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Cao A, Zhao R, Chen C, Wu C, Zhang Y, Huang C, Zhu B. Circulating tsRNAs serve as potential biomarkers for predicting postoperative delirium in elderly patients receiving lower extremity orthopedic surgery. Front Psychiatry 2025; 16:1522984. [PMID: 40206643 PMCID: PMC11980442 DOI: 10.3389/fpsyt.2025.1522984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/24/2025] [Indexed: 04/11/2025] Open
Abstract
Background Postoperative delirium (POD) is a serious neuropsychiatric complication in elderly surgical patients, yet its pathogenesis remains incompletely understood. Transfer RNA-derived small RNAs (tsRNAs) have emerged as crucial regulators in neurological disorders. We investigated whether specific tsRNAs could serve as predictive biomarkers for POD. Methods This study conducted a prospective case-control study of 158 elderly patients (≥60 years) undergoing orthopedic surgery. Plasma samples were collected preoperatively and on postoperative day 3.tsRNA expression profiles were analyzed using RNA sequencing and validated by RT-qPCR. Propensity score matching was performed to balance demographic and clinical variables. The predictive value of candidate tsRNAs was assessed using ROC analysis, and their potential functions were explored through bioinformatic analyses. Results Among 128 non-POD and 30 POD patients, two tsRNAs (Other-14: 31-tRNA-Gly-CCC-3 and Other-39: 73-tRNA-Arg-TCG-5) showed significantly elevated preoperative levels in POD patients (p<0.001).ROC analysis revealed strong predictive performance (AUC=0.868 and 0.956, respectively).These differences persisted in the propensity-matched cohort (29 pairs).Bioinformatic analyses indicated enrichment in pathways related to neurotransmission, inflammation, and metabolism. Conclusion This study identified novel tsRNA biomarkers that robustly predict POD risk and provide insights into its molecular pathogenesis. These findings may facilitate early risk stratification and preventive interventions.
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Affiliation(s)
- Angyang Cao
- Department of Anesthesiology, The First Affliated Hospital of Ningbo University, Ningbo, China
- School of Medicine, Ningbo University, Ningbo, China
| | - Rui Zhao
- Department of Anesthesiology, The First Affliated Hospital of Ningbo University, Ningbo, China
- School of Medicine, Ningbo University, Ningbo, China
| | - Chunqu Chen
- School of Medicine, Ningbo University, Ningbo, China
- Department of imaging, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Can Wu
- School of Medicine, Ningbo University, Ningbo, China
- Department of Clinical laboratory, Jinhua Maternal and Child Health Care Hospital, Jinhua, China
| | - Yiwei Zhang
- Department of Anesthesiology, The First Affliated Hospital of Ningbo University, Ningbo, China
- School of Medicine, Ningbo University, Ningbo, China
| | - Changshun Huang
- Department of Anesthesiology, The First Affliated Hospital of Ningbo University, Ningbo, China
- School of Medicine, Ningbo University, Ningbo, China
| | - Binbin Zhu
- Department of Anesthesiology, The First Affliated Hospital of Ningbo University, Ningbo, China
- School of Medicine, Ningbo University, Ningbo, China
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2
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Arsalan HM, Mumtaz H, Lagana AS. Biomarkers of endometriosis. Adv Clin Chem 2025; 126:73-120. [PMID: 40185537 DOI: 10.1016/bs.acc.2025.01.004] [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: 04/07/2025]
Abstract
Endometriosis represents a diverse disease characterized by three distinct phenotypes: superficial peritoneal lesions, ovarian endometriomas, and deep infiltrating endometriosis. The most widely accepted pathophysiological hypothesis for endometriosis is rooted in retrograde menstruation, a phenomenon observed in most patients. Endometriosis is closely linked to infertility, but having endometriosis does not necessarily imply infertility. The disease can impact fertility through various mechanisms affecting the pelvic cavity, ovaries, and the uterus itself. MicroRNAs (miRNAs) indeed represent a fascinating and essential component of the regulatory machinery within cells. Discovered in the early 1990s, miRNAs have since been identified as critical players in gene expression control. Unfortunately, ovarian endometrioma is a common gynecologic disorder for which specific serum markers are currently lacking. Some have examined urocortin for its ability to differentiate endometriomas from other benign ovarian cysts. Another potential marker, Cancer Antigen 125 (CA-125) is a well-established indicator for epithelial cell ovarian cancer and its levels can be elevated in conditions such as endometriosis. CA-125 is derived from coelomic epithelia, including the endometrium, fallopian tube, ovary, and peritoneum. In this review we examine the pathophysiologic basis for endometriosis and highlight potential markers to more fully characterize the underlying biochemical processes linked to this multifaceted disease state.
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Affiliation(s)
- Hafiz Muhammad Arsalan
- Faculty of General Medicine, Altamimi International Medical University, Bishkek, Kyrgyzstan.
| | - Hina Mumtaz
- Department of Biochemistry, University of Central Punjab, Lahore, Pakistan.
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3
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Mukherjee A, Verma A, Das T, Ghosh B, Ghosh Z. Circulating microRNAs in Body Fluid: "Fingerprint" RNA Snippets Deeply Impact Reproductive Biology. Reprod Sci 2025; 32:555-574. [PMID: 39658771 DOI: 10.1007/s43032-024-01753-y] [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: 07/01/2024] [Accepted: 11/22/2024] [Indexed: 12/12/2024]
Abstract
Circulating miRNAs (C-miRNAs) occuring in a cell-free form within body fluids and other extracellular environments have garnered attention in recent times. They offer deeper insight into various physiological and pathological processes which include reproductive health. This review delves into their diagnostic potential across a spectrum of reproductive disorders, including conditions affecting ovarian function, male infertility and post pregnancy issues. Through analysis of C-miRNA profiles in bodily fluids, researchers uncover crucial markers indicative of reproductive challenges. Dysregulated C-miRNAs emerge as important players in the progression of several reproductive disorders which is the main focus of this review. Advancements in technology, facilitate precise detection and quantification of C-miRNAs, paving the way for innovative diagnostic approaches. Challenges in studying C-miRNAs, such as their low abundance and variability in expression levels, underscore the need for standardized protocols and rigorous validation methods. Despite these challenges, ongoing research endeavors aim to unravel the complex regulatory roles of C-miRNAs in reproductive biology, with potential implications for clinical practice and therapeutic interventions.
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Affiliation(s)
- Ayan Mukherjee
- Department of Animal Biotechnology, West Bengal University of Animal and Fishery Sciences, Mohanpur, West Bengal, 741252, India.
| | - Arpana Verma
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India
| | - Troyee Das
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India
| | - Byapti Ghosh
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India
| | - Zhumur Ghosh
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India.
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Trotta MC, Esposito D, Carotenuto R, di Fraia R, Selvaggio LD, Allosso F, Russo M, Accardo G, Alfano R, D'Amico M, Pasquali D. Thyroid dysfunction in Hashimoto's thyroiditis: a pilot study on the putative role of miR-29a and TGFβ1. Endocrine 2024; 86:1090-1096. [PMID: 39023839 PMCID: PMC11554689 DOI: 10.1007/s12020-024-03965-3] [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: 05/21/2024] [Accepted: 07/09/2024] [Indexed: 07/20/2024]
Abstract
PURPOSE Hashimoto's thyroiditis (HT) is one of the most common causes of thyroid dysfunction in iodine sufficient worldwide areas, but its molecular mechanisms are not completely understood. To this regard, this study aimed to assess serum levels of miRNA-29a (miR-29a) and transforming growth factor beta 1 (TGFβ1) in HT patients with different patterns of thyroid function. METHODS A total of 29 HT patients, with a median age of 52 years (21-68) were included. Of these, 13 had normal thyroid function (Eu-HT); 8 had non-treated hypothyroidism (Hypo-HT); 8 had hypothyroidism on replacement therapy with LT4 (subst-HT). All patients had serum miR-29a assayed through qRT-PCR and serum TGFβ1 assayed by ELISA. RESULTS Serum miR-29a levels were significantly down-regulated in patients with Hypo-HT compared to Eu-HT patients (P < 0.01) and subst-HT patients (P < 0.05). A significant negative correlation was detected between serum miR-29a levels and TSH levels (r = -0.60, P < 0.01). Serum TGFβ1 levels were significantly higher in Hypo-HT than both Eu-HT (P < 0.01) and subst-HT patients (P < 0.05). A negative correlation was observed between serum miR-29a and TGFβ1 (r = -0.75, P < 0.01). CONCLUSIONS In conclusion, Hypo-HT patients had lower levels of serum miR-29a and higher levels of TGFβ1 in comparison with Eu-HT patients. Worthy of note, subst-HT patients showed restored serum miR-29a levels compared with Hypo-HT group, associated with lower serum TGFβ1. These novel findings may suggest a possible impact of replacement therapy with levothyroxine on serum miR-29a levels in HT.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Daniela Esposito
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Raffaela Carotenuto
- Department of Advanced Medical and Surgical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Rosa di Fraia
- Department of Advanced Medical and Surgical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Lucia Digitale Selvaggio
- Department of Advanced Medical and Surgical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Francesca Allosso
- Department of Advanced Medical and Surgical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Marina Russo
- PhD Course in National Interest in Public Administration and Innovation for Disability and Social Inclusion, Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
- School of Pharmacology and Clinical Toxicology, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy
| | | | - Roberto Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Daniela Pasquali
- Department of Advanced Medical and Surgical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy.
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5
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Elshafie NO, Gribskov M, Lichti NI, Sayedahmed EE, Childress MO, Pires dos Santos A. MicroRNAs implicated in canine diffuse large B-cell lymphoma prognosis. FEBS Open Bio 2024; 14:1899-1913. [PMID: 39218619 PMCID: PMC11532975 DOI: 10.1002/2211-5463.13887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 07/16/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL) in domestic dogs, with many similarities to its human counterpart. The progression of the disease is rapid, and treatment must be initiated early to achieve cancer remission and extend life. This study examined the relationship between progression-free survival (PFS) and microRNA (miRNA) expression in dogs with DLBCL. miRNAs are small non-coding RNA molecules that typically regulate gene expression post-transcriptionally. They are involved in several pathophysiological processes, including the growth and progression of cancer. Based on the analysis of small RNA sequencing (sRNA-seq) data, we validated a group of miRNAs in lymph nodes from 44 DLBCL-affected dogs with known outcomes. We used quantitative PCR to quantify their expression and report a specific subset of miRNAs is associated with decreased PFS in dogs with DLBCL. The miR-192-5p and miR-16-5p expression were significantly downregulated in dogs with increased PFS. These results indicate that miRNA profiling may potentially identify dogs with DLBCL that will experience poor outcomes following treatment. Identifying specific miRNAs that correlate with the progression of canine DLBCL could aid the development of individualized treatment regimens for dogs.
