|
1
|
He Z, Zheng N, Guo XQ, Wang GG, Lin M. Effects of Hsa-miR-4741/LILRB2 on Senescence of Nucleus Pulposus Cells and Their Prognostic Values in Lumbar Disc Herniation. J INVEST SURG 2025; 38:2458180. [PMID: 39894455 DOI: 10.1080/08941939.2025.2458180] [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: 07/29/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND The incidence of lumbar disk herniation (LDH) is usually caused by lumbar disk degeneration. Surgery is a common treatment strategy for LDH, but it can recur, resulting in recurrent disk herniation (RDH). PURPOSE To explore the predictive value of hsa-miR-4741 and LILRB2 in the prognosis of LDH surgery and the mechanism of nucleus pulposus senescence. METHOD The ROC curves of RDH based on hsa-miR-4741 and LILRB2 were constructed to evaluate their predictive values in the prognosis of LDH surgery. Human nucleus pulposus cells (NPC) was treated by TNF-α to construct a cell senescence model, studying the senescence mechanism. Oxidative stress and senescence markers were detected after overexpression of hsa-miR-4741 and LILRB2 to evaluate their effects on the senescence of NPC. Dual luciferase assay and the transfection of hsa-miR-4741 mimics or inhibitor were used to investigate the targeted regulation of it to LILRB2. RESULTS The combination of hsa-miR-4741 and LILRB2 showed higher accuracy in predicting the outcome of RDH (AUC = 0.9367), compared with a single molecule. Overexpression of hsa-miR-4741 enhanced TNF-α-induced oxidative stress and senescence, while LILRB2 overexpression had the opposite effect. Hsa-miR-4741 mimics attenuated the luciferase activity of NPC transfected with wt-LILRB2 vector and significantly down-regulated LILRB2 expression. In addition, the antioxidant NAC reversed the promotion of hsa-miR-4741 on NPC senescence. CONCLUSION The combination of hsa-miR-4741 and LILRB2 was a good predictor of LDH prognosis. Hsa-miR-4741 promoted oxidative stress-induced NPC senescence by negatively regulating LILRB2.
Collapse
Affiliation(s)
- Zhendong He
- Department of Spinal Surgery, The Third People's Hospital of Gansu Province, Lanzhou, Gansu, China
| | - Nan Zheng
- Department of Orthopedics, The 983 Hospital of Joint Logistic Support Force of PLA, Tianjin, China
| | - Xiu-Quan Guo
- Department of Spinal Surgery, Zhucheng People's Hospital, Weifang, Shandong, China
| | - Gang-Gang Wang
- Department of Hand and Foot Surgery, Zhucheng People's Hospital, Weifang, Shandong, China
| | - Mingjian Lin
- Department of Neurosurgery, Gaozhou People's Hospital, Maoming, Guangdong, China
| |
Collapse
|
|
2
|
Keshavarz S, Alavi CE, Aghayan H, Jafari-Shakib R, Vojoudi E. Advancements in Degenerative Disc Disease Treatment: A Regenerative Medicine Approach. Stem Cell Rev Rep 2025:10.1007/s12015-025-10882-z. [PMID: 40232618 DOI: 10.1007/s12015-025-10882-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 04/16/2025]
Abstract
Regenerative medicine represents a transformative approach to treating nucleus pulposus degeneration and offers hope for patients suffering from chronic low back pain due to disc degeneration. By focusing on restoring the natural structure and function of the nucleus pulposus rather than merely alleviating symptoms, these innovative therapies hold the potential to significantly improve patient outcomes. As research continues to advance in this field, we may soon witness a paradigm shift in how we approach spinal health and degenerative disc disease. The main purpose of this review is to provide an overview of the various regenerative approaches that target the restoration of the nucleus pulposus, a primary site for initiation of intervertebral disc degeneration.
Collapse
Affiliation(s)
- Samaneh Keshavarz
- School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Cyrus Emir Alavi
- Department of Anesthesiology, Neuroscience Research Center, Avicenna University Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Hamidreza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Jafari-Shakib
- Department of Immunology, School of Medicine, Guilan University of Medical Sciences, P.O.Box 41635 - 3363, Rasht, Iran.
| | - Elham Vojoudi
- Regenerative Medicine, Organ Procurement and Transplantation Multidisciplinary Center, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.
| |
Collapse
|
|
3
|
Ding Y, Li F, Wang Y, Pan W, Fu X, Tan S. Nanomedicine Approaches for Intervertebral Disc Regeneration: From Bench to Bedside. Pharmaceutics 2025; 17:313. [PMID: 40142977 PMCID: PMC11944988 DOI: 10.3390/pharmaceutics17030313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/18/2025] [Accepted: 02/27/2025] [Indexed: 03/28/2025] Open
Abstract
Intervertebral disc degeneration (IDD) is a leading cause of low back pain (LBP) and neurological dysfunction, contributing significantly to disability-adjusted life years globally. The progression of IDD is driven by excessive oxidative stress, inflammation, apoptosis, and fibrosis, which disrupt the balance between anabolic and catabolic processes, leading to extracellular matrix (ECM) degradation and IDD. Current treatment options, such as conservative therapy and surgical intervention, are limited in halting the disease progression and often exacerbate degeneration in adjacent discs. This review highlights the challenges in treating IDD, particularly due to the limited drug delivery efficiency to the intervertebral disc (IVD). It explores the potential of nanobiomedicine and various nanomaterial-based delivery systems, including nanoparticles, microspheres, gene-nanocomplexes, fullerene, exosomes, and nanomaterial-composite hydrogels. These advanced delivery systems can enhance targeted drug delivery, improve local drug concentration, and sustain drug retention within the IVD, offering promising therapeutic strategies to address IDD. The review also examines the therapeutic effects of these nanomaterials on IDD, focusing on their impact on metabolism, inflammation, apoptosis, fibrosis, and stem cell migration and differentiation, aiming to provide innovative strategies for intervertebral disc regeneration.
Collapse
Affiliation(s)
- Yifan Ding
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.D.); (F.L.)
| | - Fan Li
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.D.); (F.L.)
| | - Yunyun Wang
- Department of Cardiology, the Fifth Hospital of Wuhan, Jianghan University, Wuhan 430030, China;
| | - Weizhen Pan
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Xiangning Fu
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.D.); (F.L.)
| | - Songwei Tan
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| |
Collapse
|
|
4
|
Hong JY, Kim H, Jeon WJ, Yeo C, Kim H, Lee J, Lee YJ, Ha IH. Animal Models of Intervertebral Disc Diseases: Advantages, Limitations, and Future Directions. Neurol Int 2024; 16:1788-1818. [PMID: 39728755 DOI: 10.3390/neurolint16060129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Animal models are valuable tools for studying the underlying mechanisms of and potential treatments for intervertebral disc diseases. In this review, we discuss the advantages and limitations of animal models of disc diseases, focusing on lumbar spinal stenosis, disc herniation, and degeneration, as well as future research directions. The advantages of animal models are that they enable controlled experiments, long-term monitoring to study the natural history of the disease, and the testing of potential treatments. However, they also have limitations, including species differences, ethical concerns, a lack of standardized protocols, and short lifespans. Therefore, ongoing research focuses on improving animal model standardization and incorporating advanced imaging and noninvasive techniques, genetic models, and biomechanical analyses to overcome these limitations. These future directions hold potential for improving our understanding of the underlying mechanisms of disc diseases and for developing new treatments. Overall, although animal models can provide valuable insights into pathophysiology and potential treatments for disc diseases, their limitations should be carefully considered when interpreting findings from animal studies.
