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Han Y, Guo XP, Zhi QM, Xu JJ, Liu F, Kuang YT. Circulating exosomal miR-17-92 cluster serves as a novel noninvasive diagnostic marker for patients with gastric cancer. World J Gastrointest Oncol 2025; 17:104776. [DOI: 10.4251/wjgo.v17.i5.104776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/25/2025] [Accepted: 03/13/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is among the most common malignant tumors and remains a leading cause of cancer-related mortality worldwide. Furthermore, exosomal miRNAs are regarded as promising noninvasive biomarkers for diagnosing malignant tumors.
AIM To investigate the expression of exosomal miR-17-92 clusters and develop a potential biomarker for GC diagnosis
METHODS Exosomes were isolated from serum samples obtained from 72 GC patients and 20 healthy controls. The isolated exosomes were validated using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Exosomal RNA was then extracted, and the expression profile of the miR-17-92 cluster was analyzed using qRT-PCR. Statistical methods were employed to evaluate the relationship between the serum exosomal miR-17-92 cluster expression and the clinicopathological parameters of GC patients as well as to assess the diagnostic utility of these miRNAs.
RESULTS The expression of four members of the exosomal miR-17-92 cluster-miR-17, miR-18, miR-19a, and miR-92-was significantly upregulated in the serum samples of patients with GC compared with those of healthy controls. The miR-17-92 cluster panel demonstrated substantially higher clinical diagnostic value for GC than any individual component or pair. Additionally, the expression of traditional tumor biomarkers-carcinoembryonic antigen and carbohydrate antigen 19-9-was significantly elevated in the serum of patients with GC compared with that of healthy controls. Each biomarker, whether alone or in combination, effectively differentiated the patients from healthy controls. Furthermore, a combined panel of the two traditional tumor biomarkers and the four miR-17-92 cluster members exhibited the highest diagnostic accuracy for GC. Elevated miR-17-92 expression was also strongly associated with tumor size, tumor depth, lymph node metastasis, distant metastasis, and tumor-node-metastasis stage.
CONCLUSION Our findings revealed that the circulating exosomal miR-17-92 cluster may be used as a potential noninvasive biomarker to improve diagnostic efficiency for GC.
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Affiliation(s)
- Ye Han
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Xing-Po Guo
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Qiao-Ming Zhi
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Jing-Jing Xu
- Department of Central Laboratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Fei Liu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Yu-Ting Kuang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
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Liu Z, Zhao Z, Xiao Z, Li M, Wang X, Huang Y, Li Y. Extracellular vesicles derived from bone marrow mesenchymal stem cells regulate SREBF2/HMGB1 axis by transporting miR-378a-3p to inhibit ferroptosis in intestinal ischemia-reperfusion injury. Cell Death Discov 2025; 11:223. [PMID: 40335466 PMCID: PMC12058992 DOI: 10.1038/s41420-025-02509-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 04/17/2025] [Accepted: 04/24/2025] [Indexed: 05/09/2025] Open
Abstract
Intestinal ischemia-reperfusion (II/R) injury represents a life-threatening and complex pathophysiological process that remains challenging to treat clinically, and emerging evidence suggests that ferroptosis plays an essential role in its pathogenesis. This study aimed to investigate whether extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) can mitigate II/R-induced ferroptosis in a murine model. Using a bioinformatics database, we initially identified genes with abnormal expression patterns in II/R injury. Then, we confirmed the association between II/R injury, ferroptosis, and the HMGB1/SREBF2 axis through in vivo and in vitro experiments. To determine the role of HMGB1 in hypoxia/reoxygenation (H/R)-induced ferroptosis in Caco-2 cells, we transfected cells with either sh-HMGB1 or control sh-NC constructs and developed an H/R model in vitro. Subsequently, we examined factors regulating HMGB1-mediated ferroptosis in Caco-2 cells and assessed the effect of BMSC-EVs on this process. To further explore the mechanism underlying the protective effects of BMSC-EVs in II/R injury, we screened for miRNAs with reduced expression during II/R and verified their involvement. Among these, miR-378a-3p was identified as a candidate for regulating ferroptosis. To confirm its functional role, we treated II/R mice with BMSC-EVs overexpressing miR-378a-3p and assessed the outcomes. Our findings revealed that HMGB1, which is a key regulatory factor of ferroptosis, was significantly upregulated during II/R injury, and its knockdown alleviated H/R-induced ferroptosis in Caco-2 cells. We also found that SREBF2 directly regulates HMGB1 expression to promote H/R-induced ferroptosis in vitro. Importantly, BMSC-EVs alleviated II/R injury by suppressing ferroptosis in Caco-2 cells, and mechanistically, miR-378a-3p, a miRNA derived from BMSC-EVs, inhibited II/R-induced ferroptosis by modulating the SREBF2/HMGB1 axis. In conclusion, BMSC-EVs may exert protective effects against II/R injury by delivering miR-378a-3p, which regulates the SREBF2/HMGB1 axis to suppress ferroptosis, providing important insights into the pathological mechanisms underlying II/R injury and potential therapeutic strategies for its management.
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Affiliation(s)
- Zan Liu
- Department of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan children's hospital), Changsha, PR China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, College of Pharmacy, Changsha Medical University, Changsha, PR China
| | - Zitong Zhao
- Center of Reproductive Medicine, Changsha Hospital for Maternal and Child Health Care of Hunan Normal University, Changsha, PR China
| | - Zhenghui Xiao
- Emergency center of Hunan Children's Hospital, Changsha, Hunan, PR China
| | - Ming Li
- Department of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan children's hospital), Changsha, PR China
| | - Xiyang Wang
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Yan Huang
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, PR China.
- Hunan Provincial Key Laboratory of Neurorestoration, Changsha, Hunan, PR China.
| | - Yong Li
- Department of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan children's hospital), Changsha, PR China.
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3
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Xia W, Tan Y, Liu Y, Xie N, Zhu H. Prospect of extracellular vesicles in tumor immunotherapy. Front Immunol 2025; 16:1525052. [PMID: 40078996 PMCID: PMC11897508 DOI: 10.3389/fimmu.2025.1525052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 01/28/2025] [Indexed: 03/14/2025] Open
Abstract
Extracellular vesicles (EVs), as cell-derived small vesicles, facilitate intercellular communication within the tumor microenvironment (TME) by transporting biomolecules. EVs from different sources have varied contents, demonstrating differentiated functions that can either promote or inhibit cancer progression. Thus, regulating the formation, secretion, and intake of EVs becomes a new strategy for cancer intervention. Advancements in EV isolation techniques have spurred interest in EV-based therapies, particularly for tumor immunotherapy. This review explores the multifaceted functions of EVs from various sources in tumor immunotherapy, highlighting their potential in cancer vaccines and adoptive cell therapy. Furthermore, we explore the potential of EVs as nanoparticle delivery systems in tumor immunotherapy. Finally, we discuss the current state of EVs in clinical settings and future directions, aiming to provide crucial information to advance the development and clinical application of EVs for cancer treatment.
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Affiliation(s)
- Wenbo Xia
- Department of Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yunhan Tan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yongen Liu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Na Xie
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Huili Zhu
- Department of Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China
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4
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Rafanan J, Ghani N, Kazemeini S, Nadeem-Tariq A, Shih R, Vida TA. Modernizing Neuro-Oncology: The Impact of Imaging, Liquid Biopsies, and AI on Diagnosis and Treatment. Int J Mol Sci 2025; 26:917. [PMID: 39940686 PMCID: PMC11817476 DOI: 10.3390/ijms26030917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/18/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Advances in neuro-oncology have transformed the diagnosis and management of brain tumors, which are among the most challenging malignancies due to their high mortality rates and complex neurological effects. Despite advancements in surgery and chemoradiotherapy, the prognosis for glioblastoma multiforme (GBM) and brain metastases remains poor, underscoring the need for innovative diagnostic strategies. This review highlights recent advancements in imaging techniques, liquid biopsies, and artificial intelligence (AI) applications addressing current diagnostic challenges. Advanced imaging techniques, including diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS), improve the differentiation of tumor progression from treatment-related changes. Additionally, novel positron emission tomography (PET) radiotracers, such as 18F-fluoropivalate, 18F-fluoroethyltyrosine, and 18F-fluluciclovine, facilitate metabolic profiling of high-grade gliomas. Liquid biopsy, a minimally invasive technique, enables real-time monitoring of biomarkers such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating tumor cells (CTCs), and tumor-educated platelets (TEPs), enhancing diagnostic precision. AI-driven algorithms, such as convolutional neural networks, integrate diagnostic tools to improve accuracy, reduce interobserver variability, and accelerate clinical decision-making. These innovations advance personalized neuro-oncological care, offering new opportunities to improve outcomes for patients with central nervous system tumors. We advocate for future research integrating these tools into clinical workflows, addressing accessibility challenges, and standardizing methodologies to ensure broad applicability in neuro-oncology.
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Affiliation(s)
| | | | | | | | | | - Thomas A. Vida
- Department of Medical Education, Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA; (J.R.); (N.G.); (S.K.); (A.N.-T.); (R.S.)
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Ismail M, Fadul MM, Taha R, Siddig O, Elhafiz M, Yousef BA, Jiang Z, Zhang L, Sun L. Dynamic role of exosomal long non-coding RNA in liver diseases: pathogenesis and diagnostic aspects. Hepatol Int 2024; 18:1715-1730. [PMID: 39306594 DOI: 10.1007/s12072-024-10722-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/15/2024] [Indexed: 12/11/2024]
Abstract
BACKGROUND Liver disease has emerged as a significant health concern, characterized by high rates of morbidity and mortality. Circulating exosomes have garnered attention as important mediators of intercellular communication, harboring protein and stable mRNAs, microRNAs, and long non-coding RNAs (lncRNA). This review highlights the involvement of exosomal lncRNA in the pathogenesis and diagnosis of various liver diseases. Notably, exosomal lncRNAs exhibit therapeutic potential as targets for conditions including hepatic carcinoma, hepatic fibrosis, and hepatic viral infections. METHOD An online screening process was employed to identify studies investigating the association between exosomal lncRNA and various liver diseases. RESULT Our study revealed a diverse array of lncRNAs carried by exosomes, including H19, Linc-ROR, VLDLR, MALAT1, DANCR, HEIH, ENSG00000248932.1, ENST00000457302.2, ZSCAN16-AS1, and others, exhibiting varied levels across different liver diseases compared to normal liver tissue. These exosomal-derived lncRNAs are increasingly recognized as pivotal biomarkers for diagnosing and prognosticating liver diseases, supported by emerging evidence. However, the precise mechanisms underlying the involvement of certain exosomal lncRNAs remain incompletely understood. Furthermore, the combined analysis of serum exosomes using ENSG00000258332.1, LINC00635, and serum AFP may serve as novel and valuable biomarker for HCC. Clinically, exosomal ATB expression is upregulated in HCC, while exosomal HEIH and RP11-513I15.6 have shown potential for distinguishing HCC related to HCV infection. CONCLUSION The lack of reliable biomarkers for liver diseases, coupled with the high specificity and sensitivity of exosomal lncRNA and its non-invasive detection, promotes exploring their role in pathogenesis and biomarker for diagnosis, prognosis, and response to treatment liver diseases.