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Affiliation(s)
- Nelly O. Elshafie
- Department of Comparative PathobiologyPurdue UniversityWest LafayetteINUSA
| | - Michael Gribskov
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
| | | | | | - Michael O. Childress
- Department of Veterinary Clinical SciencesPurdue UniversityWest LafayetteINUSA
- Purdue Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| | - Andrea Pires dos Santos
- Department of Comparative PathobiologyPurdue UniversityWest LafayetteINUSA
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
- Bindley Bioscience CenterPurdue UniversityWest LafayetteINUSA
- Department of Veterinary Clinical SciencesPurdue UniversityWest LafayetteINUSA
- Purdue Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
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6
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Kanannejad Z, Arab S, Soleimanian S, Mazare A, Kheshtchin N. Exosomes in asthma: Underappreciated contributors to the pathogenesis and novel therapeutic tools. Immun Inflamm Dis 2024; 12:e1325. [PMID: 38934401 PMCID: PMC11209551 DOI: 10.1002/iid3.1325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
OBJECTIVE Asthma, a chronic inflammatory disease with diverse pathomechanisms, presents challenges in developing personalized diagnostic and therapeutic approaches. This review aims to provide a comprehensive overview of the role of exosomes, small extracellular vesicles, in asthma pathophysiology and explores their potential as diagnostic biomarkers and therapeutic tools. METHODS A literature search was conducted to identify recent studies investigating the involvement of exosomes in asthma. The retrieved articles were analyzed to extract relevant information on the role of exosomes in maintaining lung microenvironment homeostasis, regulating inflammatory responses, and their diagnostic and therapeutic potential for asthma. RESULTS Exosomes secreted by various cell types, have emerged as crucial mediators of intercellular communication in healthy and diseased conditions. Evidence suggest that exosomes play a significant role in maintaining lung microenvironment homeostasis and contribute to asthma pathogenesis by regulating inflammatory responses. Differential exosomal content between healthy individuals and asthmatics holds promise for the development of novel asthma biomarkers. Furthermore, exosomes secreted by immune and nonimmune cells, as well as those detected in biofluids, demonstrate potential in promoting or regulating immune responses, making them attractive candidates for designing new treatment strategies for inflammatory conditions such as asthma. CONCLUSION Exosomes, with their ability to modulate immune responses and deliver therapeutic cargo, offer potential as targeted therapeutic tools in asthma management. Further research and clinical trials are required to fully understand the mechanisms underlying exosome-mediated effects and translate these findings into effective diagnostic and therapeutic strategies for asthma patients.
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Affiliation(s)
- Zahra Kanannejad
- Allergy Research CenterShiraz University of Medical SciencesShirazIran
| | - Samaneh Arab
- Department of Tissue Engineering and Applied Cell Sciences, School of MedicineSemnan University of Medical SciencesSemnanIran
| | | | - Amirhossein Mazare
- Department of Immunology, School of MedicineShiraz University of Medical SciencesShirazIran
| | - Nasim Kheshtchin
- Allergy Research CenterShiraz University of Medical SciencesShirazIran
- Department of Immunology, School of MedicineShiraz University of Medical SciencesShirazIran
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7
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Ryningen A, Rostad K, Ersvær E, Sjøholt G, Paulsen G, Gundersen H, Kristoffersen M, Bjørkhaug L. Acute response in circulating microRNAs following a single bout of short-sprint and heavy strength training in well-trained cyclists. Front Physiol 2024; 15:1365357. [PMID: 38532845 PMCID: PMC10963392 DOI: 10.3389/fphys.2024.1365357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024] Open
Abstract
Background: Heavy strength (HS) and short-sprint (SS) are commonly used training methods for competitive road cyclists, with the aim to improve the anaerobic power and short time cycling performance. Knowledge of how such training methods affects biochemical as well as molecular factors, are particularly important for determining individual recovery and long-term adaptations. The primary aim of the current study was to investigate the expression levels of small non-coding RNAs in response to HS and SS training in elite cyclists as potential biomarkers for individual optimal restitution time. Methods: Eleven well trained cyclists performed one session of HS training and one session of SS training on separate days. Blood samples were taken at baseline and 5 min, 1 h and 21 h post training. Along with physiological measurements and biochemical factors (serum creatine kinase, myoglobin, human growth hormone and plasma lactate), real-time quantitative PCR was used to explore whether HS and/or SS training influenced the abundance of 24 circulating miRNAs, in serum, associated with muscle development, angiogenesis, and/or inflammation. Results: Based on complete miRNA profiles from nine cyclists, the miRNAs showing most altered expression after both training sessions included the three striated muscle-specific miRNAs (myomiRs) miR-1-3p, 133a-3p and 133b-3p. While all three miRNAs showed significantly highest expression at 1 h post HS session, the acute effect of the SS session included a significantly higher level of miR-1-3p alone, at 5 min (highest), as well as at 1 h and 21 h post session. Correlation (negative) with biochemical markers was only shown for miR-133a-3p and CK (r = -0.786, p = 0.041) and between miR-133b-3p and [La-] (r = -0.711, p = .032), at 21 h post SS session. Conclusion: Our findings support that unique myomiRs are regulated by HS and SS training. Such knowledge may be important for individually adjusted restitution times.
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Affiliation(s)
- Anita Ryningen
- Department of Safety, Chemistry and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
| | - Kari Rostad
- Department of Safety, Chemistry and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
| | - Elisabeth Ersvær
- Department of Safety, Chemistry and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
- Department of Biotechnology, Inland Norway University of Applied Sciences, Lillehammer, Norway
| | - Gry Sjøholt
- Department of Safety, Chemistry and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
| | - Gøran Paulsen
- Department of Sport, Food and Natural Sciences, Western Norway University of Applied Sciences, Sogndal, Norway
- Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway
| | - Hilde Gundersen
- Department of Sport and Physical Activity, Western Norway University of Applied Sciences, Bergen, Norway
| | - Morten Kristoffersen
- Department of Sport and Physical Activity, Western Norway University of Applied Sciences, Bergen, Norway
| | - Lise Bjørkhaug
- Department of Safety, Chemistry and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
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8
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Mathur P, Saxena S, Saxena B, Rani V. MicroRNAs Targeting Critical Molecular Pathways in Diabetic Cardiomyopathy Emerging Valuable for Therapy. Cardiovasc Hematol Agents Med Chem 2024; 22:298-307. [PMID: 38265401 DOI: 10.2174/0118715257265947231129074526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 10/09/2023] [Accepted: 10/17/2023] [Indexed: 01/25/2024]
Abstract
MicroRNAs have emerged as an important regulator of post-transcriptional gene expression studied extensively in many cancers, fetal development, and cardiovascular diseases. Their endogenous nature and easy manipulation have made them potential diagnostic and therapeutic molecules. Diseases with complex pathophysiology such as Diabetic Cardiomyopathy display symptoms at a late stage when the risk of heart failure has become very high. Therefore, the utilization of microRNAs as a tool to study pathophysiology and device-sustainable treatments for DCM could be considered. The present review focuses on the mechanistic insights of diabetic cardiomyopathy and the potential role of microRNAs.
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Affiliation(s)
- Priyanka Mathur
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector- 62, Noida, 201307, Uttar Pradesh, India
| | - Sharad Saxena
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector- 62, Noida, 201307, Uttar Pradesh, India
| | - Bhawna Saxena
- Department of Computer Science & Engineering and Information Technology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, 201307, Uttar Pradesh, India
| | - Vibha Rani
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector- 62, Noida, 201307, Uttar Pradesh, India
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Abstract
The remarkable diversity of lymphocytes, essential components of the immune system, serves as an ingenious mechanism for maximizing the efficient utilization of limited host defense resources. While cell adhesion molecules, notably in gut-tropic T cells, play a central role in this mechanism, the counterbalancing molecular details have remained elusive. Conversely, we've uncovered the molecular pathways enabling extracellular vesicles secreted by lymphocytes to reach the gut's mucosal tissues, facilitating immunological regulation. This discovery sheds light on immune fine-tuning, offering insights into immune regulation mechanisms.
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Affiliation(s)
- Yasunari Matsuzaka
- Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
| | - Ryu Yashiro
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Higashimurayama, Tokyo, Japan
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10
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Elshafie NO, Gribskov M, Lichti NI, Sayedahmed EE, Childress MO, dos Santos AP. miRNome expression analysis in canine diffuse large B-cell lymphoma. Front Oncol 2023; 13:1238613. [PMID: 37711209 PMCID: PMC10499539 DOI: 10.3389/fonc.2023.1238613] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/04/2023] [Indexed: 09/16/2023] Open
Abstract
Introduction Lymphoma is a common canine cancer with translational relevance to human disease. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, contributing to almost fifty percent of clinically recognized lymphoma cases. Identifying new biomarkers capable of early diagnosis and monitoring DLBCL is crucial for enhancing remission rates. This research seeks to advance our knowledge of the molecular biology of DLBCL by analyzing the expression of microRNAs, which regulate gene expression by negatively impacting gene expression via targeted RNA degradation or translational repression. The stability and accessibility of microRNAs make them appropriate biomarkers for the diagnosis, prognosis, and monitoring of diseases. Methods We extracted and sequenced microRNAs from ten fresh-frozen lymph node tissue samples (six DLBCL and four non-neoplastic). Results Small RNA sequencing data analysis revealed 35 differently expressed miRNAs (DEMs) compared to controls. RT-qPCR confirmed that 23/35 DEMs in DLBCL were significantly upregulated (n = 14) or downregulated (n = 9). Statistical significance was determined by comparing each miRNA's average expression fold-change (2-Cq) between the DLCBL and healthy groups by applying the unpaired parametric Welch's 2-sample t-test and false discovery rate (FDR). The predicted target genes of the DEMs were mainly enriched in the PI3K-Akt-MAPK pathway. Discussion Our data point to the potential value of miRNA signatures as diagnostic biomarkers and serve as a guideline for subsequent experimental studies to determine the targets and functions of these altered miRNAs in canine DLBCL.
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Affiliation(s)
- Nelly O. Elshafie
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Michael Gribskov
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Nathanael I. Lichti
- Bindley Bioscience Center, Purdue University, West Lafayette, IN, United States
| | - Ekramy. E. Sayedahmed
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Michael O. Childress
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States
| | - Andrea P. dos Santos
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
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11
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Jimenez SA, Piera-Velazquez S. Probable role of exosomes in the extension of fibrotic alterations from affected to normal cells in systemic sclerosis. Rheumatology (Oxford) 2023; 62:999-1008. [PMID: 35944210 PMCID: PMC9977136 DOI: 10.1093/rheumatology/keac451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/14/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
SSc is a systemic autoimmune disease of unknown etiology characterized by frequently progressive cutaneous and internal organ fibrosis causing severe disability, organ failure and high mortality. A remarkable feature of SSc is the extension of the fibrotic alterations to nonaffected tissues. The mechanisms involved in the extension of fibrosis have remained elusive. We propose that this process is mediated by exosome microvesicles released from SSc-affected cells that induce an activated profibrotic phenotype in normal or nonaffected cells. Exosomes are secreted microvesicles involved in an intercellular communication system. Exosomes can transfer their macromolecular content to distant target cells and induce paracrine effects in the recipient cells, changing their molecular pathways and gene expression. Confirmation of this hypothesis may identify the molecular mechanisms responsible for extension of the SSc fibrotic process from affected cells to nonaffected cells and may allow the development of novel therapeutic approaches for the disease.
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Affiliation(s)
- Sergio A Jimenez
- Jefferson Institute of Molecular Medicine and The Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sonsoles Piera-Velazquez
- Jefferson Institute of Molecular Medicine and The Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, USA
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12
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Tosevska A, Morselli M, Basak SK, Avila L, Mehta P, Wang MB, Srivatsan ES, Pellegrini M. Cell-Free RNA as a Novel Biomarker for Response to Therapy in Head & Neck Cancer. Front Oncol 2022; 12:869108. [PMID: 35600369 PMCID: PMC9121879 DOI: 10.3389/fonc.2022.869108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 03/23/2022] [Indexed: 12/17/2022] Open
Abstract
Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. In a new paradigm of cancer treatment, a synergistic botanical drug combination (APG-157) consisting of multiple molecules, is emerging as a new class of cancer therapeutics, targeting multiple pathways and providing a durable clinical response, wide therapeutic window and high level of safety. Monitoring the efficacy of such drugs involves assessing multiple molecules and cellular events simultaneously. We report, for the first time, a methodology that uses circulating plasma cell-free RNA (cfRNA) as a sensitive indicator of patient response upon drug treatment. Plasma was collected from six patients with head and neck cancer (HNC) and four healthy controls receiving three doses of 100 or 200 mg APG-157 or placebo through an oral mucosal route, before treatment and on multiple points post-dosing. Circulating cfRNA was extracted from plasma at 0-, 3- and 24-hours post-treatment, followed by RNA sequencing. We performed comparative analyses of the circulating transcriptome and were able to detect significant perturbation following APG-157 treatment. Transcripts associated with inflammatory response, leukocyte activation and cytokine were upregulated upon treatment with APG-157 in cancer patients, but not in healthy or placebo-treated patients. A platelet-related transcriptional signature could be detected in cancer patients but not in healthy individuals, indicating a platelet-centric pathway involved in the development of HNC. These results from a Phase 1 study are a proof of principle of the utility of cfRNAs as non-invasive circulating biomarkers for monitoring the efficacy of APG-157 in HNC.