Collapse
Affiliation(s)
- Jin Young Hong
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Hyunseong Kim
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Wan-Jin Jeon
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Changhwan Yeo
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Hyun Kim
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Junseon Lee
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Yoon Jae Lee
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - In-Hyuk Ha
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| |
Collapse
|
|
5
|
DaCunza JT, Wickman JR, Ajit SK. miRNA packaging into small extracellular vesicles and implications in pain. Pain Rep 2024; 9:e1198. [PMID: 39450410 PMCID: PMC11500789 DOI: 10.1097/pr9.0000000000001198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/17/2024] [Accepted: 06/30/2024] [Indexed: 10/26/2024] Open
Abstract
Extracellular vesicles (EVs) are a heterogenous group of lipid bilayer bound particles naturally released by cells. These vesicles are classified based on their biogenesis pathway and diameter. The overlap in size of exosomes generated from the exosomal pathway and macrovesicles that are pinched off from the surface of the plasma membrane makes it challenging to isolate pure populations. Hence, isolated vesicles that are less than 200 nm are called small extracellular vesicles (sEVs). Extracellular vesicles transport a variety of cargo molecules, and multiple mechanisms govern the packaging of cargo into sEVs. Here, we discuss the current understanding of how miRNAs are targeted into sEVs, including the role of RNA binding proteins and EXOmotif sequences present in miRNAs in sEV loading. Several studies in human pain disorders and rodent models of pain have reported alterations in sEV cargo, including miRNAs. The sorting mechanisms and target regulation of miR-939, a miRNA altered in individuals with complex regional pain syndrome, is discussed in the context of inflammation. We also provide a broad overview of the therapeutic strategies being pursued to utilize sEVs in the clinic and the work needed to further our understanding of EVs to successfully deploy sEVs as a pain therapeutic.
Collapse
Affiliation(s)
- Jason T. DaCunza
- Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
- Molecular & Cell Biology & Genetics Graduate Program, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Jason R. Wickman
- Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Seena K. Ajit
- Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
| |
Collapse
|
|
6
|
Li JL, Han YB, Yang GY, Tian M, Shi CS, Tian D. Inflammation in Hernia and the epigenetic control. Semin Cell Dev Biol 2024; 154:334-339. [PMID: 37080853 DOI: 10.1016/j.semcdb.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/13/2023] [Accepted: 04/01/2023] [Indexed: 04/22/2023]
Abstract
Inflammation is much more intrinsic to hernia then is what is generally appreciated. The occurrence of hernias is associated with swelling, stress and inflammation. Surgery remains an important intervention to treat hernias and for many years, post-surgical levels of inflammatory cytokines have been evaluated to compare the different strategies for their comparative advantages. All surgical procedures elicit some sort of inflammatory response and moreover the meshes used for hernia repair are also associated with elevated inflammatory response, although some favor predominantly a pro-inflammatory response while the other meshes favor anti-inflammatory response. An estimated more than 90% of hernia repairs involve some meshes with polypropylene considered as the gold standard. Efforts are underway to modulate polypropylene meshes associated inflammation through use of alternative materials as well as modifications to polypropylene meshes themselves. In the last one decade, miRNAs have entered hernia research and the data on a role of miRNAs in different hernias is slowly emerging, providing the first evidence of epigenetics in hernia. Some reports are connecting miRNAs with inflammation in hernia. All these aspects, such as, surgery-related to mesh-related inflammation as well as miRNA-related inflammation, are discussed in this article to present an up-to-date information on the topic.
Collapse
Affiliation(s)
- Jin-Long Li
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ying-Bo Han
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Gui-Yun Yang
- Department of Operating Room, The Second Hospital of Jilin University, Changchun, China
| | - Miao Tian
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, China
| | - Chang-Sai Shi
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Dan Tian
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
7
|
Sluka KA, Wager TD, Sutherland SP, Labosky PA, Balach T, Bayman EO, Berardi G, Brummett CM, Burns J, Buvanendran A, Caffo B, Calhoun VD, Clauw D, Chang A, Coffey CS, Dailey DL, Ecklund D, Fiehn O, Fisch KM, Frey Law LA, Harris RE, Harte SE, Howard TD, Jacobs J, Jacobs JM, Jepsen K, Johnston N, Langefeld CD, Laurent LC, Lenzi R, Lindquist MA, Lokshin A, Kahn A, McCarthy RJ, Olivier M, Porter L, Qian WJ, Sankar CA, Satterlee J, Swensen AC, Vance CG, Waljee J, Wandner LD, Williams DA, Wixson RL, Zhou XJ. Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures. Pain 2023; 164:1912-1926. [PMID: 37326643 PMCID: PMC10436361 DOI: 10.1097/j.pain.0000000000002938] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/02/2023] [Accepted: 03/02/2023] [Indexed: 06/17/2023]
Abstract
ABSTRACT Chronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps.