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Affiliation(s)
- Mohammed Ismail
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Department of Pharmacology, Faculty of Medicine and Health Science, Dongola University, Dongola, Sudan
| | - Missaa M Fadul
- Department of Pharmacology, Faculty of Medicine and Health Science, Dongola University, Dongola, Sudan
| | - Reham Taha
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Orwa Siddig
- Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Muhanad Elhafiz
- Department of Pharmacology, Faculty of Pharmacy, Omdurman Islamic University, Khartoum, Sudan
| | - Bashir A Yousef
- Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan
| | - Zhenzhou Jiang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
- Centre for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Lixin Sun
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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Bin Islam MK, Marcus RK. Isolation and quantification of human urinary exosomes using a Tween-20 elution solvent from polyester, capillary-channeled polymer fiber columns. Anal Chim Acta 2024; 1329:343242. [PMID: 39396305 PMCID: PMC11471952 DOI: 10.1016/j.aca.2024.343242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/08/2024] [Accepted: 09/11/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Exosomes, a subset of extracellular vesicles (EVs), are a type of membrane-secreted vesicle essential for intercellular communication. There is a great deal of interest in developing methods to isolate and quantify exosomes to study their role in intercellular processes and as potential therapeutic delivery systems. Polyester, capillary-channeled polymer fiber columns and spin-down tips are highly efficient, low-cost means of exosome isolation. As the methodology evolves, there remain questions as to the optimum elution solvent for specific end-uses of the recovered vesicles; fundamental biochemistry, clinical diagnostics, or therapeutic vectors. RESULTS While both acetonitrile and glycerol have been proven highly successful in terms of EV recoveries in the hydrophobic interaction chromatography workflow, many biological studies entail the use of the non-ionic detergent, Tween-20, as a working solvent. Here we evaluate the use of Tween-20 as the elution solvent for the recovery of exosomes. A novel 10-min, two-step gradient elution method, employing 0.1 % v/v Tween-20, efficiently isolated EVs at a concentration of ∼1011 EV mL-1 from a 100 μL urine injection. Integration of absorbance and multi-angle light scattering detectors in standard HPLC instrumentation enables a comprehensive single-injection determination of eluted exosome concentration and sizes. Transmission electron microscopy verifies the retention of the vesicular structure of the exosomes. The micro-bicinchoninic acid protein quantification assay confirmed high-purity isolations of exosomes (∼99 % removal of background proteins) SIGNIFICANCE: The effective use of Tween-20 as an elution solvent for exosome isolation/purification using capillary-channeled polymer fiber columns adds greater versatility to the portfolio of the approach. The proposed method holds promise for a wide range of fundamental biochemistry, clinical diagnostics, and therapeutic applications, marking a significant advancement in EV-based methodologies.
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Affiliation(s)
- Md Khalid Bin Islam
- Department of Chemistry, Biosystems Research Complex, Clemson University, Clemson, SC, 29634-0973, USA
| | - R Kenneth Marcus
- Department of Chemistry, Biosystems Research Complex, Clemson University, Clemson, SC, 29634-0973, USA.
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7
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Ellakany AR, El Baz H, Shoheib ZS, Elzallat M, Ashour DS, Yassen NA. Stem cell-derived exosomes as a potential therapy for schistosomal hepatic fibrosis in experimental animals. Pathog Glob Health 2024; 118:429-449. [PMID: 37519008 PMCID: PMC11338202 DOI: 10.1080/20477724.2023.2240085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023] Open
Abstract
Schistosomiasis is a neglected tropical disease. Egg-induced granuloma formation and tissue fibrosis are the main causes of the high morbidity and mortality of schistosomiasis. Mesenchymal stem cells (MSCs)-derived exosomes play an important role with a superior safety profile than MSCs in the treatment of liver fibrosis. Therefore, the aim of this study was to investigate the potential therapeutic effect of MSCs-derived exosomes on schistosomal hepatic fibrosis. Exosomes were isolated from bone marrow MSCs and characterized. A total of 85 mice were divided into four groups: group I (control group), group II (PZQ group) infected and treated with PZQ, group III (EXO group) infected and treated with MSCs-derived exosomes and group IV (PZQ+EXO group) infected and treated with both PZQ and MSCs-derived exosomes. Assessment of treatment efficacy was evaluated by histopathological and immunohistochemical examination of liver sections by proliferating cell nuclear antigen (PCNA) and nuclear factor-κB (NF-κB). The results showed significant reduction of the number and diameter of hepatic granulomas, hepatic fibrosis, upregulation of PCNA expression and reduction of NF-κB expression in EXO and PZQ+EXO groups as compared to other groups at all durations post infection. Additionally, more improvement was observed in PZQ+EXO group. In conclusion, MSCs-derived exosomes are a promising agent for the treatment of schistosomal hepatic fibrosis, and their combination with PZQ shows a synergistic action including antifibrotic and anti-inflammatory effects. However, further studies are required to establish their functional components and their mechanisms of action.
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Affiliation(s)
- Asmaa R. Ellakany
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hanan El Baz
- Immunology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Zeinab S. Shoheib
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Elzallat
- Immunology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Dalia S. Ashour
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Nabila A. Yassen
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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8
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Hasaniani N, Nouri S, Shirzad M, Rostami-Mansoor S. Potential therapeutic and diagnostic approaches of exosomes in multiple sclerosis pathophysiology. Life Sci 2024; 347:122668. [PMID: 38670451 DOI: 10.1016/j.lfs.2024.122668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/15/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Exosomes are bilayer lipid vesicles that are released by cells and contain proteins, nucleic acids, and lipids. They can be internalized by other cells, inducing inflammatory responses and instigating toxicities in the recipient cells. Exosomes can also serve as therapeutic vehicles by transporting protective cargo to maintain homeostasis. Multiple studies have shown that exosomes can initiate and participate in the regulation of neuroinflammation, improve neurogenesis, and are closely related to the pathogenesis of central nervous system (CNS) diseases, including multiple sclerosis (MS). Exosomes can be secreted by both neurons and glial cells in the CNS, and their contents change with disease occurrence. Due to their ability to penetrate the blood-brain barrier and their stability in peripheral fluids, exosomes are attractive biomarkers of CNS diseases. In recent years, exosomes have emerged as potential therapeutic agents for CNS diseases, including MS. However, the molecular pathways in the pathogenesis of MS are still unknown, and further research is needed to fully understand the role of exosomes in the occurrence or improvement of MS disease. Thereby, in this review, we intend to provide a more complete understanding of the pathways in which exosomes are involved and affect the occurrence or improvement of MS disease.
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Affiliation(s)
- Nima Hasaniani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Sina Nouri
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Urmia University of Medical Sciences, Urmia, Iran
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Sahar Rostami-Mansoor
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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Abdul-Rahman T, Roy P, Herrera-Calderón RE, Khidri FF, Omotesho QA, Rumide TS, Fatima M, Roy S, Wireko AA, Atallah O, Roy S, Amekpor F, Ghosh S, Agyigra IA, Horbas V, Teslyk T, Bumeister V, Papadakis M, Alexiou A. Extracellular vesicle-mediated drug delivery in breast cancer theranostics. Discov Oncol 2024; 15:181. [PMID: 38780753 PMCID: PMC11116322 DOI: 10.1007/s12672-024-01007-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] [Received: 02/08/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Breast cancer (BC) continues to be a significant global challenge due to drug resistance and severe side effects. The increasing prevalence is alarming, requiring new therapeutic approaches to address these challenges. At this point, Extracellular vesicles (EVs), specifically small endosome-released nanometer-sized EVs (SEVs) or exosomes, have been explored by literature as potential theranostics. Therefore, this review aims to highlight the therapeutic potential of exosomes in BC, focusing on their advantages in drug delivery and their ability to mitigate metastasis. Following the review, we identified exosomes' potential in combination therapies, serving as miRNA carriers and contributing to improved anti-tumor effects. This is evident in clinical trials investigating exosomes in BC, which have shown their ability to boost chemotherapy efficacy by delivering drugs like paclitaxel (PTX) and doxorubicin (DOX). However, the translation of EVs into BC therapy is hindered by various challenges. These challenges include the heterogeneity of EVs, the selection of the appropriate parent cell, the loading procedures, and determining the optimal administration routes. Despite the promising therapeutic potential of EVs, these obstacles must be addressed to realize their benefits in BC treatment.
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Affiliation(s)
| | - Poulami Roy
- Department of Medicine, North Bengal Medical College and Hospital, Siliguri, India
| | - Ranferi Eduardo Herrera-Calderón
- Center for Research in Health Sciences (CICSA), Faculty of Medicine, Anahuac University North Campus, 52786, Huixquilucan, Mexico
| | | | | | | | | | - Sakshi Roy
- School of Medicine, Queens University Belfast, Northern Ireland, UK
| | | | - Oday Atallah
- Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Subham Roy
- Hull York Medical School, University of York, York, UK
| | - Felix Amekpor
- Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Shankhaneel Ghosh
- Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan, Bhubaneswar, India
| | | | | | | | | | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, Heusnerstrasse 40, University of Witten-Herdecke, 42283, Wuppertal, Germany.
| | - Athanasios Alexiou
- University Centre for Research and Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India.
- Department of Research and Development, Funogen, 11741, Athens, Greece.
- Department of Research and Development, AFNP Med, 1030, Vienna, Austria.
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia.
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Choi W, Cho JH, Park SH, Kim DS, Lee HP, Kim D, Kim HS, Kim JH, Cho JY. Ginseng root-derived exosome-like nanoparticles protect skin from UV irradiation and oxidative stress by suppressing activator protein-1 signaling and limiting the generation of reactive oxygen species. J Ginseng Res 2024; 48:211-219. [PMID: 38465216 PMCID: PMC10920011 DOI: 10.1016/j.jgr.2024.01.001] [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: 04/04/2023] [Revised: 12/05/2023] [Accepted: 01/10/2024] [Indexed: 03/12/2024] Open
Abstract
Background Recently, plant-derived exosome-like nanoparticles (PDENs) have been isolated, and active research was focusing on understanding their properties and functions. In this study, the characteristics and molecular properties of ginseng root-derived exosome-like nanoparticles (GrDENs) were examined in terms of skin protection. Methods HPLC-MS protocols were used to analyze the ginsenoside contents in GrDENs. To investigate the beneficial effect of GrDENs on skin, HaCaT cells were pre-treated with GrDENs (0-2 × 109 particles/mL), and followed by UVB irradiation or H2O2 exposure. In addition, the antioxidant activity of GrDENs was measured using a fluorescence microscope or flow cytometry. Finally, molecular mechanisms were examined with immunoblotting analysis. Results GrDENs contained detectable levels of ginsenosides (Re, Rg1, Rb1, Rf, Rg2 (S), Gyp17, Rd, C-Mc1, C-O, and F2). In UVB-irradiated HaCaT cells, GrDENs protected cells from death and reduced ROS production. GrDENs downregulated the mRNA expression of proapoptotic genes, including BAX, caspase-1, -3, -6, -7, and -8 and the ratio of cleaved caspase-8, -9, and -3 in a dose-dependent manner. In addition, GrDENs reduced the mRNA levels of aging-related genes (MMP2 and 3), proinflammatory genes (COX-2 and IL-6), and cellular senescence biomarker p21, possibly by suppressing activator protein-1 signaling. Conclusions This study demonstrates the protective effects of GrDENs against skin damage caused by UV and oxidative stress, providing new insights into beneficial uses of ginseng. In particular, our results suggest GrDENs as a potential active ingredient in cosmeceuticals to promote skin health.
