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Zhao Y, Zhang Y, Liu X, Zhang J, Gao Y, Li S, Chang C, Liu X, Yang G. Comparative proteomic analysis of plasma exosomes reveals the functional contribution of N-acetyl-alpha-glucosaminidase to Parkinson's disease. Neural Regen Res 2025; 20:2998-3012. [PMID: 38993127 PMCID: PMC11826475 DOI: 10.4103/nrr.nrr-d-23-01500] [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: 09/05/2023] [Revised: 01/12/2024] [Accepted: 04/08/2024] [Indexed: 07/13/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202510000-00029/figure1/v/2024-11-26T163120Z/r/image-tiff Parkinson's disease is the second most common progressive neurodegenerative disorder, and few reliable biomarkers are available to track disease progression. The proteins, DNA, mRNA, and lipids carried by exosomes reflect intracellular changes, and thus can serve as biomarkers for a variety of conditions. In this study, we investigated alterations in the protein content of plasma exosomes derived from patients with Parkinson's disease and the potential therapeutic roles of these proteins in Parkinson's disease. Using a tandem mass tag-based quantitative proteomics approach, we characterized the proteomes of plasma exosomes derived from individual patients, identified exosomal protein signatures specific to patients with Parkinson's disease, and identified N-acetyl-alpha-glucosaminidase as a differentially expressed protein. N-acetyl-alpha-glucosaminidase expression levels in exosomes from the plasma of patients and healthy controls were validated by enzyme-linked immunosorbent assay and western blot. The results demonstrated that the exosomal N-acetyl-alpha-glucosaminidase concentration was not only lower in Parkinson's disease, but also decreased with increasing Hoehn-Yahr stage, suggesting that N-acetyl-alpha-glucosaminidase could be used to rapidly evaluate Parkinson's disease severity. Furthermore, western blot and immunohistochemistry analysis showed that N-acetyl-alpha-glucosaminidase levels were markedly reduced both in cells treated with 1-methyl-4-phenylpyridinium and cells overexpressing α-synuclein compared with control cells. Additionally, N-acetyl-alpha-glucosaminidase overexpression significantly increased cell viability and inhibited α-synuclein expression in 1-methyl-4-phenylpyridinium-treated cells. Taken together, our findings demonstrate for the first time that exosomal N-acetyl-alpha-glucosaminidase may serve as a biomarker for Parkinson's disease diagnosis, and that N-acetyl-alpha-glucosaminidase may reduce α-synuclein expression and 1-methyl-4-phenylpyridinium-induced neurotoxicity, thus providing a new therapeutic target for Parkinson's disease.
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Affiliation(s)
- Yuan Zhao
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Yidan Zhang
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Xin Liu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Jian Zhang
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Ya Gao
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Shuyue Li
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Cui Chang
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Xiang Liu
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Guofeng Yang
- Department of Geriatrics, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
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Mojadadi M, Amin B, Zeinali H, Nazemi S. Targeting glial activation to mitigate mirror-image and extraterritorial neuropathic pain in a CCI model of neuropathic pain in male rats. Physiol Rep 2025; 13:e70318. [PMID: 40268880 PMCID: PMC12018164 DOI: 10.14814/phy2.70318] [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: 12/12/2024] [Revised: 03/13/2025] [Accepted: 04/02/2025] [Indexed: 04/25/2025] Open
Abstract
Neuropathic pain (NP) arises from nerve damage or compression and often extends to the contralateral side of the body (mirror-image pain, MP) and adjacent non-injured areas (extraterritorial pain). This study investigates whether altered sensitivity in these contralateral and peripheral regions is mediated by glial cells, using the chronic constriction injury (CCI) model of NP. Thirty-two male Wistar rats were randomly assigned into four groups (8/group): sham, CCI + vehicle, CCI + minocycline (MIN;10 mg/kg), and CCI + pentoxifylline (PTX;8 mg/kg). The CCI model was employed for NP induction. MIN and PTX were administered intraperitoneally from postoperative days (POD)4 to POD14, once daily. Pain responses were assessed on POD0, 2, 6, 10, and14 using Hargreaves, von Frey, and Tail-flick tests. Western blot analysis was performed on POD14 to measure Iba1 and GFAP protein expression in the spinal cord hemispheres. Results revealed that post-injury treatment with MIN and PTX significantly reduced contralateral thermal hyperalgesia, mechanical allodynia, and tail-flick responses. Correspondingly, the contralateral spinal cord exhibited significantly decreased GFAP and Iba1 protein expression compared to the CCI + vehicle treated group. These findings suggest that post-injury glial cell inhibition effectively mitigates neuropathic pain and prevents the development of MP and extraterritorial pain. This highlights the potential for clinical applications targeting glial cells to manage NP even after nerve injury.
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Affiliation(s)
- Mohammad‐Shafi Mojadadi
- Department of Immunology, School of MedicineSabzevar University of Medical SciencesSabzevarIran
| | - Bahareh Amin
- Department of Physiology and Pharmacology, School of MedicineSabzevar University of Medical SciencesSabzevarIran
| | - Hossein Zeinali
- Department of Physiology and Pharmacology, School of MedicineQom University of Medical SciencesQomIran
| | - Samad Nazemi
- Department of Physiology and Pharmacology, Cellular and Molecular Research Center, School of MedicineSabzevar University of Medical SciencesSabzevarIran
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Erbacher C, Vaknine-Treidel S, Madrer N, Weinbender S, Evdokimov D, Unterecker S, Moshitzky G, Sommer C, Greenberg DS, Soreq H, Üçeyler N. Altered blood and keratinocyte microRNA/transfer RNA fragment profiles related to fibromyalgia syndrome and its severity. Pain 2024:00006396-990000000-00784. [PMID: 39679614 DOI: 10.1097/j.pain.0000000000003499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/05/2024] [Indexed: 12/17/2024]
Abstract
ABSTRACT Fibromyalgia syndrome (FMS) is a debilitating widespread chronic pain condition of unclear pathophysiology. We studied small noncoding RNAs as potential classifiers and mediators of FMS. Blood and keratinocyte microRNAs (miRs) and transfer RNA fragments (tRFs) were profiled by small RNA-sequencing within a comprehensively phenotyped female cohort of 53 patients with FMS vs 34 healthy controls (hCOs) and 15 patients with major depression and chronic physical pain (disease controls). Small RNAs were quantified via RNA-sequencing and candidates validated via qRT-PCR. MicroRNAs and tRFs were tested for association with FMS symptoms and their potential regulatory roles. miR and tRF profiles were altered in FMS compared to hCO in whole blood (n = 69; n = 22) and keratinocytes (n = 41; n = 55). Receiver operating characteristic analysis of blood miR candidates hsa-miR-148a-3p and hsa-miR-182-5p, and tRF candidate tRF-21-WB8647O5D levels separated FMS from hCO. In blood, hsa-miR-182-5p and hsa-miR-576-5p upregulation was validated via qRT-PCR, showing even higher expression in disease control, while TRF-20-40KK5Y93 was selectively increased in FMS. MicroRNAs in blood and keratinocytes were associated with how widespread pain manifested in patients. Keratinocyte tRFs correlated with loss of skin innervation. In blood, altered small RNAs were linked to immune and RNA processes, whereas in keratinocytes, adhesion and epithelial functions were targeted. Modulated tRFs shared sequence motifs in patients with FMS, which may promote concerted pathway regulation. Our findings show miRs/tRFs as key small RNAs dysregulation in FMS pathophysiology and open new perspectives for FMS diagnostics, symptom monitoring, and clinical management.
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Affiliation(s)
- Christoph Erbacher
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Shani Vaknine-Treidel
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Nimrod Madrer
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Sofia Weinbender
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Dimitar Evdokimov
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Stefan Unterecker
- Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Würzburg, Würzburg, Germany
| | - Gilli Moshitzky
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Claudia Sommer
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - David S Greenberg
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hermona Soreq
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
- The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Nurcan Üçeyler
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
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Basu P, Taylor BK. Neuropeptide Y Y2 receptors in acute and chronic pain and itch. Neuropeptides 2024; 108:102478. [PMID: 39461244 DOI: 10.1016/j.npep.2024.102478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/29/2024]
Abstract
Pain and itch are regulated by a diverse array of neuropeptides and their receptors in superficial laminae of the spinal cord dorsal horn (DH). Neuropeptide Y (NPY) is normally expressed on DH neurons but not sensory neurons. By contrast, the Npy2r receptor (Y2) is expressed on the central and peripheral terminals of sensory neurons but not on DH neurons. Neurophysiological slice recordings indicate that Y2-selective agonists inhibits spinal neurotransmitter release from sensory neurons. However, behavioral pharmacology studies indicate that Y2 agonists exert minimal changes in nociception, even after injury. Additional discrepancies in the behavioral actions of the Y2-antagonist BIIE0246 - reports of either pronociception or antinociception - have now been resolved. In the normal state, spinally-directed (intrathecal) administration of BIIE0246 elicits ongoing nociception, hypersensitivity to sensory stimulation, and aversion. Conversely, in the setting of nerve injury and inflammation, intrathecal BIIE024 reduced not only mechanical and thermal hypersensitivity, but also a measure of the affective dimension of pain (conditioned place preference). When administered in chronic pain models of latent sensitization, BIIE0246 produced a profound reinstatement of pain-like behaviors. We propose that tissue or nerve injury induces a G protein switch in the action of NPY-Y2 signaling from antinociception in the naïve state to the inhibition of mechanical and heat hyperalgesia in the injured state, and then a switch back to antinociception to keep LS in a state of remission. This model clarifies the pharmacotherapeutic potential of Y2 research, pointing to the development of a new non-opioid pharmacotherapy for chronic pain using Y2 antagonists in patients who do not develop LS.
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Affiliation(s)
- Paramita Basu
- Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for Pain Research, Pittsburgh Project to end Opioid Misuse, United States of America
| | - Bradley K Taylor
- Department of Anesthesiology and Perioperative Medicine, Pittsburgh Center for Pain Research, Pittsburgh Project to end Opioid Misuse, United States of America; Department of Pharmacology and Chemical Biology, United States of America; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States of America.
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Saateh A, Ansaryan S, Gao J, de Miranda LO, Zijlstra P, Altug H. Long-Term and Continuous Plasmonic Oligonucleotide Monitoring Enabled by Regeneration Approach. Angew Chem Int Ed Engl 2024; 63:e202410076. [PMID: 39146470 DOI: 10.1002/anie.202410076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/17/2024]
Abstract
The demand for continuous monitoring of biochemical markers for diagnostic purposes is increasing as it overcomes the limitations of traditional intermittent measurements. This study introduces a method for long-term, continuous plasmonic biosensing of oligonucleotides with high temporal resolution. Our method is based on a regeneration-based reversibility approach that ensures rapid reversibility in less than 1 minute, allowing the sensor to fully reset after each measurement. We investigated label-free and AuNP enhancements for different dynamic ranges and sensitivities, achieving a limit of detection down to pM levels. We developed a regeneration-based reversibility approach for continuous biosensing, optimizing buffer conditions using the Taguchi method to achieve rapid, consistent reversibility, ensuring reliable performance for long-term monitoring. We detected oligonucleotides in buffered and complex solutions, including undiluted and unfiltered human serum, for up to 100 sampling cycles in a day. Moreover, we showed the long-term stability of the sensor for monitoring capabilities in buffered solutions and human serum, with minimal signal value drift and excellent sensor reversibility for up to 9 days. Our method opens the door to new prospects in continuous biosensing by providing insights beyond intermittent measurements for numerous analytical and diagnostic applications.
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Affiliation(s)
- Abtin Saateh
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland
| | - Saeid Ansaryan
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland
| | - Jiarui Gao
- Department of Chemical Engineering, Tsinghua University, 100084, Beijing, P. R. China
| | - Livio Oliveira de Miranda
- Department of Applied Physics and Science Education, Eindhoven University of Technology, 5600 MB, Eindhoven, The Netherlands
| | - Peter Zijlstra
- Department of Applied Physics and Science Education, Eindhoven University of Technology, 5600 MB, Eindhoven, The Netherlands
| | - Hatice Altug
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland
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Tumolo MR, Bodini A, Bagordo F, Leo CG, Mincarone P, De Matteis E, Sabina S, Grassi T, Scoditti E. MiRNA Expression in Long-Distance Runners with Musculoskeletal Pain: Implications for Pain Pathophysiology. Biomedicines 2024; 12:2494. [PMID: 39595060 PMCID: PMC11591860 DOI: 10.3390/biomedicines12112494] [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: 09/10/2024] [Revised: 10/16/2024] [Accepted: 10/25/2024] [Indexed: 11/28/2024] Open
Abstract
Background: miRNAs are short, non-coding RNAs whose deregulation has been shown in painful processes, including musculoskeletal pain. This condition, which causes disability, impacts quality of life, and contributes to substantial healthcare costs, is also a critical issue in sports. In this case-control study, we evaluated the expression of four miRNAs involved in inflammation in runners with musculoskeletal pain and elucidated their functions and pathophysiological implications. Methods: A total of 17 runners with musculoskeletal pain and 17 age- and sex-matched runners without pain participated in this study. The levels of the miRNAs were evaluated by qRT-PCR. Bioinformatic tools were employed to identify the target genes and biological processes regulated by these miRNAs. Results: Compared to the controls, the runners with musculoskeletal pain exhibited significantly higher plasma levels of miR-133b (p = 0.02), miR-155-5p (p = 0.003) and let-7a-5p (p = 0.02). Multivariable regression analysis indicated that these three miRNAs exhibit a positive correlation (p < 0.05) with the presence of musculoskeletal pain, adjusted for age. Bioinformatic analysis suggested that the miRNAs hub genes are involved in regulatory processes, neuroinflammatory pathways, and human diseases that are associated with pain pathology. Conclusions: These results enhance our understanding of the potential role of miR-133b, miR-155-5p and let-7a-5p in pain-associated biological processes. The miRNA-mediated negative regulation of genes identified could explain the inflammatory and tissue repair processes in this population. Further studies are needed to confirm and validate the role of these miRNAs in painful conditions, especially considering the significant public health implications of managing inflammatory pain in sports.