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Affiliation(s)
- Anela Tosevska
- Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, United States
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Marco Morselli
- Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, United States
| | - Saroj K Basak
- Department of Surgery, Veterans Administration Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
| | - Luis Avila
- Aveta Biomics Inc, Bedford, MA, United States
| | - Parag Mehta
- Aveta Biomics Inc, Bedford, MA, United States
| | - Marilene B Wang
- Department of Surgery, Veterans Administration Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
- Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States
| | - Eri S Srivatsan
- Department of Surgery, Veterans Administration Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
- Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States
- Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA, United States
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, United States
- Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States
- Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA, United States
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Biernacki T, Kokas Z, Sandi D, Füvesi J, Fricska-Nagy Z, Faragó P, Kincses TZ, Klivényi P, Bencsik K, Vécsei L. Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations. Int J Mol Sci 2022; 23:ijms23063383. [PMID: 35328802 PMCID: PMC8951485 DOI: 10.3390/ijms23063383] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/12/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Multiple Sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS) affecting young people. This is due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on a patient's health-related quality of life. It is of great importance to recognise it in time and commence adequate treatment at an early stage. The currently used disease-modifying therapies (DMT) aim to reduce disease activity and thus halt disability development, which in current clinical practice are monitored by clinical and imaging parameters but not by biomarkers found in blood and/or the cerebrospinal fluid (CSF). Both clinical and radiological measures routinely used to monitor disease activity lack information on the fundamental pathophysiological features and mechanisms of MS. Furthermore, they lag behind the disease process itself. By the time a clinical relapse becomes evident or a new lesion appears on the MRI scan, potentially irreversible damage has already occurred in the CNS. In recent years, several biomarkers that previously have been linked to other neurological and immunological diseases have received increased attention in MS. Additionally, other novel, potential biomarkers with prognostic and diagnostic properties have been detected in the CSF and blood of MS patients. AREAS COVERED In this review, we summarise the most up-to-date knowledge and research conducted on the already known and most promising new biomarker candidates found in the CSF and blood of MS patients. DISCUSSION the current diagnostic criteria of MS relies on three pillars: MRI imaging, clinical events, and the presence of oligoclonal bands in the CSF (which was reinstated into the diagnostic criteria by the most recent revision). Even though the most recent McDonald criteria made the diagnosis of MS faster than the prior iteration, it is still not an infallible diagnostic toolset, especially at the very early stage of the clinically isolated syndrome. Together with the gold standard MRI and clinical measures, ancillary blood and CSF biomarkers may not just improve diagnostic accuracy and speed but very well may become agents to monitor therapeutic efficacy and make even more personalised treatment in MS a reality in the near future. The major disadvantage of these biomarkers in the past has been the need to obtain CSF to measure them. However, the recent advances in extremely sensitive immunoassays made their measurement possible from peripheral blood even when present only in minuscule concentrations. This should mark the beginning of a new biomarker research and utilisation era in MS.
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Affiliation(s)
- Tamás Biernacki
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Zsófia Kokas
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Dániel Sandi
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Judit Füvesi
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Zsanett Fricska-Nagy
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Péter Faragó
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Tamás Zsigmond Kincses
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
- Albert Szent-Györgyi Clinical Centre, Department of Radiology, Albert Szent-Györgyi Faculty of Medicine, University of Szeged, 6725 Szeged, Hungary
| | - Péter Klivényi
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - Krisztina Bencsik
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
| | - László Vécsei
- Albert Szent-Györgyi Clinical Centre, Department of Neurology, Faculty of General Medicine, University of Szeged, 6725 Szeged, Hungary; (T.B.); (Z.K.); (D.S.); (J.F.); (Z.F.-N.); (P.F.); (T.Z.K.); (P.K.); (K.B.)
- MTA-SZTE Neuroscience Research Group, University of Szeged, 6725 Szeged, Hungary
- Correspondence: ; Tel.: +36-62-545-356; Fax: +36-62-545-597
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Exosome-derived miR-200a promotes esophageal cancer cell proliferation and migration via the mediating Keap1 expression. Mol Cell Biochem 2022; 477:1295-1308. [PMID: 35137328 DOI: 10.1007/s11010-022-04353-z] [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: 06/09/2021] [Accepted: 01/06/2022] [Indexed: 12/18/2022]
Abstract
Previous studies have reported that exosomes bearing certain microRNAs (miRNAs) are related to the physiological functions of different types of cancer cells. Our study aimed to elucidate the role of miR-200a in esophageal squamous cell carcinoma (ESCC). We observed that miR-200a expression is higher in esophageal carcinoma cells, tissues, and exosomes than in normal cells and healthy tissues. We showed that exosome-shuttled miR-200a promotes the proliferation, migration, and invasion of esophageal cells and inhibits apoptosis, thereby leading to the progression of ESCC. We showed that miR-200a exerts its effects through its interaction with Keap1, thus altering the Keap1/Nrf2 signaling pathway. Our results suggest that exosome-shuttled miR-200a might be useful as a biomarker for prognosis in patients with ESCC.
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15
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Yan W, Song L, Wang H, Yang W, Hu L, Yang Y. Extracellular vesicles carrying miRNA-181b-5p affects the malignant progression of acute lymphoblastic leukemia. J Transl Med 2021; 19:511. [PMID: 34922585 PMCID: PMC8684212 DOI: 10.1186/s12967-021-03174-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 11/30/2021] [Indexed: 11/10/2022] Open
Abstract
Objective To investigate how serum extracellular vesicles (EVs)-carried miRNA-181b-5p affected the proliferation, cell cycle and apoptosis of acute lymphoblastic leukemia (ALL) cells. Methods Differentially expressed miRNAs related to ALL were screened by bioinformatics analysis, and the localization of target miRNA was searched by its expression. qRT-PCR was adopted to confirm the expression of miRNA-181b-5p. Flow cytometry and fluorescence microscopy were applied to evaluate EVs internalization. MTT assay was employed to verify the proliferation of ALL cells. Cell cycle and apoptosis were analyzed by flow cytometry. Transwell assay was applied to evaluate migration and invasion abilities. Results High expression of miRNA-181b-5p was proved in ALL cell lines, and miRNA-181b-5p enriched in the exosomes and vesicles of blood cells. In the meantime, it was found that EVs carrying miRNA-181b-5p could be internalized by ALL cells and thus the expression of miRNA-181b-5p was up-regulated. Cell function assays showed that the proliferation, migration, invasion abilities of ALL cell lines were promoted in miRNA-181b-5p mimic group or the group co-culturing ALL-derived EVs and BALL-1 cell lines. The percentage of cells in G0/G1 phase was reduced and cell apoptosis was also inhibited. Conclusion miRNA-181b-5p carried by EVs in peripheral blood of ALL patients can enter ALL cells and thus promote the malignancy of ALL cells.
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Affiliation(s)
- Wei Yan
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, 110000, People's Republic of China
| | - Li Song
- National Drug Clinical Trial Institute Office, Qingdao Women and Children's Hospital, Qingdao, China
| | - Huihan Wang
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, 110000, People's Republic of China
| | - Wei Yang
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, 110000, People's Republic of China
| | - Liang Hu
- Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, China
| | - Ying Yang
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, 110000, People's Republic of China.
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16
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Tesfaye D, Menjivar N, Gebremedhn S. Current knowledge and the future potential of extracellular vesicles in mammalian reproduction. Reprod Fertil Dev 2021; 34:174-189. [PMID: 35231266 DOI: 10.1071/rd21277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs), which contain various functional classes of vesicles, namely exosomes, microvesicles, and apoptotic bodies, represent the major nano-shuttle to transfer bioactive molecules from donor to recipient cells to facilitate cell-to-cell communication in the follicular, oviduct, and uterine microenvironments. In addition to transferring various molecular cargos in the form of miRNAs, mRNAs, proteins, lipids, and DNA molecules, the relative proportion of those molecular cargos in the reproductive fluids can be associated with the physiological and pathological condition of the host animal. Inside the follicle, EV-mediated circulation of miRNAs has been reported to be associated with the growth status of the enclosed oocytes, the metabolic status, and the advanced maternal aging of the animal. Importantly, EVs have the potential to protect their cargo molecules from extracellular degradation or modification while travelling to the recipient cells. This fact together with the enormous availability in almost all biological fluids and spent culture media make them attractive in the search for biomarkers of oocyte/embryo developmental competence, receptive maternal environment and a multitude of reproductive pathophysiological conditions. One of the key factors that have contributed to the lower efficiency of assisted reproductive technologies (ART) is the absence of several maternal in vivo factors in the ART procedures. For this, several studies have been conducted to supplement various components present in the follicular and oviductal fluids into the existing ART procedures and significant positive impacts have been observed in terms of embryo cleavage rate, blastocyst rate, resistance to stress, and survival after cryopreservation. The potential of EVs in shuttling protective messages against environmental and physiological stressors has been evidenced. The effective use of the EV-coupled molecular signals against stress-associated conditions has the potential to pave the path for the application of these protective signals against oxidative stress-associated pathological conditions including PCOS, ageing, and endometritis. In this review, we provide current knowledge and potential future use of EVs as remedies in reproductive pathophysiological conditions, mainly in follicular and oviductal microenvironments.
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Affiliation(s)
- Dawit Tesfaye
- Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, 3051 Rampart Road, Fort Collins, CO 80521, USA
| | - Nico Menjivar
- Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, 3051 Rampart Road, Fort Collins, CO 80521, USA
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Yamana K, Inoue J, Yoshida R, Sakata J, Nakashima H, Arita H, Kawaguchi S, Gohara S, Nagao Y, Takeshita H, Maeshiro M, Liu R, Matsuoka Y, Hirayama M, Kawahara K, Nagata M, Hirosue A, Toya R, Murakami R, Kuwahara Y, Fukumoto M, Nakayama H. Extracellular vesicles derived from radioresistant oral squamous cell carcinoma cells contribute to the acquisition of radioresistance via the miR-503-3p-BAK axis. J Extracell Vesicles 2021; 10:e12169. [PMID: 34894384 PMCID: PMC8665688 DOI: 10.1002/jev2.12169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Despite advancements in treatments, oral squamous cell carcinoma (OSCC) has not significantly improved in prognosis or survival rate primarily due to the presence of treatment-resistant OSCC. The intercellular communication between tumour cells is a molecular mechanism involved in acquiring OSCC treatment resistance. Extracellular vesicles (EVs) and encapsulated miRNAs are important mediators of intercellular communication. Here, we focused on EVs released from clinically relevant radioresistant (CRR) OSCC cells. Additionally, we evaluated the correlation between miRNA expression in the serum samples of patients who showed resistance to radiotherapy and in EVs released from CRR OSCC cells. We found that EVs released from CRR OSCC cells conferred radioresistance to radiosensitive OSCC cells via miR-503-3p contained in EVs. This miR-503-3p inhibited BAK and impaired the caspase cascade to suppress radiation-induced apoptosis. Furthermore, OSCC cells with BAK knockdown had increased radioresistance. Additionally, the expression of circulating miR-503-3p in patients with OSCC was correlated with a poor treatment response and prognosis of radiotherapy. Our results provide new insights into the relationship between EVs and the radioresistance of OSCC and suggest that the miR-503-3p-BAK axis may be a therapeutic target and that circulating miR-503-3p is a useful prognostic biomarker in the radiotherapy of OSCC.
