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Zimmermann D, Kress M, Nagy I. Established and emerging roles of protein kinases in regulating primary sensory neurons in injury-and inflammation-associated pain. Expert Opin Ther Targets 2025; 29:267-280. [PMID: 40200157 DOI: 10.1080/14728222.2025.2489540] [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: 08/26/2024] [Revised: 03/06/2025] [Accepted: 04/02/2025] [Indexed: 04/10/2025]
Abstract
INTRODUCTION Recent seminal neuroscience research has significantly increased our knowledge on cellular and molecular responses of various cells in the pain pathway to peripheral nerve injuries and inflammatory processes. Transcriptomic and epigenetic analysis of primary sensory neurons (PSNs) in animal models of peripheral injuries revealed new insights into altered gene expression profiles and epigenetic modifications, which, via increasing spinal nociceptive input, lead to the development of pain. Among the various classes of molecules involved in driving differential gene expression, protein kinases, the enzymes that catalyze the phosphorylation of molecules, are emerging to control histone modification and chromatin remodeling needed for the alteration in transcriptional activity. AREAS COVERED Here, we focused on how protein kinases contribute to transcriptomic changes and pathways of induced reprogramming within PSNs upon peripheral nerve injury and inflammation. We conducted systematic literature search across multiple databases, including PubMed, NIH ClinicalTrials.gov portal and GEOData from 1980 to 2024 and compared protein kinase expression frequencies between publicly available RNA sequencing datasets of PSNs and investigated differences in protein kinase expression levels after peripheral nerve injury. EXPERT OPINION Novel findings support a new concept that protein kinases constitute regulatory hubs of reprogramming of PSNs, which offers novel analgesic approaches.
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Affiliation(s)
- David Zimmermann
- Institute of Physiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Michaela Kress
- Institute of Physiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Istvan Nagy
- Department of Surgery and Cancer, Nociception group, Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College, London, UK
- Department of Physiology, University of Debrecen, Debrecen, Hungary
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Peng BG. Fundamentals of intervertebral disc degeneration and related discogenic pain. World J Orthop 2025; 16:102119. [PMID: 39850042 PMCID: PMC11752479 DOI: 10.5312/wjo.v16.i1.102119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
Lumbar intervertebral disc degeneration is thought to be the main cause of low back pain, although the mechanisms by which it occurs and leads to pain remain unclear. In healthy adult discs, vessels and nerves are present only in the outer layer of the annulus fibrosus and in the bony endplate. Animal models, and histological and biomechanical studies have shown that annulus tear or endplate injury is the initiating factor for painful disc degeneration. Injury to the disc triggers a local inflammatory repair response that activates nociceptors and promotes the synthesis of neuropeptides such as substance P and calcitonin gene-related peptide, by dorsal root ganglion neurons. These neuropeptides are transported to injured discs and act as pro-inflammatory molecules, promoting the production of an "inflammatory soup" by inducing vasodilatation and plasma extravasation as well as by promoting the release of chemical mediators from disc cells and infiltrating immune cells, causing neurogenic inflammation that leads to progressive disc degeneration and discogenic pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
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Peng BG, Li YC, Yang L. Role of neurogenic inflammation in intervertebral disc degeneration. World J Orthop 2025; 16:102120. [PMID: 39850033 PMCID: PMC11752484 DOI: 10.5312/wjo.v16.i1.102120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Yong-Chao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People’s Armed Police Forces, Tianjin 300000, China
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Li Y, Dai C, Wu B, Yang L, Yan X, Liu T, Chen J, Zheng Z, Peng B. Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs. Spine J 2024; 24:1527-1537. [PMID: 38608821 DOI: 10.1016/j.spinee.2024.04.002] [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: 10/22/2023] [Revised: 03/14/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND CONTEXT Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? PURPOSE This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. STUDY DESIGN This was an experimental study. METHODS Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8-9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1β, and IL-6 mRNA levels in the injured (Co8-9) and adjacent discs (Co7-8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7-8 and Co8-9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7-8 and Co8-9 intervertebral discs showed roughly the same trend as mRNA levels. CONCLUSIONS Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. CLINICAL SIGNIFICANCE This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain.