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Affiliation(s)
- Maria Rosaria Tumolo
- Department of Biological & Environmental Sciences & Technology, University of Salento, 73100 Lecce, Italy;
- Branch of Lecce, National Research Council, Institute of Clinical Physiology, 73100 Lecce, Italy or (C.G.L.); (E.S.)
| | - Antonella Bodini
- National Research Council, Institute for Applied Mathematics & Information Technologies ‘E. Magenes’, 20133 Milan, Italy;
| | - Francesco Bagordo
- Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125 Bari, Italy;
| | - Carlo Giacomo Leo
- Branch of Lecce, National Research Council, Institute of Clinical Physiology, 73100 Lecce, Italy or (C.G.L.); (E.S.)
- MOVE-mentis s.r.l., 47522 Cesena, Italy;
| | - Pierpaolo Mincarone
- MOVE-mentis s.r.l., 47522 Cesena, Italy;
- Research Unit of Brindisi, National Research Council, Institute for Research on Population & Social Policies, 72100 Brindisi, Italy
| | | | - Saverio Sabina
- Branch of Lecce, National Research Council, Institute of Clinical Physiology, 73100 Lecce, Italy or (C.G.L.); (E.S.)
- MOVE-mentis s.r.l., 47522 Cesena, Italy;
| | - Tiziana Grassi
- Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy;
| | - Egeria Scoditti
- Branch of Lecce, National Research Council, Institute of Clinical Physiology, 73100 Lecce, Italy or (C.G.L.); (E.S.)
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Chen M, Yang Y, Cui J, Qiu L, Zou X, Zeng X. Upstream Stimulating Factor 2 Aggravates Spinal Nerve Ligation-Induced Neuropathic Pain in Mice via Regulating SNHG5/miR-181b-5p. Dev Neurosci 2024; 47:1-11. [PMID: 38471480 DOI: 10.1159/000538178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
INTRODUCTION Upstream stimulating factor 2 (USF2) belongs to basic Helix-Loop-Helix-Leucine zipper transcription factor family, regulating expression of genes involved in immune response or energy metabolism network. Role of USF2 in neuropathic pain was evaluated. METHODS Mice were intraspinally injected with adenovirus for knockdown of USF2 (Ad-shUSF2) and then subjected to spinal nerve ligation (SNL) to induce neuropathic pain. Distribution and expression of USF2 were detected by western blot and immunofluorescence. Mechanical and thermal pain sensitivity were examined by paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL). Chromatin immunoprecipitation (ChIP) and luciferase activity assays were performed to detect binding ability between USF2 and SNHG5. RESULTS The expression of USF2 was elevated and colocalized with astrocytes and microglia in L5 dorsal root ganglion (DRG) of SNL-induced mice. Injection of Ad-shUSF2 attenuated SNL-induced decrease of PWT and PWL in mice. Knockdown of USF2 increased the level of IL-10 but decreased TNF-α, IL-1β, and IL-6 in SNL-induced mice. Silence of USF2 enhanced protein expression of CD206 while reducing expression of CD16 and CD32 in SNL-induced mice. USF2 binds to promoter of SNHG5 and weakens SNL-induced up-regulation of SNHG5. SNHG5 binds to miR-181b-5p, and miR-181b-5p to interact with CXCL5. CONCLUSION Silence of USF2 ameliorated neuropathic pain, suppressed activation of M1 microglia, and inhibited inflammation in SNL-induced mice through regulation of SNHG5/miR-181b-5p/CXCL5 axis. Therefore, USF2/SNHG5/miR-181b-5p/CXCL5 might be a promising target for neuropathic pain. However, the effect of USF2/SNHG5/miR-181b-5p/CXCL5 on neuropathic pain should also be investigated in further research.
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Affiliation(s)
- Mi Chen
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yang Yang
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jiatian Cui
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Li Qiu
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaohua Zou
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xianggang Zeng
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
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Vali R, Azadi A, Tizno A, Farkhondeh T, Samini F, Samarghandian S. miRNA contributes to neuropathic pains. Int J Biol Macromol 2023; 253:126893. [PMID: 37730007 DOI: 10.1016/j.ijbiomac.2023.126893] [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: 05/13/2023] [Revised: 08/29/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023]
Abstract
Neuropathic pain (NP) is a kind of chronic pain caused by direct injury to the peripheral or central nervous system (CNS). microRNAs (miRNAs) are small noncoding RNAs that mostly interact with the 3 untranslated region of messenger RNAs (mRNAs) to regulate the expression of multiple genes. NP is characterized by changes in the expression of receptors and mediators, and there is evidence that miRNAs may contribute to some of these alterations. In this review, we aimed to fully comprehend the connection between NP and miRNA; and also, to establish a link between neurology, biology, and dentistry. Studies have shown that targeting miRNAs may be an effective therapeutic strategy for the treatment of chronic pain and potential target for the prevention of NP.
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Affiliation(s)
- Reyhaneh Vali
- Department of Biology, Faculty of Modern Science, Tehran Medical Branch, Islamic Azad University, Tehran, Iran; Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Azadi
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ashkan Tizno
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Farkhondeh
- Neuroscience Research Center, Kamyab Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariborz Samini
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran.
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Pando M, Yang R, Dimitrov G, Chavez R, Garza T, Trevino AV, Gautam A, Stark TR, Hammamieh R, Clifford J, Sosanya NM. Identifying Stress-Exacerbated Thermal-Injury Induced MicroRNAs. THE JOURNAL OF PAIN 2023; 24:2294-2308. [PMID: 37468024 DOI: 10.1016/j.jpain.2023.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 06/26/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023]
Abstract
Using a model of combat and operational stress reaction (COSR), our lab recently showed that exposure to an unpredictable combat stress (UPCS) procedure prior to a thermal injury increases pain sensitivity in male rats. Additionally, our lab has recently shown that circulating extracellular vesicle-microRNAs (EV-miRNAs), which normally function to suppress inflammation, were downregulated in a male rat model of neuropathic pain. In this current study, male and female rats exposed to UPCS, followed by thermal injury, were evaluated for changes in circulating EV-miRNAs. Adult female and male Sprague Dawley rats were exposed to a UPCS procedure for either 2 or 4 weeks. Groups consisted of the following: nonstress (NS), stress (S), NS + thermal injury (TI), and S + TI. Mechanical sensitivity was measured, and plasma was collected at baseline, throughout the UPCS exposure, and post-thermal injury. EV-miRNA isolation was performed, followed by small RNA sequencing and subsequent data analysis. UPCS exposure alone resulted in mechanical allodynia in both male and female rats at specific time points. Thermal-injury induction occurring at peak UPCS resulted in increased mechanical allodynia in the injured hind paw compared to thermal injury alone. Differential expression of the EV-miRNAs was observed between the NS and S groups as well as between NS + TI and S + TI groups. Consistent differences in EV-miRNAs are detectable in both COSR as well as during the development of mechanical sensitivity and potentially serve as key regulators, biomarkers, and targets in the treatment of COSR and thermal-injury induced mechanical sensitivity. PERSPECTIVE: This article presents the effects of unpredictable combat stress and thermal injury on EV-contained microRNAs in an animal model. These same mechanisms may exist in clinical patients and could be future prognostic and diagnostic biomarkers.
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Affiliation(s)
- Miryam Pando
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
| | - Ruoting Yang
- Medical Readiness Systems Biology Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland
| | - George Dimitrov
- Medical Readiness Systems Biology Branch, The Geneva Foundation, Tacoma, Washington
| | - Roger Chavez
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
| | - Thomas Garza
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
| | - Alex V Trevino
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
| | - Aarti Gautam
- Medical Readiness Systems Biology Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland
| | - Thomas R Stark
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
| | - Rasha Hammamieh
- Medical Readiness Systems Biology Branch, The Geneva Foundation, Tacoma, Washington
| | - John Clifford
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
| | - Natasha M Sosanya
- US Army Institute of Surgical Research (USAISR), JBSA Ft Sam Houston, San Antonio, Texas
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10
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Basu P, Maier C, Averitt DL, Basu A. NLR family pyrin domain containing 3 (NLRP3) inflammasomes and peripheral neuropathic pain - Emphasis on microRNAs (miRNAs) as important regulators. Eur J Pharmacol 2023; 955:175901. [PMID: 37451423 DOI: 10.1016/j.ejphar.2023.175901] [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: 02/18/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Neuropathic pain is caused by the lesion or disease of the somatosensory system and can be initiated and/or maintained by both central and peripheral mechanisms. Nerve injury leads to neuronal damage and apoptosis associated with the release of an array of pathogen- or damage-associated molecular patterns to activate inflammasomes. The activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to neuropathic pain and may represent a novel target for pain therapeutic development. In the current review, we provide an up-to-date summary of the recent findings on the involvement of NLRP3 inflammasome in modulating neuropathic pain development and maintenance, focusing on peripheral neuropathic conditions. Here we provide a detailed review of the mechanisms whereby NLRP3 inflammasomes contribute to neuropathic pain via (1) neuroinflammation, (2) apoptosis, (3) pyroptosis, (4) proinflammatory cytokine release, (5) mitochondrial dysfunction, and (6) oxidative stress. We then present the current research literature reporting on the antinociceptive effects of several natural products and pharmacological interventions that target activation, expression, and/or regulation of NLRP3 inflammasome. Furthermore, we emphasize the effects of microRNAs as another regulator of NLRP3 inflammasome. In conclusion, we summarize the possible caveats and future perspectives that might provide successful therapeutic approaches against NLRP3 inflammasome for treating or preventing neuropathic pain conditions.
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Affiliation(s)
- Paramita Basu
- Pittsburgh Center for Pain Research, The Pittsburgh Project to End Opioid Misuse, Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
| | - Camelia Maier
- Division of Biology, School of the Sciences, Texas Woman's University, Denton, TX, 76204-5799, USA.
| | - Dayna L Averitt
- Division of Biology, School of the Sciences, Texas Woman's University, Denton, TX, 76204-5799, USA.
| | - Arpita Basu
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, NV, 89154, USA.
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11
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Reddy D, Wickman JR, Ajit SK. Epigenetic regulation in opioid induced hyperalgesia. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2023; 14:100146. [PMID: 38099284 PMCID: PMC10719581 DOI: 10.1016/j.ynpai.2023.100146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/14/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023]
Abstract
About 25 million American adults experience pain daily and one of the most commonly prescribed drugs to treat pain are opioids. Prolonged opioid usage and dose escalations can cause a paradoxical response where patients experience enhanced pain sensitivity. This opioid induced hyperalgesia (OIH) is a major hurdle when treating pain in the clinic because its underlying mechanisms are still not fully understood. OIH is also commonly overlooked and lacks guidelines to prevent its onset. Research on pain disorders and opioid usage have recognized potential epigenetic drivers of disease including DNA methylation, histone modifications, miRNA regulation, but their involvement in OIH has not been well studied. This article discusses epigenetic changes that may contribute to pathogenesis, with an emphasis on miRNA alterations in OIH. There is a crucial gap in knowledge including how multiple epigenetic modulators contribute to OIH. Elucidating the epigenetic changes underlying OIH and the crosstalk among these mechanisms could lead to the development of novel targets for the prevention and treatment of this painful phenomena.
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Affiliation(s)
- Deepa Reddy
- Department of Pharmacology & Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Jason R. Wickman
- Department of Pharmacology & Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Seena K. Ajit
- Department of Pharmacology & Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
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12
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Demartini C, Francavilla M, Zanaboni AM, Facchetti S, De Icco R, Martinelli D, Allena M, Greco R, Tassorelli C. Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings. Int J Mol Sci 2023; 24:ijms24065334. [PMID: 36982428 PMCID: PMC10049673 DOI: 10.3390/ijms24065334] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 03/14/2023] Open
Abstract
In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.