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Affiliation(s)
- Keisuke Yamana
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Junki Inoue
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Ryoji Yoshida
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Junki Sakata
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Hikaru Nakashima
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Hidetaka Arita
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Sho Kawaguchi
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Shunsuke Gohara
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Yuka Nagao
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Hisashi Takeshita
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Manabu Maeshiro
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Rin Liu
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Yuichiro Matsuoka
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Masatoshi Hirayama
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Kenta Kawahara
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Masashi Nagata
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Akiyuki Hirosue
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Ryo Toya
- Department of Radiation OncologyKumamoto University Hospital, Kumamoto, Japan
| | - Ryuji Murakami
- Department of Medical Imaging, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
| | - Yoshikazu Kuwahara
- Radiation Biology and Medicine, Faculty of MedicineTohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Manabu Fukumoto
- Department of Molecular PathologyTokyo Medical University, Tokyo, Japan
| | - Hideki Nakayama
- Department of Oral and Maxillofacial Surgery, Faculty of Life SciencesKumamoto University, Kumamoto, Japan
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Prieto-Vila M, Yoshioka Y, Ochiya T. Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer. Front Cell Dev Biol 2021; 9:620498. [PMID: 34527665 PMCID: PMC8435577 DOI: 10.3389/fcell.2021.620498] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/30/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.
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Affiliation(s)
| | | | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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19
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Vahabi M, Blandino G, Di Agostino S. MicroRNAs in head and neck squamous cell carcinoma: a possible challenge as biomarkers, determinants for the choice of therapy and targets for personalized molecular therapies. Transl Cancer Res 2021; 10:3090-3110. [PMID: 35116619 PMCID: PMC8797920 DOI: 10.21037/tcr-20-2530] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) are referred to a group of heterogeneous cancers that include structures of aerodigestive tract such as oral and nasal cavity, salivary glands, oropharynx, pharynx, larynx, paranasal sinuses, and local lymph nodes. HNSCC is characterized by frequent alterations of several genes such as TP53, PIK3CA, CDKN2A, NOTCH1, and MET as well as copy number increase in EGFR, CCND1, and PIK3CA. These genomic alterations play a role in terms of resistance to chemotherapy, molecular targeted therapy, and prediction of patient outcome. MicroRNAs (miRNAs) are small single-stranded noncoding RNAs which are about 19-25 nucleotides. They are involved in the tumorigenesis of HNSCC including dysregulation of cell survival, proliferation, cellular differentiation, adhesion, and invasion. The discovery of the stable presence of the miRNAs in all human body made them attractive biomarkers for diagnosis and prognosis or as targets for novel therapeutic ways, enabling personalized treatment for HNSCC. In recent times the number of papers concerning the characterization of miRNAs in the HNSCC tumorigenesis has grown a lot. In this review, we discuss the very recent studies on different aspects of miRNA dysregulation with their clinical significance and we apologize for the many past and most recent works that have not been mentioned. We also discuss miRNA-based therapy that are being tested on patients by clinical trials.
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Affiliation(s)
- Mahrou Vahabi
- IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Laboratory, via Elio Chianesi, Rome, Italy
| | - Giovanni Blandino
- IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Laboratory, via Elio Chianesi, Rome, Italy
| | - Silvia Di Agostino
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, viale Europa, Catanzaro, Italy
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20
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MAGEA4 Coated Extracellular Vesicles Are Stable and Can Be Assembled In Vitro. Int J Mol Sci 2021; 22:ijms22105208. [PMID: 34069064 PMCID: PMC8155938 DOI: 10.3390/ijms22105208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/02/2021] [Accepted: 05/11/2021] [Indexed: 12/18/2022] Open
Abstract
Extracellular vesicles (EVs) are valued candidates for the development of new tools for medical applications. Vesicles carrying melanoma-associated antigen A (MAGEA) proteins, a subfamily of cancer-testis antigens, are particularly promising tools in the fight against cancer. Here, we have studied the biophysical and chemical properties of MAGEA4-EVs and show that they are stable under common storage conditions such as keeping at +4 °C and -80 °C for at least 3 weeks after purification. The MAGEA4-EVs can be freeze-thawed two times without losing MAGEA4 in detectable quantities. The attachment of MAGEA4 to the surface of EVs cannot be disrupted by high salt concentrations or chelators, but the vesicles are sensitive to high pH. The MAGEA4 protein can bind to the surface of EVs in vitro, using robust passive incubation. In addition, EVs can be loaded with recombinant proteins fused to the MAGEA4 open reading frame within the cells and also in vitro. The high stability of MAGEA4-EVs ensures their potential for the development of EV-based anti-cancer applications.
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21
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Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope. BMC Biotechnol 2021; 21:20. [PMID: 33691652 PMCID: PMC7945253 DOI: 10.1186/s12896-021-00683-w] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/28/2021] [Indexed: 12/16/2022] Open
Abstract
Over the past decade, therapeutic messenger RNAs (mRNAs) have emerged as a highly promising new class of drugs for protein replacement therapies. Due to the recent developments, the incorporation of modified nucleotides in synthetic mRNAs can lead to maximizing protein expression and reducing adverse immunogenicity. Despite these stunning improvements, mRNA therapy is limited by the need for the development of safe and efficient carriers to protect the mRNA integrity for in vivo applications. Recently, leading candidates for in vivo drug delivery vehicles are cell-derived exosomes, which have fewer immunogenic responses. In the current study, the key hurdles facing mRNA-based therapeutics, with an emphasis on recent strategies to overcoming its immunogenicity and instability, were highlighted. Then the immunogenicity and toxicity of exosomes derived from various cell sources were mentioned in detail. Finally, an overview of the recent strategies in using exosomes for mRNA delivery in the treatment of multiple diseases was stated.
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Mazzarella R, Bastos NM, Bridi A, Del Collado M, Andrade GM, Pinzon J, Prado CM, Silva LA, Meirelles FV, Pugliesi G, Perecin F, da Silveira JC. Changes in Oviductal Cells and Small Extracellular Vesicles miRNAs in Pregnant Cows. Front Vet Sci 2021; 8:639752. [PMID: 33748215 PMCID: PMC7969882 DOI: 10.3389/fvets.2021.639752] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/02/2021] [Indexed: 11/13/2022] Open
Abstract
Early embryonic development occurs in the oviduct, where an ideal microenvironment is provided by the epithelial cells and by the oviductal fluid produced by these cells. The oviductal fluid contains small extracellular vesicles (sEVs), which through their contents, including microRNAs (miRNAs), can ensure proper cell communication between the mother and the embryo. However, little is known about the modulation of miRNAs within oviductal epithelial cells (OECs) and sEVs from the oviductal fluid in pregnant cows. In this study, we evaluate the miRNAs profile in sEVs from the oviductal flushing (OF-sEVs) and OECs from pregnant cows compared to non-pregnant, at 120 h after ovulation induction. In OF-sEVs, eight miRNAs (bta-miR-126-5p, bta-miR-129, bta-miR-140, bta-miR-188, bta-miR-219, bta-miR-345-3p, bta-miR-4523, and bta-miR-760-3p) were up-regulated in pregnant and one miRNA (bta-miR-331-5p) was up-regulated in non-pregnant cows. In OECs, six miRNAs (bta-miR-133b, bta-miR-205, bta-miR-584, bta-miR-551a, bta-miR-1193, and bta-miR-1225-3p) were up-regulated in non-pregnant and none was up-regulated in pregnant cows. Our results suggest that embryonic maternal communication mediated by sEVs initiates in the oviduct, and the passage of gametes and the embryo presence modulate miRNAs contents of sEVs and OECs. Furthermore, we demonstrated the transcriptional levels modulation of selected genes in OECs in pregnant cows. Therefore, the embryonic-maternal crosstalk potentially begins during early embryonic development in the oviduct through the modulation of miRNAs in OECs and sEVs in pregnant cows.
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Affiliation(s)
- Rosane Mazzarella
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Natália Marins Bastos
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Alessandra Bridi
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Maite Del Collado
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Gabriella Mamede Andrade
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Jorge Pinzon
- Graduate Department, Faculty of Veterinary Medicine and Animal Science, National University of Colombia, Bogotá, Colombia
| | - Cibele Maria Prado
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Luciano Andrade Silva
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Flávio Vieira Meirelles
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Guilherme Pugliesi
- Molecular Endocrinology Physiology Laboratory, Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Felipe Perecin
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Juliano Coelho da Silveira
- Molecular Morphology and Development Laboratory, Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
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Potential Role of microRNAs in inducing Drug Resistance in Patients with Multiple Myeloma. Cells 2021; 10:cells10020448. [PMID: 33672466 PMCID: PMC7923438 DOI: 10.3390/cells10020448] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/08/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
The prognosis for newly diagnosed subjects with multiple myeloma (MM) has significantly progressed in recent years. However, most MM patients relapse and after several salvage therapies, the onset of multidrug resistance provokes the occurrence of a refractory disease. A continuous and bidirectional exchange of information takes place between the cells of the microenvironment and neoplastic cells to solicit the demands of cancer cells. Among the molecules serving as messengers, there are microRNAs (miRNA), a family of small noncoding RNAs that regulate gene expression. Numerous miRNAs are associated with drug resistance, also in MM, and the modulation of their expression or activity might be explored to reverse it. In this review we report the most recent studies concerning the relationship between miRNAs and chemoresistance to the most frequently used drugs, such as proteasome inhibitors, steroids, alkylating agents and immunomodulators. The experimental use of antagomirs or miRNA mimics have successfully been proven to counteract chemoresistance and display synergistic effects with antimyeloma drugs which could represent a fundamental moment to overcome resistance in MM treatment.
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Ojima K, Muroya S, Wada H, Ogawa K, Oe M, Takimoto K, Nishimura T. Immature adipocyte-derived exosomes inhibit expression of muscle differentiation markers. FEBS Open Bio 2021; 11:768-781. [PMID: 33527775 PMCID: PMC7931241 DOI: 10.1002/2211-5463.13100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/24/2020] [Accepted: 01/27/2021] [Indexed: 11/16/2022] Open
Abstract
Exosomes are released from a variety of cells to communicate with recipient cells. Exosomes contain microRNAs (miRNAs), which are noncoding RNAs that suppress target genes. Our previous proteomic study (FEBS Open Bio 2016, 6, 816–826) demonstrated that 3T3‐L1 adipocytes secrete exosome components as well as growth factors, inspiring us to investigate what type of miRNA is involved in adipocyte‐secreted exosomes and what functions they carry out in recipient cells. Here, we profiled miRNAs in 3T3‐L1 adipocyte‐secreted exosomes and revealed suppression of muscle differentiation by adipocyte‐derived exosomes. Through our microarray analysis, we detected over 300 exosomal miRNAs during adipocyte differentiation. Exosomal miRNAs present during adipocyte differentiation included not only pro‐adipogenic miRNAs but also miRNAs associated with muscular dystrophy. Gene ontology analysis predicted that the target genes of miRNAs are associated primarily with transcriptional regulation. To further investigate whether adipocyte‐secreted exosomes regulate the expression levels of genes involved in muscle differentiation, we treated cultured myoblasts with adipocyte‐derived exosome fractions. Intriguingly, the expression levels of myogenic regulatory factors, Myog and Myf6, and other muscle differentiation markers, myosin heavy‐chain 3 and insulin‐like growth factor 2, were significantly downregulated in myoblasts treated with adipocyte‐derived exosomes. Immature adipocyte‐derived exosomes exhibited a stronger suppressive effect than mature adipocyte‐derived exosomes. Our results suggest that adipocytes suppress the expression levels of muscle differentiation‐associated genes in myoblasts via adipocyte‐secreted exosomes containing miRNAs.