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Affiliation(s)
- Yongchao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Chen Dai
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Bing Wu
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People's Armed Police Forces, 220 Chenglin Road, Dongli District, Tianjin, P.R. China
| | - Xiujie Yan
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Tanghua Liu
- Algology Institute of Sino-US Zhongguancun Precision Medicine Academy, 45 Beiwa Road, Haidian District, Beijing, P.R. China
| | - Jindong Chen
- Department of Orthopaedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, 21 South Silver Spring Road, Qingyuan, P.R. China
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan No. 2 Road, Guangzhou, P.R. China; Pain Research Center, Sun Yat-sen University, 135 Xingang West Road, Haizhu District, Guangzhou, P.R. China.
| | - Baogan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China.
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Shi Y, Wan S, Song X. Role of neurogenic inflammation in the pathogenesis of alopecia areata. J Dermatol 2024; 51:621-631. [PMID: 38605467 DOI: 10.1111/1346-8138.17227] [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: 12/15/2023] [Revised: 03/04/2024] [Accepted: 03/28/2024] [Indexed: 04/13/2024]
Abstract
Alopecia areata refers to an autoimmune illness indicated by persistent inflammation. The key requirement for alopecia areata occurrence is the disruption of immune-privileged regions within the hair follicles. Recent research has indicated that neuropeptides play a role in the damage to hair follicles by triggering neurogenic inflammation, stimulating mast cells ambient the follicles, and promoting apoptotic processes in keratinocytes. However, the exact pathogenesis of alopecia areata requires further investigation. Recently, there has been an increasing focus on understanding the mechanisms of immune diseases resulting from the interplay between the nervous and the immune system. Neurogenic inflammation due to neuroimmune disorders of the skin system may disrupt the inflammatory microenvironment of the hair follicle, which plays a crucial part in the progression of alopecia areata.
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Affiliation(s)
- Yetan Shi
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Sheng Wan
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, Zhejiang, China
| | - Xiuzu Song
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, Zhejiang, China
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Xu Y, Cao S, Wang SF, Ma W, Gou XJ. Zhisou powder suppresses airway inflammation in LPS and CS-induced post-infectious cough model mice via TRPA1/TRPV1 channels. JOURNAL OF ETHNOPHARMACOLOGY 2024; 324:117741. [PMID: 38224794 DOI: 10.1016/j.jep.2024.117741] [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: 11/08/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/17/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zhisou Powder (ZSP), a traditional Chinese medicine (TCM) prescription, has been widely used in the clinic for the treatment of post-infectious cough (PIC). However, the exact mechanism is not clear. AIM OF THE STUDY The aim of this study was to investigate the ameliorative effect of ZSP on PIC in mice. The possible mechanisms of action were screened based on network pharmacology, and the potential mechanisms were explored through molecular docking and in vivo experimental validation. MATERIALS AND METHODS Lipopolysaccharide (LPS) (80μg/50 μL) was used to induce PIC in mice, followed by daily exposure to cigarette smoke (CS) for 30 min for 30 d to establish PIC model. The effects of ZSP on PIC mice were observed by detecting the number of coughs and cough latency, peripheral blood and bronchoalveolar lavage fluid (BALF) inflammatory cell counts, enzyme-linked immunosorbent assay (ELISA), and histological analysis. The core targets and key pathways of ZSP on PIC were analyzed using network pharmacology, and TRPA1 and TRPV1 were validated using RT-qPCR and western blotting assays. RESULTS ZSP effectively reduced the number of coughs and prolonged the cough latency in PIC mice. Airway inflammation was alleviated by reducing the expression levels of the inflammatory mediators TNF-α and IL-1β. ZSP modulated the expression of Substance P, Calcitonin gene-related peptide (CGRP), and nerve growth factor (NGF) in BALF. Based on the results of network pharmacology, the mechanism of action of ZSP may exert anti-neurogenic airway-derived inflammation by regulating the expression of TRPA1 and TRPV1 through the natural active ingredients α-spinastero, shionone and didehydrotuberostemonine. CONCLUSION ZSP exerts anti-airway inflammatory effects through inhibition of TRPA1/TRPV1 channels regulating neuropeptides to alleviate cough hypersensitivity and has a favorable therapeutic effect on PIC model mice. It provides theoretical evidence for the clinical application of ZSP.