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Affiliation(s)
- Chiara Demartini
- Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Miriam Francavilla
- Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Anna Maria Zanaboni
- Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Sara Facchetti
- Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy
| | - Roberto De Icco
- Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Daniele Martinelli
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Marta Allena
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Rosaria Greco
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
- Correspondence: ; Tel.: +39-(0382)-380255
| | - Cristina Tassorelli
- Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy
- Unit of Translational Neurovascular Research, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
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13
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Morchio M, Sher E, Collier DA, Lambert DW, Boissonade FM. The Role of miRNAs in Neuropathic Pain. Biomedicines 2023; 11:biomedicines11030775. [PMID: 36979754 PMCID: PMC10045079 DOI: 10.3390/biomedicines11030775] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Neuropathic pain is a debilitating condition affecting around 8% of the adult population in the UK. The pathophysiology is complex and involves a wide range of processes, including alteration of neuronal excitability and synaptic transmission, dysregulated intracellular signalling and activation of pro-inflammatory immune and glial cells. In the past 15 years, multiple miRNAs–small non-coding RNA–have emerged as regulators of neuropathic pain development. They act by binding to target mRNAs and preventing the translation into proteins. Due to their short sequence (around 22 nucleotides in length), they can have hundreds of targets and regulate several pathways. Several studies on animal models have highlighted numerous miRNAs that play a role in neuropathic pain development at various stages of the nociceptive pathways, including neuronal excitability, synaptic transmission, intracellular signalling and communication with non-neuronal cells. Studies on animal models do not always translate in the clinic; fewer studies on miRNAs have been performed involving human subjects with neuropathic pain, with differing results depending on the specific aetiology underlying neuropathic pain. Further studies using human tissue and liquid samples (serum, plasma, saliva) will help highlight miRNAs that are relevant to neuropathic pain diagnosis or treatment, as biomarkers or potential drug targets.
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Affiliation(s)
- Martina Morchio
- School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK
- The Neuroscience Institute, University of Sheffield, Sheffield S10 2TN, UK
| | - Emanuele Sher
- UK Neuroscience Hub, Eli Lilly and Company, Bracknell RG12 1PU, UK
| | - David A. Collier
- UK Neuroscience Hub, Eli Lilly and Company, Bracknell RG12 1PU, UK
| | - Daniel W. Lambert
- School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK
- The Neuroscience Institute, University of Sheffield, Sheffield S10 2TN, UK
| | - Fiona M. Boissonade
- School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK
- The Neuroscience Institute, University of Sheffield, Sheffield S10 2TN, UK
- Correspondence:
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14
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Giordano R, Gerra MC, Okutani H, Lo Vecchio S, Stensballe A, Petersen KKS, Arendt-Nielsen L. The temporal expression of circulating microRNAs after acute experimental pain in humans. Eur J Pain 2023; 27:366-377. [PMID: 36453122 DOI: 10.1002/ejp.2062] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/17/2022] [Accepted: 11/27/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) can modulate several biological systems, including the pain system. This study aimed to evaluate the temporal expression of circulating miRNAs in the plasma of healthy volunteers as a marker for epigenetic changes before and after an acute, experimental, pain provocation by intramuscular hypertonic saline injection. METHODS Twenty volunteers were randomly allocated into two groups and received either hypertonic (pain) or isotonic (control) saline injection in the first dorsal interosseous muscle of their dominant hand. Pain intensity was continuously recorded for 20 minutes after injection on a VAS scale from 0 to 100 (0 indicates no pain and 100 the worst imaginable pain). Blood samples were taken at baseline, 30 minutes, 3 hours, and 24 hours post-injection, and plasma was separated. MiRNA extracts were used for RNA sequencing with the Illumina NextSeq platform. MiRNA transcripts were compared between the pain and the no-pain, control group at every time point. Significant differences were considered when folds were >2 and the False Discovery Rate was p < 0.05. RESULTS After 30 minutes, 4 miRNAs were significantly altered in the pain group compared to controls, which increased to 24 after 3 hours and to 42 after 24 hours from baseline (p < 0.0001). Two miRNAs were consistently upregulated throughout the experiment. Enrichment analysis showed significant miRNAs involved in brain perception of pain, brain signalling and response to stimuli. CONCLUSIONS This exploratory study is the first to report on the temporal expression of circulating miRNAs after an acute, human experimental muscle pain model. SIGNIFICANCE This exploratory study evaluated the temporal profile of circulating miRNAs in the plasma of healthy subjects after acute experimental pain. Several miRNAs were altered in subjects at the times of follow-up after the acute pain model when compared to controls. MiRNAs previously associated with pain processes were altered in the pain group. Our results, by showing the fast and prolonged modifications of miRNA elicited by the acute experimental pain model, add new perspectives to the topic of epigenetics and pain.
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Affiliation(s)
- Rocco Giordano
- Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Department of Health Science and Technology, Faculty of Medicine, Aalborg, Denmark
| | - Maria Carla Gerra
- Department of Chemistry, Life science, and Environmental Sustainability, University of Parma, Parma, Italy
| | - Hiroai Okutani
- Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Department of Health Science and Technology, Faculty of Medicine, Aalborg, Denmark
- Department of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Silvia Lo Vecchio
- Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Department of Health Science and Technology, Faculty of Medicine, Aalborg, Denmark
| | - Allan Stensballe
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Kristian Kjaer-Staal Petersen
- Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Department of Health Science and Technology, Faculty of Medicine, Aalborg, Denmark
- Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA), Aalborg University, Department of Material and Production, Faculty of Engineering and Science, Aalborg, Denmark
| | - Lars Arendt-Nielsen
- Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Department of Health Science and Technology, Faculty of Medicine, Aalborg, Denmark
- Department of Gastroenterology & Hepatology, (Mech-Sense), Aalborg University Hospital, Aalborg, Denmark
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15
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Lu Y, Liu M, Guo X, Wang P, Zeng F, Wang H, Tang J, Qin Z, Tao T. miR-26a-5p alleviates CFA-induced chronic inflammatory hyperalgesia through Wnt5a/CaMKII/NFAT signaling in mice. CNS Neurosci Ther 2023; 29:1254-1271. [PMID: 36756710 PMCID: PMC10068476 DOI: 10.1111/cns.14099] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Inflammation often leads to the occurrence of chronic pain, and many miRNAs have been shown to play a key role in the development of inflammatory pain. However, whether miR-26a-5p relieves pain induced by inflammation and its possible mechanism are still unclear. METHODS The complete Freund's adjuvant (CFA)-induced inflammatory pain mouse model was employed. Intrathecal or subcutaneous injection of miR-26a-5p agomir was performed after modeling to study its antinociceptive effect and the comparison of different administration methods. Bioinformatics analysis of miRNAs was performed to study the downstream mechanisms of miR-26a-5p. HE staining, RT-qPCR, Western blotting, and immunofluorescence were used for further validation. RESULTS A single intrathecal and subcutaneous injection of miR-26a-5p both reversed mechanical hypersensitivity and thermal latency in the left hind paw of mice with CFA-induced inflammatory pain. HE staining and immunofluorescence studies found that both administrations of miR-26a-5p alleviated inflammation in the periphery and spinal cord. Bioinformatics analysis and dual-luciferase reporter gene analysis identified Wnt5a as a direct downstream target gene of miR-26a-5p. Wnt5a was mainly expressed in neurons and microglia in the spinal cord of mice with inflammatory pain. Intrathecal injection of miR-26a-5p could significantly reduce the expression level of Wnt5a and inhibit the downstream molecules of noncanonical Wnt signaling Camk2/NFAT, inhibiting the release of spinal cord inflammatory factors and alleviating the activation of microglia. In addition, miR-26a-5p could also inhibit lipopolysaccharide (LPS)-stimulated BV2 cell inflammation in vitro through a noncanonical Wnt signaling pathway. CONCLUSIONS miR-26a-5p is a promising therapy for CFA-induced inflammatory pain. Both intrathecal and subcutaneous injections provide relief for inflammatory pain. miR-26a-5p regulated noncanonical Wnt signaling to be involved in analgesia partly through antineuroinflammation, suggesting a pain-alleviating effect via noncanonical Wnt signaling pathway in the CFA-induced inflammatory pain model in vivo.
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Affiliation(s)
- Yitian Lu
- Department of Anesthesiology, Nanfang hospital, Southern Medical University, Guangzhou, China.,Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, China
| | - Maozhu Liu
- Department of pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangna Guo
- Department of Anesthesiology, Nanfang hospital, Southern Medical University, Guangzhou, China
| | - Peng Wang
- Department of Anesthesiology, Nanfang hospital, Southern Medical University, Guangzhou, China
| | - Fanning Zeng
- Department of Anesthesiology, Nanfang hospital, Southern Medical University, Guangzhou, China
| | - Haitao Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jing Tang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang hospital, Southern Medical University, Guangzhou, China
| | - Tao Tao
- Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, China
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16
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Zhang C, Talifu Z, Xu X, Liu W, Ke H, Pan Y, Li Y, Bai F, Jing Y, Li Z, Li Z, Yang D, Gao F, Du L, Li J, Yu Y. MicroRNAs in spinal cord injury: A narrative review. Front Mol Neurosci 2023; 16:1099256. [PMID: 36818651 PMCID: PMC9931912 DOI: 10.3389/fnmol.2023.1099256] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/12/2023] [Indexed: 02/05/2023] Open
Abstract
Spinal cord injury (SCI) is a global medical problem with high disability and mortality rates. At present, the diagnosis and treatment of SCI are still lacking. Spinal cord injury has a complex etiology, lack of diagnostic methods, poor treatment effect and other problems, which lead to the difficulty of spinal cord regeneration and repair, and poor functional recovery. Recent studies have shown that gene expression plays an important role in the regulation of SCI repair. MicroRNAs (miRNAs) are non-coding RNA molecules that target mRNA expression in order to silence, translate, or interfere with protein synthesis. Secondary damage, such as oxidative stress, apoptosis, autophagy, and inflammation, occurs after SCI, and differentially expressed miRNAs contribute to these events. This article reviews the pathophysiological mechanism of miRNAs in secondary injury after SCI, focusing on the mechanism of miRNAs in secondary neuroinflammation after SCI, so as to provide new ideas and basis for the clinical diagnosis and treatment of miRNAs in SCI. The mechanisms of miRNAs in neurological diseases may also make them potential biomarkers and therapeutic targets for spinal cord injuries.
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Affiliation(s)
- Chunjia Zhang
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Zuliyaer Talifu
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China
| | - Xin Xu
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Wubo Liu
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China,Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Han Ke
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China,Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Yunzhu Pan
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China
| | - Yan Li
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Fan Bai
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Yingli Jing
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Zihan Li
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Zehui Li
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Degang Yang
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Feng Gao
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Liangjie Du
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Jianjun Li
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China,Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China,*Correspondence: Jianjun Li,
| | - Yan Yu
- School of Rehabilitation, Capital Medical University, Beijing, China,,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,Yan Yu,
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17
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Hussein M, Fathy W, Abdelaleem EA, Nasser M, Yehia A, Elanwar R. The Impact of Micro RNA-320a Serum Level on Severity of Symptoms and Cerebral Processing of Pain in Patients with Fibromyalgia. PAIN MEDICINE (MALDEN, MASS.) 2022; 23:2061-2072. [PMID: 35587745 DOI: 10.1093/pm/pnac076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/28/2022] [Accepted: 05/10/2022] [Indexed: 11/12/2022]
Abstract
OBJECTIVES The aim of this work was to explore the expression of miR-320a level in fibromyalgia patients in comparison to healthy controls, and to clarify its impact on the severity of symptoms and the cerebral processing of pain assessed by middle latency somatosensory evoked potentials (SSEPs). DESIGN Case-control study. SETTING Rheumatology and Neurology outpatient clinics. SUBJECTS Seventy-four fibromyalgia patients and seventy-four normal healthy controls. METHODS The included patients were subjected to detailed history taking, assessment of severity of fibromyalgia symptoms using the Fibromyalgia Impact Questionnaire Revised (FIQR), assessment of pain intensity using the Neuropathic Pain Symptom Inventory (NPSI), measurement of the serum level of miR-320a in addition to of measurement peak latencies and amplitudes of middle latency SSEPs. RESULTS Fibromyalgia patients had significantly higher micro-RNA-320a levels (0.907 ± 0.022) in comparison to controls (0.874 ± 0.015) (P-value < .001). The mean values of micro-RNA-320a levels were significantly higher in fibromyalgia patients with insomnia, chronic fatigue syndrome, persistent depressive disorder, and primary headache disorder than those without (P-value = .024, <.001, .006, .036 respectively). There were statistically significant positive correlations between micro-RNA-320a levels, and disease duration, FIQR, and NPSI total scores (P-value <0.001, 0.003, 0.002 respectively). There were no statistically significant correlations between micro-RNA-320a levels and middle latency SSEPs. DISCUSSION Micro-RNA-320a level is significantly upregulated in fibromyalgia patient. It has a crucial impact on the severity of symptoms but not related to the cerebral processing of pain.