Collapse
Affiliation(s)
- Kathleen A. Sluka
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Tor D. Wager
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH
| | - Stephani P. Sutherland
- Department of Biostatistics, Johns Hopkins Bloomberg Schools of Public Health, Baltimore, MD
| | - Patricia A. Labosky
- Office of Strategic Coordination, Division of Program Coordination, Planning and Strategic Initiatives, Office of the Director, National Institutes of Health, Bethesda, MD
| | - Tessa Balach
- Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago, Chicago, IL
| | - Emine O. Bayman
- Clinical Trials and Data Management Center, Department of Biostatistics, University of Iowa, Iowa City, IA
| | - Giovanni Berardi
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Chad M. Brummett
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI
| | - John Burns
- Division of Behavioral Sciences, Rush Medical College, Chicago, IL
| | | | - Brian Caffo
- Department of Biostatistics, Johns Hopkins Bloomberg Schools of Public Health, Baltimore, MD
| | - Vince D. Calhoun
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State, Georgia Tech, and Emory University, Atlanta, GA
| | - Daniel Clauw
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI
| | - Andrew Chang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI
| | - Christopher S. Coffey
- Clinical Trials and Data Management Center, Department of Biostatistics, University of Iowa, Iowa City, IA
| | - Dana L. Dailey
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Dixie Ecklund
- Clinical Trials and Data Management Center, Department of Biostatistics, University of Iowa, Iowa City, IA
| | - Oliver Fiehn
- University of California, Davis, Davis, CA, United States
| | - Kathleen M. Fisch
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Diego, San Diego, CA, United States
- Center for Computational Biology and Bioinformatics, University of California San Diego, San Diego, CA, United States
| | - Laura A. Frey Law
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Richard E. Harris
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI
| | - Steven E. Harte
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI
| | - Timothy D. Howard
- Department of Biochemistry, Center for Precision Medicine, Wake Forest School of Medicine, Winstom-Salem, NC
- Center for Precision Medicine, Wake Forest School of Medicine, Winstom-Salem, NC
| | - Joshua Jacobs
- Department of Orthopedic Surgery, Rush Medical College, CHicago, IL
| | - Jon M. Jacobs
- Environmental and Molecular Sciences Laboratory, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA
| | | | | | - Carl D. Langefeld
- Center for Precision Medicine, Wake Forest School of Medicine, Winstom-Salem, NC
- Department of Biostatistics and Data Science, Center for Precision Medicine, Wake Forest School of Medicine, Winstom-Salem, NC
| | - Louise C. Laurent
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Diego, San Diego, CA, United States
| | - Rebecca Lenzi
- Office of Strategic Coordination, Division of Program Coordination, Planning and Strategic Initiatives, Office of the Director, National Institutes of Health, Bethesda, MD
| | - Martin A. Lindquist
- Department of Biostatistics, Johns Hopkins Bloomberg Schools of Public Health, Baltimore, MD
| | | | - Ari Kahn
- Texas Advanced Computing Center, University of Texas, AUstin, TX
| | | | - Michael Olivier
- Center for Precision Medicine, Wake Forest School of Medicine, Winstom-Salem, NC
- Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winstom-Salem, NC
| | - Linda Porter
- National Institute of Neurological Disorders and Stroke, Bethesda, MD
- Office of Pain Policy and Planning National Institutes of Health, Bethesda, MD
| | - Wei-Jun Qian
- Environmental and Molecular Sciences Laboratory, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA
| | - Cheryse A. Sankar
- National Institute of Neurological Disorders and Stroke, Bethesda, MD
| | | | - Adam C. Swensen
- Environmental and Molecular Sciences Laboratory, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA
| | - Carol G.T. Vance
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Jennifer Waljee
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI
| | - Laura D. Wandner
- National Institute of Neurological Disorders and Stroke, Bethesda, MD
| | - David A. Williams
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI
| | | | - Xiaohong Joe Zhou
- Center for MR Research and Departments of Radiology, Neurosurgery, and Bioengineering, University of Illinois College of Medicine at Chicago, Chicago, IL, United States
| |
Collapse
|
|
8
|
Zhang L, Liu J, Zhou C. Current aspects of small extracellular vesicles in pain process and relief. Biomater Res 2023; 27:78. [PMID: 37563666 PMCID: PMC10416402 DOI: 10.1186/s40824-023-00417-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/04/2023] [Indexed: 08/12/2023] Open
Abstract
Small extracellular vesicles (sEVs) have been identified as a noteworthy paracrine mechanism of intercellular communication in diagnosing and managing neurological disorders. Current research suggests that sEVs play a pivotal role in the pathological progression of pain, emphasizing their critical function in the pathological progression of pain in acute and chronic pain models. By facilitating the transfer of diverse molecules, such as proteins, nucleic acids, and metabolites, sEVs can modulate pain signaling transmission in both the central and peripheral nervous systems. Furthermore, the unique molecules conveyed by sEVs in pain disorders indicate their potential as diagnostic biomarkers. The application of sEVs derived from mesenchymal stem cells (MSCs) in regenerative pain medicine has emerged as a promising strategy for pain management. Moreover, modified sEVs have garnered considerable attention in the investigation of pathological processes and therapeutic interventions. This review presents a comprehensive overview of the current knowledge regarding the involvement of sEVs in pain pathogenesis and treatment. Nevertheless, additional research is imperative to facilitate their clinical implementation. Schematic diagram of sEVs in the biogenesis, signal transmission, diagnosis, and treatment of pain disorders. Small extracellular vesicles (sEVs) are secreted by multiple cells, loading with various biomolecules, such as miRNAs, transmembrane proteins, and amino acids. They selectively target other cells and regulating pain signal transmission. The composition of sEVs can serve as valuable biomarkers for pain diagnosis. In particular, mesenchymal stem cell-derived sEVs have shown promise as regenerative medicine for managing multiple pain disorders. Furthermore, by modifying the structure or contents of sEVs, they could potentially be used as a potent analgesic method.
Collapse
Affiliation(s)
- Lanyu Zhang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Anesthesia & Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jin Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng Zhou
- Laboratory of Anesthesia & Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
| |
Collapse
|
|
9
|
Samanta A, Lufkin T, Kraus P. Intervertebral disc degeneration-Current therapeutic options and challenges. Front Public Health 2023; 11:1156749. [PMID: 37483952 PMCID: PMC10359191 DOI: 10.3389/fpubh.2023.1156749] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/12/2023] [Indexed: 07/25/2023] Open
Abstract
Degeneration of the intervertebral disc (IVD) is a normal part of aging. Due to the spine's declining function and the development of pain, it may affect one's physical health, mental health, and socioeconomic status. Most of the intervertebral disc degeneration (IVDD) therapies today focus on the symptoms of low back pain rather than the underlying etiology or mechanical function of the disc. The deteriorated disc is typically not restored by conservative or surgical therapies that largely focus on correcting symptoms and structural abnormalities. To enhance the clinical outcome and the quality of life of a patient, several therapeutic modalities have been created. In this review, we discuss genetic and environmental causes of IVDD and describe promising modern endogenous and exogenous therapeutic approaches including their applicability and relevance to the degeneration process.
Collapse
Affiliation(s)
| | | | - Petra Kraus
- Department of Biology, Clarkson University, Potsdam, NY, United States
| |
Collapse
|
|
10
|
Differential Expression of microRNAs in Serum of Patients with Chronic Painful Polyneuropathy and Healthy Age-Matched Controls. Biomedicines 2023; 11:biomedicines11030764. [PMID: 36979743 PMCID: PMC10045018 DOI: 10.3390/biomedicines11030764] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Polyneuropathies (PNP) are the most common type of disorder of the peripheral nervous system in adults. However, information on microRNA expression in PNP is lacking. Following microRNA sequencing, we compared the expression of microRNAs in the serum of patients experiencing chronic painful PNP with healthy age-matched controls. We have been able to identify four microRNAs (hsa-miR-3135b, hsa-miR-584-5p, hsa-miR-12136, and hsa-miR-550a-3p) that provide possible molecular links between degenerative processes, blood flow regulation, and signal transduction, that eventually lead to PNP. In addition, these microRNAs are discussed regarding the targeting of proteins that are involved in high blood flow/pressure and neural activity dysregulations/disbalances, presumably resulting in PNP-typical symptoms such as chronical numbness/pain. Within our study, we have identified four microRNAs that may serve as potential novel biomarkers of chronic painful PNP, and that may potentially bear therapeutic implications.