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Affiliation(s)
- Yuan Xu
- Respiratory Department and Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai 201999, China; School of Pharmacy, Shaanxi Univesity of Chinese Medicine, Shaanxi, Xianyang 712046, China
| | - Shan Cao
- Respiratory Department and Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai 201999, China
| | - Shu-Fei Wang
- School of Pharmacy, Shaanxi Univesity of Chinese Medicine, Shaanxi, Xianyang 712046, China
| | - Wei Ma
- Respiratory Department and Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai 201999, China.
| | - Xiao-Jun Gou
- Respiratory Department and Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai 201999, China.
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Hayes BW, Choi HW, Rathore APS, Bao C, Shi J, Huh Y, Kim MW, Mencarelli A, Bist P, Ng LG, Shi C, Nho JH, Kim A, Yoon H, Lim D, Hannan JL, Todd Purves J, Hughes FM, Ji RR, Abraham SN. Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity. Sci Immunol 2024; 9:eadi5578. [PMID: 38427717 PMCID: PMC11149582 DOI: 10.1126/sciimmunol.adi5578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 02/07/2024] [Indexed: 03/03/2024]
Abstract
Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.
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Affiliation(s)
- Byron W Hayes
- Department of Pathology, Duke University Medical Center; Durham, NC, USA
| | - Hae Woong Choi
- Division of Life Sciences, Korea University; Seoul, 02841, South Korea
| | - Abhay PS Rathore
- Department of Pathology, Duke University Medical Center; Durham, NC, USA
- Program in Emerging Infectious Diseases, Duke-National University of Singapore; Singapore 169857, Singapore
| | - Chunjing Bao
- Department of Pathology, Duke University Medical Center; Durham, NC, USA
| | - Jianling Shi
- Department of Pathology, Duke University Medical Center; Durham, NC, USA
| | - Yul Huh
- Department of Cell Biology, Duke University Medical Center; Durham, NC, USA
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center; Durham, NC, US
| | - Michael W Kim
- Department of Pathology, Duke University Medical Center; Durham, NC, USA
| | - Andrea Mencarelli
- Program in Emerging Infectious Diseases, Duke-National University of Singapore; Singapore 169857, Singapore
| | - Pradeep Bist
- Program in Emerging Infectious Diseases, Duke-National University of Singapore; Singapore 169857, Singapore
| | - Lai Guan Ng
- Singapore Immunology Network, Agency for Science, Technology and Research, Immunos, Biopolis; 138648, Singapore
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changming Shi
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Joo Hwan Nho
- Division of Life Sciences, Korea University; Seoul, 02841, South Korea
| | - Aram Kim
- Department of Urology, Konkuk University Hospital, Konkuk University School of Medicine; Seoul, 05029, South Korea
| | - Hana Yoon
- Department of Urology, Ewha Womans University, College of Medicine; Seoul, 07804, South Korea
| | - Donghoon Lim
- Department of Urology, Chosun University School of Medicine; Gwangju, Korea
| | - Johanna L Hannan
- Department of Physiology, Brody School of Medicine, East Carolina University; Greenville, NC, USA
| | - J Todd Purves
- Department of Surgery, Division of Urology, Duke University Medical Center; Durham, NC, USA
| | - Francis M Hughes
- Department of Surgery, Division of Urology, Duke University Medical Center; Durham, NC, USA
| | - Ru-Rong Ji
- Department of Cell Biology, Duke University Medical Center; Durham, NC, USA
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center; Durham, NC, US
- Department of Neurobiology, Duke University Medical Center; Durham, North Carolina, USA
| | - Soman N Abraham
- Department of Pathology, Duke University Medical Center; Durham, NC, USA
- Department of Cell Biology, Duke University Medical Center; Durham, NC, USA
- Program in Emerging Infectious Diseases, Duke-National University of Singapore; Singapore 169857, Singapore
- Department of Immunology, Duke University Medical Center; Durham, NC, USA
- Department of Molecular Genetics & Microbiology, Duke University Medical Center; Durham, NC, USA
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Singh G, O-Sullivan I, Natarajan Anbazhagan A, Ranjan K C, Farooqui Z, Ma K, Wang J, Mwale F, Votta-Velis G, Bruce B, Ronald Kahn C, van Wijnen AJ, Im HJ. Loss of PKCδ/Prkcd prevents cartilage degeneration in joints but exacerbates hyperalgesia in an experimental osteoarthritis mouse model. Gene 2024; 893:147920. [PMID: 37890601 DOI: 10.1016/j.gene.2023.147920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/06/2023] [Accepted: 10/23/2023] [Indexed: 10/29/2023]