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Affiliation(s)
- Wooram Choi
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jeong Hun Cho
- Research and Innovation Center, AMOREPACIFIC, Yongin, Republic of Korea
| | - Sang Hee Park
- Department of Biocosmetics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Dong Seon Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Hwa Pyoung Lee
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Donghyun Kim
- Research and Innovation Center, AMOREPACIFIC, Yongin, Republic of Korea
| | - Hyun Soo Kim
- Research and Innovation Center, AMOREPACIFIC, Yongin, Republic of Korea
| | - Ji Hye Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
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11
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Ashoub MH, Salavatipour MS, Kasgari FH, Valandani HM, Khalilabadi RM. Extracellular microvesicles: biologic properties, biogenesis, and applications in leukemia. Mol Cell Biochem 2024; 479:419-430. [PMID: 37084166 DOI: 10.1007/s11010-023-04734-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/07/2023] [Indexed: 04/22/2023]
Abstract
Microvesicles are cellular membrane vesicles of which size is limited to 30-1000 nm. Almost all cells release them in response to activation signals and apoptosis. Their ability for intercellular communication and enhancement of potential for information exchange (between them) has attracted much interest. Their content is affected by the content of the mother cell, which can help identify their origin. Furthermore, these particles can change the physiology of the target cells by transferring a set of molecules to them and changing the epigenetics of the cells by transferring DNA and RNA. These changes can be induced in cells close to the mother and distant cells. Significant activities of these microvesicles are known both in physiological and pathologic conditions. In this regard, we have reviewed these small particle elements, their contents, and the way of synthesis. Finally, we discussed their current known roles to reveal more potential applications in leukemia.
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Affiliation(s)
- Muhammad Hossein Ashoub
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Samareh Salavatipour
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Hoseinpour Kasgari
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hajar Mardani Valandani
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Roohollah Mirzaee Khalilabadi
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran.
- Student Research Committee, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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12
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Kumar P, Gupta S, Das BC. Saliva as a potential non-invasive liquid biopsy for early and easy diagnosis/prognosis of head and neck cancer. Transl Oncol 2024; 40:101827. [PMID: 38042138 PMCID: PMC10701368 DOI: 10.1016/j.tranon.2023.101827] [Citation(s) in RCA: 40] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 12/04/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the most devastating diseases in India and southeast Asia. It is a preventable and curable disease if detected early. Tobacco and alcohol consumption are the two major risk-factors but infection of high-risk HPVs are also associated with development of predominantly oral and oropharyngeal carcinomas. Interestingly, unlike cervical cancer, HPV-induced HNSCCs show good prognosis and better survival in contrast, majority of tobacco-associated HPV-ve HNSCCs are highly aggressive with poor clinical outcome. Biomarker analysis in circulatory body-fluids for early cancer diagnosis, prognosis and treatment monitoring are becoming important in clinical practice. Early diagnosis using non-invasive saliva for oral or other diseases plays an important role in successful treatment and better prognosis. Saliva mirrors the body's state of health as it comes into direct contact with oral lesions and needs no trained manpower to collect, making it a suitable bio-fluid of choice for screening. Saliva can be used to detect not only virus, bacteria and other biomarkers but variety of molecular and genetic markers for an early detection, treatment and monitoring cancer and other diseases. The performance of saliva-based diagnostics are reported to be highly (≥95 %) sensitive and specific indicating the test's ability to correctly identify true positive or negative cases. This review focuses on the potentials of saliva in the early detection of not only HPV or other pathogens but also identification of highly reliable gene mutations, oral-microbiomes, metabolites, salivary cytokines, non-coding RNAs and exosomal miRNAs. It also discusses the importance of saliva as a reliable, cost-effective and an easy alternative to invasive procedures.
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Affiliation(s)
- Prabhat Kumar
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India
| | - Shilpi Gupta
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India
| | - Bhudev C Das
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India.
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13
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Ishii N, Noguchi K, Ikemoto MJ, Yohda M, Odahara T. Optimizing Exosome Preparation Based on Size and Morphology: Insights From Electron Microscopy. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2023; 29:2068-2079. [PMID: 37831006 DOI: 10.1093/micmic/ozad103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/14/2023] [Accepted: 09/08/2023] [Indexed: 10/14/2023]
Abstract
Extracellular vesicles (EVs), including exosomes, are crucial in intercellular communication, but differentiating between exosomes and microvesicles is challenging due to their similar morphology and size. This study focuses on multivesicular bodies (MVBs), where exosomes mature, and optimizes exosome isolation using transmission electron microscopy (TEM) for size information. Considering that EVs are nanocolloidal particles, a salt-free Bis-Tris buffer is found to maintain EV integrity better than phosphate-buffered saline (PBS). Dynamic light scattering (DLS) and TEM analysis confirm that intact exosome fractions under the salt-free Bis-Tris buffer condition exhibit polydispersity, including a unique population of <50 nm vesicles resembling intraluminal membrane vesicles (ILVs) in MVBs, alongside larger populations. This <50 nm population disappears in PBS or Bis-Tris buffer with 140 mM NaCl, transforming into a monodisperse population >100 nm. Immunoelectron microscopy also validates the presence of CD63, an exosome biomarker, on approximately 50 nm EVs. These findings provide valuable insights into exosome characterization and isolation, essential for future biomedical applications in diagnostics and drug delivery.
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Affiliation(s)
- Noriyuki Ishii
- Cellular and Molecular Biotechnology Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central-6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
- Electron Microscopy Facility, Open Research Facilities Station, Open Research Platform Unit, Tsukuba Innovation Arena (TIA) Central Office, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central-6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
- The United Graduate School of Agricultural Science, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan
| | - Keiichi Noguchi
- Instrumentation Analysis Center, Tokyo University of Agriculture and Technology, 2-24-16 Naka, Koganei, Tokyo 184-8588, Japan
| | - Mitsushi J Ikemoto
- Health and Medical Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central-6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
- Graduate School of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
| | - Masafumi Yohda
- Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka, Koganei, Tokyo 184-8588, Japan
| | - Takayuki Odahara
- Biomedical Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central-6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
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14
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Altıntaş Ö, Saylan Y. Exploring the Versatility of Exosomes: A Review on Isolation, Characterization, Detection Methods, and Diverse Applications. Anal Chem 2023; 95:16029-16048. [PMID: 37874907 DOI: 10.1021/acs.analchem.3c02224] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2023]
Abstract
Extracellular vesicles (EVs) are crucial mediators of intercellular communication and can be classified based on their physical properties, biomolecular structure, and origin. Among EVs, exosomes have garnered significant attention due to their potential as therapeutic and diagnostic tools. Exosomes are released via fusion of multivesicular bodies on plasma membranes and can be isolated from various biofluids using methods such as differential ultracentrifugation, immune affinity capture, ultrafiltration, and size exclusion chromatography. Herein, an overview of different techniques for exosome characterization and isolation, as well as the diverse applications of exosome detection, including their potential use in drug delivery and disease diagnosis, is provided. Additionally, we discuss the emerging field of exosome detection by sensors, which offers an up-and-coming avenue for point-of-care diagnostic tools development. Overall, this review aims to provide a exhaustive and up-to-date summary of the current state of exosome research.
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Affiliation(s)
- Özge Altıntaş
- Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey
| | - Yeşeren Saylan
- Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey
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15
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Fu Y, Xiong S. Differential traits between microvesicles and exosomes in enterovirus infection. MedComm (Beijing) 2023; 4:e384. [PMID: 37752943 PMCID: PMC10518433 DOI: 10.1002/mco2.384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/05/2023] [Accepted: 08/28/2023] [Indexed: 09/28/2023] Open
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are released by most cell types into the extracellular space and represent the pathophysiological condition of their source cells. Recent studies demonstrate that EVs derived from infected cells and tumors contribute to disease pathogenesis. However, very few studies have rigorously characterized exosomes and microvesicles in infectious diseases. In this study, we focused on subpopulations of EVs during the human enterovirus infection and explored the distinct traits and functions of EVs. We construct an effective immunomagnetic method to isolate exosomes and MVs from enterovirus-infected cells excluding virion. The morphology and sizes of exosomes and MVs have no significant alteration after enterovirus infection. Meanwhile, our study observed that the enterovirus infection could induce exosome secretion but not MVs. In vivo study showed that there was differential biodistribution between exosomes and MVs. Using deep RNA sequencing, we found that the cargo information in MVs rather than in exosomes could accurately reflect pathological condition of original cells. Our study demonstrated that it should be considered to use MVs as clinical diagnostics during in enterovirus infection because their composition is reflective of pathological changes.
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Affiliation(s)
- Yuxuan Fu
- Jiangsu Key Laboratory of Infection and ImmunityInstitutes of Biology and Medical SciencesSoochow UniversitySuzhouChina
| | - Sidong Xiong
- Jiangsu Key Laboratory of Infection and ImmunityInstitutes of Biology and Medical SciencesSoochow UniversitySuzhouChina
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16
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Mot YY, Moses EJ, Mohd Yusoff N, Ling KH, Yong YK, Tan JJ. Mesenchymal Stromal Cells-Derived Exosome and the Roles in the Treatment of Traumatic Brain Injury. Cell Mol Neurobiol 2023; 43:469-489. [PMID: 35103872 PMCID: PMC11415182 DOI: 10.1007/s10571-022-01201-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 01/23/2022] [Indexed: 12/19/2022]
Abstract
Traumatic brain injury (TBI) could result in life-long disabilities and death. Though the mechanical insult causes primary injury, the secondary injury due to dysregulated responses following neuronal apoptosis and inflammation is often the cause for more detrimental consequences. Mesenchymal stromal cell (MSC) has been extensively investigated as the emerging therapeutic for TBI, and the functional properties are chiefly attributed to their secretome, especially the exosomes. Delivering these nanosize exosomes have shown to ameliorate post-traumatic injury and restore brain functions. Recent technology advances also allow engineering MSC-derived exosomes to carry specific biomolecules of interest to augment their therapeutic outcome. In this review, we discuss the pathophysiology of TBI and summarize the recent progress in the applications of MSCs-derived exosomes, the roles and the signalling mechanisms underlying the protective effects in the treatment of the TBI.
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Affiliation(s)
- Yee Yik Mot
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, BertamKepala Batas, 13200, Pulau Pinang, Malaysia
| | - Emmanuel Jairaj Moses
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, BertamKepala Batas, 13200, Pulau Pinang, Malaysia.
| | - Narazah Mohd Yusoff
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, BertamKepala Batas, 13200, Pulau Pinang, Malaysia
| | - King-Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Yoke Keong Yong
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Jun Jie Tan
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, BertamKepala Batas, 13200, Pulau Pinang, Malaysia.
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17
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Liu M, Liu X, Pan M, Zhang Y, Tang X, Liu W, Zhao M, Ma J, Zhou N, Jiang Y, Wang W, Liu M. Characterization and microRNA Expression Analysis of Serum-Derived Extracellular Vesicles in Severe Liver Injury from Chronic HBV Infection. Life (Basel) 2023; 13:life13020347. [PMID: 36836704 PMCID: PMC9967308 DOI: 10.3390/life13020347] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Extracellular vesicle (EV) microRNAs have been documented in several studies to have significantly different expressions in hepatitis B virus (HBV)-related liver diseases, such as hepatocellular carcinoma (HCC). The current work aimed to observe the characteristics of EVs and EV miRNA expressions in patients with severe liver injury chronic hepatitis B (CHB) and patients with HBV-associated decompensated cirrhosis (DeCi). METHODS The characterization of the EVs in the serum was carried out for three different groups, namely, patients with severe liver injury-CHB, patients with DeCi, and healthy controls. EV miRNAs were analyzed using miRNA-seq and RT-qPCR arrays. Additionally, we assessed the predictive and observational values of the miRNAs with significant differential expressions in serum EVs. RESULTS Patients with severe liver injury-CHB had the highest EV concentrations when compared to the normal controls (NCs) and patients with DeCi (p < 0.001). The miRNA-seq of the NC and severe liver injury-CHB groups identified 268 differentially expressed miRNAs (|FC| > 2, p < 0.05). In this case, 15 miRNAs were verified using RT-qPCR, and it was found that novel-miR-172-5p and miR-1285-5p in the severe liver injury-CHB group showed marked downregulation in comparison to the NC group (p < 0.001). Furthermore, compared with the NC group, three EV miRNAs (novel-miR-172-5p, miR-1285-5p, and miR-335-5p) in the DeCi group showed various degrees of downregulated expression. However, when comparing the DeCi group with the severe liver injury-CHB group, only the expression of miR-335-5p in the DeCi group decreased significantly (p < 0.05). For the severe liver injury-CHB and DeCi groups, the addition of miR-335-5p improved the predictive accuracy of the serological levels, while miR-335-5p was significantly correlated with ALT, AST, AST/ALT, GGT, and AFP. Conclusions: The patients with severe liver injury-CHB had the highest number of EVs. The combination of novel-miR-172-5p and miR-1285-5p in serum EVs helped in predicting the progression of the NCs to severe liver injury-CHB, while the addition of EV miR-335-5p improved the serological accuracy of predicting the progression of severe liver injury-CHB to DeCi.