Collapse
|
|
11
|
Microglia and macrophages contribute to the development and maintenance of sciatica in lumbar disc herniation. Pain 2023; 164:362-374. [PMID: 36170151 DOI: 10.1097/j.pain.0000000000002708] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023]
Abstract
ABSTRACT Lumbar disc herniation (LDH) is a major cause of sciatica. Emerging evidence indicated that inflammation induced by the herniated nucleus pulposus (NP) tissues plays a major role in the pathogenesis of sciatica. However, the underlying mechanisms are still elusive. Although microglia and macrophages have been implicated in nerve injury-induced neuropathic pain, their roles in LDH-induced sciatica largely remain unknown. This study successfully established and modified a mouse model of LDH. We found that nerve root compression using degenerated NP tissues can initiate remarkable and persistent sciatica, with increased and prolonged macrophage infiltration in dorsal root ganglia (DRG) and significant activation of microglia in the spinal dorsal horn. Instead, compression of the nerve root with nondegenerated NP tissues only led to transient sciatica, with transient infiltration and activation of macrophages and microglia. Moreover, continuous treatment of PLX5622, a specific colony-stimulating factor 1 receptor antagonist, ablated both macrophages and microglia, which effectively alleviated LDH-induced sciatica. However, mechanical allodynia reoccurred along with the repopulation of macrophages and microglia after the withdrawal of PLX5622. Using RNA sequencing analysis, the current study depicted transcriptional profile changes of DRG after LDH and identified several macrophage-related potential target candidates. Our results suggested that microglia and macrophages may play an essential role in the development and maintenance of LDH-induced sciatica. Targeting microglia and macrophages may be a promising treatment for chronic LDH-induced sciatica.
Collapse
|
|
12
|
Bahar ME, Hwang JS, Ahmed M, Lai TH, Pham TM, Elashkar O, Akter KM, Kim DH, Yang J, Kim DR. Targeting Autophagy for Developing New Therapeutic Strategy in Intervertebral Disc Degeneration. Antioxidants (Basel) 2022; 11:antiox11081571. [PMID: 36009290 PMCID: PMC9405341 DOI: 10.3390/antiox11081571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/11/2022] [Accepted: 08/11/2022] [Indexed: 12/25/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) is a prevalent cause of low back pain. IVDD is characterized by abnormal expression of extracellular matrix components such as collagen and aggrecan. In addition, it results in dysfunctional growth, senescence, and death of intervertebral cells. The biological pathways involved in the development and progression of IVDD are not fully understood. Therefore, a better understanding of the molecular mechanisms underlying IVDD could aid in the development of strategies for prevention and treatment. Autophagy is a cellular process that removes damaged proteins and dysfunctional organelles, and its dysfunction is linked to a variety of diseases, including IVDD and osteoarthritis. In this review, we describe recent research findings on the role of autophagy in IVDD pathogenesis and highlight autophagy-targeting molecules which can be exploited to treat IVDD. Many studies exhibit that autophagy protects against and postpones disc degeneration. Further research is needed to determine whether autophagy is required for cell integrity in intervertebral discs and to establish autophagy as a viable therapeutic target for IVDD.
Collapse
Affiliation(s)
- Md Entaz Bahar
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Jin Seok Hwang
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Mahmoud Ahmed
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Trang Huyen Lai
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Trang Minh Pham
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Omar Elashkar
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Kazi-Marjahan Akter
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, GyeongNam, Korea
| | - Dong-Hee Kim
- Department of Orthopaedic Surgery, Institute of Health Sciences, Gyeongsang National University Hospital and Gyeongsang National University College of Medicine, Jinju 52727, GyeongNam, Korea
| | - Jinsung Yang
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, GyeongNam, Korea
- Correspondence: ; Tel.: +82-55-772-8054
| |
Collapse
|
|
13
|
Morteza Bagi H, Ahmadi S, Tarighat F, Rahbarghazi R, Soleimanpour H. Interplay between exosomes and autophagy machinery in pain management: State of the art. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2022; 12:100095. [PMID: 35720640 PMCID: PMC9198378 DOI: 10.1016/j.ynpai.2022.100095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/04/2022] [Accepted: 06/04/2022] [Indexed: 05/30/2023]
Abstract
Despite recent progress regarding inexpensive medical approaches, many individuals suffer from moderate to severe pain globally. The discovery and advent of exosomes, as biological nano-sized vesicles, has revolutionized current knowledge about underlying mechanisms associated with several pathological conditions. Indeed, these particles are touted as biological bio-shuttles with the potential to carry specific signaling biomolecules to cells in proximity and remote sites, maintaining cell-to-cell communication in a paracrine manner. A piece of evidence points to an intricate relationship between exosome biogenesis and autophagy signaling pathways at different molecular levels. A close collaboration of autophagic response with exosome release can affect the body's hemostasis and physiology of different cell types. This review is a preliminary attempt to highlight the possible interface of autophagy flux and exosome biogenesis on pain management with a special focus on neuropathic pain. It is thought that this review article will help us to understand the interplay of autophagic response and exosome biogenesis in the management of pain under pathological conditions. The application of therapies targeting autophagy pathway and exosome abscission can be an alternative strategy in the regulation of pain.
Collapse
Key Words
- Autophagy
- CESC-Exo, cartilage endplate stem cell-derived Exo
- Cell Therapy
- ER, endoplasmic reticulum
- ESCRT, endosomal sorting complex required for transport
- HSPA8, heat shock protein family A member 8
- LAMP2, lysosomal‑associated membrane protein type 2
- LAT1, large amino acid transporter
- LTs, leukotrienes
- MAPK8/JNK, mitogen-activated protein kinase 8p-/c-Jun N-terminal Kinase
- MMP, matrix metalloproteinase
- MVBs, multivesicular bodies
- NFKB/NF-κB, nuclear factor of kappa light polypeptide gene enhancer in B cells
- NPCs, nucleus pulposus cells
- NPCs-Exo, NPCs-derived Exo
- Neural Exosome
- Pain Management
- SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptors
- TLR4, Toll-like receptor 4
- TRAF6, TNF receptor-associated factor 6
- nSMase, ceramide-generating enzyme neutral sphingomyelinases
Collapse
Affiliation(s)
- Hamidreza Morteza Bagi
- Emergency and Trauma Care Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Ahmadi
- Emergency and Trauma Care Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Tarighat
- Emergency and Trauma Care Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Soleimanpour
- Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
14
|
Sabina S, Panico A, Mincarone P, Leo CG, Garbarino S, Grassi T, Bagordo F, De Donno A, Scoditti E, Tumolo MR. Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies. Int J Mol Sci 2022; 23:ijms23116016. [PMID: 35682695 PMCID: PMC9181121 DOI: 10.3390/ijms23116016] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 02/01/2023] Open
Abstract
Chronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.