Abstract
Pain is the prime symptom of osteoarthritis (OA) that directly affects the quality of life. Protein kinase Cδ (PKCδ/Prkcd) plays a critical role in OA pathogenesis; however, its significance in OA-related pain is not entirely understood. The present study investigated the functional role of PKCδ in OA pain sensation. OA was surgically induced in control (Prkcdfl/fl), global- (Prkcdfl/fl; ROSACreERT2), and sensory neuron-specific conditional knockout (cKO) mice (Prkcdfl/fl; NaV1.8/Scn10aCreERT2) followed by comprehensive analysis of longitudinal behavioral pain, histopathology and immunofluorescence studies. GlobalPrkcd cKO mice prevented cartilage deterioration by inhibiting matrix metalloproteinase-13 (MMP13) in joint tissues but significantly increased OA pain. Sensory neuron-specificdeletion of Prkcd in mice did not protect cartilage from degeneration but worsened OA-associated pain. Exacerbated pain sensitivity observed in global- and sensory neuron-specific cKO of Prkcd was corroborated with markedly increased specific pain mediators in knee synovium and dorsal root ganglia (DRG). These specific pain markers include nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), and their cognate receptors, including tropomyosin receptor kinase A (TrkA) and vascular endothelial growth factor receptor-1 (VEGFR1). The increased levels of NGF/TrkA and VEGF/VEGFR1 were comparable in both global- and sensory neuron-specific cKO groups. These data suggest that the absence of Prkcd gene expression in the sensory neurons is strongly associated with OA hyperalgesia independent of cartilage protection. Thus, inhibition of PKCδ may be beneficial for cartilage homeostasis but could aggravate OA-related pain symptoms.
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Affiliation(s)
- Gurjit Singh
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - InSug O-Sullivan
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA.
| | | | | | - Zeba Farooqui
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA.
| | - Kaige Ma
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jun Wang
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA.
| | - Fackson Mwale
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital and Department of Surgery, McGill University, Montreal, QC H3T 1E2, Canada.
| | - Gina Votta-Velis
- Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Benjamin Bruce
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - C Ronald Kahn
- Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, 02215, MA, USA.
| | - Andre J van Wijnen
- Department of Biochemistry, University of Vermont, Burlington, VT, 05405, USA.
| | - Hee-Jeong Im
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
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Gollamudi J, Karkoska KA, Gbotosho OT, Zou W, Hyacinth HI, Teitelbaum SL. A bone to pick-cellular and molecular mechanisms of bone pain in sickle cell disease. FRONTIERS IN PAIN RESEARCH 2024; 4:1302014. [PMID: 38239327 PMCID: PMC10794347 DOI: 10.3389/fpain.2023.1302014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/04/2023] [Indexed: 01/22/2024] Open
Abstract
The bone is one of the most commonly affected organs in sickle cell disease (SCD). Repeated ischemia, oxidative stress and inflammation within the bone is largely responsible for promoting bone pain. As more individuals with SCD survive into adulthood, they are likely to experience a synergistic impact of both aging and SCD on their bone health. As bone health deteriorates, bone pain will likely exacerbate. Recent mechanistic and observational studies emphasize an intricate relationship between bone remodeling and the peripheral nervous system. Under pathological conditions, abnormal bone remodeling plays a key role in the propagation of bone pain. In this review, we first summarize mechanisms and burden of select bone complications in SCD. We then discuss processes that contribute to pathological bone pain that have been described in both SCD as well as non-sickle cell animal models. We emphasize the role of bone-nervous system interactions and pitfalls when designing new therapies especially for the sickle cell population. Lastly, we also discuss future basic and translational research in addressing questions about the complex role of stress erythropoiesis and inflammation in the development of SCD bone complications, which may lead to promising therapies and reduce morbidity in this vulnerable population.