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Affiliation(s)
- Koichi Ojima
- Muscle Biology Research Unit, Division of Animal Products Research, National Institute of Livestock and Grassland Science, NARO, Tsukuba, Japan
| | - Susumu Muroya
- Muscle Biology Research Unit, Division of Animal Products Research, National Institute of Livestock and Grassland Science, NARO, Tsukuba, Japan
| | - Hiromu Wada
- Ion Channel Laboratory, Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Japan
| | - Kotaro Ogawa
- Ion Channel Laboratory, Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Japan
| | - Mika Oe
- Muscle Biology Research Unit, Division of Animal Products Research, National Institute of Livestock and Grassland Science, NARO, Tsukuba, Japan
| | - Koichi Takimoto
- Ion Channel Laboratory, Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Japan
| | - Takanori Nishimura
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
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25
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Gebremedhn S, Ali A, Gad A, Prochazka R, Tesfaye D. Extracellular Vesicles as Mediators of Environmental and Metabolic Stress Coping Mechanisms During Mammalian Follicular Development. Front Vet Sci 2020; 7:602043. [PMID: 33330723 PMCID: PMC7710682 DOI: 10.3389/fvets.2020.602043] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular vesicles are evolutionarily conserved nano-sized phospholipid membraned structures and released from virtually all types of cells into the extracellular space. Their ability to carry various molecular cargos (mRNA, miRNA, proteins, and lipids) from one cell to the other to exert functional impact on the target cells enables them to play a significant role in cell to cell communication during follicular development. As the molecular signals carried by extracellular vesicles reflect the physiological status of the cells of origin, they are expected to mediate any effect of environmental or metabolic stress on the follicualr cells and the growing oocyte. Recent studies have evidenced that reproductive cells exposed to various environmental stressors (heat and oxidative stress) released extracellular vesicles enriched with mRNA and miRNA associated with stress response mechanisms. Moreover, the metabolic status of post-calving cows could be well-reflected in the follicular extracellular vesicle's miRNA profile, which signified the potential role of extracellular cellular vesicle molecular signals in mediating the effect of metabolic stress on follicular and oocyte development. In the present review, the potential role of extracellular vesicles in mediating the effect of environmental and metabolic stress in various reproductive cells and oocytes are thoroughly discussed Moreover, considering the importance of extracellular vesicles in shuttling protective or rescuing molecular signals during stress, their potential usage as means of targeted delivery of molecules to mitigate the effect of stress on oocytes are addressed as the focus of future research.
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Affiliation(s)
- Samuel Gebremedhn
- Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.,Department of Animal, Rangeland and Wildlife Sciences, Mekelle University, Mekelle, Ethiopia
| | - Asghar Ali
- Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
| | - Ahmed Gad
- Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Liběchov, Czechia.,Department of Animal Production, Faculty of Agriculture, Cairo University, Giza, Egypt
| | - Radek Prochazka
- Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Liběchov, Czechia
| | - Dawit Tesfaye
- Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.,Department of Animal, Rangeland and Wildlife Sciences, Mekelle University, Mekelle, Ethiopia
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Małczyńska-Sims P, Chalimoniuk M, Sułek A. The Effect of Endurance Training on Brain-Derived Neurotrophic Factor and Inflammatory Markers in Healthy People and Parkinson's Disease. A Narrative Review. Front Physiol 2020; 11:578981. [PMID: 33329027 PMCID: PMC7711132 DOI: 10.3389/fphys.2020.578981] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/06/2020] [Indexed: 12/15/2022] Open
Abstract
Background: One purpose of the training conducted by people is to lose bodyweight and improve their physical condition. It is well-known that endurance training provides many positive changes in the body, not only those associated with current beauty standards. It also promotes biochemical changes such as a decreased inflammatory status, memory improvements through increased brain-derived neurotrophic factor levels, and reduced stress hormone levels. The positive effects of training may provide a novel solution for people with Parkinson's disease, as a way to reduce the inflammatory status and decrease neurodegeneration through stimulation of neuroplasticity and improved motor conditions. Aim: This narrative review aims to focus on the relationship between an acute bout of endurance exercise, endurance training (continuous and interval), brain-derived neurotrophic factor and inflammatory status in the three subject groups (young adults, older adult, and patients with Parkinson's disease), and to review the current state of knowledge about the possible causes of the differences in brain-derived neurotrophic factor and inflammatory status response to a bout of endurance exercise and endurance training. Furthermore, short practical recommendations for PD patients were formulated for improving the efficacy of the training process during rehabilitation. Methods: A narrative review was performed following an electronic search of the database PubMed/Medline and Web of Science for English-language articles between January 2010 and January 2020. Results: Analysis of the available publications with partial results revealed (1) a possible connection between the brain-derived neurotrophic factor level and inflammatory status, and (2) a more beneficial influence of endurance training compared with acute bouts of endurance exercise. Conclusion: Despite the lack of direct evidence, the results from studies show that endurance training may have a positive effect on inflammatory status and brain-derived neurotrophic factor levels. Introducing endurance training as part of the rehabilitation in Parkinson's disease might provide benefits for patients in addition to pharmacological therapy supplementation.
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Affiliation(s)
| | - Małgorzata Chalimoniuk
- Department of Physical Education and Health in Biała Podlaska, Józef Piłsudski University of Physical Education in Warsaw, Warsaw, Poland
| | - Anna Sułek
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
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27
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Bagheri Hashkavayi A, Cha BS, Lee ES, Kim S, Park KS. Advances in Exosome Analysis Methods with an Emphasis on Electrochemistry. Anal Chem 2020; 92:12733-12740. [PMID: 32902258 DOI: 10.1021/acs.analchem.0c02745] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Exosomes, small extracellular vesicles, are released by various cell types. They are found in bodily fluids, including blood, urine, serum, and saliva, and play essential roles in intercellular communication. Exosomes contain various biomarkers, such as nucleic acids and proteins, that reflect the status of their parent cells. Since they influence tumorigenesis and metastasis in cancer patients, exosomes are excellent noninvasive potential indicators for early cancer detection. Aptamers with specific binding properties have distinct advantages over antibodies, making them effective versatile bioreceptors for the detection of exosome biomarkers. Here, we review various aptamer-based exosome detection approaches based on signaling methods, such as fluorescence, colorimetry, and chemiluminescence, focusing on electrochemical strategies that are easier, cost-effective, and more sensitive than others. Further, we discuss the clinical applications of electrochemical exosome analysis strategies as well as future research directions in this field.
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Affiliation(s)
- Ayemeh Bagheri Hashkavayi
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Byung Seok Cha
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Eun Sung Lee
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Seokjoon Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Ki Soo Park
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea
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28
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Nomura S, Taniura T, Ito T. Extracellular Vesicle-Related Thrombosis in Viral Infection. Int J Gen Med 2020; 13:559-568. [PMID: 32904587 PMCID: PMC7457561 DOI: 10.2147/ijgm.s265865] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/28/2020] [Indexed: 12/17/2022] Open
Abstract
Although the outcomes of viral infectious diseases are remarkably varied, most infections cause acute diseases after a short period. Novel coronavirus disease 2019, which recently spread worldwide, is no exception. Extracellular vesicles (EVs) are small circulating membrane-enclosed entities shed from the cell surface in response to cell activation or apoptosis. EVs transport various kinds of bioactive molecules between cells, including functional RNAs, such as viral RNAs and proteins. Therefore, when EVs are at high levels, changes in cell activation, inflammation, angioplasty and transportation suggest that EVs are associated with various diseases. Clinical research on EVs includes studies on the coagulatory system. In particular, abnormal enhancement of the coagulatory system through EVs can cause thrombosis. In this review, we address the functions of EVs, thrombosis, and their involvement in viral infection.
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Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | | | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
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29
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Verdelli C, Sansoni V, Perego S, Favero V, Vitale J, Terrasi A, Morotti A, Passeri E, Lombardi G, Corbetta S. Circulating fractures-related microRNAs distinguish primary hyperparathyroidism-related from estrogen withdrawal-related osteoporosis in postmenopausal osteoporotic women: A pilot study. Bone 2020; 137:115350. [PMID: 32380256 DOI: 10.1016/j.bone.2020.115350] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 03/18/2020] [Accepted: 03/30/2020] [Indexed: 12/12/2022]
Abstract
Primary hyperparathyroidism (PHPT) represents a common cause of secondary osteoporosis in postmenopausal women, where the negative effect of estrogen withdrawal and that of hyperparathyroidism on bone mineralization coexist. Circulating microRNAs (miRNAs) expression profile has been correlated to both osteoporosis and fragility fractures. The study aimed to profile a set of miRNAs associated with osteoporotic fractures, namely miR-21-5p, miR-23a-5p, miR-24-2-5p, miR-24-3p, miR-93-5p, miR-100-5p, miR-122-5p, miR-124-3p, miR-125b-5p and miR-148-3p, in the plasma of 20 postmenopausal PHPT women. PHPT miRNAs profiles were compared with those detected in 10 age-matched postmenopausal non-PHPT osteoporotic women (OP). All the 10 miRNAs were detected in the plasma samples of both PHPT and OP women. The miRNA profiles clearly distinguished PHPT from OP samples, and identified within the PHPT group, two clusters differing for the PHPT severity, in term of ionized calcium and bone mineralization. In particular, miR-93-5p was significantly downregulated in PHPT samples, while miR-24-3p negatively correlated with the T-score at lumbar, femur neck and total hip sites. PHPT women who experienced osteoporotic fractures had plasma miR-24-3p levels higher than those detected in unfractured PHPT women. In conclusion, PHPT may modulate circulating fractures-related miRNAs, in particular, miR-93-5p, which may distinguish estrogen-related from PHPT-related osteoporosis.
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Affiliation(s)
- C Verdelli
- Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy.
| | - V Sansoni
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy.
| | - S Perego
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy.
| | - V Favero
- Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy; Department of Clinical and Community Sciences for Health, University of Milan, via F.Sforza 35, 20122 Milan, Italy.
| | - J Vitale
- Laboratory of Movement and Sport Science, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy.
| | - A Terrasi
- Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F.Sforza 35, 20122 Milan, Italy.
| | - A Morotti
- Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F.Sforza 35, 20122 Milan, Italy.
| | - E Passeri
- Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy
| | - G Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy; Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Królowej Jadwigi 27/39, 61-871 Poznań, Poland.
| | - S Corbetta
- Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161 Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan, via C.Pascal 36, 20100 Milan, Italy.
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30
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Shomali N, Hemmatzadeh M, Yousefzadeh Y, Soltani-Zangbar MS, Hamdi K, Mehdizadeh A, Yousefi M. Exosomes: Emerging biomarkers and targets in folliculogenesis and endometriosis. J Reprod Immunol 2020; 142:103181. [PMID: 32717674 DOI: 10.1016/j.jri.2020.103181] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 06/14/2020] [Accepted: 07/18/2020] [Indexed: 12/31/2022]
Abstract
An appropriate connection of the cells in the ovary follicles is vital for a healthy ovule maturation and fertilization, and also for endometrium preparation for implantation that can cause endometriosis. Cellular communication within the follicle and endometrial epithelium involve many signaling molecules. Recent studies indicate that cellular communication can be enclosed by secretion and absorption of small membrane carriers which are named extracellular vesicles including exosomes and microvesicles. Understanding and defining these EVs (Extracellular vesicles) population are important for future studies and clinical translation. Here, we describe the various important cargos which are carried by exosomes during folliculogenesis and endometriosis. Additionally, the current knowledge of exosomes and their cargo within the FF (Follicular fluid) during the folliculogenesis and also in the intrauterine cavity which are involved in endometriosis lesions have also been summarized. Considering the potential importance of this form of the cell to cell communication in the reproductive system, the vital issues under discussion lead to a new insight in this rapidly expanding field and it may be an interesting approach for diagnostic, prognostic and especially therapeutic strategies in the field of infertility and assisted reproductive technology (ART).