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Affiliation(s)
- Mona Hussein
- Department of Neurology, Beni-Suef University, Beni-Suef, Egypt
| | - Wael Fathy
- Department of Anaesthesia, Surgical ICU and Pain management, Beni-Suef University, Beni-Suef, Egypt
| | - Enas A Abdelaleem
- Department of Rheumatology and Rehabilitation, Beni-Suef University, Beni-Suef, Egypt
| | - Mona Nasser
- Department of Clinical and Chemical pathology, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed Yehia
- Department of Internal medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Rehab Elanwar
- Neuro diagnostic research center, Beni-Suef University, Beni-Suef, Egypt
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18
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Wang ZY, Wen ZJ, Xu HM, Zhang Y, Zhang YF. Exosomal noncoding RNAs in central nervous system diseases: biological functions and potential clinical applications. Front Mol Neurosci 2022; 15:1004221. [PMID: 36438184 PMCID: PMC9681831 DOI: 10.3389/fnmol.2022.1004221] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/18/2022] [Indexed: 09/26/2023] Open
Abstract
Central nervous system (CNS) disease is a general term for a series of complex and diverse diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), CNS tumors, stroke, epilepsy, and amyotrophic lateral sclerosis (ALS). Interneuron and neuron-glia cells communicate with each other through their homeostatic microenvironment. Exosomes in the microenvironment have crucial impacts on interneuron and neuron-glia cells by transferring their contents, such as proteins, lipids, and ncRNAs, constituting a novel form of cell-to-cell interaction and communication. Exosomal noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI-interacting RNAs (piRNAs), regulate physiological functions and maintain CNS homeostasis. Exosomes are regarded as extracellular messengers that transfer ncRNAs between neurons and body fluids due to their ability to cross the blood-brain barrier. This review aims to summarize the current understanding of exosomal ncRNAs in CNS diseases, including prospective diagnostic biomarkers, pathological regulators, therapeutic strategies and clinical applications. We also provide an all-sided discussion of the comparison with some similar CNS diseases and the main limitations and challenges for exosomal ncRNAs in clinical applications.
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Affiliation(s)
- Zhong-Yu Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Zeng-Jin Wen
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Hai-Ming Xu
- Department of Occupational and Environmental Medicine, School of Public Health and Management, Ningxia Medical University, Yinchuan, China
- The Key Laboratory of Environmental Factors and Chronic Disease Control of Ningxia, Ningxia Medical University, Yinchuan, China
| | - Yu Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Yin-Feng Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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Giordano R, Kjær-Staal Petersen K, Arendt-Nielsen L. The link between epigenetics, pain sensitivity and chronic pain. Scand J Pain 2022; 22:664-666. [PMID: 36149940 DOI: 10.1515/sjpain-2022-0086] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/18/2022] [Indexed: 11/15/2022]
Abstract
Increasing evidence suggests an association between gene expression and clinical pain. Epigenetic modifications are the main modulators of gene expression or protein translation in response to environmental stimuli and pathophysiological conditions. Preclinical and clinical studies indicate that epigenetic modifications could also impact the development of pain, the transition from acute to chronic pain, and the maintenance hereof.
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Affiliation(s)
- Rocco Giordano
- Center for Neuroplasticity and Pain (CNAP), SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Kristian Kjær-Staal Petersen
- Center for Neuroplasticity and Pain (CNAP), SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
- Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA), Department of Material and Production, Faculty of Engineering and Science, Aalborg University, Aalborg, Denmark
| | - Lars Arendt-Nielsen
- Center for Neuroplasticity and Pain (CNAP), SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
- Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA), Department of Material and Production, Faculty of Engineering and Science, Aalborg University, Aalborg, Denmark
- Department of Medical Gastroenterology, Mech-Sense, Aalborg University Hospital, Aalborg, Denmark
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20
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Ye Q, Huang Z, Lu W, Yan F, Zeng W, Xie J, Zhong W. Identification of the common differentially expressed genes and pathogenesis between neuropathic pain and aging. Front Neurosci 2022; 16:994575. [PMCID: PMC9626798 DOI: 10.3389/fnins.2022.994575] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 10/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background Neuropathic pain is a debilitating disease caused by damage or diseases of the somatosensory nervous system. Previous research has indicated potential associations between neuropathic pain and aging. However, the mechanisms by which they are interconnected remain unclear. In this study, we aim to identify the common differentially expressed genes (co-DEGs) between neuropathic pain and aging through integrated bioinformatics methods and further explore the underlying molecular mechanisms. Methods The microarray datasets GSE24982, GSE63442, and GSE63651 were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and co-DEGs were first identified. Functional enrichment analyses, protein-protein Interaction (PPI) network, module construction and hub genes identification were performed. Immune infiltration analysis was conducted. Targeted transcription factors (TFs), microRNAs (miRNAs) and potential effective drug compounds for hub genes were also predicted. Results A total of 563 and 1,250 DEGs of neuropathic pain and aging were screened, respectively. 16 genes were further identified as co-DEGs. The functional analysis emphasizes the vital roles of the humoral immune response and complement and coagulation cascades in these two diseases. Cxcl14, Fblim1, RT1-Da, Serping1, Cfd, and Fcgr2b were identified as hub genes. Activated B cell, mast cell, activated dendritic cell, CD56 bright natural killer cell, effector memory CD8 + T cell, and type 2 T helper cell were significantly up-regulated in the pain and aging condition. Importantly, hub genes were found to correlate with the activated B cell, activated dendritic cell, Gamma delta T cell, central memory CD4 + T cell and mast cell in pain and aging diseases. Finally, Spic, miR-883-5p, and miR-363-5p et al. were predicted as the potential vital regulators for hub genes. Aldesleukin, Valziflocept, MGD-010, Cinryze, and Rhucin were the potential effective drugs in neuropathic pain and aging. Conclusion This study identified co-DEGs, revealed molecular mechanisms, demonstrated the immune microenvironment, and predicted the possible TFs, miRNAs regulation networks and new drug targets for neuropathic pain and aging, providing novel insights into further research.
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Aczél T, Benczik B, Ágg B, Körtési T, Urbán P, Bauer W, Gyenesei A, Tuka B, Tajti J, Ferdinandy P, Vécsei L, Bölcskei K, Kun J, Helyes Z. Disease- and headache-specific microRNA signatures and their predicted mRNA targets in peripheral blood mononuclear cells in migraineurs: role of inflammatory signalling and oxidative stress. J Headache Pain 2022; 23:113. [PMID: 36050647 PMCID: PMC9438144 DOI: 10.1186/s10194-022-01478-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Migraine is a primary headache with genetic susceptibility, but the pathophysiological mechanisms are poorly understood, and it remains an unmet medical need. Earlier we demonstrated significant differences in the transcriptome of migraineurs' PBMCs (peripheral blood mononuclear cells), suggesting the role of neuroinflammation and mitochondrial dysfunctions. Post-transcriptional gene expression is regulated by miRNA (microRNA), a group of short non-coding RNAs that are emerging biomarkers, drug targets, or drugs. MiRNAs are emerging biomarkers and therapeutics; however, little is known about the miRNA transcriptome in migraine, and a systematic comparative analysis has not been performed so far in migraine patients. METHODS We determined miRNA expression of migraineurs' PBMC during (ictal) and between (interictal) headaches compared to age- and sex-matched healthy volunteers. Small RNA sequencing was performed from the PBMC, and mRNA targets of miRNAs were predicted using a network theoretical approach by miRNAtarget.com™. Predicted miRNA targets were investigated by Gene Ontology enrichment analysis and validated by comparing network metrics to differentially expressed mRNA data. RESULTS In the interictal PBMC samples 31 miRNAs were differentially expressed (DE) in comparison to healthy controls, including hsa-miR-5189-3p, hsa-miR-96-5p, hsa-miR-3613-5p, hsa-miR-99a-3p, hsa-miR-542-3p. During headache attacks, the top DE miRNAs as compared to the self-control samples in the interictal phase were hsa-miR-3202, hsa-miR-7855-5p, hsa-miR-6770-3p, hsa-miR-1538, and hsa-miR-409-5p. MiRNA-mRNA target prediction and pathway analysis indicated several mRNAs related to immune and inflammatory responses (toll-like receptor and cytokine receptor signalling), neuroinflammation and oxidative stress, also confirmed by mRNA transcriptomics. CONCLUSIONS We provide here the first evidence for disease- and headache-specific miRNA signatures in the PBMC of migraineurs, which might help to identify novel targets for both prophylaxis and attack therapy.
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Affiliation(s)
- Timea Aczél
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Bettina Benczik
- Cardiometabolic and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Bence Ágg
- Cardiometabolic and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Tamás Körtési
- MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary
| | - Péter Urbán
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Witold Bauer
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Attila Gyenesei
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Bernadett Tuka
- MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary
| | - János Tajti
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary
| | - Péter Ferdinandy
- Cardiometabolic and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - László Vécsei
- MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary
| | - Kata Bölcskei
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - József Kun
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary.
- PharmInVivo Ltd., Pécs, Hungary.
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti út 12, 7624, Pécs, Hungary.
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Liu Y, Jeon SM, Caterina MJ, Qu L. miR-544-3p mediates arthritis pain through regulation of FcγRI. Pain 2022; 163:1497-1510. [PMID: 34784311 PMCID: PMC9095766 DOI: 10.1097/j.pain.0000000000002531] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/15/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Chronic joint pain is a major symptom in rheumatoid arthritis (RA) and its adequate treatment represents an unmet medical need. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of RA as negative regulators of specific target mRNAs. Yet, their significance in RA pain is still not well defined. We and other groups recently identified neuronally expressed FcγRI as a key driver of arthritis pain in mouse RA models. Thus, we tested the hypothesis that miRNAs that target and regulate neuronal FcγRI attenuate RA pain. Here, we show that miR-544-3p was robustly downregulated, whereas FcγRI was significantly upregulated in the dorsal root ganglion (DRG) in mouse RA models. Intrathecal injection of miR-544-3p mimic attenuated established mechanical and heat hyperalgesia partly through the downregulation of FcγRI in the DRG in a mouse model of collagen II-induced arthritis. Moreover, this effect was likely mediated, at least in part, by FcγRI because miR-544-3p mimic downregulated Fcgr1 mRNA expression in the DRG during arthritis and genetic deletion of Fcgr1 produced similar antihyperalgesic effects in the collagen II-induced arthritis model. This notion was further supported by a dual luciferase assay showing that miR-544-3p directly targeted Fcgr1 3'UTR. In naïve mice, miR-544-3p mediated acute joint pain hypersensitivity induced by IgG immune complex through the regulation of FcγRI. These findings suggest that miR-544-3p causally participates in the maintenance of arthritis pain by targeting neuronal FcγRI, and thus define miR-544-3p as a new potential therapeutic target for treating RA pain.
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Affiliation(s)
- Yan Liu
- Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Sang-Min Jeon
- Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Michael J. Caterina
- Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD United States
- Department of Biological Chemistry, Johns Hopkins School of Medicine Baltimore, MD United Sates
| | - Lintao Qu
- Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD, United States
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Huang B, Guo S, Zhang Y, Lin P, Lin C, Chen M, Zhu S, Huang L, He J, Zhang L, Zheng Y, Wen Z. MiR-223-3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling. Brain Behav 2022; 12:e2634. [PMID: 35608154 PMCID: PMC9304854 DOI: 10.1002/brb3.2634] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 03/13/2022] [Accepted: 04/28/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Trigeminal neuralgia (TN) is a neuropathic pain that occurs in branches of the trigeminal nerve. MicroRNAs (miRNAs) have been considered key mediators of neuropathic pain. This study was aimed to elucidate the pathophysiological function and mechanisms of miR-223-3p in mouse models of TN. METHODS Infraorbital nerve chronic constriction injury (CCI-ION) was applied in male C57BL/6J mice to establish mouse models of TN. Pain responses were assessed utilizing Von Frey method. The expression of miR-223-3p, MKNK2, and MAPK/ERK pathway protein in trigeminal ganglions (TGs) of CCI-ION mice was measured using RT-qPCR and Western blotting. The concentrations of inflammatory cytokines were evaluated using Western blotting. The relationship between miR-223-3p and MKNK2 was tested by a luciferase reporter assay. RESULTS We found that miR-223-3p was downregulated, while MKNK2 was upregulated in TGs of CCI-ION mice. MiR-223-3p overexpression by an intracerebroventricular injection of Lv-miR-223-3p attenuated trigeminal neuropathic pain in CCI-ION mice, as well as reduced the protein levels of pro-inflammatory cytokines in TGs of CCI-ION mice. MKNK2 was verified to be targeted by miR-223-3p. Additionally, miR-223-3p overexpression decreased the phosphorylation levels of ERK1/2, JNK, and p38 protein in TGs of CCI-ION mice to inhibit MAPK/ERK signaling. CONCLUSIONS Overall, miR-223-3p attenuates the development of TN by targeting MKNK2 to suppress MAPK/ERK signaling.