Collapse
Affiliation(s)
- Saverio Sabina
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
| | - Alessandra Panico
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| | - Pierpaolo Mincarone
- Institute for Research on Population and Social Policies, National Research Council, c/o ex Osp. Di Summa, Piazza Di Summa, 72100 Brindisi, Italy;
| | - Carlo Giacomo Leo
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
| | - Sergio Garbarino
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal/Child Sciences, University of Genoa, 16132 Genoa, Italy;
| | - Tiziana Grassi
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| | - Francesco Bagordo
- Department of Pharmacy-Pharmaceutical Science, University of Bari Aldo Moro, Via Edoardo Orabona, 70126 Bari, Italy;
| | - Antonella De Donno
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| | - Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
- Correspondence: ; Tel.: +39-(08)-3229-8860
| | - Maria Rosaria Tumolo
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| |
Collapse
|
|
15
|
Yaobishu Regulates Inflammatory, Metabolic, Autophagic, and Apoptosis Pathways to Attenuate Lumbar Disc Herniation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3861380. [PMID: 35615578 PMCID: PMC9125431 DOI: 10.1155/2022/3861380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/18/2022] [Accepted: 04/16/2022] [Indexed: 12/03/2022]
Abstract
Objective Here, we aimed to explore the main mechanism of Yaobishu (YBS) in lumbar disc herniation (LDH). Methods and Results Eighteen compounds that might act on LDH were obtained through a combination of network pharmacology prediction and identification by high-performance liquid chromatography-mass spectrometry. The key compounds were palmitic acid and trans-4-hydroxy-3-methoxycinnamate (cinnamate). KEGG analysis demonstrated that palmitic acid target genes mainly regulate the PPAR signaling pathway, Ras signaling pathway, and fatty acid metabolism. Cinnamate target genes were primarily involved in chemical carcinogenesis-receptor activation, lipid and atherosclerosis, the HIF-1 signaling pathway, and nitrogen metabolism. The rat LDH model was constructed using autologous nucleus pulposus tissue implantation. Differential expression gene (DEGs) related to metabolism (CDKN1A and UHRF1), inflammation (S100A9 and SOCS3), autophagy (DCN and LEPR), and apoptosis (CTSW and BCL2A1) in dorsal root ganglion (DRG) tissues of the control and LDH groups was evaluated by RNA-Seq. TNF-α stimulated DRG neuronal cells were used to establish an in vitro LDH model. YBS, palmitic acid, and cinnamate reduced the expression of substance P, CGRP, S100A9, CTSW, and cleaved caspase-3, while enhancing the expression of CDKN1A, UHRF1, PCNA, Ki67, SOCS3, DCN, LEPR, and BCL2A1, as well as telomerase activity. Pearson's correlation analysis confirmed that DCN was positively correlated with BCL2A1, indicating that autophagy might be negatively correlated with apoptosis in LDH. YBS, palmitic acid, and cinnamate reduced the Siegal neurological score and serum IL-1β and IL-18 levels, while increasing changes in the hind paw mechanical withdrawal threshold. The RNA-Seq results further showed that YBS downregulated S100A9 and CTSW expression, while upregulating SOCS3, CDKN1A, UHRF1, DCN, LEPR, and BCL2A1 expression. Conclusion YBS and its compounds, palmitic acid, and cinnamate, attenuated LDH by regulating the inflammatory, metabolic, autophagic, and apoptotic pathways. Our results might improve the theoretical and experimental basis for clinical applications of LDH disease treatment.
Collapse
|
|
16
|
DiStefano TJ, Vaso K, Danias G, Chionuma HN, Weiser JR, Iatridis JC. Extracellular Vesicles as an Emerging Treatment Option for Intervertebral Disc Degeneration: Therapeutic Potential, Translational Pathways, and Regulatory Considerations. Adv Healthc Mater 2022; 11:e2100596. [PMID: 34297485 PMCID: PMC8783929 DOI: 10.1002/adhm.202100596] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/08/2021] [Indexed: 12/14/2022]
Abstract
Emergent approaches in regenerative medicine look toward the use of extracellular vesicles (EVs) as a next-generation treatment strategy for intervertebral disc (IVD) degeneration (IVDD) because of their ability to attenuate chronic inflammation, reduce apoptosis, and stimulate proliferation in a number of tissue systems. Yet, there are no Food and Drug Administration (FDA)-approved EV therapeutics in the market with an indication for IVDD, which motivates this article to review the current state of the field and provide an IVD-specific framework to assess its efficacy. In this systematic review, 29 preclinical studies that investigate EVs in relation to the IVD are identified, and additionally, the regulatory approval process is reviewed in an effort to accelerate emerging EV-based therapeutics toward FDA submission and timeline-to-market. The majority of studies focus on nucleus pulposus responses to EV treatment, where the main findings show that stem cell-derived EVs can decelerate the progression of IVDD on the molecular, cellular, and organ level. The findings also highlight the importance of the EV parent cell's pathophysiological and differentiation state, which affects downstream treatment responses and therapeutic outcomes. This systematic review substantiates the use of EVs as a promising cell-free strategy to treat IVDD and enhance endogenous repair.
Collapse
Affiliation(s)
- Tyler J. DiStefano
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York NY, USA
| | - Keti Vaso
- Department of Chemical Engineering, The Cooper Union for the Advancement of Science and Art, New York NY, USA
| | - George Danias
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York NY, USA
| | - Henry N. Chionuma
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York NY, USA
| | - Jennifer R. Weiser
- Department of Chemical Engineering, The Cooper Union for the Advancement of Science and Art, New York NY, USA
| | - James C. Iatridis
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York NY, USA
| |
Collapse
|
|
17
|
Yang W, Huang XD, Zhang T, Zhou YB, Zou YC, Zhang J. LncRNA MIR155HG functions as a ceRNA of miR-223-3p to promote cell pyroptosis in human degenerative NP cells. Clin Exp Immunol 2021; 207:241-252. [PMID: 35020847 PMCID: PMC8982970 DOI: 10.1093/cei/uxab030] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/19/2021] [Accepted: 11/26/2021] [Indexed: 02/03/2023] Open
Abstract
Nucleus pulposus (NP) cell pyroptosis plays a critical role in the pathogenesis of intervertebral disk degeneration (IDD). MIR155 host gene (MIR155HG) is a long non-coding RNA with pro-inflammatory activity. However, very little is known about its role in NP cell pyroptosis. This study aimed to observe the impact of MIR155HG on cell pyroptosis and to explore the underlying mechanism in human degenerative NP cells. Our results demonstrated that MIR155HG expression was significantly increased in human degenerative NP tissue samples and showed a positive correlation with Pfirrmann score. Overexpression of MIR155HG through a lentiviral vector decreased miR-223-3p levels, up-regulated NLRP3 expression and induced cell pyroptosis in human degenerative NP cells. A ceRNA action mode was identified among MIR155HG, miR-223-3p, and NLRP3. The stimulatory effect of MIR155HG on human degenerative NP cell pyroptosis was significantly reversed by pretreatment with miR-223-3p mimic or NLRP3 siRNA. In summary, these data suggest that MIR155HG sponges miR-223-3p to promote NLRP3 expression, leading to induction of cell pyroptosis in human degenerative NP cells. Targeting MIR155HG could be a novel and promising strategy to slow down the progression of IDD.
Collapse
Affiliation(s)
- Wei Yang
- The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xu-Dong Huang
- The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Tao Zhang
- The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - You-Bin Zhou
- The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yong-Cheng Zou
- The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jian Zhang
- The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, China,Correspondence: Jian Zhang, The First Affiliated Hospital, Orthopedic Center, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| |
Collapse
|
|
18
|
Zhou YK, Patel HH, Roth DM. Extracellular Vesicles: A New Paradigm for Cellular Communication in Perioperative Medicine, Critical Care, and Pain Management. Anesth Analg 2021; 133:1162-1179. [PMID: 34304233 PMCID: PMC8542619 DOI: 10.1213/ane.0000000000005655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Extracellular vesicles (EVs) play critical roles in many health and disease states, including ischemia, inflammation, and pain, which are major concerns in the perioperative period and in critically ill patients. EVs are functionally active, nanometer-sized, membrane-bound vesicles actively secreted by all cells. Cell signaling is essential to physiological and pathological processes, and EVs have recently emerged as key players in intercellular communication. Recent studies in EV biology have improved our mechanistic knowledge of the pathophysiological processes in perioperative and critical care patients. Studies also show promise in using EVs in novel diagnostic and therapeutic clinical applications. This review considers the current advances and gaps in knowledge of EVs in the areas of ischemia, inflammation, pain, and in organ systems that are most relevant to anesthesiology, perioperative medicine, critical care, and pain management. We expect the reader will better understand the relationship between EVs and perioperative and critical care pathophysiological states and their potential use as novel diagnostic and therapeutic modalities.