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Affiliation(s)
- Min Liu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Xionghao Liu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
- Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410078, China
- Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha 410078, China
| | - Mengmeng Pan
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Yu Zhang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Xiangling Tang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Wanxi Liu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Mingri Zhao
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Jing Ma
- Department of Infectious Disease, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Ning Zhou
- Department of Infectious Disease, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yongfang Jiang
- Department of Infectious Disease, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Wenlong Wang
- Department of Infectious Disease, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Correspondence: (W.W.); (M.L.)
| | - Mujun Liu
- Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410078, China
- Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha 410078, China
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410013, China
- Correspondence: (W.W.); (M.L.)
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18
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Urinary Extracellular Vesicles in Chronic Kidney Disease: From Bench to Bedside? Diagnostics (Basel) 2023; 13:diagnostics13030443. [PMID: 36766548 PMCID: PMC9913975 DOI: 10.3390/diagnostics13030443] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
Extracellular vesicles are a diverse group of particles that include exosomes, microvesicles, and apoptotic bodies and are defined by size, composition, site of origin, and density. They incorporate various bioactive molecules from their cell of origin during formation, such as soluble proteins, membrane receptors, nucleic acids (mRNAs and miRNAs), and lipids, which can then be transferred to target cells. Extracellular vesicles/exosomes have been extensively studied as a critical factor in pathophysiological processes of human diseases. Urinary extracellular vesicles could be a promising liquid biopsy for determining the pattern and/or severity of kidney histologic injury. The signature of urinary extracellular vesicles may pave the way for noninvasive methods to supplement existing testing methods for diagnosing kidney diseases. We discuss the potential role of urinary extracellular vesicles in various chronic kidney diseases in this review, highlighting open questions and discussing the potential for future research.
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19
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Fu Y, Xiong S. Exosomes mediate Coxsackievirus B3 transmission and expand the viral tropism. PLoS Pathog 2023; 19:e1011090. [PMID: 36634130 PMCID: PMC9888687 DOI: 10.1371/journal.ppat.1011090] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 01/31/2023] [Accepted: 12/28/2022] [Indexed: 01/13/2023] Open
Abstract
Specific virus-receptor interactions are important determinants in viral host range, tropism and pathogenesis, influencing the location and initiation of primary infection as well as viral spread to other target organs/tissues in the postviremic phase. Coxsackieviruses of Group B (CVB) and its six serotypes (CVB1-6) specifically interact with two receptor proteins, coxsackievirus-adenovirus receptor (CAR) and decay-accelerating factor (DAF), and cause various lesions in most permissive tissues. However, our previous data and other studies revealed that virus receptor-negative cells or tissues can be infected with CVB type 3 (CVB3), which can also effectively replicate. To study this interesting finding, we explored the possibility that exosomes are involved in CVB3 tropism and that exosomes functionally enhance CVB3 transmission. We found that exosomes carried and delivered CVB3 virions, resulting in efficient infection in receptor-negative host cells. We also found that delivery of CVB3 virions attached to exosomes depended on the virus receptor CAR. Importantly, exosomes carrying CVB3 virions exhibited greater infection efficiency than free virions because they accessed various entry routes, overcoming restrictions to viral tropism. In vivo experiments demonstrated that inhibition of exosome coupling with virions attenuated CVB3-induced immunological system dysfunction and reduced mortality. Our study describes a new mechanism in which exosomes contribute to viral tropism, spread, and pathogenesis.
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Affiliation(s)
- Yuxuan Fu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Sidong Xiong
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
- * E-mail:
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20
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Yang Q, Xu J, Gu J, Shi H, Zhang J, Zhang J, Chen Z, Fang X, Zhu T, Zhang X. Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201609. [PMID: 36253096 PMCID: PMC9731723 DOI: 10.1002/advs.202201609] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 09/10/2022] [Indexed: 06/16/2023]
Abstract
Extracellular vesicles (EVs) are cell-derived nanosized vesicles that mediate cell-to-cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial-mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed.
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Affiliation(s)
- Qiurong Yang
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityZhenjiangJiangsu212013China
| | - Jing Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityZhenjiangJiangsu212013China
| | - Jianmei Gu
- Departmemt of Clinical Laboratory MedicineNantong Tumor HospitalNantongJiangsu226361China
| | - Hui Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityZhenjiangJiangsu212013China
| | - Jiayin Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityZhenjiangJiangsu212013China
| | - Jianye Zhang
- Guangdong Provincial Key Laboratory of Molecular Target and Clinical PharmacologySchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhouGuangdong511436China
| | - Zhe‐Sheng Chen
- College of Pharmacy and Health SciencesSt. John's UniversityQueensNY11439USA
| | - Xinjian Fang
- Department of OncologyLianyungang Hospital Affiliated to Jiangsu UniversityLianyungangJiangsu222000China
| | - Taofeng Zhu
- Department of Pulmonary and Critical Care MedicineYixing Hospital affiliated to Jiangsu UniversityYixingJiangsu214200China
| | - Xu Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityZhenjiangJiangsu212013China
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21
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Rezaie J, Feghhi M, Etemadi T. A review on exosomes application in clinical trials: perspective, questions, and challenges. Cell Commun Signal 2022; 20:145. [PMID: 36123730 PMCID: PMC9483361 DOI: 10.1186/s12964-022-00959-4] [Citation(s) in RCA: 298] [Impact Index Per Article: 99.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/16/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Exosomes are progressively known as significant mediators of cell-to-cell communication. They convey active biomolecules to target cells and have vital functions in several physiological and pathological processes, and show substantial promise as novel treatment strategies for diseases. METHODS In this review study, we studied numerous articles over the past two decades published on application of exosomes in different diseases as well as on perspective and challenges in this field. RESULTS The main clinical application of exosomes are using them as a biomarker, cell-free therapeutic agents, drug delivery carriers, basic analysis for exosome kinetics, and cancer vaccine. Different exosomes from human or plant sources are utilized in various clinical trials. Most researchers used exosomes from the circulatory system for biomarker experiments. Mesenchymal stem cells (MSCs) and dendritic cells (DCs) are two widely held cell sources for exosome use. MSCs-derived exosomes are commonly used for inflammation treatment and drug delivery, while DCs-exosomes are used to induce inflammation response in cancer patients. However, the clinical application of exosomes faces various questions and challenges. In addition, translation of exosome-based clinical trials is required to conform to specific good manufacturing practices (GMP). In this review, we summarize exosomes in the clinical trials according to the type of application and disease. We also address the main questions and challenges regarding exosome kinetics and clinical applications. CONCLUSIONS Exosomes are promising platforms for treatment of many diseases in clinical trials. This exciting field is developing hastily, understanding of the underlying mechanisms that direct the various observed roles of exosomes remains far from complete and needs further multidisciplinary research in working with these small vesicles. Video Abstract.
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Affiliation(s)
- Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Shafa St, Ershad Blvd., P.O. BoX: 1138, Urmia, 57147, Iran.
| | - Maryam Feghhi
- Institute of Molecular Biophysics, Florida State University, Florida, USA
| | - Tahereh Etemadi
- Department of Biology, Faculty of Science, Arak University, Arak, Iran
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22
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Xiang H, Zhang C, Xiong J. Emerging role of extracellular vesicles in kidney diseases. Front Pharmacol 2022; 13:985030. [PMID: 36172178 PMCID: PMC9510773 DOI: 10.3389/fphar.2022.985030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
Many types of renal disease eventually progress to end-stage renal disease, which can only be maintained by renal replacement therapy. Therefore, kidney diseases now contribute significantly to the health care burden in many countries. Many new advances and strategies have been found in the research involving kidney diseases; however, there is still no efficient treatment. Extracellular vesicles (EVs) are cell-derived membrane structures, which contains proteins, lipids, and nucleic acids. After internalization by downstream cells, these components can still maintain functional activity and regulate the phenotype of downstream cells. EVs drive the information exchange between cells and tissues. Majority of the cells can produce EVs; however, its production, contents, and transportation may be affected by various factors. EVs have been proved to play an important role in the occurrence, development, and treatment of renal diseases. However, the mechanism and potential applications of EVs in kidney diseases remain unclear. This review summarizes the latest research of EVs in renal diseases, and provides new therapeutic targets and strategies for renal diseases.
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Weng S, Lai QL, Wang J, Zhuang L, Cheng L, Mo Y, Liu L, Zhao Z, Zhang Y, Qiao S. The Role of Exosomes as Mediators of Neuroinflammation in the Pathogenesis and Treatment of Alzheimer’s Disease. Front Aging Neurosci 2022; 14:899944. [PMID: 35837481 PMCID: PMC9273880 DOI: 10.3389/fnagi.2022.899944] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 06/10/2022] [Indexed: 12/21/2022] Open
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive dementia. Accumulation of β–amyloid peptide 1–42 and phosphorylation of tau protein in the brain are the two main pathological features of AD. However, comprehensive studies have shown that neuroinflammation also plays a crucial role in the pathogenesis of AD. Neuroinflammation is associated with neuronal death and abnormal protein aggregation and promotes the pathological process of β-amyloid peptide 1–42 and tau protein. The inflammatory components associated with AD include glial cells, complement system, cytokines and chemokines. In recent years, some researchers have focused on exosomes, a type of membrane nano vesicles. Exosomes can transport proteins, lipids, microRNAs and other signaling molecules to participate in a variety of signaling pathways for signal transmission or immune response, affecting the activity of target cells and participating in important pathophysiological processes. Therefore, exosomes play an essential role in intercellular communication and may mediate neuroinflammation to promote the development of AD. This paper reviews the occurrence and development of neuroinflammation and exosomes in AD, providing a deeper understanding of the pathogenesis of AD. Furthermore, the role of exosomes in the pathogenesis and treatment of AD is further described, demonstrating their potential as therapeutic targets for neuroinflammation and AD in the future.