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Affiliation(s)
- Bixia Huang
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Shaoyong Guo
- Department of Stomatology, The First Hospital of Putian City, Putian, China
| | - Yipan Zhang
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Pengxing Lin
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Changgui Lin
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Meixia Chen
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Shengyin Zhu
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Liyu Huang
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Junwei He
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Lingfeng Zhang
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Yanping Zheng
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Zhipeng Wen
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
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Diaz MM, Caylor J, Strigo I, Lerman I, Henry B, Lopez E, Wallace MS, Ellis RJ, Simmons AN, Keltner JR. Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain. FRONTIERS IN PAIN RESEARCH 2022; 3:869215. [PMID: 35634449 PMCID: PMC9130475 DOI: 10.3389/fpain.2022.869215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/21/2022] [Indexed: 01/09/2023] Open
Abstract
Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.
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Affiliation(s)
- Monica M. Diaz
- Department of Neurology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
| | - Jacob Caylor
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Irina Strigo
- Department of Psychiatry, San Francisco Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Imanuel Lerman
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Brook Henry
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - Eduardo Lopez
- Department of Psychiatry, San Francisco Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Mark S. Wallace
- Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States
| | - Ronald J. Ellis
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Alan N. Simmons
- Department of Psychiatry, San Diego & Center of Excellence in Stress and Mental Health, Veteran Affairs Health Care System, University of California, San Diego, San Diego, CA, United States
| | - John R. Keltner
- Department of Psychiatry, San Diego & San Diego VA Medical Center, University of California, San Diego, San Diego, CA, United States
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Distinct CholinomiR Blood Cell Signature as a Potential Modulator of the Cholinergic System in Women with Fibromyalgia Syndrome. Cells 2022; 11:cells11081276. [PMID: 35455956 PMCID: PMC9031252 DOI: 10.3390/cells11081276] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 11/25/2022] Open
Abstract
Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson’s disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.
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26
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Yin X, Zheng W, He L, Mu S, Shen Y, Wang J. CircHIPK3 alleviates inflammatory response and neuronal apoptosis via regulating miR-382-5p/DUSP1 axis in spinal cord injury. Transpl Immunol 2022; 73:101612. [DOI: 10.1016/j.trim.2022.101612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 10/18/2022]
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Mesenchymal Stem Cell-Derived Extracellular Vesicles and Their Therapeutic Use in Central Nervous System Demyelinating Disorders. Int J Mol Sci 2022; 23:ijms23073829. [PMID: 35409188 PMCID: PMC8998258 DOI: 10.3390/ijms23073829] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 02/04/2023] Open
Abstract
Autoimmune demyelinating diseases-including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease, acute disseminated encephalomyelitis, and glial fibrillary acidic protein (GFAP)-associated meningoencephalomyelitis-are a heterogeneous group of diseases even though their common pathology is characterized by neuroinflammation, loss of myelin, and reactive astrogliosis. The lack of safe pharmacological therapies has purported the notion that cell-based treatments could be introduced to cure these patients. Among stem cells, mesenchymal stem cells (MSCs), obtained from various sources, are considered to be the ones with more interesting features in the context of demyelinating disorders, given that their secretome is fully equipped with an array of anti-inflammatory and neuroprotective molecules, such as mRNAs, miRNAs, lipids, and proteins with multiple functions. In this review, we discuss the potential of cell-free therapeutics utilizing MSC secretome-derived extracellular vesicles-and in particular exosomes-in the treatment of autoimmune demyelinating diseases, and provide an outlook for studies of their future applications.
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28
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Analysis of Potential Hub Genes for Neuropathic Pain Based on Differential Expression in Rat Models. Pain Res Manag 2022; 2022:6571987. [PMID: 35281346 PMCID: PMC8913144 DOI: 10.1155/2022/6571987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/03/2022] [Accepted: 01/21/2022] [Indexed: 11/30/2022]
Abstract
Objective Neuropathic pain (NP) is a type of intractable chronic pain with complicated etiology. The exact molecular mechanism underlying NP remains unclear. In this study, we searched for molecular biomarkers of NP. Methods Differentially expressed genes (DEGs) were predicted by analyzing three NP-related microarray datasets in Gene Expression Omnibus with robust rank aggregation. A weighted gene coexpression network analysis was conducted to construct a network of differentially expressed genes, followed by the evaluation of correlations between gene sets and the determination of hub genes. The candidate genes from the key module were identified using a gene set enrichment analysis. Results In total, 353 upregulated and 383 downregulated genes were obtained, among which five hub genes were determined to be related to pain phenotypes. Reverse transcription-quantitative polymerase chain reaction was performed to verify the expression of these hub genes in the dorsal root ganglia of rats with spared nerve injury, which revealed the decreased expression of EMC4. Hence, EMC4 was defined as a biomarker for NP development. Conclusions The results of this study form a basis for further research into the mechanism of NP development and are expected to aid in the development of novel therapeutic strategies.
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Huang A, Ji L, Huang Y, Yu Q, Li Y. miR-185-5p alleviates CCI-induced neuropathic pain by repressing NLRP3 inflammasome through dual targeting MyD88 and CXCR4. Int Immunopharmacol 2022; 104:108508. [PMID: 34999395 DOI: 10.1016/j.intimp.2021.108508] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/28/2021] [Accepted: 12/28/2021] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are important modulators in the evolvement and progression of neuropathic pain (NP). According to reports, miR-185-5p contributes to various diseases and inflammatory responses. However, it is not clear whether miR-185-5p mediates neuroinflammation and NP following chronic constrictive injury (CCI). The CCI model was constructed in rats to induce NP. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were employed to evaluate pain threshold in CCI rats. The expression of miR-185-5p, GFAP, Iba1, Caspase-3-positive cells, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-labeled apoptotic neurons, inflammatory mediators, including interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) in lumbar portion (L4-L6) of CCI rats were determined. Furthermore, the targets of miR-185-5p were predicted by the Starbase, and the binding association between miR-185-5p and MyD88, miR-185-5p and CXCR4 was verified by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. As shown by the data, miR-185-5p was distinctly reduced in L4-L6 spinal cord tissues of rats after CCI. Up-regulating miR-185-5p alleviated mechanical and thermal hyperalgesia, inactivated microglia and astrocytes accumulation, and abated the contents of IL-1β, IL-6 and TNF-α in L4-L6 spinal cord tissues of CCI rats. Bioinformatics analysis suggested that MyD88 and CXCR4 were potential target genes of miR-185-5p. Increasing miR-185-5p expression notably impeded the expression of MyD88, CXCR4 and NLRP3 inflammasome in BV2 microglia, while attenuating miR-185-5p expression exerted the opposite effects. Notably, down-regulating MyD88 and CXCR4 significantly enhanced the miR-185-5p-mediated anti-inflammatory effects, and reversed miR-185-5p inhibitor-mediated proinflammatory effects. Additionally, up-regulating miR-185-5p repressed BV2-induced neuronal apoptosis and increased neuronal viability. In conclusion, this study suggested that miR-185-5p chokes CCI-induced NP and neuroinflammation by targeting MyD88 and CXCR4, indicating that miR-186-5p is an underlying therapeutic target for NP.
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Affiliation(s)
- Airu Huang
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, PR China
| | - Ling Ji
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, PR China
| | - Yilong Huang
- Gastrointestinal surgery, Pidu District People's Hospital, Chengdu, Sichuan 611730, PR China
| | - Qian Yu
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, PR China.
| | - Yufeng Li
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, PR China.
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Hu C, He M, Xu Q, Tian W. Advances With Non-coding RNAs in Neuropathic Pain. Front Neurosci 2022; 15:760936. [PMID: 35002601 PMCID: PMC8733285 DOI: 10.3389/fnins.2021.760936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/29/2021] [Indexed: 12/22/2022] Open
Abstract
Neuropathic pain (NP) is one of the most common types of clinical pain. The common causes of this syndrome include injury to the central or peripheral nervous systems and pathological changes. NP is characterized by spontaneous pain, hyperalgesia, abnormal pain, and paresthesia. Because of its diverse etiology, the pathogenesis of NP has not been fully elucidated and has become one of the most challenging problems in clinical medicine. This kind of pain is extremely resistant to conventional treatment and is accompanied by serious complications. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), contribute to diverse biological processes by regulating the expression of various mRNAs involved in pain-related pathways, at the posttranscriptional level. Abnormal regulation of ncRNAs is closely related to the occurrence and development of NP. In this review, we summarize the current state of understanding of the roles of different ncRNAs in the development of NP. Understanding these mechanisms can help develop novel therapeutic strategies to prevent or treat chronic pain.
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Affiliation(s)
- Cheng Hu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Menglin He
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Qian Xu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Weiqian Tian
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
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Ouerdane Y, Hassaballah MY, Nagah A, Ibrahim TM, Mohamed HAH, El-Baz A, Attia MS. Exosomes in Parkinson: Revisiting Their Pathologic Role and Potential Applications. Pharmaceuticals (Basel) 2022; 15:76. [PMID: 35056133 PMCID: PMC8778520 DOI: 10.3390/ph15010076] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, and tremor. Considerable progress has been made to understand the exact mechanism leading to this disease. Most of what is known comes from the evidence of PD brains' autopsies showing a deposition of Lewy bodies-containing a protein called α-synuclein (α-syn)-as the pathological determinant of PD. α-syn predisposes neurons to neurotoxicity and cell death, while the other associated mechanisms are mitochondrial dysfunction and oxidative stress, which are underlying precursors to the death of dopaminergic neurons at the substantia nigra pars compacta leading to disease progression. Several mechanisms have been proposed to unravel the pathological cascade of these diseases; most of them share a particular similarity: cell-to-cell communication through exosomes (EXOs). EXOs are intracellular membrane-based vesicles with diverse compositions involved in biological and pathological processes, which their secretion is driven by the NLR family pyrin domain-containing three proteins (NLRP3) inflammasome. Toxic biological fibrils are transferred to recipient cells, and the disposal of damaged organelles through generating mitochondrial-derived vesicles are suggested mechanisms for developing PD. EXOs carry various biomarkers; thus, they are promising to diagnose different neurological disorders, including neurodegenerative diseases (NDDs). As nanovesicles, the applications of EXOs are not only restricted as diagnostics but also expanded to treat NDDs as therapeutic carriers and nano-scavengers. Herein, the aim is to highlight the potential incrimination of EXOs in the pathological cascade and progression of PD and their role as biomarkers and therapeutic carriers for diagnosing and treating this neuro-debilitating disorder.
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Affiliation(s)
| | - Mohamed Y. Hassaballah
- Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (M.Y.H.); (A.N.); (H.A.H.M.); (A.E.-B.)
| | - Abdalrazeq Nagah
- Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (M.Y.H.); (A.N.); (H.A.H.M.); (A.E.-B.)
| | - Tarek M. Ibrahim
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Hosny A. H. Mohamed
- Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (M.Y.H.); (A.N.); (H.A.H.M.); (A.E.-B.)
| | - Areej El-Baz
- Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; (M.Y.H.); (A.N.); (H.A.H.M.); (A.E.-B.)
| | - Mohamed S. Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
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Expression of Selected microRNAs in Migraine: A New Class of Possible Biomarkers of Disease? Processes (Basel) 2021. [DOI: 10.3390/pr9122199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Preliminary but convergent findings suggest a role for microRNAs (miRNAs) in the generation and maintenance of chronic pain and migraine. Initial observations showed that serum levels of miR-382-5p and miR-34a-5p expression were increased in serum during the migraine attack, with miR-382-5p increasing in the interictal phase as well. By contrast, miR-30a-5p levels were lower in migraine patients compared to healthy controls. Of note, antimigraine treatments proved to be capable of influencing the expression of these miRNAs. Altogether, these observations suggest that miRNAs may represent migraine biomarkers, but several points are yet to be elucidated. A major concern is that these miRNAs are altered in a broad spectrum of painful and non-painful conditions, and thus it is not possible to consider them as truly “migraine-specific” biomarkers. We feel that these miRNAs may represent useful tools to uncover and define different phenotypes across the migraine spectrum with different treatment susceptibilities and clinical features, although further studies are needed to confirm our hypothesis. In this narrative review we provide an update and a critical analysis of available data on miRNAs and migraines in order to propose possible interpretations. Our main objective is to stimulate research in an area that holds promise when it comes to providing reliable biomarkers for theoretical and practical scientific advances.
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Cámara MS, Martín Bujanda M, Mendioroz Iriarte M. Epigenetic changes in headache. NEUROLOGÍA (ENGLISH EDITION) 2021; 36:369-376. [PMID: 34714235 DOI: 10.1016/j.nrleng.2017.10.006] [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: 10/06/2017] [Accepted: 10/10/2017] [Indexed: 10/26/2022] Open
Abstract
INTRODUCTION Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target. METHODS We performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA. RESULTS A total of 15 English-language publications related to the above terms were obtained. CONCLUSION There is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets.
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Affiliation(s)
- M S Cámara
- Servicio de Neurología, Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Spain
| | - M Martín Bujanda
- Servicio de Neurología, Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Spain
| | - M Mendioroz Iriarte
- Servicio de Neurología, Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Spain; Laboratorio de Neuroepigenética, Navarrabiomed, IdiSNA, Pamplona, Spain.
