The name was recently changed to telocytes (TCs), and their typical thin, long processes have been named telopodes (Tp). TCs regulate the contractile activity of smooth muscle cells and play a role in regulating vessel contractions. Although the placenta is not an innervated organ, we believe that TCs are present in the placenta. We studied placenta samples from physiological pregnancies and in different variants of preeclampsia (PE). We examined these samples using light microscopy of semi-thin sections, transmission electron microscopy, and immunohistochemistry. Immunohistochemical examination was performed with primary antibodies to CD34, CD117, SMA, and vimentin, and TMEM16a (DOG-1), the latter was used for the diagnosis of gastrointestinal stromal tumours (GIST) consisting of TCs. We have identified a heterogenetic population of ТСs in term placentas, as these cell types differed in their localization, immunophenotype and ultrastructural characteristics. We assume TMEM16a could be used as the marker for identification of TCs. In PE we have revealed telocyte-like cells with ultrastructural signs of fibrocytes (significant process thickening and the granular endoplasmic reticulum content was increased) and a loss of TMEM16a immunohistochemical staining.
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Affiliation(s)
- Natalia V Nizyaeva
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia.
| | - Tatiana V Sukhacheva
- A.N. Bakulev National Medical Research Center of Cardiovascular Surgery, Moscow, 119991, Russia
| | - Roman A Serov
- A.N. Bakulev National Medical Research Center of Cardiovascular Surgery, Moscow, 119991, Russia
| | - Galina V Kulikova
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia
| | - Marina N Nagovitsyna
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia
| | - Natalia E Kan
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia.,I.M. Sechenov First Moscow State Medical University, Moscow, 121552, Russia
| | - Victor L Tyutyunnik
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia.,I.M. Sechenov First Moscow State Medical University, Moscow, 121552, Russia
| | - Stanislav V Pavlovich
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia.,I.M. Sechenov First Moscow State Medical University, Moscow, 121552, Russia
| | - Rimma A Poltavtseva
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia
| | - Ekaterina L Yarotskaya
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia
| | - Aleksandr I Shchegolev
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia
| | - Gennadiy T Sukhikh
- National Medical Research Center for Obstetrics Gynecology and Perinatology, Moscow, 117997, Russia.,I.M. Sechenov First Moscow State Medical University, Moscow, 121552, Russia
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Integration of miRNA and mRNA expression profiles reveals microRNA-regulated networks during muscle wasting in cardiac cachexia. Sci Rep 2017; 7:6998. [PMID: 28765595 PMCID: PMC5539204 DOI: 10.1038/s41598-017-07236-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 06/28/2017] [Indexed: 12/28/2022] Open
Abstract
Cardiac cachexia (CC) is a common complication of heart failure (HF) associated with muscle wasting and poor patient prognosis. Although different mechanisms have been proposed to explain muscle wasting during CC, its pathogenesis is still not understood. Here, we described an integrative analysis between miRNA and mRNA expression profiles of muscle wasting during CC. Global gene expression profiling identified 1,281 genes and 19 miRNAs differentially expressed in muscle wasting during CC. Several of these deregulated genes are known or putative targets of the altered miRNAs, including miR-29a-3p, miR-29b-3p, miR-210-5p, miR-214, and miR-489. Gene ontology analysis on integrative mRNA/miRNA expression profiling data revealed miRNA interactions affecting genes that regulate extra-cellular matrix (ECM) organization, proteasome protein degradation, citric acid cycle and respiratory electron transport. We further identified 11 miRNAs, including miR-29a-3p and miR-29b-3p, which target 21 transcripts encoding the collagen proteins related to ECM organization. Integrative miRNA and mRNA global expression data allowed us to identify miRNA target genes involved in skeletal muscle wasting in CC. Our functional experiments in C2C12 cells confirmed that miR-29b down-regulates collagen genes and contributes to muscle cell atrophy. Collectively, our results suggest that key ECM-associated miRNAs and their target genes may contribute to CC in HF.
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