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Affiliation(s)
- Navid Shomali
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yousef Yousefzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Kobra Hamdi
- Reproductive Biology Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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31
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Gao R, Chen C, Zhao Q, Li M, Wang Q, Zhou L, Chen E, Chen H, Zhang Y, Cai X, Liu C, Cheng X, Zhang S, Mao X, Qiu Y, Gan L, Yu H, Liu J, Zhu T. Identification of the Potential Key Circular RNAs in Elderly Patients With Postoperative Cognitive Dysfunction. Front Aging Neurosci 2020; 12:165. [PMID: 32655392 PMCID: PMC7324535 DOI: 10.3389/fnagi.2020.00165] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 05/13/2020] [Indexed: 02/05/2023] Open
Abstract
Background Postoperative cognitive dysfunction (POCD) is one of the severe complications after surgery, inducing low life quality and high mortality, especially in elderly patients. However, the underlying molecular mechanism of POCD remains largely unknown, and the ideal biomarker for clinical diagnosis and prognosis is lacking. Circular RNAs (circRNAs), as a unique class of non-coding RNAs, were characterized by its stability and conservativeness, serving as novel biomarkers in various diseases. Nevertheless, the role of circRNAs in the occurrence of POCD remains elusive. Methods To investigate the differentially expressed circRNAs in the serum of POCD patients and its potential role in the development of POCD, we performed a circRNA microarray to screen the differentially expressed circRNAs in the serum samples from three patients of the POCD group and three paired patients of the non-POCD group. Subsequently, quantitative real-time polymerase chain reaction analysis (qRT-PCR) was utilized to verify the microarray data with the serum samples from 10 paired patients. Cytoscape software was used to construct the circRNA–miRNA–mRNA network for circRNAs with different expression levels as well as the target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed the biological functions of the differentially expressed circRNAs target genes. Results In total, we have analyzed 10,198 circRNAs through the microarray. Compared with the non-POCD patient group, there were 210 differentially expressed circRNAs with 133 upregulated and 77 downregulated in the POCD group (≥2-fold differential expression, P ≤ 0.05). The qRT-PCR confirmed 10 circRNAs with different expressed levels, and the results were consistent with the microarray findings. Among them, hsa_circRNA_001145, hsa_circRNA_101138, and hsa_circRNA_061570 had the highest magnitude of change. The GO analysis showed that the differentially expressed circRNAs were associated with the regulation of the developmental process, cell-to-cell adhesion, and nervous system development. The KEGG analysis showed that the target genes of circRNAs were enriched in the MAPK signaling pathway and RAS signaling pathway. According to the targetscan7.1 and mirdbV5 databases, the circRNA–miRNA–mRNA network was constructed, and these results provided a vital landscape of circRNA expression profile in POCD. Conclusions Our study provides an essential perspective for the differential expression of circRNAs in POCD patients. Further studies need to be performed to explore their potential therapeutic roles in the development of POCD.
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Affiliation(s)
- Rui Gao
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chan Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qi Zhao
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Li
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiao Wang
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Zhou
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Erya Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hai Chen
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yue Zhang
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xingwei Cai
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Changliang Liu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xu Cheng
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shu Zhang
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaobo Mao
- Department of Neurology, Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Yanhua Qiu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Gan
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hai Yu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jin Liu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Zhu
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
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Zhang Y, Han F, Gu L, Ji P, Yang X, Liu M, Tao K, Hu D. Adipose mesenchymal stem cell exosomes promote wound healing through accelerated keratinocyte migration and proliferation by activating the AKT/HIF-1α axis. J Mol Histol 2020; 51:375-383. [PMID: 32556903 DOI: 10.1007/s10735-020-09887-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 06/13/2020] [Indexed: 12/16/2022]
Abstract
Accelerating wound healing is a key consideration for surgeons. The three stages of wound healing include the inflammatory response, cell proliferation and tissue repair, and much research has focused on the migration and proliferation of epidermal cells, since this is one of the most important steps in wound healing. Studies have shown that adipose mesenchymal stem cells (ADSCs) can promote wound healing by releasing exosomes, although the specific mechanism remains unclear. To clarify the role of adipose mesenchymal stem cell exosomes (ADSCs-exo), we constructed a HaCaT cells model and a mouse wound healing model to examine the effects of ADSCs-exo on wound healing. CCK8 assays and the scratch test showed that ADSCs-exo could promote the proliferation and migration of HaCaT cells. Western blotting and real-time PCR showed that ADSCs-exo upregulated the phosphorylation of AKT and the expression of HIF-1α in HaCaT cells. HIF-1α expression was reduced by inhibiting AKT phosphorylation,and the migration of HaCaT cells simultaneously slowed. These results were also confirmed in vivo. In conclusion, we confirmed that ADSCs-exo promote the proliferation and migration of HaCaT cells by regulating the activation of the AKT/HIF-1α signaling pathway, thus promoting wound healing.
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Affiliation(s)
- Yue Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Fei Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Lan Gu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Peng Ji
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Xuekang Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Mengdong Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Ke Tao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China.
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi, 710032, China.
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Sinha N, Kumar V, Puri V, Nada R, Rastogi A, Jha V, Puri S. Urinary exosomes: Potential biomarkers for diabetic nephropathy. Nephrology (Carlton) 2020; 25:881-887. [PMID: 32323449 DOI: 10.1111/nep.13720] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 03/04/2020] [Accepted: 04/02/2020] [Indexed: 12/22/2022]
Abstract
Diabetic nephropathy is the most common diabetic complication culminating often into end-stage renal disease. Classically, it is defined by the presence of albuminuria which has limited ability to be detected at early stages but deterioration in kidney function generally precedes albuminuria. This necessitates the development of newer diagnostic assays for diabetic nephropathy to determine the progression of the disease. Kidney associated diseases with non-albuminuria further complicates a timely diagnosis and thus demands an early biomarker. Urinary exosomes, the nanovesicular entities are released by every epithelial cells of the nephron. Their protein or molecular cargo varies in the diseased state which may provide the pathophysiology of the kidney associated diseases. This drives them to be exploited as non-invasive biomarker. This review thus integrates the recent findings on the significance of the urinary exosomes as diagnostic biomarker in kidney-associated diseases, primarily in diabetic nephropathy.
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Affiliation(s)
- Nisha Sinha
- Centre for Stem Cell & Tissue Engineering and Excellence in Biomedical Sciences, Punjab University, Chandigarh, India.,Department of Nephrology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Vivek Kumar
- Department of Nephrology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Veena Puri
- Centre for Systems Biology & Bioinformatics, Punjab University, Chandigarh, India
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Ashu Rastogi
- Department of Endocrinology and Metabolism, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Vivekanand Jha
- George Institute for Global Health, UNSW, India. George Institute for Global Health, University of Oxford, Oxford, UK. Manipal Academy of Higher Education, Manipal, India
| | - Sanjeev Puri
- Department of Biotechnology, University Institute of Engineering & Technology (UIET), Punjab University, Chandigarh, India
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Casadei L, Pollock RE. Extracellular vesicle cross-talk in the liposarcoma microenvironment. Cancer Lett 2020; 487:27-33. [PMID: 32470489 DOI: 10.1016/j.canlet.2020.04.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/14/2020] [Accepted: 04/30/2020] [Indexed: 12/19/2022]
Abstract
Liposarcoma (LPS) is the most prevalent soft tissue sarcoma; among the four different LPS subtypes, dedifferentiated liposarcoma (DDLPS) is especially worrisome given its propensity for local and distant recurrence, with an overall survival rate of only 10% at 10 years. Our understanding of the molecular drivers of this disease is rudimentary at best; knowledge about how DDLPS interacts with cells in the tumor microenvironment (TME) is also lacking. Extracellular vesicle (EVs) have been studied in a number of different systems concerning their ability to influence the TME transferring bioactive molecules. In this review, we outline the role of the TME in the DDLPS progression and recurrence, focusing on the interplay between EVs released from the tumor and their target recipient cells in the TME. Success in the understanding of this process will be critical to an enhanced understanding of the underlying biologic drivers at play, potentially leading to new therapeutic strategies of benefit to patients with this disease.
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Affiliation(s)
- Lucia Casadei
- The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Raphael E Pollock
- The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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35
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Donzelli S, Farneti A, Marucci L, Ganci F, Sacconi A, Strano S, Sanguineti G, Blandino G. Non-coding RNAs as Putative Biomarkers of Cancer-Associated Cachexia. Front Cell Dev Biol 2020; 8:257. [PMID: 32373612 PMCID: PMC7187787 DOI: 10.3389/fcell.2020.00257] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 03/27/2020] [Indexed: 01/06/2023] Open
Abstract
Cachexia is a complex metabolic syndrome that determines a severe body weight loss characterized by a marked reduction in muscle mass. About 80% of patients with advanced cancer develop cachexia due to both the tumor itself and cancer treatment (radiotherapy and/or chemotherapy), which is associated to a worse prognosis. Despite its clinical relevance, this syndrome is still under-diagnosed and it lacks effective treatments. Radio-chemotherapy treatment is essential in patients with advanced head and neck cancers (HNSCC). Although this treatment has improved patients' life expectancy, it has also dramatically increased their need for assistance and support. The management of adverse symptoms, including cachexia, is of great importance in order to avoid delays in therapy, reduction of dosages and hospitalizations. MicroRNAs (miRNAs) are small non-coding RNA molecules, which have emerged as powerful biomarkers in stratifying human cancers. Due to their high stability in body fluids, miRNAs might be excellent non-invasive biomarkers for the early detection and follow-up of cancer patients. Here, we will summarize the current knowledge and debate the strong need to identify circulating biomarkers for the early diagnosis of cachexia. We will propose circulating non-coding RNAs as biomarkers for detecting early cachexia and implementing specific treatment. We will also discuss the potential use of circulating miRNAs as biomarkers of cachexia in HNSCC patients' blood samples collected before and after radio-chemotherapy treatment. Our intent is to pave the way to the identification of specific circulating miRNAs associated to cachexia occurrence and to the design of specific interventions aimed at improving the quality of life of cancer patients.
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Affiliation(s)
- Sara Donzelli
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Alessia Farneti
- Radiotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Laura Marucci
- Radiotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Federica Ganci
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Andrea Sacconi
- UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Sabrina Strano
- SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giuseppe Sanguineti
- Radiotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
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36
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Tesfaye D, Hailay T, Salilew-Wondim D, Hoelker M, Bitseha S, Gebremedhn S. Extracellular vesicle mediated molecular signaling in ovarian follicle: Implication for oocyte developmental competence. Theriogenology 2020; 150:70-74. [PMID: 32088041 DOI: 10.1016/j.theriogenology.2020.01.075] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 12/18/2022]
Abstract
The bidirectional communication between the oocyte and the companion somatic cells in the follicular environment is known to be mediated by either a direct communication via gap junction or transzonal projections or indirectly through endocrine, paracrine and autocrine signaling factors. Extracellular vesicles (EVs), which are found in various biological fluids, including follicular fluid (FF) are known to play important roles in mediating the communication between the oocyte and the surrounding somatic cells through shuttling bioactive molecules to facilitate follicular growth and oocyte maturation. As vesicles in the extracellular space are known to reflect the physiological status of the donor or the releasing cells, molecules carried by the EVs in the follicular environment could be markers of the internal and external stressors. EVs exhibit greater degree of heterogeneity in their size, biogenesis and the bioactive molecule they carry. The process of biogenesis of EVs is known to be regulated by several proteins associated with the endosomal sorting complex required for transport (ESCRT) proteins. The type of EVs and surface proteins markers vary according to the type of protein involved in their biogenesis. EVs are recently reported to play indispensable role in promoting cell-to-cell communication during follicular growth. Recent advancements in EV research opened the possibilities to load EVs with specific molecules like miRNA, siRNA, CRISPR-cas9 complex and protein, which showed a new horizon for their application in therapeutics. The present review explores the biogenesis, the role and the future prospects of EVs with a special emphasis given to follicular growth and oocyte maturation.