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Begenisic T, Pavese C, Aiachini B, Nardone A, Rossi D. Dynamics of biomarkers across the stages of traumatic spinal cord injury - implications for neural plasticity and repair. Restor Neurol Neurosci 2021; 39:339-366. [PMID: 34657853 DOI: 10.3233/rnn-211169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Traumatic spinal cord injury (SCI) is a complex medical condition causing significant physical disability and psychological distress. While the adult spinal cord is characterized by poor regenerative potential, some recovery of neurological function is still possible through activation of neural plasticity mechanisms. We still have limited knowledge about the activation of these mechanisms in the different stages after human SCI. OBJECTIVE In this review, we discuss the potential role of biomarkers of SCI as indicators of the plasticity mechanisms at work during the different phases of SCI. METHODS An extensive review of literature related to SCI pathophysiology, neural plasticity and humoral biomarkers was conducted by consulting the PubMed database. Research and review articles from SCI animal models and SCI clinical trials published in English until January 2021 were reviewed. The selection of candidates for humoral biomarkers of plasticity after SCI was based on the following criteria: 1) strong evidence supporting involvement in neural plasticity (mandatory); 2) evidence supporting altered expression after SCI (optional). RESULTS Based on selected findings, we identified two main groups of potential humoral biomarkers of neural plasticity after SCI: 1) neurotrophic factors including: Brain derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrofin-3 (NT-3), and Insulin-like growth factor 1 (IGF-1); 2) other factors including: Tumor necrosis factor-alpha (TNF-α), Matrix Metalloproteinases (MMPs), and MicroRNAs (miRNAs). Plasticity changes associated with these biomarkers often can be both adaptive (promoting functional improvement) and maladaptive. This dual role seems to be influenced by their concentrations and time-window during SCI. CONCLUSIONS Further studies of dynamics of biomarkers across the stages of SCI are necessary to elucidate the way in which they reflect the remodeling of neural pathways. A better knowledge about the mechanisms underlying plasticity could guide the selection of more appropriate therapeutic strategies to enhance positive spinal network reorganization.
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Affiliation(s)
- Tatjana Begenisic
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Chiara Pavese
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Beatrice Aiachini
- Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Antonio Nardone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurorehabilitation and Spinal Units, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
| | - Daniela Rossi
- Laboratory for Research on Neurodegenerative Disorders, ICS Maugeri SPA SB, Institute of Pavia, IRCCS, Pavia, Italy
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Qureshi AG, Jha SK, Iskander J, Avanthika C, Jhaveri S, Patel VH, Rasagna Potini B, Talha Azam A. Diagnostic Challenges and Management of Fibromyalgia. Cureus 2021; 13:e18692. [PMID: 34786265 PMCID: PMC8580749 DOI: 10.7759/cureus.18692] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
The World Health Organization regards chronic pain to be a public health concern. In clinical medicine, fibromyalgia (FM) is the most prevalent chronic widespread pain disease. In terms of impairment, consumption of health and social resources, and impact on primary and speciality care systems, it has reached worrisome proportions. This disease is frequently managed by primary care providers. Because of its intricacy, fibromyalgia diagnosis and treatment can be difficult. Fibromyalgia is a controversial condition. It might appear ill-defined in comparison to other pain conditions, with no clear knowledge of pathophysiology and hence no particular targeted therapy. This invariably sparks debates and challenges. There is no obvious cut-off point that distinguishes FM from non-FM. The diagnosis of fibromyalgia has been complicated by several factors, including patients' health-seeking behaviour, symptom identification, and physician labelling of the disease. Fibromyalgia is currently considered a centralized pain condition, according to research that has improved our understanding of its etiopathology. A multidisciplinary strategy combining pharmacological and non-pharmacological therapies based on a biopsychosocial paradigm can result in effective therapy. Cultural and psychosocial variables appear to be a recent development in fibromyalgia, and they appear to have a larger influence on physician diagnosis than severe symptom levels in FM patients. Although physicians rely on FM criteria as the only way to classify FM patients in research and clinical settings, some crucial elements of the diagnostic challenge of fibromyalgia remain unsolved - invalidation, psychosocial variables, and diverse illness manifestation are some examples. Beyond the existing constructional scores, physicians' judgment gained in real communicative contexts with patients, appears to be the only dependable route for a more accurate diagnosis for fibromyalgia. We have performed an exhaustive review of the literature using the keywords "Fibromyalgia", "challenges" and "diagnosis" in PubMed and Google Scholar indexes up to September 2021. This article aims to examine the causes, diagnosis, and current treatment protocols of FM, as well as discuss some continuing debates and diagnostic challenges which physicians face in accurately diagnosing fibromyalgia.
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Affiliation(s)
- Aniqa G Qureshi
- Medicine and Surgery, Jinggangshan Medical University, Jian, CHN
| | - Saurav K Jha
- Internal Medicine, Kankai Hospital, Birtamode, NPL
| | - John Iskander
- Family Medicine, American University of Antigua, St. John's, ATG
| | - Chaithanya Avanthika
- Medicine and Surgery, Karnataka Institute of Medical Sciences, Hubli, IND
- Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
| | - Sharan Jhaveri
- Medicine, Smt Nathiba Hargovandas Lakhmichand Municipal Medical College (NHLMMC), Ahmedabad, IND
| | - Vithi Hitendra Patel
- Family Medicine, GMERS Medical College and Hospital, Valsad, IND
- Internal Medicine, Gujarat Cancer Society Medical College and Research Center, Ahmedabad, IND
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Cai M, Chai S, Xiong T, Wei J, Mao W, Zhu Y, Li X, Wei W, Dai X, Yang B, Liu W, Shu B, Wang M, Lu T, Cai Y, Zheng Z, Mei Z, Zhou Y, Yang J, Zhao J, Shen L, Ho JWK, Chen J, Xiong N. Aberrant Expression of Circulating MicroRNA Leads to the Dysregulation of Alpha-Synuclein and Other Pathogenic Genes in Parkinson's Disease. Front Cell Dev Biol 2021; 9:695007. [PMID: 34497805 PMCID: PMC8419519 DOI: 10.3389/fcell.2021.695007] [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: 04/14/2021] [Accepted: 07/05/2021] [Indexed: 12/23/2022] Open
Abstract
A group of circulating microRNAs (miRNAs) have been implicated in the pathogenesis of Parkinson’s disease. However, a comprehensive study of the interactions between pathogenic miRNAs and their downstream Parkinson’s disease (PD)-related target genes has not been performed. Here, we identified the miRNA expression profiles in the plasma and circulating exosomes of Parkinson’s disease patients using next-generation RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that the miRNA target genes were enriched in axon guidance, neurotrophin signaling, cellular senescence, and the Transforming growth factor-β (TGF-β), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) signaling pathways. Furthermore, a group of aberrantly expressed miRNAs were selected and further validated in individual patient plasma, human neural stem cells (NSCs) and a rat model of PD. More importantly, the full scope of the regulatory network between these miRNAs and their PD-related gene targets in human neural stem cells was examined, and the findings revealed a similar but still varied downstream regulatory cascade involving many known PD-associated genes. Additionally, miR-23b-3p was identified as a novel direct regulator of alpha-synuclein, which is possibly the key component in PD. Our current study, for the first time, provides a glimpse into the regulatory network of pathogenic miRNAs and their PD-related gene targets in PD. Moreover, these PD-associated miRNAs may serve as biomarkers and novel therapeutic targets for PD.
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Affiliation(s)
- Meng Cai
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,iRegene Therapeutics, Wuhan, China
| | - Songshan Chai
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Tao Xiong
- Department of Neurology, Fifth Hospital in Wuhan, Wuhan, China
| | - Jun Wei
- iRegene Therapeutics, Wuhan, China
| | | | | | - Xiang Li
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Wei
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xuan Dai
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bangkun Yang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wen Liu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bing Shu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengyang Wang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Taojunjin Lu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuankun Cai
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhixin Zheng
- The Second Clinical College of Wuhan University, Wuhan, China
| | - Zhimin Mei
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yixuan Zhou
- The Second Clinical College of Wuhan University, Wuhan, China
| | - Jingyi Yang
- The Second Clinical College of Wuhan University, Wuhan, China
| | - Jingwei Zhao
- The Second Clinical College of Wuhan University, Wuhan, China
| | - Lei Shen
- The Second Clinical College of Wuhan University, Wuhan, China
| | - Joshua Wing Kei Ho
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Jincao Chen
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Nanxiang Xiong
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
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Gao P, Zeng X, Zhang L, Wang L, Shen LL, Hou YY, Zhou F, Zhang X. Overexpression of miR-378 Alleviates Chronic Sciatic Nerve Injury by Targeting EZH2. Neurochem Res 2021; 46:3213-3221. [PMID: 34406548 DOI: 10.1007/s11064-021-03424-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 07/12/2021] [Accepted: 08/06/2021] [Indexed: 11/25/2022]
Abstract
In numerous studies, microRNAs (miRNAs) have been authenticated to play vital roles in the pathophysiology of neuropathic pain and other neurological diseases. In our study, we focused on evaluating miR-378 and its potential effects in neuropathic pain development, as well as the underlying molecular mechanisms. Primarily, a chronic sciatic nerve injury (CCI) rat model was established. Next, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to measure the expression levels of miR-378 and EZH2 mRNA; the EZH2 protein expression levels were detected by western blot. A luciferase activity assay monitored the interaction of miR-378 and EZH2. Mechanical and thermal hyperalgesia was also performed to quantitate the effects of overexpression of miR-378 or EZH2 on the CCI rats. We found that miR-378 was down-regulated in the CCI rats, and the overexpression of miR-378 produced significant relief in their pain management. EZH2 was the downstream gene of miR-378 and was negatively regulated by miR-378. The up-regulation of EZH2 reduced the inhibitory effects of miR-378 on the development of neuropathic pain in the CCI rats. miR-378 acts as an inhibitor in the progression of neuropathic pain via targeting EZH2; the miR-378/EZH2 axis may be a novel target for the diagnosis and therapy of neuropathic pain in clinical treatment.
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Affiliation(s)
- Pengfei Gao
- Department of Anesthesiology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xin Zeng
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Hubei Province, Wuhan, China
| | - Lin Zhang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Hubei Province, Wuhan, China
| | - Long Wang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Hubei Province, Wuhan, China
| | - Lu-Lu Shen
- Department of Anesthesiology, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, 66 Huaihai South Road, Huai'an, Jiangsu, China
| | - Ya-Yun Hou
- Department of Anesthesiology, Huai'an Hospital of Traditional Chinese Medicine, 3 Heping Road, Huai'an, Jiangsu, China
| | - Fang Zhou
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Hubei Province, Wuhan, China
| | - Xianlong Zhang
- Department of Anesthesiology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
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Insights into the role of epigenetic mechanisms in migraine: the future perspective of disease management. THE NUCLEUS 2021. [DOI: 10.1007/s13237-021-00366-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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Giordano R, Petersen KK, Santoro M, Pazzaglia C, Simonsen O, Valeriani M, Arendt-Nielsen L. Circulating long non-coding RNA signature in knee osteoarthritis patients with postoperative pain one-year after total knee replacement. Scand J Pain 2021; 21:823-830. [PMID: 34323060 DOI: 10.1515/sjpain-2021-0069] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The incidence of chronic postoperative pain after total knee replacement (TKR) is approx. 20%, and hence preoperative risk factors are important to identify. Recent studies have indicated that preoperative inflammatory markers might hold prognostic information for the development of chronic postoperative pain. Long non-coding RNA (lncRNA) regulates the expression of genes related to e.g. inflammatory processes. The current study aimed to investigate the preoperative lncRNA signature as possible preoperative predictive markers for chronic postoperative pain following TKR. METHODS Serum samples, collected preoperatively from 20 knee osteoarthritis (KOA) patients, were analyzed for 84 validated circulatory lncRNA. Pain intensity was assessed using a visual analog scale (VAS) before and one-year after TKR. Differences for the lncRNA expression were analyzed between patients with chronic postoperative pain (VAS≥3) and those with a normal postoperative recovery (VAS<3). RESULTS LncRNA Myeloid Zinc Finger 1 Antisense RNA 1 (MZF1-AS1) (fold change -3.99; p-value: 0.038) (shown to be involved neuropathic pain) Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (fold change -3.39; p-value: 0.044) (shown to be involved neuropathic pain); Patched 1 pseudogene (LOC100287846) (fold change -6.99; p-value: 0.029) (unknown in pain) were down-regulated preoperatively in the group with chronic postoperative pain compared to the group normal postoperative pain recovery. CONCLUSIONS These findings suggest, that TKR patients with chronic postoperative pain present preoperative downregulations of three specific lncRNA detectable at the systemic level. The presented study might give new insights into the complexity of chronic postoperative pain development and show how non-coding RNA plays a role in the underlying molecular mechanisms of pain.