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Affiliation(s)
- Shiting Weng
- The Second Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou, China
| | - Qi-Lun Lai
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Junjun Wang
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Liying Zhuang
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Lin Cheng
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Yejia Mo
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Lu Liu
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Zexian Zhao
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
| | - Ying Zhang
- Department of Neurology, Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Song Qiao
- Department of Neurology, Zhejiang Hospital, Hangzhou, China
- *Correspondence: Song Qiao,
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Kim YB, Lee GB, Moon MH. Size Separation of Exosomes and Microvesicles Using Flow Field-Flow Fractionation/Multiangle Light Scattering and Lipidomic Comparison. Anal Chem 2022; 94:8958-8965. [PMID: 35694825 DOI: 10.1021/acs.analchem.2c00806] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Extracellular vesicles (EVs) are cell-derived membrane-bound particles, including exosomes and microvesicles that differ in cellular origin, content, and lipid composition. This study reports that exosomes and microvesicles can be simultaneously separated by size using flow field-flow fractionation (FlFFF) employed with field programming and that the detection of low-concentration EV species can be significantly improved using multiangle light scattering (MALS). The efficiency of ultracentrifugation (UC) and ultrafiltration (UF) in isolating EVs from the culture media of DU145 cells was compared, and the results showed that UF retrieves more EVs than UC. Two size fractions (small and large) of both exosomes and microvesicles were collected during the FlFFF runs and examined using Western blotting to confirm each EV, and transmission electron microscopy was performed for size analysis. Sizes were compared using the root-mean-square radius obtained from the MALS calculation. The collected fractions were further examined using nanoflow ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry for the size-dependent lipidomic profiles of exosomes and microvesicles, showing that lipids were more enriched in the fraction containing large exosomes than in that containing small exosomes; however, an opposite trend was observed with microvesicles. The present study demonstrated that UF followed by FlFFF-MALS can be utilized for the size separation of exosomes and microvesicles without sequential centrifugation, which is useful for monitoring the changes in the size distribution of EVs depending on the biological status along with generating size-dependent lipidomic profiles.
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Affiliation(s)
- Young Beom Kim
- Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seoul 03722, South Korea
| | - Gwang Bin Lee
- Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seoul 03722, South Korea
| | - Myeong Hee Moon
- Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seoul 03722, South Korea
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Thome AD, Thonhoff JR, Zhao W, Faridar A, Wang J, Beers DR, Appel SH. Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation. Front Immunol 2022; 13:875825. [PMID: 35812435 PMCID: PMC9258040 DOI: 10.3389/fimmu.2022.875825] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vehicles (EVs) are efficient biomarkers of disease and participate in disease pathogenesis; however, their use as clinical therapies to modify disease outcomes remains to be determined. Cell-based immune therapies, including regulatory T cells (Tregs), are currently being clinically evaluated for their usefulness in suppressing pro-inflammatory processes. The present study demonstrates that ex vivo expanded Tregs generate a large pool of EVs that express Treg-associated markers and suppress pro-inflammatory responses in vitro and in vivo. Intravenous injection of Treg EVs into an LPS-induced mouse model of inflammation reduced peripheral pro-inflammatory transcripts and increased anti-inflammatory transcripts in myeloid cells as well as Tregs. Intranasal administration of enriched Treg EVs in this model also reduced pro-inflammatory transcripts and the associated neuroinflammatory responses. In a mouse model of amyotrophic lateral sclerosis, intranasal administration of enriched Treg EVs slowed disease progression, increased survival, and modulated inflammation within the diseased spinal cord. These findings support the therapeutic potential of expanded Treg EVs to suppress pro-inflammatory responses in human disease.
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Affiliation(s)
- Aaron D Thome
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Jason R Thonhoff
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Weihua Zhao
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Alireza Faridar
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Jinghong Wang
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - David R Beers
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Stanley H Appel
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
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Soukup J, Kostelanská M, Kereïche S, Hujacová A, Pavelcová M, Petrák J, Kubala Havrdová E, Holada K. Flow Cytometry Analysis of Blood Large Extracellular Vesicles in Patients with Multiple Sclerosis Experiencing Relapse of the Disease. J Clin Med 2022; 11:jcm11102832. [PMID: 35628959 PMCID: PMC9145450 DOI: 10.3390/jcm11102832] [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: 03/15/2022] [Revised: 05/11/2022] [Accepted: 05/11/2022] [Indexed: 11/23/2022] Open
Abstract
The number of people living with multiple sclerosis (MS) in developed countries is increasing. The management of patients is hindered by the absence of reliable laboratory tests accurately reflecting the disease activity. Extracellular vesicles (EVs) of different cell origin were reportedly elevated in MS patients. We assessed the diagnostic potential, with flow cytometry analysis, of fresh large EVs (lEVs), which scattered more light than the 590 nm silica beads and were isolated from the blood plasma of relapsing remitting MS patients. Venous blood was collected from 15 patients and 16 healthy controls (HC). The lEVs were isolated from fresh platelet-free plasma by centrifugation, labelled with antibodies and the presence of platelet (CD41+, CD36+), endothelial (CD105+), erythrocyte (CD235a+), leukocyte (CD45+, CD19+, CD3+) and phosphatidylserine (Annexin V+) positive lEVs was analyzed using standard flow cytometry. Cryo-electron microscopy was used to verify the presence of EVs in the analyzed plasma fractions. MS patients experiencing acute relapse had slightly reduced relative levels (% of positive lEVs) of CD105+, CD45+, CD3+, CD45+CD3+ or CD19+ labelled lEVs in comparison to healthy controls. An analysis of other markers or a comparison of absolute lEV counts (count of lEVs/µL) did not yield any significant differences. Our data do not support the hypothesis that the exacerbation of the disease in RRMS patients leads to an increased numbers of circulating plasma lEVs which can be monitored by standard flow cytometry.
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Affiliation(s)
- Jakub Soukup
- Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (J.S.); (M.K.); (A.H.)
- Department of Genetics and Microbiology, Faculty of Science, Charles University, 128 44 Prague, Czech Republic
| | - Marie Kostelanská
- Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (J.S.); (M.K.); (A.H.)
| | - Sami Kereïche
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic;
| | - Andrea Hujacová
- Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (J.S.); (M.K.); (A.H.)
| | - Miluše Pavelcová
- Department of Neurology and Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, 128 21 Prague, Czech Republic; (M.P.); (E.K.H.)
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic;
| | - Eva Kubala Havrdová
- Department of Neurology and Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, 128 21 Prague, Czech Republic; (M.P.); (E.K.H.)
| | - Karel Holada
- Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (J.S.); (M.K.); (A.H.)
- Correspondence:
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hMSCs-derived exosome circCDK13 inhibits liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B. Cell Biol Toxicol 2022:10.1007/s10565-022-09714-4. [PMID: 35484432 DOI: 10.1007/s10565-022-09714-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 04/06/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVE To investigate the effects of human bone marrow mesenchymal stem cells (hMSCs)-derived exosome circCDK13 on liver fibrosis and its mechanism. METHODS Exosomes derived from hMSCs were extracted and identified by flow cytometry and osteogenic and adipogenic induction, and the expressions of marker proteins on the surface of exosomes were detected by western blot. Cell proliferation was measured by CCK8 assay, the expression of active markers of HSCs by immunofluorescence, and the expressions of fibrosis-related factors by western blot. A mouse model of liver fibrosis was established by intraperitoneal injection of thioacetamide (TAA). Fibrosis was detected by HE staining, Masson staining, and Sirius red staining. Western blot was utilized to test the expressions of PI3K/AKT and NF-κB pathway related proteins, dual-luciferase reporter assay and RIP assay to validate the binding between circCDK13 and miR-17-5p as well as between miR-17-5p and KAT2B, and ChIP to validate the effect of KAT2B on H3 acetylation and MFGE8 transcription. RESULTS hMSCs-derived exosomes inhibited liver fibrosis mainly through circCDK13. Dual-luciferase reporter assay and RIP assay demonstrated the binding between circCDK13 and miR-17-5p as well as between miR-17-5p and KAT2B. Further experimental results indicated that circCDK13 mediated liver fibrosis by regulating the miR-17-5p/KAT2B axis, and KAT2B promoted MFGE8 transcription by H3 acetylation. Exo-circCDK13 inhibited PI3K/AKT and NF-κB signaling pathways activation through regulating the miR-17-5p/KAT2B axis. CONCLUSION hMSCs-derived exosome circCDK13 inhibited liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B axis.
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Buliga-Finis ON, Ouatu A, Badescu MC, Dima N, Tanase DM, Richter P, Rezus C. Beyond the Cardiorenal Syndrome: Pathophysiological Approaches and Biomarkers for Renal and Cardiac Crosstalk. Diagnostics (Basel) 2022; 12:diagnostics12040773. [PMID: 35453821 PMCID: PMC9028970 DOI: 10.3390/diagnostics12040773] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/17/2022] [Accepted: 03/19/2022] [Indexed: 02/04/2023] Open
Abstract
Cardiorenal syndrome encompasses complex multifactorial facets and carries significant morbidity and mortality worldwide. The bi-directional relationship between the heart and kidneys, where dysfunction in one organ worsens the function of the other, has been the leading motor for research in the last few years. In the pathophysiological process, small noncoding RNAs, epigenetics, vascular growth factors, oxidative stress, hemodynamic factors, and biomarkers play a pivotal role in the development of cardiorenal syndrome. It is therefore important to elucidate all the mechanisms in order to provide diagnostic and treatments tools. This review summarizes the hemodynamic and non-hemodynamic pathways along with biomarkers that could be the next target for diagnosis, treatment, and prognosis in cardiorenal syndrome.
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Affiliation(s)
- Oana Nicoleta Buliga-Finis
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Anca Ouatu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
- Correspondence: ; Tel.: +40-722899045
| | - Minerva Codruta Badescu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Nicoleta Dima
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Daniela Maria Tanase
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Patricia Richter
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Rheumatology Clinic, Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (O.N.B.-F.); (M.C.B.); (N.D.); (D.M.T.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
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Lin M, Chen Y, Zhao S, Tang R, Nie Z, Xing H. A Biomimetic Approach for Spatially Controlled Cell Membrane Engineering Using Fusogenic Spherical Nucleic Acid. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202111647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Minjie Lin
- Institute of Chemical Biology and Nanomedicine State Key Laboratory of Chemo/Biosensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology College of Chemistry and Chemical Engineering Hunan University Changsha 410082 China
| | - Yuanyuan Chen
- Institute of Chemical Biology and Nanomedicine State Key Laboratory of Chemo/Biosensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology College of Chemistry and Chemical Engineering Hunan University Changsha 410082 China
| | - Sisi Zhao
- Institute of Chemical Biology and Nanomedicine College of Biology Hunan University Changsha 410082 China
| | - Rui Tang
- Institute of Chemical Biology and Nanomedicine State Key Laboratory of Chemo/Biosensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology College of Chemistry and Chemical Engineering Hunan University Changsha 410082 China
| | - Zhou Nie
- Institute of Chemical Biology and Nanomedicine State Key Laboratory of Chemo/Biosensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology College of Chemistry and Chemical Engineering Hunan University Changsha 410082 China
| | - Hang Xing
- Institute of Chemical Biology and Nanomedicine State Key Laboratory of Chemo/Biosensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology College of Chemistry and Chemical Engineering Hunan University Changsha 410082 China
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Ceprian N, Valera G, Caro J, Yuste C, Serroukh N, González de Pablos I, Oliva C, Figuer A, Praga M, Alique M, Ramirez R, Morales E, Carracedo J. Effect of Kidney Transplantation on Accelerated Immunosenescence and Vascular Changes Induced by Chronic Kidney Disease. Front Med (Lausanne) 2021; 8:705159. [PMID: 34646838 PMCID: PMC8502880 DOI: 10.3389/fmed.2021.705159] [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: 05/04/2021] [Accepted: 08/31/2021] [Indexed: 11/13/2022] Open
Abstract
Kidney transplantation is the best option for patients with end-stage renal disease. Despite the improvement in cardiovascular burden (leading cause of mortality among patients with chronic kidney disease), cardiovascular adverse outcomes related to the inflammatory process remain a problem. Thus, the aim of the present study was to characterize the immune profile and microvesicles of patients who underwent transplantation. We investigated the lymphocyte phenotype (CD3, CD4, CD8, CD19, and CD56) and monocyte phenotype (CD14, CD16, CD86, and CD54) in peripheral blood, and endothelium-derived microvesicles (annexin V+CD31+CD41–) in plasma of patients with advanced chronic kidney disease (n = 40), patients with transplantation (n = 40), and healthy subjects (n = 18) recruited from the University Hospital “12 de Octubre” (Madrid, Spain). Patients with kidney transplantation had B-cell lymphopenia, an impairment in co-stimulatory (CD86) and adhesion (CD54) molecules in monocytes, and a reduction in endothelium-derived microvesicles in plasma. The correlations between those parameters explained the modifications in the expression of co-stimulatory and adhesion molecules in monocytes caused by changes in lymphocyte populations, as well as the increase in the levels of endothelial-derived microvesicles in plasma caused by changes in lymphocyte and monocytes populations. Immunosuppressive treatment could directly or indirectly induce those changes. Nevertheless, the particular characteristics of these cells may partly explain the persistence of cardiovascular and renal alterations in patients who underwent transplantation, along with the decrease in arteriosclerotic events compared with advanced chronic kidney disease. In conclusion, the expression of adhesion molecules by monocytes and endothelial-derived microvesicles is related to lymphocyte alterations in patients with kidney transplantation.