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Affiliation(s)
- Jahnavi Gollamudi
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Kristine A Karkoska
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Oluwabukola T Gbotosho
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Wei Zou
- Department of Medicine, Division of Bone and Mineral Diseases, and Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO, United States
| | - Hyacinth I Hyacinth
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Steven L Teitelbaum
- Department of Medicine, Division of Bone and Mineral Diseases, and Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO, United States
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Schumacher MA. Peripheral Neuroinflammation and Pain: How Acute Pain Becomes Chronic. Curr Neuropharmacol 2024; 22:6-14. [PMID: 37559537 PMCID: PMC10716877 DOI: 10.2174/1570159x21666230808111908] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/05/2023] [Accepted: 04/26/2023] [Indexed: 08/11/2023] Open
Abstract
The number of individuals suffering from severe chronic pain and its social and financial impact is staggering. Without significant advances in our understanding of how acute pain becomes chronic, effective treatments will remain out of reach. This mini review will briefly summarize how critical signaling pathways initiated during the early phases of peripheral nervous system inflammation/ neuroinflammation establish long-term modifications of sensory neuronal function. Together with the recruitment of non-neuronal cellular elements, nociceptive transduction is transformed into a pathophysiologic state sustaining chronic peripheral sensitization and pain. Inflammatory mediators, such as nerve growth factor (NGF), can lower activation thresholds of sensory neurons through posttranslational modification of the pain-transducing ion channels transient-receptor potential TRPV1 and TRPA1. Performing a dual role, NGF also drives increased expression of TRPV1 in sensory neurons through the recruitment of transcription factor Sp4. More broadly, Sp4 appears to modulate a nociceptive transcriptome including TRPA1 and other genes encoding components of pain transduction. Together, these findings suggest a model where acute pain evoked by peripheral injury-induced inflammation becomes persistent through repeated cycles of TRP channel modification, Sp4-dependent overexpression of TRP channels and ongoing production of inflammatory mediators.
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Affiliation(s)
- Mark A Schumacher
- Department of Anesthesia and Perioperative Care and the UCSF Pain and Addiction Research Center, University of California, San Francisco, California, 94143 USA
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11
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Scher AI, McGinley JS, VanDam LR, Campbell AM, Chai X, Collins B, Klimp SA, Finkel AG, Schwab K, Lipton RB, Johnson KW. Plasma calcitonin gene-related peptide and nerve growth factor as headache and pain biomarkers in recently deployed soldiers with and without a recent concussion. Headache 2023; 63:1240-1250. [PMID: 37796114 DOI: 10.1111/head.14635] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 08/23/2023] [Accepted: 08/30/2023] [Indexed: 10/06/2023]
Abstract
OBJECTIVE The objective of this study was to characterize the utility of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) as potential biomarkers for headache and pain disorders in the post-military deployment setting. BACKGROUND The need to improve recognition, assessment, and prognoses of individuals with posttraumatic headache or other pain has increased interest in the potential of CGRP and NGF as biomarkers. METHODS The Warrior Strong Study (NCT01847040) is an observational longitudinal study of United States-based soldiers who had recently returned from deployment to Afghanistan or Iraq from 2009 to 2014. The present nested cross-sectional analysis uses baseline data collected from soldiers returning to Fort Bragg, North Carolina. RESULTS In total, 264 soldiers (mean (standard deviation [SD] age 28.1 [6.4] years, 230/264 [87.1%] men, 171/263 [65.0%] White) were analyzed. Mean (SD) plasma levels of CGRP were 1.3 (1.1) pg/mL and mean levels of NGF were 1.4 (0.4) pg/mL. Age was negatively correlated with NGF (-0.01 pg/mL per year, p = 0.007) but was not associated with CGRP. Men had higher mean (SD) CGRP plasma levels than women (1.4 95% confidence interval [CI; 1.2] vs. 0.9 95% CI [0.5] pg/mL, p < 0.002, Kruskal-Wallis test). CGRP levels were lower in participants who had a headache at the time of the blood draw (1.0 [0.6] pg/mL vs. 1.4 [1.2] pg/mL, p = 0.024). NGF was lower in participants with continuous pain (all types; 1.2 [0.4] vs. 1.4 [0.4] pg/mL, p = 0.027) and was lower in participants with traumatic brain injury (TBI) + posttraumatic headache (PTH) versus TBI without PTH (1.3 [0.3] vs. 1.4 [0.4] pg/mL, p = 0.021). Otherwise, CGRP and NGF were not associated with migraine-like headache, TBI status, or headache burden as measured by the number of medical encounters in crude or adjusted models. CONCLUSION In this exploratory study, plasma levels of NGF and CGRP showed promise as biomarkers for headache and other types of pain. These findings need to be replicated in other cohorts.