Collapse
Affiliation(s)
- Yingqiu K. Zhou
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| | - Hemal H. Patel
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| | - David M. Roth
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| |
Collapse
|
|
19
|
Krut Z, Pelled G, Gazit D, Gazit Z. Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration. Cells 2021; 10:cells10092241. [PMID: 34571890 PMCID: PMC8471333 DOI: 10.3390/cells10092241] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) occurs as a result of an imbalance of the anabolic and catabolic processes in the intervertebral disc, leading to an alteration in the composition of the extracellular matrix (ECM), loss of nucleus pulposus (NP) cells, excessive oxidative stress and inflammation. Degeneration of the IVD occurs naturally with age, but mechanical trauma, lifestyle factors and certain genetic abnormalities can increase the likelihood of symptomatic disease progression. IVDD, often referred to as degenerative disc disease (DDD), poses an increasingly substantial financial burden due to the aging population and increasing incidence of obesity in the United States. Current treatments for IVDD include pharmacological and surgical interventions, but these lack the ability to stop the progression of disease and restore the functionality of the IVD. Biological therapies have been evaluated but show varying degrees of efficacy in reversing disc degeneration long-term. Stem cell-based therapies have shown promising results in the regeneration of the IVD, but face both biological and ethical limitations. Exosomes play an important role in intercellular communication, and stem cell-derived exosomes have been shown to maintain the therapeutic benefit of their origin cells without the associated risks. This review highlights the current state of research on the use of stem-cell derived exosomes in the treatment of IVDD.
Collapse
Affiliation(s)
- Zoe Krut
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Gadi Pelled
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dan Gazit
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Zulma Gazit
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Correspondence:
| |
Collapse
|
|
20
|
Lin X, Lin Q. MiRNA-495-3p Attenuates TNF-α Induced Apoptosis and Inflammation in Human Nucleus Pulposus Cells by Targeting IL5RA. Inflammation 2021; 43:1797-1805. [PMID: 32445070 DOI: 10.1007/s10753-020-01254-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Intervertebral disc degeneration (IVDD) is considered to be the fundamental cause of the occurrence and development of lumbar disc herniation (LDH). The degeneration of IVDD is mainly caused by the participation of inflammatory factors. Thus, it is of great significance to analyze the pathogenesis of IVDD, which may guide clinical prevention and treatment of LDH. Our current study aims to identify the role of miR-495-3p in LDH and to further unravel the underlying mechanisms. Results in the current study showed that TNF-α treatment markedly inhibited cell viability of HNPC, increased the IL-1β level, and decreased the mRNA level of miR-495-3p in HNPC in a time-dependent manner. Up-regulation of miR-495-3p promoted cell proliferation and inhibited inflammation and apoptosis in TNF-α-induced HNPCs. To investigate the underlying molecular mechanism through which miR-495-3p regulates TNF-α-induced inflammation and apoptosis in HNPCs, we explored the possible target gene of miR-495-3p. Bioinformatics analysis indicated that IL5RA, which is an important gene for TNF-α-induced HNPC injury, was also a target gene of miR-495-3p. A luciferase reporter assay was applied to test and verify the direct target association between miR-495-3p and IL5RA. The results discovered that down-regulation of miR-495-3p markedly reversed the anti-apoptosis and anti-inflammation of sh-IL5RA. In short, the present study evaluated the roles of miR-495-3p and IL5RA in IVDD development and progression. All the data indicated that miRNA-495-3p may play a protective role via inhibiting inflammation and apoptosis in human nucleus pulposus cells by targeting IL5RA pathway. Therefore, miRNA-495-3p may be a potential agent for LDH, and our study may provide a novel strategy in LDH treatment.
Collapse
Affiliation(s)
- Xi Lin
- Department of Emergency Surgery, Center for Trauma Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.
| | - Qi Lin
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| |
Collapse
|
|
21
|
Cata JP, Uhelski ML, Gorur A, Dougherty PM. Nociception and Pain: New Roles for Exosomes. Neuroscientist 2021; 28:349-363. [PMID: 34166130 DOI: 10.1177/10738584211027105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The interchange of information from one cell to another relies on the release of hundreds of different molecules including small peptides, amino acids, nucleotides, RNA, steroids, retinoids, or fatty acid metabolites. Many of them are released to the extracellular matrix as free molecules and others can be part of the cargo of cellular vesicles. Small extracellular vesicles (30-150 nm), also known as exosomes, are a known mechanism of cell-to-cell communication in the nervous system. Exosomes participate in the pathogenesis of several neurological conditions including Alzheimer's and Parkinson's disease. However, exciting emerging evidence demonstrates that exosomes also regulate mechanisms of the sensory process including nociception. The goal of this review is to summarize the literature on exosome biogenesis, methods of small vesicle isolation and purification, and their role in nociception. We also provide insights on the potential applications of exosomes as pain biomarkers or as novel therapeutics.
Collapse
Affiliation(s)
- Juan P Cata
- Department of Anesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.,Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - Megan L Uhelski
- Department of Pain Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA
| | - Aysegul Gorur
- Department of Anesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.,Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - Patrick M Dougherty
- Department of Pain Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
22
|
Hu ZL, Li HY, Chang X, Li YY, Liu CH, Gao XX, Zhai Y, Chen YX, Li CQ. Exosomes derived from stem cells as an emerging therapeutic strategy for intervertebral disc degeneration. World J Stem Cells 2020; 12:803-813. [PMID: 32952860 PMCID: PMC7477652 DOI: 10.4252/wjsc.v12.i8.803] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/09/2020] [Accepted: 07/05/2020] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc (IVD) degenerative diseases are a common problem in the world, and they cause substantial social and economic burdens for people. The current methods for treating IVD degenerative diseases mainly include surgery and conservative treatment, which cannot fundamentally restore the normal structure of the disc. With continuous research on the mechanism of degeneration and the development of regenerative medicine, rapid progress has been made in the field of regenerative medicine regarding the use of stem cell-derived exosomes, which are active biological substances used in intercellular communication, because they show a strong effect in promoting tissue regeneration. The study of exosomes in the field of IVD degeneration has just begun, and many surprising achievements have been made. This paper mainly reviews the biological characteristics of exosomes and highlights the current status of exosomes in the field of IVD degeneration, as well as future developments regarding exosomes.