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Affiliation(s)
- Dawit Tesfaye
- Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory (ARBL), Colorado State University, Fort Collins, CO, USA.
| | - Tsige Hailay
- Institute of Animal Sciences, Department of Animal Breeding and Husbandry, University of Bonn, Bonn, Germany
| | - Dessie Salilew-Wondim
- Institute of Animal Sciences, Department of Animal Breeding and Husbandry, University of Bonn, Bonn, Germany
| | - Michael Hoelker
- Institute of Animal Sciences, Department of Animal Breeding and Husbandry, University of Bonn, Bonn, Germany
| | - Simret Bitseha
- Hawassa University, College of Agriculture, Department of Animal Sciences, Hawassa, Ethiopia
| | - Samuel Gebremedhn
- Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory (ARBL), Colorado State University, Fort Collins, CO, USA
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Moufarrej MN, Wong RJ, Shaw GM, Stevenson DK, Quake SR. Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation. Front Pediatr 2020; 8:605219. [PMID: 33381480 PMCID: PMC7767905 DOI: 10.3389/fped.2020.605219] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 11/12/2020] [Indexed: 12/11/2022] Open
Abstract
In recent years, there have been major advances in the application of non-invasive techniques to predict pregnancy-related complications, for example by measuring cell-free RNA (cfRNA) in maternal blood. In contrast to cell-free DNA (cfDNA), which is already in clinical use to diagnose fetal aneuploidy, circulating RNA levels can correspond with tissue-specific gene expression and provide a snapshot of prenatal health across gestation. Here, we review the physiologic origins of cfRNA and its novel applications and corresponding challenges to monitor fetal and maternal health and predict pregnancy-related complications.
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Affiliation(s)
- Mira N Moufarrej
- Departments of Bioengineering and Applied Physics, Stanford University, and Chan Zuckerberg Biohub, Stanford, CA, United States
| | - Ronald J Wong
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Gary M Shaw
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - David K Stevenson
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Stephen R Quake
- Departments of Bioengineering and Applied Physics, Stanford University, and Chan Zuckerberg Biohub, Stanford, CA, United States
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38
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Efficient nanocarriers of siRNA therapeutics for cancer treatment. Transl Res 2019; 214:62-91. [PMID: 31369717 DOI: 10.1016/j.trsl.2019.07.006] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/01/2019] [Accepted: 07/15/2019] [Indexed: 02/02/2023]
Abstract
Nanocarriers as drug delivery systems are promising and becoming popular, especially for cancer treatment. In addition to improving the pharmacokinetics of poorly soluble hydrophobic drugs by solubilizing them in a hydrophobic core, nanocarriers allow cancer-specific combination drug deliveries by inherent passive targeting phenomena and adoption of active targeting strategies. Nanoparticle-drug formulations can enhance the safety, pharmacokinetic profiles, and bioavailability of locally or systemically administered drugs, leading to improved therapeutic efficacy. Gene silencing by RNA interference (RNAi) is rapidly developing as a personalized field of cancer treatment. Small interfering RNAs (siRNAs) can be used to switch off specific cancer genes, in effect, "silence the gene, silence the cancer." siRNA can be used to silence specific genes that produce harmful or abnormal proteins. The activity of siRNA can be used to harness cellular machinery to destroy a corresponding sequence of mRNA that encodes a disease-causing protein. At present, the main barrier to implementing siRNA therapies in clinical practice is the lack of an effective delivery system that protects the siRNA from nuclease degradation, delivers to it to cancer cells, and releases it into the cytoplasm of targeted cancer cells, without creating adverse effects. This review provides an overview of various nanocarrier formulations in both research and clinical applications with a focus on combinations of siRNA and chemotherapeutic drug delivery systems for the treatment of multidrug resistant cancer. The use of various nanoparticles for siRNA-drug delivery, including liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles, exosomes, and red blood cells for targeted drug delivery in cancer is discussed.
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Urabe F, Kosaka N, Ito K, Kimura T, Egawa S, Ochiya T. Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am J Physiol Cell Physiol 2019; 318:C29-C39. [PMID: 31693397 DOI: 10.1152/ajpcell.00280.2019] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Extracellular vesicles (EVs) are small lipid membrane vesicles that are secreted from almost all kinds of cells into the extracellular space. EVs are widely accepted to be involved in various cellular processes; in particular, EVs derived from cancer cells have been reported to play important roles in modifying the tumor microenvironment and promoting tumor progression. In addition, EVs derived from cancer cells encapsulate various kinds of tumor-specific molecules, such as proteins and RNAs, which contribute to cancer malignancy. Therefore, the unveiling of the precise mechanism of intercellular communication via EVs in cancer patients will provide a novel strategy for cancer treatment. Furthermore, a focus on the contents of EVs could promote the use of EVs in body fluids as clinically useful diagnostic and prognostic biomarkers. In this review, we summarize the current research knowledge on EVs as biomarkers and therapeutic targets and discuss their potential clinical applications.
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Affiliation(s)
- Fumihiko Urabe
- Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan.,Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuyoshi Kosaka
- Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan
| | - Kagenori Ito
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shin Egawa
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan
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Oh JG, Watanabe S, Lee A, Gorski PA, Lee P, Jeong D, Liang L, Liang Y, Baccarini A, Sahoo S, Brown BD, Hajjar RJ, Kho C. miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy. Circ Res 2019; 123:673-685. [PMID: 30355233 DOI: 10.1161/circresaha.118.312751] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
RATIONALE Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously, we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown. OBJECTIVE To examine miR-146a-mediated SUMO1 regulation and its consequent effects on cardiac morphology and function. METHODS AND RESULTS In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery, and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by examining the major miR-146a-producing cell types and transfer mechanisms. Notably, transdifferentiation of fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular vesicle-associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility. CONCLUSIONS Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery in the heart, which can be targeted for therapeutic intervention.
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Affiliation(s)
- Jae Gyun Oh
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Shin Watanabe
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Ahyoung Lee
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Przemek A Gorski
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Philyoung Lee
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Dongtak Jeong
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Lifan Liang
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Yaxuan Liang
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Alessia Baccarini
- Department of Genetics and Genomic Sciences (A.B., B.D.B.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York
| | - Susmita Sahoo
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Brian D Brown
- Department of Genetics and Genomic Sciences (A.B., B.D.B.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York
| | - Roger J Hajjar
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
| | - Changwon Kho
- From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.)
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Serasanambati M, Broza YY, Haick H. Volatile Compounds Are Involved in Cellular Crosstalk and Upregulation. ACTA ACUST UNITED AC 2019; 3:e1900131. [PMID: 32648725 DOI: 10.1002/adbi.201900131] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 08/16/2019] [Indexed: 12/14/2022]
Abstract
Cell-cell cross talk is of great importance in cancer research due to its major role in proliferation, differentiation, migration, and influence on the apoptotic pathway. Different cell-cell communication mechanisms have come mainly from proteomic and genomic approaches. In this paper, a new route is reported for cross talk between cancer cells that occurs, even when they are far away from each other. Single-cell and culture analysis shows that upregulation of cancer cells emits hundreds of volatile organic compounds (VOCs) into their headspace. Part of the VOCs remains without any change, disregarding the biological environment around it. The other part of the VOCs is exchanged between monocultures of the cells as well as between co-cultures of the cells with no physical contact between them, leading to different changes in growth than when left on their own. The chemical nature and composition of these VOCs have been determined and are discussed herein. Cell-to-cell cross talk has the advantage of being suitable for transfer/diffusion over relatively long distances. It would thus be expected to serve as a shuttling pad toward the development of advanced approaches that could enable very early detection of cancer and/or monitoring of metastasis and related cancer therapy.
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Affiliation(s)
- Mamatha Serasanambati
- Department of Chemical Engineering, Technion - Israel Institute of Technology, Technion City, Haifa, 3200003, Israel
| | - Yoav Y Broza
- Department of Chemical Engineering, Technion - Israel Institute of Technology, Technion City, Haifa, 3200003, Israel
| | - Hossam Haick
- Department of Chemical Engineering, Technion - Israel Institute of Technology, Technion City, Haifa, 3200003, Israel.,Russell Berries Nanotechnology Institute, Technion - Israel Institute of Technology, Technion City, Haifa, 3200003, Israel.,Technion Integrated Cancer Center, The Ruth and Bruce Rappaport Faculty of Medicine, 1-Efron St. Bat Galim, Haifa, 3525433, Israel
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Wang Y, Nicholes K, Shih IM. The Origin and Pathogenesis of Endometriosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 15:71-95. [PMID: 31479615 DOI: 10.1146/annurev-pathmechdis-012419-032654] [Citation(s) in RCA: 250] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.
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Affiliation(s)
- Yeh Wang
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; , ,
| | - Kristen Nicholes
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; , ,
| | - Ie-Ming Shih
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; , , .,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Oxidized Cell-Free DNA Is a Factor of Stress Signaling in Radiation-Induced Bystander Effects in Different Types of Human Cells. Int J Genomics 2019; 2019:9467029. [PMID: 31531341 PMCID: PMC6721096 DOI: 10.1155/2019/9467029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 04/05/2019] [Accepted: 08/01/2019] [Indexed: 11/21/2022] Open
Abstract
In pathology or under damaging conditions, the properties of cell-free DNA (cfDNA) change. An example of such change is GC enrichment, which drastically alters the biological properties of cfDNA. GC-rich cfDNA is a factor of stress signaling, whereas genomic cfDNA is biologically inactive. GC-rich cfDNA stimulates TLR9-MyD88-NF-κB signaling cascade, leading to an increase in proinflammatory cytokine levels in the organism. In addition, GC-rich DNA is prone to oxidation and oxidized cfDNA can stimulate secondary oxidative stress. This article is a review of works dedicated to the investigation of a low-dose ionizing radiation effect, a bystander effect, and the role of cfDNA in both of these processes.
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Nagano T, Katsurada M, Dokuni R, Hazama D, Kiriu T, Umezawa K, Kobayashi K, Nishimura Y. Crucial Role of Extracellular Vesicles in Bronchial Asthma. Int J Mol Sci 2019; 20:ijms20102589. [PMID: 31137771 PMCID: PMC6566667 DOI: 10.3390/ijms20102589] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 05/24/2019] [Accepted: 05/25/2019] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.
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Affiliation(s)
- Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Masahiro Katsurada
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Ryota Dokuni
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Daisuke Hazama
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Tatsunori Kiriu
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Kanoko Umezawa
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Kazuyuki Kobayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Yoshihiro Nishimura
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
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Vu LT, Peng B, Zhang DX, Ma V, Mathey-Andrews CA, Lam CK, Kiomourtzis T, Jin J, McReynolds L, Huang L, Grimson A, Cho WC, Lieberman J, Le MT. Tumor-secreted extracellular vesicles promote the activation of cancer-associated fibroblasts via the transfer of microRNA-125b. J Extracell Vesicles 2019; 8:1599680. [PMID: 31044053 PMCID: PMC6484490 DOI: 10.1080/20013078.2019.1599680] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/15/2019] [Accepted: 03/21/2019] [Indexed: 12/12/2022] Open
Abstract
Tumour cells release large quantities of extracellular vesicles (EVs) to mediate their interactions with other cells in the tumour microenvironment. To identify host cells that naturally take up EVs from tumour cells, we created breast cancer cell lines secreting fluorescent EVs. These fluorescent EVs are taken up most robustly by fibroblasts within the tumour microenvironment. RNA sequencing indicated that miR-125b is one of the most abundant microRNAs secreted by mouse triple-negative breast cancer 4T1 and 4TO7 cells. Treatment with 4T1 EVs leads to an increase in fibroblast activation in isogenic 4TO7 tumours, which is reversed by blocking miR-125b in 4T1 EVs; hence, miR-125b delivery by EVs is responsible for fibroblast activation in mouse tumour models. miR-125b is also secreted by human breast cancer cells and the uptake of EVs from these cells significantly increases cellular levels of miR-125b and expression of multiple cancer-associated fibroblast markers in resident fibroblasts. Overexpression of miR-125b in both mouse and human fibroblasts leads to an activated phenotype similar to the knockdown of established miR-125b target mRNAs. These data indicate that miR-125b is transferred through EVs from breast cancer cells to normal fibroblasts within the tumour microenvironment and contributes to their development into cancer-associated fibroblasts.