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Affiliation(s)
- Noemi Ceprian
- Departamento de Genética, Fisiología y Microbiología, Universidad Complutense de Madrid, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Gemma Valera
- Departamento Biología de Sistemas (Unidad Fisiología), Facultad de Medicina, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Alcalá de Henares, Madrid, Spain
| | - Jara Caro
- Departamento de Nefrología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria 12 de Octubre, Madrid, Spain
| | - Claudia Yuste
- Departamento de Nefrología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria 12 de Octubre, Madrid, Spain
| | - Nadia Serroukh
- Departamento de Genética, Fisiología y Microbiología, Universidad Complutense de Madrid, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | | | - Carlos Oliva
- Departamento de Genética, Fisiología y Microbiología, Universidad Complutense de Madrid, Madrid, Spain
| | - Andrea Figuer
- Departamento Biología de Sistemas (Unidad Fisiología), Facultad de Medicina, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Alcalá de Henares, Madrid, Spain
| | - Manuel Praga
- Departamento de Nefrología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria 12 de Octubre, Madrid, Spain
| | - Matilde Alique
- Departamento Biología de Sistemas (Unidad Fisiología), Facultad de Medicina, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Alcalá de Henares, Madrid, Spain
| | - Rafael Ramirez
- Departamento Biología de Sistemas (Unidad Fisiología), Facultad de Medicina, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Alcalá de Henares, Madrid, Spain
| | - Enrique Morales
- Departamento de Nefrología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria 12 de Octubre, Madrid, Spain
| | - Julia Carracedo
- Departamento de Genética, Fisiología y Microbiología, Universidad Complutense de Madrid, Instituto de Investigacin Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
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Lin M, Chen Y, Zhao S, Tang R, Nie Z, Xing H. A Biomimetic Approach for Spatially Controlled Cell Membrane Engineering Using Fusogenic Spherical Nucleic Acid. Angew Chem Int Ed Engl 2021; 61:e202111647. [PMID: 34637590 DOI: 10.1002/anie.202111647] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Indexed: 11/06/2022]
Abstract
Engineering of the cell plasma membrane using functional DNA is important for studying and controlling cellular behaviors. However, most efforts to apply artificial DNA interactions on cells are limited to external membrane surface due to the lack of suitable synthetic tools to engineer the intracellular side, which impedes many applications in cell biology. Inspired by the natural extracellular vesicle-cell fusion process, we have developed a fusogenic spherical nucleic acid construct to realize robust DNA functionalization on both external and internal cell surfaces via liposome fusion-based transport (LiFT) strategy, which enables applications including the construction of heterotypic cell assembly for programmed signaling pathway and detection of intracellular metabolites. This approach can engineer cell membranes in a highly efficient and spatially controlled manner, allowing one to build anisotropic membrane structures with two orthogonal DNA functionalities.
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Affiliation(s)
- Minjie Lin
- Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
| | - Yuanyuan Chen
- Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
| | - Sisi Zhao
- Institute of Chemical Biology and Nanomedicine, College of Biology, Hunan University, Changsha, 410082, China
| | - Rui Tang
- Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
| | - Zhou Nie
- Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
| | - Hang Xing
- Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
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Barzegar M, Allahbakhshian Farsan M, Amiri V, Mohammadi S, Shahsavan S, Mirzaeian A, Mohammadi MH. AML-derived Extracellular Vesicles Confer De Novo Chemoresistance to Leukemic Myeloblast Cells by Promoting Drug Export Genes Expression and ROS Inhibition. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:384-397. [PMID: 34400967 PMCID: PMC8170774 DOI: 10.22037/ijpr.2020.113272.14199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
In spite of successful initial remission, chemo-resistance and relapse are still concerning points in acute myeloid leukemia (AML) treatment strategies. Multidrug resistance (MDR) appears to be the major contributor of chemo-resistance, arising in some sub-clones of cancers and could be developed in others. The aim of this study was to investigate the role of extracellular vesicles (EVs) derived from AML patients on the transmission of chemo-resistance phenotype. Ultracentrifugation was employed to isolate EVs from healthy controls, new cases, and relapsed AML patients. The EVs size, morphology, and immunophenotype were determined by dynamic light scattering, TEM, and flow cytometry respectively. Bradford assay was performed to measure the protein content of EVs. MTT assay and flow cytometry analysis were also used to determine the viability index, induction of apoptosis, and ROS generation in U937 cells. The expression level of two efflux pumps was assessed using qRT-PCR analysis. Findings of TEM, DLS, and flow cytometry confirmed that EVs had a desirable shape, size, and surface markers. EVs derived from both new cases and relapsed AML patients significantly reduced idarubicin-induced apoptosis in the U937 cells. The analysis of drug efflux pumps gens revealed that EVs over-express MRD1 and MRP1 in the target cells. These findings suggested a novel role of EVs in mediating the acquired chemo-resistance in AML patients by inducing the expression of the drug efflux pumps; however, further investigations will be required to elucidate other underlying mechanisms of resistance that are mediated by EVs.
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Affiliation(s)
- Mohieddin Barzegar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Allahbakhshian Farsan
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Amiri
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Mohammadi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Shahsavan
- HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amin Mirzaeian
- HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wu HY, Zhang XC, Jia BB, Cao Y, Yan K, Li JY, Tao L, Jie ZG, Liu QW. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acetaminophen-induced acute liver failure through activating ERK and IGF-1R/PI3K/AKT signaling pathway. J Pharmacol Sci 2021; 147:143-155. [PMID: 34294366 DOI: 10.1016/j.jphs.2021.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/16/2022] Open
Abstract
This study aimed to investigate the therapeutic potential of human umbilical cord mesenchymal stem cells derived exosomes (hUCMSC-Exo) in acute liver failure (ALF) in mice as well as its underlying mechanism. We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over production of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways.
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Affiliation(s)
- Han-You Wu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, 330031, PR China
| | - Xiang-Cheng Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Bing-Bing Jia
- Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, Hangzhou, 310013, PR China
| | - Ye Cao
- Information Engineering School of NanChang University, Nanchang, 330031, PR China
| | - Kai Yan
- Department of Pediatrics, The First Affiliated Hospital of NanChang University, NanChang, 330006, PR China
| | - Jing-Yuan Li
- School of Chemistry, Biology and Material Science, East China University of Technology, Nanchang, 330013, China
| | - Li Tao
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Zhi-Gang Jie
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Quan-Wen Liu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, 330031, PR China.
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Perocheau D, Touramanidou L, Gurung S, Gissen P, Baruteau J. Clinical applications for exosomes: Are we there yet? Br J Pharmacol 2021; 178:2375-2392. [PMID: 33751579 PMCID: PMC8432553 DOI: 10.1111/bph.15432] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/18/2021] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
Exosomes are a subset of extracellular vesicles essential for cell-cell communication in health and disease with the ability to transport nucleic acids, functional proteins and other metabolites. Their clinical use as diagnostic biomarkers and therapeutic carriers has become a major field of research over recent years, generating rapidly expanding scientific interest and financial investment. Their reduced immunogenicity compared to liposomes or viral vectors and their ability to cross major physiological barriers like the blood-brain barrier make them an appealing and innovative option as biomarkers and therapeutic agents. Here, we review the latest clinical developments of exosome biotechnology for diagnostic and therapeutic purposes, including the most recent COVID-19-related exosome-based clinical trials. We present current exosome engineering strategies for optimal clinical safety and efficacy, and assess the technology developed for good manufacturing practice compliant scaling up and storage approaches along with their limitations in pharmaceutical industry.
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Affiliation(s)
- Dany Perocheau
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Loukia Touramanidou
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Sonam Gurung
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Paul Gissen
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.,Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Julien Baruteau
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.,Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
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Mahajan SD, Ordain NS, Kutscher H, Karki S, Reynolds JL. HIV Neuroinflammation: The Role of Exosomes in Cell Signaling, Prognostic and Diagnostic Biomarkers and Drug Delivery. Front Cell Dev Biol 2021; 9:637192. [PMID: 33869183 PMCID: PMC8047197 DOI: 10.3389/fcell.2021.637192] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/17/2021] [Indexed: 12/20/2022] Open
Abstract
Fifty to sixty percent of HIV-1 positive patients experience HIV-1 associated neurocognitive disorders (HAND) likely due to persistent inflammation and blood-brain barrier (BBB) dysfunction. The role that microglia and astrocytes play in HAND pathogenesis has been well delineated; however, the role of exosomes in HIV neuroinflammation and neuropathogenesis is unclear. Exosomes are 50-150 nm phospholipid bilayer membrane vesicles that are responsible for cell-to-cell communication, cellular signal transduction, and cellular transport. Due to their diverse intracellular content, exosomes, are well poised to provide insight into HIV neuroinflammation as well as provide for diagnostic and predictive information that will greatly enhance the development of new therapeutic interventions for neuroinflammation. Exosomes are also uniquely positioned to be vehicles to delivery therapeutics across the BBB to modulate HIV neuroinflammation. This mini-review will briefly discuss what is known about exosome signaling in the context of HIV in the central nervous system (CNS), their potential for biomarkers as well as their potential for vehicles to deliver various therapeutics to treat HIV neuroinflammation.
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Affiliation(s)
- Supriya D. Mahajan
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Nigel Smith Ordain
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Hilliard Kutscher
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
- Institute for Laser, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, NY, United States
- Department of Anesthesiology, State University of New York at Buffalo, Buffalo, NY, United States
| | - Shanta Karki
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Jessica L. Reynolds
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
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Lu Y, Zheng Z, Yuan Y, Pathak JL, Yang X, Wang L, Ye Z, Cho WC, Zeng M, Wu L. The Emerging Role of Exosomes in Oral Squamous Cell Carcinoma. Front Cell Dev Biol 2021; 9:628103. [PMID: 33718365 PMCID: PMC7951141 DOI: 10.3389/fcell.2021.628103] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/03/2021] [Indexed: 12/12/2022] Open
Abstract
Oral cancer constitutes approximately 2% of all cancers, while the most common type, oral squamous cell carcinoma (OSCC) represents 90% of oral cancers. Although the treatment of OSCC has improved recently, it still has a high rate of local recurrence and poor prognosis, with a 5-year survival rate of only 50%. Advanced stage OSCC tends to metastasize to lymph nodes. Thus, exploring new therapeutic strategies for OSCC is therefore an urgent priority. Exosomes, the small membrane vesicles derived from endosomes, have been detected in a wide array of bodily fluids. Exosomes contain a diversity of proteins, mRNAs, and non-coding RNAs, including microRNAs, long non-coding RNAs, piRNAs, circular RNAs, tsRNAs, and ribosomal RNAs, which are delivered to neighboring cells or even transported to distant sites. Exosomes have been associated with the tumorigenesis of OSCC, promote the proliferation, colonization, and metastasis of OSCC by transferring their contents to the target cells. Furthermore, exosomes are involved in the regulation of the tumor microenvironment to transform conditions favoring cancer progression in vivo. In this review, we summarize the crucial role of exosomes in the tumorigenesis and progression of OSCC and discuss the potential clinical application of exosomes in OSCC treatment.