Collapse
Affiliation(s)
- Zhi-Lei Hu
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Hai-Yin Li
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Xian Chang
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Yue-Yang Li
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Chen-Hao Liu
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Xiao-Xin Gao
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Yu Zhai
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Yu-Xuan Chen
- Center of Traumatic Orthopedics, People's Liberation Army 990 Hospital, Xinyang 46400, Henan Province, China
| | - Chang-Qing Li
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| |
Collapse
|
|
23
|
Polli A, Godderis L, Ghosh M, Ickmans K, Nijs J. Epigenetic and miRNA Expression Changes in People with Pain: A Systematic Review. THE JOURNAL OF PAIN 2020; 21:763-780. [DOI: 10.1016/j.jpain.2019.12.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 09/30/2019] [Accepted: 12/02/2019] [Indexed: 01/13/2023]
|
|
24
|
Piazza N, Dehghani M, Gaborski TR, Wuertz-Kozak K. Therapeutic Potential of Extracellular Vesicles in Degenerative Diseases of the Intervertebral Disc. Front Bioeng Biotechnol 2020; 8:311. [PMID: 32363187 PMCID: PMC7181459 DOI: 10.3389/fbioe.2020.00311] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/23/2020] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are lipid membrane particles carrying proteins, lipids, DNA, and various types of RNA that are involved in intercellular communication. EVs derived from mesenchymal stem cells (MSCs) have been investigated extensively in many different fields due to their crucial role as regeneration drivers, but research for their use in degenerative diseases of the intervertebral disc (IVD) has only started recently. MSC-derived EVs not only promote extracellular matrix synthesis and proliferation in IVD cells, but also reduce apoptosis and inflammation, hence having multifunctional beneficial effects that seem to be mediated by specific miRNAs (such as miR-233 and miR-21) within the EVs. Aside from MSC-derived EVs, IVD-derived EVs (e.g., stemming from notochordal cells) also have important functions in IVD health and disease. This article will summarize the current knowledge on MSC-derived and IVD-derived EVs and will highlight areas of future research, including the isolation and analysis of EV subpopulations or exposure of MSCs to cues that may enhance the therapeutic potential of released EVs.
Collapse
Affiliation(s)
- Nathan Piazza
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY, United States
| | - Mehdi Dehghani
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY, United States
| | - Thomas R. Gaborski
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY, United States
| | - Karin Wuertz-Kozak
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY, United States
- Institute for Biomechanics, Zurich, Switzerland
- Spine Center, Schön Clinic Munich Harlaching, Munich, Germany
- Academic Teaching Hospital and Spine Research Institute, Paracelsus Medical University, Salzburg, Austria
| |
Collapse
|
|
25
|
Manvati MKS, Khan J, Verma N, Dhar PK. Association of miR-760 with cancer: An overview. Gene 2020; 747:144648. [PMID: 32251703 DOI: 10.1016/j.gene.2020.144648] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 04/01/2020] [Accepted: 04/02/2020] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules of around 22 nucleotides in length. They are crucially involved in the post transcriptional regulation and thus play a significant role in the modulation of different diseases. Several studies have suggested that miRNA expression is dysregulated in various cancers through different mechanisms and the dysregulated miRNA in return affects different cancer hallmarks including cell proliferation, cell death suppression, metastasis and angiogenesis. Compilation of the available miRNA data can be a stimulator for proper understanding of the correlation between the miRNA expression and cancer progression. In this review, we have focussed on the role of miR-760 in the progression of different cancer. MicroRNA-760 (miR-760) has been found to be down regulated in various cancers, thus it can be utilized as a possible prognostic marker for cancer detection. Here, we have tried to fill a gap regarding the role of miR-760 in relation to cervical cancer also. Moreover, unravelling the role of miR-760 in different cancers will enlighten the researchers with proper understanding of biology of miR-760 in regulation of different cancers.
Collapse
Affiliation(s)
| | - Juveria Khan
- School of Biotechnology, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India
| | - Neeraj Verma
- School of Biotechnology, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India
| | - Pawan K Dhar
- School of Biotechnology, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India.
| |
Collapse
|
|
26
|
Nik Mohamed Kamal NNSB, Shahidan WNS. Non-Exosomal and Exosomal Circulatory MicroRNAs: Which Are More Valid as Biomarkers? Front Pharmacol 2020; 10:1500. [PMID: 32038230 PMCID: PMC6984169 DOI: 10.3389/fphar.2019.01500] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 11/19/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs with approximately 19–25 nucleotides that are involved in regulating a range of developmental and physiological processes. Non-exosomal circulating and exosomal miRNAs have also been proposed to be useful in diagnostics as biomarkers for diseases and different types of cancer. In this review, the quantity of miRNAs and of reliable experimental data analyses of miRNAs that come from exosomal and non-exosomal sources are discussed from the perspective of their use as biomarkers for cancer and other diseases, including viral infections, nervous system disorders, cardiovascular disorders, and diabetes. We summarize other research findings regarding the use of miRNA from these two sources as biomarkers in diagnostics and clinical use. The challenges in using miRNA from these two sources in cancer and disease diagnostics are evaluated and discussed. Validation of specific miRNA signatures as biomarkers is a critical milestone in diagnostics.
Collapse
Affiliation(s)
| | - Wan Nazatul Shima Shahidan
- Craniofacial Science Laboratory, School of Dental Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Malaysia
| |
Collapse
|
|
27
|
Jacobsen DP, Eriksen MB, Rajalingam D, Nymoen I, Nielsen MB, Einarsen S, Gjerstad J. Exposure to workplace bullying, microRNAs and pain; evidence of a moderating effect of miR-30c rs928508 and miR-223 rs3848900. Stress 2020; 23:77-86. [PMID: 31339402 DOI: 10.1080/10253890.2019.1642320] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Prolonged exposure to bullying behaviors may give rise to symptoms such as anxiety, depression and chronic pain. Earlier data suggest that these symptoms often are associated with stress-induced low-grade systemic inflammation. Here, using data from both animals and humans, we examined the moderating role of microRNAs (miRNAs, miRs) in this process. In the present study, a resident-intruder paradigm, blood samples, tissue harvesting and subsequent qPCR analyses were used to screen for stress-induced changes in circulating miRNAs in rats. The negative acts questionnaire (NAQ), TaqMan assays and a numeric rating scale (NRS) for pain intensity were then used to examine the associations among bullying behaviors, relevant miRNA polymorphisms and pain in a probability sample of 996 Norwegian employees. In rats, inhibited weight gain, reduced pituitary POMC expression, adrenal Nr3c1 mRNA downregulation, as well as increased miR-146a, miR-30c and miR-223 in plasma were observed following 1 week of repeated exposure to social stress. When following up the miRNA findings from the animal study in the human working population, a stronger relationship between NAQ and NRS scores was observed in subjects with the miR-30c GG genotype (rs928508) compared to other subjects. A stronger relationship between NAQ and NRS scores was also seen in men with the miR-223 G genotype (rs3848900) as compared to other men. Our findings show that social stress may induce many physiological changes including changed expression of miRNAs. We conclude that the miR-30c GG genotype in men and women, and the miR-223 G genotype in men, amplify the association between exposure to bullying behaviors and pain.Lay summaryUsing an animal model of social stress, we identified miR-146a, miR-30c and miR-223 as potentially important gene regulatory molecules that may be involved in the stress response. Interestingly, human genotypes affecting the expression of mature miR-30c and miR-223 had a moderating effect on the association between exposure to bullying and pain. Subjects with the miR-30c rs928508 GG genotype had a significantly stronger association between exposure to bullying behaviors and pain than other subjects. The same was observed in men with the miR-223 rs3848900 G genotype, as compared to other men.