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Affiliation(s)
- Luyen Tien Vu
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Boya Peng
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - Daniel Xin Zhang
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - Victor Ma
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Camille A. Mathey-Andrews
- Program in Cellular and Molecular Medicine, Boston Children‘s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Chun Kuen Lam
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | | | | | | | - Linfeng Huang
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, P. R. China
| | - Andrew Grimson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Judy Lieberman
- Program in Cellular and Molecular Medicine, Boston Children‘s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Minh Tn Le
- Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, P. R. China
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46
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Akazawa Y, Mizuno S, Fujinami N, Suzuki T, Yoshioka Y, Ochiya T, Nakamoto Y, Nakatsura T. Usefulness of serum microRNA as a predictive marker of recurrence and prognosis in biliary tract cancer after radical surgery. Sci Rep 2019; 9:5925. [PMID: 30976046 PMCID: PMC6459925 DOI: 10.1038/s41598-019-42392-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 03/20/2019] [Indexed: 02/06/2023] Open
Abstract
Biliary tract cancer (BTC) is an aggressive type of malignant tumour. Even after radical resection, the risk of recurrence is still high, resulting in a poor prognosis. Here, we investigated the usefulness of serum miRNAs as predictive markers of recurrence and prognosis for patients with BTC after radical surgery using 66 serum samples that were collected at three time points from 22 patients with BTC who underwent radical surgery. Using microarray analysis, we successfully identified six specific miRNAs (miR-1225-3p, miR-1234-3p, miR1260b, miR-1470, miR-6834-3p, and miR-6875-5p) associated with recurrence and prognosis of BTC after radical surgery. In addition, using a combination of these miRNAs, we developed a recurrence predictive index to predict recurrence in patients with BTC after operation with high accuracy. Patients having higher index scores (≥ cut-off) had significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with lower index scores (<cut-off). Furthermore, the index was an independent factor related to RFS and OS by univariate and multivariate analyses using a Cox hazard proportional model. Overall, our results provided compelling evidence for the potential usefulness of specific serum miRNAs as effective predictive tools for recurrence and prognosis in patients with BTC who underwent radical surgery.
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Affiliation(s)
- Yu Akazawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.,Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
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Host⁻MicroRNA⁻Microbiota Interactions in Colorectal Cancer. Genes (Basel) 2019; 10:genes10040270. [PMID: 30987065 PMCID: PMC6523287 DOI: 10.3390/genes10040270] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/21/2019] [Accepted: 03/27/2019] [Indexed: 12/12/2022] Open
Abstract
Changes in gut microbiota composition have consistently been observed in patients with colorectal cancer (CRC). Yet, it is not entirely clear how the gut microbiota interacts with tumor cells. We know that tumor cells undergo a drastic change in energy metabolism, mediated by microRNAs (miRNAs), and that tumor-derived miRNAs affect the stromal and immune cell fractions of the tumor microenvironment. Recent studies suggest that host intestinal miRNAs can also affect the growth and composition of the gut microbiota. Our previous CRC studies showed a high-level of interconnectedness between host miRNAs and their microbiota. Considering all the evidence to date, we postulate that the altered nutrient composition and miRNA expression in the CRC microenvironment selectively exerts pressure on the surrounding microbiota, leading to alterations in its composition. In this review article, we present our current understanding of the role of miRNAs in mediating host–microbiota interactions in CRC.
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Olioso D, Dauriz M, Bacchi E, Negri C, Santi L, Bonora E, Moghetti P. Effects of Aerobic and Resistance Training on Circulating Micro-RNA Expression Profile in Subjects With Type 2 Diabetes. J Clin Endocrinol Metab 2019; 104:1119-1130. [PMID: 30445461 DOI: 10.1210/jc.2018-01820] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/09/2018] [Indexed: 01/05/2023]
Abstract
CONTEXT Structured exercise programs are of great benefit for the treatment of type 2 diabetes (T2DM). However, whether aerobic (AER) or resistance (RES) exercise training exerts specific epigenetic changes through the expression profile of circulating miRNAs (c-miRNAs) is still largely unknown. OBJECTIVE To assess whether the c-miRNAs profile changes after either AER or RES training in subjects with T2DM. DESIGN Twenty-four patients with T2DM randomized to AER or RES training protocols were randomly selected from the Resistance vs. Aerobic Exercise in Type 2 Diabetes (RAED2) Trial (NAER = 12; NRES = 12). The baseline and post-training levels of 179 c-miRNAs were initially measured by RT-PCR in 6 individuals (NAER = 3; NRES = 3). C-miRNAs exhibiting ≥40% fold change variation and/or nominal significance from baseline were measured in the whole group. RESULTS Nineteen c-miRNAs were eventually assessed in the whole group. Compared with baseline, the post-training levels of miR-423-3p, miR-451a, and miR-766-3p were significantly up-regulated, irrespective of exercise type (P < 0.0026; 0.05/19), and targeted upstream pathways relevant to fatty acids biosynthesis and metabolic regulation. MiR-451a and miR-423-3p were significantly correlated with fat loss (ρ = 0.45 and 0.43, respectively) and resulted, alone or in combination, in being predictors of fat loss in generalized linear regression models including exercise type as covariate. Only the association with miR-451a eventually retained significance after further correction for age, sex, body mass index, and HbA1c. CONCLUSIONS Exercise training in T2DM is associated with substantial c-miRNAs profile changes, irrespective of exercise type and other relevant metabolic covariates. The mechanistic significance of the observed relationship between fat loss and the epigenetic modifications induced by exercise warrants further investigation in larger datasets.
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Affiliation(s)
- Debora Olioso
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
| | - Marco Dauriz
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
| | - Elisabetta Bacchi
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
| | - Carlo Negri
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
| | - Lorenza Santi
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
| | - Enzo Bonora
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
| | - Paolo Moghetti
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy
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Jafarzadeh N, Safari Z, Pornour M, Amirizadeh N, Forouzandeh Moghadam M, Sadeghizadeh M. Alteration of cellular and immune-related properties of bone marrow mesenchymal stem cells and macrophages by K562 chronic myeloid leukemia cell derived exosomes. J Cell Physiol 2019; 234:3697-3710. [PMID: 30317554 DOI: 10.1002/jcp.27142] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 07/05/2018] [Indexed: 12/19/2022]
Abstract
Leukemic cells can impact the bone marrow niche to create a tumor-favorable microenvironment using their secreted factors. Little knowledge is available about immunosuppressive and tumor-promoting properties of chronic myeloid leukemia derived exosomes in bone marrow stromal components. We report here that K562-derived exosomes can affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of bone marrow mesenchymal stem cells (BM-MSCs) and macrophages. Human BM-MSCs and mouse macrophages were treated with K562-derived exosomes. Our results demonstrated that the expression of the genes involved in hematopoietic developmental pathways and immune responses, including C-X-C motif chemokine 12 (Cxcl12), Dickkopf-related protein 1 (DKK1), wnt5a, interleukin 6 (IL-6), transforming growth factor-beta, and tumor necrosis factor-alpha (TNF-alpha), changed with respect to time and exosome concentration in BM-MSCs. The TNF-alpha level was higher in exosome-treated BM-MSCs compared with the control. Exosome treatment of BM-MSCs led to an increased production of NO and a decreased production of reactive oxygen species (ROS) in a time- and concentration-dependent manner. We have shown that K562-derived exosomes induce overexpression of IL-10 and TNF-alpha and downregulation of iNOS transcript levels in macrophages. The enzyme-linked immunosorbent assay results showed that TNF-alpha and IL-10 secretions increased in macrophages. Treatment of macrophages with purified exosomes led to reduced NO and ROS levels. These results suggest that K562-derived exosomes may alter the local bone marrow niche toward a leukemia-reinforcing microenvironment. They can modulate the inflammatory molecules (TNF-alpha and NO) and the redox potential of BM-MSCs and macrophages and direct the polarization of macrophages toward tumor-associated macrophages.
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MESH Headings
- Animals
- Cell Communication
- Cytokines/metabolism
- Exosomes/genetics
- Exosomes/immunology
- Exosomes/metabolism
- Exosomes/ultrastructure
- Female
- Humans
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Macrophages/immunology
- Macrophages/metabolism
- Mesenchymal Stem Cells/immunology
- Mesenchymal Stem Cells/metabolism
- Mice, Inbred BALB C
- Nitric Oxide/metabolism
- Nitric Oxide Synthase Type II/genetics
- Nitric Oxide Synthase Type II/metabolism
- Oxidation-Reduction
- Reactive Oxygen Species/metabolism
- Signal Transduction
- Stem Cell Niche
- Tumor Escape
- Tumor Microenvironment
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Affiliation(s)
- Nazli Jafarzadeh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zohreh Safari
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Majid Pornour
- Department of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, Academic Center for Education Culture and Research (ACECR), Tehran, Iran
| | - Naser Amirizadeh
- Blood Transfusion Research Center, High Institute for Education and Research in Transfusion Medicine, Tehran, Iran
| | - Mehdi Forouzandeh Moghadam
- Department of Medical Biotechnology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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50
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Coenen-Stass AML, Pauwels MJ, Hanson B, Martin Perez C, Conceição M, Wood MJA, Mäger I, Roberts TC. Extracellular microRNAs exhibit sequence-dependent stability and cellular release kinetics. RNA Biol 2019; 16:696-706. [PMID: 30836828 PMCID: PMC6546368 DOI: 10.1080/15476286.2019.1582956] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Multiple studies have described extracellular microRNAs (ex-miRNAs) as being remarkably stable despite the hostile extracellular environment, when stored at 4ºC or lower. Here we show that many ex-miRNAs are rapidly degraded when incubated at 37ºC in the presence of serum (thereby simulating physiologically relevant conditions). Stability varied widely between miRNAs, with half-lives ranging from ~1.5 hours to more than 13 hours. Notably, ex-miRNA half-lives calculated in two different biofluids (murine serum and C2C12 mouse myotube conditioned medium) were highly similar, suggesting that intrinsic sequence properties are a determining factor in miRNA stability. By contrast, ex-miRNAs associated with extracellular vesicles (isolated by size exclusion chromatography) were highly stable. The release of ex-miRNAs from C2C12 myotubes was measured over time, and mathematical modelling revealed miRNA-specific release kinetics. While some ex-miRNAs reached the steady state in cell culture medium within 24 hours, the extracellular level of miR-16 did not reach equilibrium, even after 3 days in culture. These findings are indicative of miRNA-specific release and degradation kinetics with implications for the utility of ex-miRNAs as biomarkers, and for the potential of ex-miRNAs to transfer gene regulatory information between cells.
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Affiliation(s)
- Anna M L Coenen-Stass
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK
| | - Marie J Pauwels
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,b VIB-UGent Center for Inflammation Research, Department of Biomedical Molecular Biology, Ghent University , Ghent , Belgium.,c Department of Biomedical Molecular Biology , Ghent University , Ghent , Belgium
| | - Britt Hanson
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,d Department of Paediatrics , University of Oxford , Oxford , UK
| | - Carla Martin Perez
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,d Department of Paediatrics , University of Oxford , Oxford , UK
| | - Mariana Conceição
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,d Department of Paediatrics , University of Oxford , Oxford , UK
| | - Matthew J A Wood
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,d Department of Paediatrics , University of Oxford , Oxford , UK
| | - Imre Mäger
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,d Department of Paediatrics , University of Oxford , Oxford , UK.,e Institute of Technology , University of Tartu , Tartu , Estonia
| | - Thomas C Roberts
- a Department of Physiology, Anatomy and Genetics , University of Oxford , Oxford , UK.,d Department of Paediatrics , University of Oxford , Oxford , UK.,f Sanford Burnham Prebys Medical Discovery Institute , Development, Aging and Regeneration Program , La Jolla , CA , USA
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