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Affiliation(s)
- Yanhui Lu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
- Guangzhou Medical University School and Hospital of Stomatology, Guangzhou, China
| | - Zhichao Zheng
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
- Guangzhou Medical University School and Hospital of Stomatology, Guangzhou, China
| | - Yunyi Yuan
- Department of Orthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Janak L. Pathak
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Xuechao Yang
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
- Guangzhou Medical University School and Hospital of Stomatology, Guangzhou, China
| | - Lijing Wang
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
- Vascular Biology Research Institute, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhitong Ye
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Mingtao Zeng
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Lihong Wu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
- Guangzhou Medical University School and Hospital of Stomatology, Guangzhou, China
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Exosomes and exosomal RNAs in breast cancer: A status update. Eur J Cancer 2021; 144:252-268. [DOI: 10.1016/j.ejca.2020.11.033] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022]
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Shkair L, Garanina EE, Stott RJ, Foster TL, Rizvanov AA, Khaiboullina SF. Membrane Microvesicles as Potential Vaccine Candidates. Int J Mol Sci 2021; 22:1142. [PMID: 33498909 PMCID: PMC7865840 DOI: 10.3390/ijms22031142] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/21/2021] [Accepted: 01/21/2021] [Indexed: 12/11/2022] Open
Abstract
The prevention and control of infectious diseases is crucial to the maintenance and protection of social and public healthcare. The global impact of SARS-CoV-2 has demonstrated how outbreaks of emerging and re-emerging infections can lead to pandemics of significant public health and socio-economic burden. Vaccination is one of the most effective approaches to protect against infectious diseases, and to date, multiple vaccines have been successfully used to protect against and eradicate both viral and bacterial pathogens. The main criterion of vaccine efficacy is the induction of specific humoral and cellular immune responses, and it is well established that immunogenicity depends on the type of vaccine as well as the route of delivery. In addition, antigen delivery to immune organs and the site of injection can potentiate efficacy of the vaccine. In light of this, microvesicles have been suggested as potential vehicles for antigen delivery as they can carry various immunogenic molecules including proteins, nucleic acids and polysaccharides directly to target cells. In this review, we focus on the mechanisms of microvesicle biogenesis and the role of microvesicles in infectious diseases. Further, we discuss the application of microvesicles as a novel and effective vaccine delivery system.
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Affiliation(s)
- Layaly Shkair
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (L.S.); (E.E.G.); (A.A.R.)
| | - Ekaterina E. Garanina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (L.S.); (E.E.G.); (A.A.R.)
- M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
| | - Robert J. Stott
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Loughborough LE12 5RD, UK; (R.J.S.); (T.L.F.)
| | - Toshana L. Foster
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Loughborough LE12 5RD, UK; (R.J.S.); (T.L.F.)
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (L.S.); (E.E.G.); (A.A.R.)
| | - Svetlana F. Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (L.S.); (E.E.G.); (A.A.R.)
- Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA
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Deciphering of Key Pharmacological Pathways of Poria Cocos Intervention in Breast Cancer Based on Integrated Pharmacological Method. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:4931531. [PMID: 33149754 PMCID: PMC7603580 DOI: 10.1155/2020/4931531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 08/25/2020] [Accepted: 09/27/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Poria cocos (Fuling), a natural plant, has recently emerged as a promising strategy for cancer treatment. However, the molecular mechanisms of Poria cocos action in breast cancer remain poorly understood. METHODS TCMSP database was used to screen the potential active ingredients in Poria cocos. GEO database was used to identify differentially expressed genes. Network pharmacology was used to identify the specific pathways and key target proteins related to breast cancer. Finally, molecular docking was used to validate the results. RESULTS In our study, 237 targets were predicted for 15 potential active ingredients found in Poria cocos. An interaction network of predicted targets and genes differentially regulated in breast cancers was constructed. Based on the constructed network and further analysis including network topology, KEGG, survival analysis, and gene set enrichment analysis, 3 primary nodes were identified as key potential targets that were significantly enriched in the PPAR signaling pathway. CONCLUSION The results showed that potential active ingredients of Poria cocos might interfere with breast cancer through synergistic regulation of PTGS2, ESR1, and FOS.
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Mohammadzadeh R, Ghazvini K, Farsiani H, Soleimanpour S. Mycobacterium tuberculosis extracellular vesicles: exploitation for vaccine technology and diagnostic methods. Crit Rev Microbiol 2020; 47:13-33. [PMID: 33044878 DOI: 10.1080/1040841x.2020.1830749] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tuberculosis (TB) is a fatal epidemic disease usually caused by Mycobacterium tuberculosis (Mtb). Pervasive latent infection, multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB), and TB/HIV co-infection make TB a global health problem, which emphasises the design and development of efficient vaccines and diagnostic biomarkers. Extracellular vesicles (EVs) secretion is a conserved phenomenon in all the domains of life. Various cargos such as nucleic acids, toxins, lipoproteins, and enzymes have been recognised in these nano-sized vesicles that may be involved in bacterial physiology and pathogenesis. The intrinsic adjuvant effect, native immunogenic cargo, sensing by host immune cells, circulation in all body fluids, and comprehensive distribution of antigens introduce EVs as a promising tool for designing novel vaccines, diagnostic biomarkers, and drug delivery systems. Genetic engineering of the EV-producing bacteria and the subsequent production of proper EVs could facilitate the development of the EV-based therapeutic applications. Recently, it was demonstrated that thick-walled mycobacteria release EVs, which contain immunodominant cargos such as lipoglycans and lipoproteins. The present article is a comprehensive review on the recent findings of Mtb EVs biology and the exploitation of EVs for the vaccine technology and diagnostic methods.
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Affiliation(s)
- Roghayeh Mohammadzadeh
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kiarash Ghazvini
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hadi Farsiani
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Reference Tuberculosis Laboratory, Mashhad University of Medical Sciences, Mashhad, Iran
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Ma ZJ, Yang JJ, Lu YB, Liu ZY, Wang XX. Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine. World J Stem Cells 2020; 12:814-840. [PMID: 32952861 PMCID: PMC7477653 DOI: 10.4252/wjsc.v12.i8.814] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/23/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with marked potential for regenerative medicine because of their strong immunosuppressive and regenerative abilities. The therapeutic effects of MSCs are based in part on their secretion of biologically active factors in extracellular vesicles known as exosomes. Exosomes have a diameter of 30-100 nm and mediate intercellular communication and material exchange. MSC-derived exosomes (MSC-Exos) have potential for cell-free therapy for diseases of, for instance, the kidney, liver, heart, nervous system, and musculoskeletal system. Hence, MSC-Exos are an alternative to MSC-based therapy for regenerative medicine. We review MSC-Exos and their therapeutic potential for a variety of diseases and injuries.
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Affiliation(s)
- Zhan-Jun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jing-Jing Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Bao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Zhao-Yang Liu
- Department of Medical Imaging, Shanxi Medical University, Jinzhong 030600, Shaanxi Province, China
| | - Xue-Xi Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China.
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Vargas F, Wangesteen R, Rodríguez-Gómez I, García-Estañ J. Aminopeptidases in Cardiovascular and Renal Function. Role as Predictive Renal Injury Biomarkers. Int J Mol Sci 2020; 21:E5615. [PMID: 32764495 PMCID: PMC7460675 DOI: 10.3390/ijms21165615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/23/2020] [Accepted: 08/03/2020] [Indexed: 01/08/2023] Open
Abstract
Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. These enzymes are especially relevant in the control of cardiovascular and renal functions. APs participate in the regulation of the systemic and local renin-angiotensin system and also modulate the activity of neuropeptides, kinins, immunomodulatory peptides, and cytokines, even contributing to cholesterol uptake and angiogenesis. This review focuses on the role of four key APs, aspartyl-, alanyl-, glutamyl-, and leucyl-cystinyl-aminopeptidases, in the control of blood pressure (BP) and renal function and on their association with different cardiovascular and renal diseases. In this context, the effects of AP inhibitors are analyzed as therapeutic tools for BP control and renal diseases. Their role as urinary biomarkers of renal injury is also explored. The enzymatic activities of urinary APs, which act as hydrolyzing peptides on the luminal surface of the renal tubule, have emerged as early predictive renal injury biomarkers in both acute and chronic renal nephropathies, including those induced by nephrotoxic agents, obesity, hypertension, or diabetes. Hence, the analysis of urinary AP appears to be a promising diagnostic and prognostic approach to renal disease in both research and clinical settings.
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Affiliation(s)
- Félix Vargas
- Depto. Fisiologia, Fac. Medicina, Universidad de Granada, 18071 Granada, Spain
| | | | | | - Joaquín García-Estañ
- Depto. Fisiologia, Fac. Medicina, IMIB, Universidad de Murcia, 30120 Murcia, Spain
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Sorop A, Iacob R, Iacob S, Constantinescu D, Chitoiu L, Fertig TE, Dinischiotu A, Chivu-Economescu M, Bacalbasa N, Savu L, Gheorghe L, Dima S, Popescu I. Plasma Small Extracellular Vesicles Derived miR-21-5p and miR-92a-3p as Potential Biomarkers for Hepatocellular Carcinoma Screening. Front Genet 2020; 11:712. [PMID: 32793278 PMCID: PMC7391066 DOI: 10.3389/fgene.2020.00712] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 06/11/2020] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Liquid biopsy using circulating microvesicles and exosomes is emerging as a new diagnostic tool that could improve hepatocellular carcinoma (HCC) early diagnosis and screening protocols. Our study aimed to investigate the utility of plasma exosomal miR-21-5p and miR-92-3p for HCC diagnosis during screening protocols. METHODS The study group included 106 subjects: 48 patients diagnosed with HCC during screening, who underwent a potentially curative treatment (surgical resection or liver transplantation), 38 patients with liver cirrhosis (LC) on the waiting list for liver transplantation, and 20 healthy volunteers. The exosomes were isolated by precipitation with a reagent based on polyethylene glycol and were characterized based on morphological aspects (i.e., diameter); molecular weight; CD63, CD9, and CD81 protein markers; and exosomal miR-21-5p and miR-92a-3p expression levels. RESULTS We first demonstrate that the exosome population isolated with the commercially available Total Exosome Isolation kit respects the same size ranging, morphological, and protein expression aspects compared to the traditional ultracentrifugation technique. The analysis of the expression profile indicates that miR-21-5p was upregulated (p = 0.017), and miR-92a-3p was downregulated (p = 0.0005) in plasma-derived exosomes from HCC subjects, independently from the patient's characteristics. AUROC for HCC diagnosis based on AFP (alpha-fetoprotein) was 0.72. By integrating AFP and the relative expression of exosomal miR-21-5p and miR-92a-3p in a logistic regression equation for HCC diagnosis, the combined AUROC of the new exosomal miR HCC score was 0.85-significantly better than serum AFP alone (p = 0.0007). CONCLUSION Together with serum AFP, plasma exosomal miR-21-5p and miR-92a-3p could be used as potential biomarkers for HCC diagnosis in patients with LC subjected to screening and surveillance.