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Affiliation(s)
- Rocco Giordano
- Department of Health Science and Technology, Faculty of Medicine, Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Aalborg, Denmark
| | - Kristian Kjær Petersen
- Department of Health Science and Technology, Faculty of Medicine, Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Aalborg, Denmark.,Department of Health Science and Technology, Faculty of Medicine, Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark
| | - Massimo Santoro
- Laboratory "Health and Environment" Division of Health Protection Technologies, ENEA-Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Rome, Italy
| | - Costanza Pazzaglia
- Unit of High Intensity Neurorehabilitation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ole Simonsen
- Orthopedic Surgery Research Unit, Aalborg University Hospital, Aalborg, Denmark
| | - Massimiliano Valeriani
- Department of Health Science and Technology, Faculty of Medicine, Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark.,Department of Neuroscience and Neurorehabilitation, Child Neurology Unit, Headache Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Lars Arendt-Nielsen
- Department of Health Science and Technology, Faculty of Medicine, Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark
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A comprehensive review on biomarkers associated with painful temporomandibular disorders. Int J Oral Sci 2021; 13:23. [PMID: 34326304 PMCID: PMC8322104 DOI: 10.1038/s41368-021-00129-1] [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: 01/12/2021] [Revised: 06/05/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023] Open
Abstract
Pain of the orofacial region is the primary complaint for which patients seek treatment. Of all the orofacial pain conditions, one condition that possess a significant global health problem is temporomandibular disorder (TMD). Patients with TMD typically frequently complaints of pain as a symptom. TMD can occur due to complex interplay between peripheral and central sensitization, endogenous modulatory pathways, and cortical processing. For diagnosis of TMD pain a descriptive history, clinical assessment, and imaging is needed. However, due to the complex nature of pain an additional step is needed to render a definitive TMD diagnosis. In this review we explicate the role of different biomarkers involved in painful TMD. In painful TMD conditions, the role of biomarkers is still elusive. We believe that the identification of biomarkers associated with painful TMD may stimulate researchers and clinician to understand the mechanism underlying the pathogenesis of TMD and help them in developing newer methods for the diagnosis and management of TMD. Therefore, to understand the potential relationship of biomarkers, and painful TMD we categorize the biomarkers as molecular biomarkers, neuroimaging biomarkers and sensory biomarkers. In addition, we will briefly discuss pain genetics and the role of potential microRNA (miRNA) involved in TMD pain.
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Giordano R, Petersen KK, Andersen HH, Lichota J, Valeriani M, Simonsen O, Arendt-Nielsen L. Preoperative serum circulating microRNAs as potential biomarkers for chronic postoperative pain after total knee replacement. Mol Pain 2021; 16:1744806920962925. [PMID: 33021154 PMCID: PMC7543153 DOI: 10.1177/1744806920962925] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Chronic postoperative pain affects approximately 20% of patients with knee
osteoarthritis after total knee replacement. Circulating microRNAs can be
found in serum and might act as biomarkers in a variety of diseases. The
current study aimed to investigate the preoperative expression of
circulating microRNAs as potential predictive biomarkers for the development
of chronic postoperative pain in the year following total knee
replacement. Methods Serum samples, collected preoperatively from 136 knee osteoarthritis
patients, were analyzed for 21 circulatory microRNAs. Pain intensity was
assessed using a visual analog scale before and one year after total knee
replacement. Patients were divided into a low-pain relief group (pain relief
percentage <30%) and a high-pain relief group (pain relief percentage
>30%) based on their pain relief one year after total knee replacement,
and differences in microRNAs expression were analyzed between the two
groups. Results We found that three microRNAs were preoperatively dysregulated in serum in
the low-pain relief group compared with the high-pain relief group.
MicroRNAs hsa-miR-146a-5p, -145-5p, and -130 b-3p exhibited fold changes of
1.50, 1.55, and 1.61, respectively, between the groups (all P
values < 0.05). Hsa-miR-146a-5p and preoperative pain intensity
correlated positively with postoperative pain relief (respectively,
R = 0.300, P = 0.006; R = 0.500, P < 0.001). Discussion This study showed that patients with a low postoperative pain relief present
a dysregulation of circulating microRNAs. Altered circulatory microRNAs
expression correlated with postoperative pain relief, indicating that
microRNAs can serve as predictive biomarkers of pain outcome after surgery
and hence may foster new strategies for preventing chronic postoperative
pain after total knee replacement (TKR).
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Affiliation(s)
- Rocco Giordano
- Center for Neuroplasticity and Pain, SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Kristian Kjær Petersen
- Center for Neuroplasticity and Pain, SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark.,Center for Sensory-Motor Interaction, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Hjalte Holm Andersen
- Center for Sensory-Motor Interaction, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Jacek Lichota
- Laboratory of Metabolism Modifying Medicine, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Massimiliano Valeriani
- Center for Sensory-Motor Interaction, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark.,Child Neurology Unit, Department of Neuroscience and Neurorehabilitation, Headache Center, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Ole Simonsen
- Orthopedic Surgery Research Unit, Aalborg University Hospital, Aalborg, Denmark
| | - Lars Arendt-Nielsen
- Center for Sensory-Motor Interaction, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
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Al-Rawaf HA, Gabr SA, Alghadir AH. Vitamin D Deficiency and Molecular Changes in Circulating MicroRNAs in Older Adults with Lower Back Pain. Pain Res Manag 2021; 2021:6662651. [PMID: 34055120 PMCID: PMC8149253 DOI: 10.1155/2021/6662651] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/16/2021] [Accepted: 05/07/2021] [Indexed: 12/24/2022]
Abstract
Background MicroRNAs play an essential role in regulating pain processing within a wide range of clinical pain disorders. Objectives The present study aimed to evaluate the role of circulating miRNAs as biomarkers of lower back pain in older adults. In addition, the correlation between miRNAs and other related cofounders such as muscle function, adiposity, malnutrition, and Ca and vitamin D intake was assessed. Methods A total of 110 older subjects with an age range of 40-60 years were included in this study. The participants were classified according to a modified Oswestry lower back pain disability questionnaire (OSW) into subjects with minimal LBP (n = 40; LBP score: 0-20%), moderate LBP (n = 35; LBP score: 20-40%), and severe LBP (n = 35; LBP score: 41-60%). RT-PCR and immunoassays were used to study the circulating miRNA profile, vitamin D status, and CRP, IL-6, TNF-α, s-Ca, s-BAP, s-OC, and s-NTX levels. In addition, malnutrition and muscle performance were estimated in all subjects as other factors related to LBP. Results In this study, normal LBP-OSW cutoff values (8.96 ± 3.6) were reported in 36.4% of the total population, whereas 63.6% of the population had higher LBP-OSW scores, classified as follows: 31.8% with moderate LBP (LBP-OSW score: 31.4 ± 9.1) and 31.8% with severe LBP (LBP-OSW score: 54.9 ± 14.6). Four circulating miRNAs, namely, miR-146a, miR-558, miR-155, and miR-124a, as biomarkers of the intensity of back pain were identified in all participants. In subjects with moderate to severe LBP, the expression levels of miR-146a and miR-558 were significantly reduced and those of miR-155 and miR-124a were significantly increased compared to subjects with minimal LBP scores. Subjects with moderate to severe LBP showed a significant increase in adiposity markers, lower PA, muscle performance, malnutrition, and lower Ca and vitamin D intake compared to normal controls. In addition, serum levels of vitamin D and circulated plasma markers of inflammation and bone metabolism such as CRP, IL-6, TNF-α, s-Ca, s-BAP, s-OC, and s-NTX were significantly reduced in severe LBP cases compared to those with minimal LBP scores. The expressed circulating miRNAs were significantly associated with the measured muscle performance, adiposity, PA score, inflammation, and bone metabolism cofounders in subjects with higher LBP-OSW scores. The expressed miRNAs, along with other LBP cofounders, were significantly associated with ∼63.9-86.4% of the incidence of LBP in older adults. Conclusions In older adults with vitamin D deficiency, the severity of LBP was significantly associated with the expression of circulating miRNAs, adiposity, bone metabolism, inflammation, and muscle performance. In addition, the expressed miRNAs, along with other LBP cofounders, were significantly associated with ∼63.9-86.4% of the incidence of LBP in older adults. These results suggest the possibility of using microRNAs as therapeutics to alleviate established pain and as biomarkers in old adults with painful conditions.
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Affiliation(s)
- Hadeel A. Al-Rawaf
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
- Departments of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sami A. Gabr
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad H. Alghadir
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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van der Feltz-Cornelis C, Brabyn S, Ratcliff J, Varley D, Allgar V, Gilbody S, Clarke C, Lagos D. Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/functional neurological disorder (CD/FND): The CANDO clinical feasibility study. Brain Behav Immun Health 2021; 13:100228. [PMID: 34589743 PMCID: PMC8474571 DOI: 10.1016/j.bbih.2021.100228] [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: 12/24/2020] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Conversion disorder/functional neurological disorder (CD/FND) occurs often in neurological settings and can lead to long-term distress, disability and demand on health care services. Systemic low-grade inflammation might play a role, however, the pathogenic mechanism is still unknown. AIM 1) To explore the feasibility to establish and assess a cohort of CD/FND with motor symptoms, involving persons with lived experience (PPI). 2) To generate proof of concept regarding a possible role for cytokines, microRNA, cortisol levels and neurocognitive symptoms in patients with motor CD/FND. METHOD Feasibility study. RESULTS The study showed active involvement of patients despite high clinical illness burden and disability, neurocognitive symptoms, childhood adverse experiences (ACE) and current life events. The study provided valuable knowledge regarding the feasibility of conducting a study in these patients that will inform future study phases. In the sample there were elevated levels of IL6, IL12, IL17A, IFNg, TNFa and VEGF-a, suggesting systemic low-grade inflammation. Also, microRNAs involved in inflammation and vascular inflammation were correlated with TNFa and VEGFa respectively, suggesting proof of concept for an epigenetic mechanism. Owing to the COVID-19 outbreak, the patient sample was limited to 15 patients. CONCLUSION It is a novelty that this study is conducted in the clinical setting. This innovative, translational study explores stress-related SLI in CD/FND patients and the feasibility of a larger project aiming to develop new treatments for this vulnerable population. Given the positive findings, there is scope to conduct further research into the mechanism of disease in CD/FND.
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Estévez-López F, Salazar-Tortosa DF, Camiletti-Moirón D, Gavilán-Carrera B, Aparicio VA, Acosta-Manzano P, Segura-Jiménez V, Álvarez-Gallardo IC, Carbonell-Baeza A, Munguía-Izquierdo D, Geenen R, Lacerda E, Delgado-Fernández M, Martínez-González LJ, Ruiz JR, Álvarez-Cubero MJ. Fatigue in Women with Fibromyalgia: A Gene-Physical Activity Interaction Study. J Clin Med 2021; 10:jcm10091902. [PMID: 33924903 PMCID: PMC8125111 DOI: 10.3390/jcm10091902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/27/2021] [Accepted: 04/06/2021] [Indexed: 11/16/2022] Open
Abstract
Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze gene-polymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni’s and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively, findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest.
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Affiliation(s)
- Fernando Estévez-López
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC University Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Diego F. Salazar-Tortosa
- Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85719, USA
- Correspondence:
| | - Daniel Camiletti-Moirón
- Department of Physical Education, Faculty of Education Sciences, University of Cádiz, 11519 Cádiz, Spain; (D.C.-M.); (B.G.-C.); (V.S.-J.); (I.C.Á.-G.); (A.C.-B.)
| | - Blanca Gavilán-Carrera
- Department of Physical Education, Faculty of Education Sciences, University of Cádiz, 11519 Cádiz, Spain; (D.C.-M.); (B.G.-C.); (V.S.-J.); (I.C.Á.-G.); (A.C.-B.)
| | - Virginia A. Aparicio
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18011 Granada, Spain;
- Biomedical Research Centre (CIBM), Institute of Nutrition and Food Technology (INYTA), University of Granada, 18016 Granada, Spain
| | - Pedro Acosta-Manzano
- Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, 18010 Granada, Spain; (P.A.-M.); (M.D.-F.)
| | - Víctor Segura-Jiménez
- Department of Physical Education, Faculty of Education Sciences, University of Cádiz, 11519 Cádiz, Spain; (D.C.-M.); (B.G.-C.); (V.S.-J.); (I.C.Á.-G.); (A.C.-B.)
| | - Inmaculada C. Álvarez-Gallardo
- Department of Physical Education, Faculty of Education Sciences, University of Cádiz, 11519 Cádiz, Spain; (D.C.-M.); (B.G.-C.); (V.S.-J.); (I.C.Á.-G.); (A.C.-B.)
| | - Ana Carbonell-Baeza
- Department of Physical Education, Faculty of Education Sciences, University of Cádiz, 11519 Cádiz, Spain; (D.C.-M.); (B.G.-C.); (V.S.-J.); (I.C.Á.-G.); (A.C.-B.)
| | - Diego Munguía-Izquierdo
- Physical Performance and Sports Research Center, Department of Sports and Computer Science, Section of Physical Education and Sports, Faculty of Sport Sciences, Universidad Pablo de Olavide, 41013 Seville, Spain;
| | - Rinie Geenen
- Department of Psychology, Faculty of Social and Behavioural Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands;
| | - Eliana Lacerda
- Department of Clinical Research, Faculty of Infectious & Tropical Disease, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK;
| | - Manuel Delgado-Fernández
- Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, 18010 Granada, Spain; (P.A.-M.); (M.D.-F.)
| | - Luis J. Martínez-González
- GENYO, Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, Av. Ilustracion, 114, 18016 Granada, Spain;
| | - Jonatan R. Ruiz
- PROFITH—“PROmoting FITness and Health Through Physical Activity” Research Group, Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, 18071 Granada, Spain;
| | - María J. Álvarez-Cubero
- Department of Biochemistry and Molecular Biology III, Faculty of Medicine, University of Granada, 18010 Granada, Spain;
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Epigenetic modification of BDNF mediates neuropathic pain via miR-30a-3p/EP300 axis in CCI rats. Biosci Rep 2021; 40:226778. [PMID: 33103739 PMCID: PMC7670569 DOI: 10.1042/bsr20194442] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 09/08/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022] Open
Abstract
Recent investigation of microRNAs on chronic pain has developed a breakthrough in neuropathic pain management. In the present study, decreased expression of miR-30a-3p was reported using qRT-PCR analysis and loss of miR-30a-3p promoted neuropathic pain progression in sciatic nerve chronic constrictive injury rats through determining the pain threshold. We predicted miR-30a-3p could target E-cadherin transcriptional activator (EP300) via bioinformatics analysis. Meanwhile, we found that brain-derived neurotrophic factor (BDNF) is involved in neuropathic pain. Here, we exhibited that EP300 epigenetically up-regulated BDNF via enhancing acetylated histone H3 and H4 on the promoter. For another, miR-30a-3p was able to modify the level of BDNF and acetylated histone H3 and H4. Loss of miR-30a-3p enhanced EP300 and BDNF colocalization in CCI rats. Subsequently, it was shown that increased EP300 induced neuropathic pain by an enhancement of neuronal BDNF level in vivo. To sum up, it was revealed that epigenetic modification of BDNF promoted neuropathic pain via EP300 induced by miR-30a-3p in CCI rats.