Collapse
Affiliation(s)
- Daniel Pitz Jacobsen
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
| | | | | | | | - Morten Birkeland Nielsen
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
- Department for Psychosocial Science, University of Bergen, Bergen, Norway
| | - Ståle Einarsen
- Department for Psychosocial Science, University of Bergen, Bergen, Norway
| | - Johannes Gjerstad
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
- Department of Biosciences, University of Oslo, Oslo, Norway
- Department for Psychosocial Science, University of Bergen, Bergen, Norway
| |
Collapse
|
|
28
|
Sosanya NM, Kumar R, Clifford JL, Chavez R, Dimitrov G, Srinivasan S, Gautam A, Trevino AV, Williams M, Hammamieh R, Cheppudira BP, Christy RJ, Crimmins SL. Identifying Plasma Derived Extracellular Vesicle (EV) Contained Biomarkers in the Development of Chronic Neuropathic Pain. THE JOURNAL OF PAIN 2020; 21:82-96. [DOI: 10.1016/j.jpain.2019.05.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 05/09/2019] [Accepted: 05/24/2019] [Indexed: 12/29/2022]
|
|
29
|
Hasvik E, Schjølberg T, Jacobsen DP, Haugen AJ, Grøvle L, Schistad EI, Gjerstad J. Up-regulation of circulating microRNA-17 is associated with lumbar radicular pain following disc herniation. Arthritis Res Ther 2019; 21:186. [PMID: 31409426 PMCID: PMC6693234 DOI: 10.1186/s13075-019-1967-y] [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: 11/20/2018] [Accepted: 07/25/2019] [Indexed: 02/07/2023] Open
Abstract
Background Previous studies suggest that regulatory microRNAs (miRs) may modulate neuro-inflammatory processes. The purpose of the present study was to examine the role of miR-17 following intervertebral disc herniation. Methods In a cohort of 97 patients with leg pain and disc herniation verified on MRI, we investigated the association between circulating miR-17 and leg pain intensity. A rat model was used to examine possible changes in miR-17 expression in nucleus pulposus (NP) associated with leak of NP tissue out of the herniated disc. The functional role of miR-17 was addressed by transfection of miR-17 into THP-1 cells (human monocyte cell line). Results An association between the level of miR-17 in serum and the intensity of lumbar radicular pain was shown. Up-regulation of miR-17 in the rat NP tissue when applied onto spinal nerve roots and increased release of TNF following transfection of miR-17 into THP-1 cells were also observed. Hence, our data suggest that miR-17 may be involved in the pathophysiology underlying lumbar radicular pain after disc herniation. Conclusions We conclude that miR-17 may be associated with the intensity of lumbar radicular pain after disc herniation, possibly through a TNF-driven pro-inflammatory mechanism. Electronic supplementary material The online version of this article (10.1186/s13075-019-1967-y) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Eivind Hasvik
- Department of Physical Medicine and Rehabilitation, Østfold Hospital Trust, Grålum, Norway.
| | - Tiril Schjølberg
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
| | - Daniel Pitz Jacobsen
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
| | | | - Lars Grøvle
- Department of Rheumatology, Østfold Hospital Trust, Grålum, Norway
| | | | - Johannes Gjerstad
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
| |
Collapse
|
|
30
|
What is normal trauma healing and what is complex regional pain syndrome I? An analysis of clinical and experimental biomarkers. Pain 2019; 160:2278-2289. [DOI: 10.1097/j.pain.0000000000001617] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
31
|
Abstract
Peripheral nerve injuries and diseases often lead to pain persisting beyond the resolution of damage, indicating an active disease-promoting process, which may result in chronic pain. This is regarded as a maladaptive mechanism resulting from neuroinflammation that originally serves to promote regeneration and healing. Knowledge on these physiological and pathophysiological processes has accumulated over the last few decades and has started to yield potential therapeutic targets. Key players are macrophages, T-lymphocytes, cytokines, and chemokines. In the spinal cord and brain, microglia and astrocytes are involved. Recently, data have been emerging on the regulation of these players. MicroRNAs and other noncoding RNAs have been discussed as potential master switches that may link nerve injury, pain, and inflammation. Clinical disorders most intensely studied in the context of neuroinflammation and pain are the complex regional pain syndrome, polyneuropathies, postherpetic neuralgia, and the fibromyalgia syndrome, in which recently a neuropathic component has been described. Research from several groups has shown an important role of both proinflammatory and anti-inflammatory cytokines in neuropathic and other chronic pain states in humans. There is ample evidence of an analgesic action of anti-inflammatory cytokines in animal models. The interplay of anti-inflammatory cytokines and the nociceptive system provides possibilities and challenges concerning treatment strategies based on this concept.
Collapse
|
|
32
|
Ren K. Exosomes in perspective: a potential surrogate for stem cell therapy. Odontology 2018; 107:271-284. [PMID: 30324571 DOI: 10.1007/s10266-018-0395-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 10/05/2018] [Indexed: 12/12/2022]
Abstract
Exosomes as a unique subtype of small extracellular vesicles (sEVs) have attracted increasing interest in recent years in the fields of mesenchymal stromal cell (MSC) research. Studies have confirmed that exosomes derived from MSCs preserve immunosuppressive phenotype and can mimic therapeutic benefits of their parent cells. This review briefly summarizes most recent findings on the potential of exosomes as an alternative of therapeutic MSCs, focusing on the role of MSCs and their secreted exosomes in regulation of immune cells, preclinical and clinical evidence of therapeutic outcomes of MSC exosomes, and the biodistribution and pharmacokinetic profile of systemically administered exosomes. It is appreciated that exosomes from MSCs of different sources have variable contents including inflammatory mediators, tropic factors, signaling molecules, and nucleic acids (DNA, mRNA, microRNA and long non-coding RNA). Diverse functions of exosomes derived from different sources are expected. More importantly, exosomes isolated in vitro may not mirror that from in vivo, where donor MSCs are exposed to specific disease or injury-related conditions. Simulating in vivo microenvironment by pretreatment of MSCs with relevant chemical mediators may lead to their secretion of therapeutically more efficient exosomes/sEVs. However, we know very little about the key molecules involved and the differences between exosomes released under different conditions. These issues would be of tremendous interest to preclinical research that pursues exosome biology-underlain therapeutic mechanisms of MSCs. Further studies are expected to demonstrate the superiority of MSC-derived exsomes/sEVs as a pharmaceutical entity with regard to efficacy, safety, and practicability.
Collapse
Affiliation(s)
- Ke Ren
- Department of Neural and Pain Sciences, School of Dentistry, & Program in Neuroscience, University of Maryland, 650 W. Baltimore St, Dental-8 South, Baltimore, MD, 21201, USA.
| |
Collapse
|