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Affiliation(s)
- Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Razvan Iacob
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
| | - Speranta Iacob
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
| | - Diana Constantinescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Leona Chitoiu
- Ultrastructural Pathology Laboratory, Victor Babeş National Institute, Bucharest, Romania
| | - Tudor Emanuel Fertig
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Ultrastructural Pathology Laboratory, Victor Babeş National Institute, Bucharest, Romania
| | | | - Mihaela Chivu-Economescu
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
| | - Nicolae Bacalbasa
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Lorand Savu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- “Titu Maiorescu” University of Medicine and Pharmacy, Bucharest, Romania
| | - Liliana Gheorghe
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
| | - Simona Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
| | - Irinel Popescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- “Titu Maiorescu” University of Medicine and Pharmacy, Bucharest, Romania
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45
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Liu S, Xu X, Liang S, Chen Z, Zhang Y, Qian A, Hu L. The Application of MSCs-Derived Extracellular Vesicles in Bone Disorders: Novel Cell-Free Therapeutic Strategy. Front Cell Dev Biol 2020; 8:619. [PMID: 32793590 PMCID: PMC7387669 DOI: 10.3389/fcell.2020.00619] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/22/2020] [Indexed: 12/11/2022] Open
Abstract
Bone is crucial for supporting the body, protecting other organs, providing minerals, and secreting hormone to regulate other organ's function. Bone disorders result in pain and disability, severely affecting human health, reducing the quality of life and increasing costs to society. With the rapid increase in the aging population worldwide, bone disorders have become one major disease. As a result, efficacious therapies of bone disorders have become the focus of attention worldwide. Mesenchymal stem cells (MSCs) have been widely explored as a new therapeutic method for numerous diseases. Recent evidence suggests that the therapeutic effects of MSCs are mainly mediated by their extracellular vesicles (EV). MSCs-derived extracellular vesicles (MSCs-EV) is indicated as a novel cell-free alternative to cell therapy with MSCs in regenerative medicine. Here, we review the current knowledge of EV and highlight the application studies of MSCs-EV in bone disorders by focusing on osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), and bone fracture. Moreover, we discuss the key issues and perspectives of MSCs-EV as a clinical therapeutic strategy for bone diseases.
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Affiliation(s)
- Shuyu Liu
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Xia Xu
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Shujing Liang
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Zhihao Chen
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Yan Zhang
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Airong Qian
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
| | - Lifang Hu
- Laboratary for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, China
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46
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Tang S, Cheng J, Yao Y, Lou C, Wang L, Huang X, Zhang Y. Combination of Four Serum Exosomal MiRNAs as Novel Diagnostic Biomarkers for Early-Stage Gastric Cancer. Front Genet 2020; 11:237. [PMID: 32256526 PMCID: PMC7089961 DOI: 10.3389/fgene.2020.00237] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 02/27/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality in the United States and China, there is an urgent need to discover novel non-invasive biomarkers for the early diagnosis of GC to improve the prognosis of GC patients. Exosomal miRNAs are considered promising biomarkers for cancer diagnosis. Using next-generation sequencing (NGS), bioinformatics and further validation, we identified and evaluated exosomal miRNAs in serum as early diagnostic markers for GC. NGS revealed that the average mappable reads in the RNA libraries were about 6.5 million per patient including miRNAs (73.38%), rRNAs (17.10%), snRNAs (8.83%), snoRNAs (0.65%), and tRNAs (0.04%). A total of 66 up and 13 down-regulated exosomal miRNAs were found in the screened cohort. In the validation cohort, by comparing with healthy individuals, higher levels of serum exosomal miR-92b-3p, let-7g-5p, miR-146b-5p, and miR-9-5p were found to be significantly associated with early-stage GC (p < 0.05). Diagnostic power of the combined panels of the exosomal miRNAs or the combination of exosomal miRNAs and CEA outperformed that of single exosomal miRNA marker for establishing a diagnosis of early-stage GC. The combined diagnosis of exosomal miR-92b-3p + let-7g-5p + miR-146b-5p + miR-9-5p with CEA had the most powerful efficiency with an AUC up to 0.786. In addition, serum levels of exosomal miR-92b-3p were significantly associated with poor cohesiveness (p = 0.0021), let-7g-5p and miR-146b-5p were significantly correlated with nerve infiltration (p = 0.0234 and p = 0.0126, respectively), and miR146b-5p was statistically correlated with tumor invasion depth in early-stage GC (p = 0.0089). In conclusion, serum exosomal miR-92b-3p, -146b-5p, -9-5p, and let-7g-5p may serve as potential non-invasive biomarkers for early diagnosis of GC.
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Affiliation(s)
- Shuli Tang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Jianan Cheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Changjie Lou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Liang Wang
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Xiaoyi Huang
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
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47
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Saber SH, Ali HEA, Gaballa R, Gaballah M, Ali HI, Zerfaoui M, Abd Elmageed ZY. Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer. Cells 2020; 9:E564. [PMID: 32121073 PMCID: PMC7140426 DOI: 10.3390/cells9030564] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/13/2022] Open
Abstract
Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.
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Affiliation(s)
- Saber H. Saber
- Laboratory of Molecular Cell Biology, Department of Zoology, Faculty of Science, Assiut University, Assiut 71515, Egypt;
| | - Hamdy E. A. Ali
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Rofaida Gaballa
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Mohamed Gaballah
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Hamed I. Ali
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Mourad Zerfaoui
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Zakaria Y. Abd Elmageed
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
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48
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Logozzi M, Spugnini E, Mizzoni D, Di Raimo R, Fais S. Extracellular acidity and increased exosome release as key phenotypes of malignant tumors. Cancer Metastasis Rev 2020; 38:93-101. [PMID: 30715644 DOI: 10.1007/s10555-019-09783-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The tumor milieu is characteristically acidic as a consequence of the fermentative metabolism of glucose that results in massive accumulation of lactic acid within the cytoplasm. Tumor cells get rid of excessive protons through exchangers that are responsible for the extracellular acidification that selects cellular clones that are more apt at surviving in this challenging and culling environment. Extracellular vesicles (EVs) are vesicles with diameters ranging from nm to μm that are released from the cells to deliver nucleic acids, proteins, and lipids to adjacent or distant cells. EVs are involved in a plethora of biological events that promote tumor progression including unrestricted proliferation, angiogenesis, migration, local invasion, preparation of the metastatic niche, metastasis, downregulation or hijacking of the immune system, and drug resistance. There is evidence that the release of specific exosomes is increased many folds in cancer patients, as shown by many techniques aimed at evaluating "liquid biopsies". The quality of the exosomal contents has been shown to vary at the different moments of tumor life such as local invasion or metastasis. In vitro studies have recently pointed out that cancer acidity is a major determinant in inducing increased exosome release by human cancer cells, by showing that exosomal release was increased as the pH moved from 7.4 pH to the typical pH of cancer that is 6.5. In this review, we emphasize the recent evidence that tumor acidity and exosomes levels are strictly related and strongly contribute to the malignant tumor phenotypes.
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Affiliation(s)
- Mariantonia Logozzi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Enrico Spugnini
- SAFU Department, Regina Elena Cancer Institute, Via Elio Chianesi 51, 00144, Rome, Italy
| | - Davide Mizzoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Rossella Di Raimo
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
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Igami K, Uchiumi T, Ueda S, Kamioka K, Setoyama D, Gotoh K, Akimoto M, Matsumoto S, Kang D. Characterization and function of medium and large extracellular vesicles from plasma and urine by surface antigens and Annexin V. PEERJ ANALYTICAL CHEMISTRY 2020. [DOI: 10.7717/peerj-achem.4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background
Extracellular vesicles (EVs) are released by most cell types and are involved in multiple basic biological processes. Medium/large EVs (m/lEVs), which are of a different size from exosomes, play an important role in the coagulation in blood, and are secreted from cancer cells, etc., suggesting functions related to malignant transformation. The m/lEVs levels in blood or urine may help unravel pathophysiological findings in many diseases. However, it remains unclear how many naturally-occurring m/lEV subtypes exist as well as how their characteristics and functions differ from one another.
Methods
We used the blood and urinal sample from each 10 healthy donors for analysis. Using a flow cytometer, we focus on characterization of EVs with large sizes (>200 nm) that are different from exosomes. We also searched for a membrane protein for characterization with a flow cytometer using shotgun proteomics. We then identified m/lEVs pelleted from plasma and urine samples by differential centrifugation and characterized by flow cytometry.
Results
Using proteomic profiling, we identified several proteins involved in m/lEV biogenesis including adhesion molecules, peptidases and exocytosis regulatory proteins. In healthy human plasma, we could distinguish m/lEVs derived from platelets, erythrocytes, monocytes/macrophages, T and B cells, and vascular endothelial cells with more than two positive surface antigens. The ratio of phosphatidylserine appearing on the membrane surface differed depending on the cell-derived m/lEVs. In urine, 50% of m/lEVs were Annexin V negative but contained various membrane peptidases derived from renal tubular villi. Urinary m/lEVs, but not plasma m/lEVs, showed peptidase activity. The knowledge of the new characteristics is considered to be useful as a diagnostic material and the newly developed method suggests the possibility of clinical application.
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Affiliation(s)
- Ko Igami
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Kyushu Pro Search Limited Liability Partnership, Fukuoka, Japan
- Business Management Division, Clinical Laboratory Business Segment, LSI Medience Corporation, Tokyo, Japan
| | - Takeshi Uchiumi
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Clinical Chemistry, Division of Biochemical Science and Technology, Department of Health Sciences, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Saori Ueda
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuyuki Kamioka
- Kyushu Pro Search Limited Liability Partnership, Fukuoka, Japan
- Department of Medical Solutions, LSI Medience Corporation, Tokyo, Japan
| | - Daiki Setoyama
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhito Gotoh
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaru Akimoto
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinya Matsumoto
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Dongchon Kang
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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50
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Ma X, Liu C, Gao C, Li J, Zhuang J, Liu L, Li H, Wang X, Zhang X, Dong S, Zhou C, Sun C. circRNA-associated ceRNA network construction reveals the circRNAs involved in the progression and prognosis of breast cancer. J Cell Physiol 2019; 235:3973-3983. [PMID: 31617204 DOI: 10.1002/jcp.29291] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/30/2019] [Indexed: 12/24/2022]
Abstract
Recently, increasing evidences show that circular RNAs (circRNAs) are important regulators of various diseases, especially cancer. However, the regulatory role and the potential mechanism of action of circRNAs in breast cancer remain largely unknown. In this study, weighted gene co-expression network analysis was conducted with the differentially expressed miRNAs and mRNAs in breast cancer from The Cancer Genome Atlas database to identify the key modules associated with the carcinogenesis of breast cancer. In the significant turquoise and brown modules, 22 miRNAs and 1877 mRNAs were identified, respectively. Then, We compared and predicted the target genes and performed survival analysis to identify the miRNAs and mRNAs related to the prognosis of breast cancer. A circRNA-related competitive endogenous RNA network was identified by database co-screening, and deleted in liver cancer 1 (DLC1) was identified as a key gene. Finally, to assess how genes in key modules and key genes contribute to the development of breast cancer, relevant pathway information was obtained through DAVID and Gene Set Enrichment Analysis. These data demonstrated that three circRNAs (hsa-circ-0083373, hsa-circ-0083374, and hsa-circ-0083375) that regulate DLC1 expression via hsa-mir-511 and are involved in the pathogenesis and development of breast cancer.
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Affiliation(s)
- Xiaoran Ma
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Cun Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Chundi Gao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Jie Li
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Jing Zhuang
- Departmen of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong, China.,Department of Oncology, Affilited Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Lijuan Liu
- Departmen of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong, China
| | - Huayao Li
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xue Wang
- College of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Xiaoming Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Shixia Dong
- Clinical Medical Colleges, Weifang Medical University, Weifang, Shandong, China
| | - Chao Zhou
- Departmen of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong, China
| | - Changgang Sun
- Department of Basic Medical Science, Qingdao University, Qingdao, 266071, China.,Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
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