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Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int J Mol Sci 2021; 22:ijms22083891. [PMID: 33918736 PMCID: PMC8068842 DOI: 10.3390/ijms22083891] [Citation(s) in RCA: 256] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Fibromyalgia is a syndrome characterized by chronic and widespread musculoskeletal pain, often accompanied by other symptoms, such as fatigue, intestinal disorders and alterations in sleep and mood. It is estimated that two to eight percent of the world population is affected by fibromyalgia. From a medical point of view, this pathology still presents inexplicable aspects. It is known that fibromyalgia is caused by a central sensitization phenomenon characterized by the dysfunction of neuro-circuits, which involves the perception, transmission and processing of afferent nociceptive stimuli, with the prevalent manifestation of pain at the level of the locomotor system. In recent years, the pathogenesis of fibromyalgia has also been linked to other factors, such as inflammatory, immune, endocrine, genetic and psychosocial factors. A rheumatologist typically makes a diagnosis of fibromyalgia when the patient describes a history of pain spreading in all quadrants of the body for at least three months and when pain is caused by digital pressure in at least 11 out of 18 allogenic points, called tender points. Fibromyalgia does not involve organic damage, and several diagnostic approaches have been developed in recent years, including the analysis of genetic, epigenetic and serological biomarkers. Symptoms often begin after physical or emotional trauma, but in many cases, there appears to be no obvious trigger. Women are more prone to developing the disease than men. Unfortunately, the conventional medical therapies that target this pathology produce limited benefits. They remain largely pharmacological in nature and tend to treat the symptomatic aspects of various disorders reported by the patient. The statistics, however, highlight the fact that 90% of people with fibromyalgia also turn to complementary medicine to manage their symptoms.
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Li X, Wang S, Yang X, Chu H. miR‑142‑3p targets AC9 to regulate sciatic nerve injury‑induced neuropathic pain by regulating the cAMP/AMPK signalling pathway. Int J Mol Med 2020; 47:561-572. [PMID: 33416140 PMCID: PMC7797458 DOI: 10.3892/ijmm.2020.4824] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to investigate the effects of microRNA (miR)-142-3p on neuropathic pain caused by sciatic nerve injury in chronic compression injury (CCI) rats, and further investigate its mechanism. Rat experiments were divided into four parts in the study. In the first part, the rats were divided into the Sham and CCI groups. The expression of miR-142-3p, AC9 and cAMP were detected. In the second part, the rats were divided into the Sham, CCI, miR-142-3p mimic, mimic-negative control (NC), miR-142-3p small interfering RNA (siRNA) and siRNA-NC groups. The expression of cAMP and the levels of AMPK pathway-related proteins were detected. In the third part, the rats were randomly divided into Sham, CCI, AC9 mimic, mi-NC, AC9 siRNA and si-NC groups. Double luciferase reporter assay was used to analyse the targeting relationship between miR-142-3p and AC9. In the fourth part, the rats were divided into the Sham, CCI, miR-142-3p siRNA, AC9 mimic, miR-142-3p siRNA + AC9 siRNA, cAMP activator (Forskolin) and miR-142-3p siRNA + cAMP inhibitor groups. The expres-sion of miR-142-3p was significantly increased while AC9 and cAMP expression significantly decreased in CCI rats. However, AC9 overexpression significantly increased the levels of cAMP protein. Luciferase reporter assay also proved that AC9 is the target gene of miR-142-3p. Moreover, miR-142-3p silencing was found to reduce neuropathic pain in CCI rats by upregulating the expression of AC9. It was also found that cAMP activation can relieve neuropathic pain and promote the expression of AMPK-related proteins in CCI rats. Silencing miR-142-3p can target AC9 to reduce the expression of inflammatory factors and neuropathic pain in CCI rats by increasing the expression of cAMP/AMPK pathway-related proteins.
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Affiliation(s)
- Xiao Li
- Department of Hand Surgery, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
| | - Shoupeng Wang
- Department of Orthopedics, Zaozhuang Hospital of Zaozhuang Mining Group, Zaozhuang, Shandong 277100, P.R. China
| | - Xiaoli Yang
- Department of Pharmacy, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264000, P.R. China
| | - Hongjun Chu
- Department of Orthopedics, Zaozhuang Hospital of Zaozhuang Mining Group, Zaozhuang, Shandong 277100, P.R. China
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LncRNA NEAT1/miR-128-3p/AQP4 axis regulating spinal cord injury-induced neuropathic pain progression. J Neuroimmunol 2020; 351:577457. [PMID: 33373887 DOI: 10.1016/j.jneuroim.2020.577457] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/29/2020] [Accepted: 12/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Neuropathic pain (NP) is the comorbidity in spinal cord injury(SCI), which is the hardest to cure. Non-coding RNA dysregulations are related to the development of NP. NEAT1(nuclear paraspeckle assembly transcript 1) is a new type of lncRNA. This study explores the role and specific mechanism of NEAT1 in SCI-mediated NP. METHODS Firstly, the NEAT1 expression in SCI rats and the control group was detected with RT-PCR to analyze the relationship between NEAT13 and NP symptoms. Then, SCI rats were intrathecally injected with NEAT13 overexpressing and knocking down lentiviruses. Afterward, ELISA was utilized to assess the expression of IL-6, IL-1β and TNFα in rats. Subsequently, immunohistochemistry was adopted to verify the activation of microglial cells. After that, bioinformatics analysis was employed to further predict the downstream target genes of NEAT1, while RT-PCR and Western blot were conducted to determine the relative expression of miR-128-3p and aquaporin-4(AQP4). Meanwhile, a dual-luciferase reporter assay was performed to further study the targeting relationship between NEAT1 and miR-128-3p, and miR-128-3p and AQP4. RESULTS SCI rats showed distinctly higher NEAT1 expression compared with that of the control group. ELISA experiment confirmed that the over-expression of NEAT1 enhanced the expression of IL-6, IL-1β, and TNFα in SCI rats. Other related mechanism studies revealed that NEAT13 targeted and inhibited miR-128-3p as its competing endogenous RNA (ceRNA), and enhanced AQP4 expression, while miR-128-3p targeted AQP4 to regulate its expression. SUMMARY NEAT1 affects AQP4 signaling pathway to alleviate the spinal cord injury-induced NP via promoting miR-128-3p expression.
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Knockdown of miR-130a-3p alleviates spinal cord injury induced neuropathic pain by activating IGF-1/IGF-1R pathway. J Neuroimmunol 2020; 351:577458. [PMID: 33360969 DOI: 10.1016/j.jneuroim.2020.577458] [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: 07/05/2020] [Revised: 09/29/2020] [Accepted: 12/06/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recent studies have elucidated the instrumental role of microRNAs (miRNAs) in neuropathic pain (NP) progression. As one member of miRNAs, miR-130a-3p has been proved as a mediator in inflammation and neuronal maturation. The present study attempted to elucidate what effect miR-130a-3p exerts on NP. MATERIALS AND METHODS The miR-130a-3p expression in the spinal cord tissues of rat with spinal cord compression injury (SCI) and LPS-induced BV2 microglia was determined with RT-PCR, which was further applied to analyze the clinical relevance between miR-130a-3p and neuropathic pain. Besides, the expression of IGF-1, IL-1β, IL-6, and TNF-α in the spinal cord tissues of rats was measured using RT-PCR and ELISA after intrathecal injection of miR-130a-3p inhibitors and tail vein injection of IGF-1 low-expression lentivirus (Lv-shIGF-1). Further, neuronal apoptosis (labeled by Caspase3) and microglial activation (labeled by Iba1) were examined by immunohistochemistry (IHC), and the levels of IGF-1, IGF-1R, NF-κB were determined by western blot. Additionally, bioinformatic was employed to analyze the potential target genes of miR-130a-3p. Furthermore, the dual luciferase activity assay and RNA immunoprecipitation assay were conducted to further substantiate whether miR-130a-3p targets IGF-1. RESULTS In comparison with the sham group, the miR-130a-3p expression was remarkably up-regulated in the spinal cord lesions of SCI rats. The ELISA results showed that inhibiting the miR-130a-3p significantly reduced NP symptoms of SCI rats, mitigated neuronal apoptosis, microglial activation, repressed NF-κB phosphorylation and the IL-1β, IL-6 and TNF-α expressions in SCI rats. Contrarily, downregulation of miR-130a-3p increased IGF-1 and IGF-1R expression. What's more, we observed the same effects in BV2 microglia. In addition, the bioinformatics analysis showed that miR-130-3p targeted at the 3'-untranslated region of IGF-1 and inhibiting its expression. However, abolishing IGF-1 not only promoted the inflammatory responses in the SCI lesions, but also aggravated NP of SCI rats, while those effects were attenuated by the downregulation of miR-130a-3p. CONCLUSION The inhibition of miR-130a-3p expression up-regulates the IGF-1/IGF-1R signaling pathway, thus reducing neuropathic pain caused by spinal cord injury.
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Kuebart A, Wollborn V, Huhn R, Hermanns H, Werdehausen R, Brandenburger T. Intraneural Application of microRNA-1 Mimetic Nucleotides Does Not Resolve Neuropathic Pain After Chronic Constriction Injury in Rats. J Pain Res 2020; 13:2907-2914. [PMID: 33223847 PMCID: PMC7671483 DOI: 10.2147/jpr.s266937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/14/2020] [Indexed: 11/23/2022] Open
Abstract
Background Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats. Methods MiR-1 mimetic nucleotides were evaluated for effectiveness, functionality, and intracellular stability by transfecting human glioblastoma cells (U-87 MG). In vivo transfection with miR-1 mimics and corresponding scrambled miRNAs serving as control was performed by repetitive injection (days 0, 3, and 7) into the sciatic nerve following chronic constriction injury (CCI) in rats. Quantitative PCR was used to measure miR-1 content. Cx43 expression was determined by Western blot analysis. Effects on neuropathic pain were assessed by detecting paw withdrawal thresholds using an automated filament application. Results Transfection of miR-1 mimics was confirmed in U-87 MG cells, with miR-1 content being increased significantly after 48 h and after 96 h (p<0.05). Effective downregulation of Cx43 expression was observed 48 and 96 h after transfection (−44 ± 0.07% and −40 ± 0.11%; p<0.05). In vivo, repetitive transfection with miR-1 mimetic nucleotides led to a 17.9-fold (± 14.2) increase of miR-1 in the sciatic nerve. However, the protein expression of Cx43 in sciatic nerves as well as paw withdrawal thresholds for mechanical stimulation was not significantly increased 10 days after chronic constriction injury. Conclusion While transfection with miR-1 mimics effective reduces Cx43 expression in vitro and restores miR-1 after CCI, we did neither observe altered levels of Cx43 protein level in nerves nor a beneficial effect on mechanical allodynia in vivo, most likely caused by insufficient Cx43 suppression.
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Affiliation(s)
- Anne Kuebart
- Department of Anesthesiology, University Hospital Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany
| | - Verena Wollborn
- Department of Anesthesiology, University Hospital Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany
| | - Ragnar Huhn
- Department of Anesthesiology, University Hospital Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany
| | - Henning Hermanns
- Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Robert Werdehausen
- Department of Anesthesiology and Intensive Care, University of Leipzig, Medical Faculty, Leipzig 04103, Germany
| | - Timo Brandenburger
- Department of Anesthesiology, University Hospital Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany
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