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Affiliation(s)
- Ann I Scher
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | | | - Lyndsey R VanDam
- Pain Research, Eli Lilly and Company, Indianapolis, Indiana, USA
| | | | - Xiyun Chai
- Precision Medicine Neuroscience, AbbVie, Chicago, Illinois, USA
| | - Billy Collins
- US Public Health Service Commissioned Corps, Fayetteville, North Carolina, USA
| | - Scott A Klimp
- Womack Army Medical Center, Fort Bragg, North Carolina, USA
| | - Alan G Finkel
- Carolina Headache Institute, Durham, North Carolina, USA
| | - Karen Schwab
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | | | - Kirk W Johnson
- Pain Research, Eli Lilly and Company, Indianapolis, Indiana, USA
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12
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Beekly BG, Rupp A, Burgess CR, Elias CF. Fast neurotransmitter identity of MCH neurons: Do contents depend on context? Front Neuroendocrinol 2023; 70:101069. [PMID: 37149229 PMCID: PMC11190671 DOI: 10.1016/j.yfrne.2023.101069] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/07/2023] [Accepted: 04/29/2023] [Indexed: 05/08/2023]
Abstract
Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.
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Affiliation(s)
- B G Beekly
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States; Elizabeth W. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, United States.
| | - A Rupp
- Elizabeth W. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, United States
| | - C R Burgess
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - C F Elias
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States; Elizabeth W. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, United States
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13
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Singh S, Maheshwari A, Namazova I, Benjamin JT, Wang Y. Respiratory Syncytial Virus Infections in Neonates: A Persisting Problem. NEWBORN (CLARKSVILLE, MD.) 2023; 2:222-234. [PMID: 38348152 PMCID: PMC10860331 DOI: 10.5005/jp-journals-11002-0073] [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] [Indexed: 02/15/2024]
Abstract
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in young infants. It is an enveloped, single-stranded, nonsegmented, negative-strand RNA virus, a member of the family Pneumoviridae. Globally, RSV is responsible for 2.3% of deaths among neonates 0-27 days of age. Respiratory syncytial virus infection is most common in children aged below 24 months. Neonates present with cough and fever. Respiratory syncytial virus-associated wheezing is seen in 20% infants during the first year of life of which 2-3% require hospitalization. Reverse transcriptase polymerase chain reaction (RT-PCR) gives fast results and has higher sensitivity compared with culture and rapid antigen tests and are not affected by passively administered antibody to RSV. Therapy for RSV infection of the LRT is mainly supportive, and preventive measures like good hygiene and isolation are the mainstay of management. Standard precautions, hand hygiene, breastfeeding and contact isolation should be followed for RSV-infected newborns. Recent AAP guidelines do not recommend pavilizumab prophylaxis for preterm infants born at 29-35 weeks without chronic lung disease, hemodynamically significant congenital heart disease and coexisting conditions. RSV can lead to long-term sequelae such as wheezing and asthma, associated with increased healthcare costs and reduced quality of life.
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Affiliation(s)
- Srijan Singh
- Neonatologist, Kailash Hospital, Noida, Uttar Pradesh, India
- Global Newborn Society (https://www.globalnewbornsociety.org/)
| | - Akhil Maheshwari
- Global Newborn Society (https://www.globalnewbornsociety.org/)
- Department of Pediatrics, Louisiana State University, Shreveport, Louisiana, United States of America
| | - Ilhama Namazova
- Global Newborn Society (https://www.globalnewbornsociety.org/)
- Department of Pediatrics, Azerbaijan Tibb Universiteti, Baku, Azerbaijan
| | - John T Benjamin
- Global Newborn Society (https://www.globalnewbornsociety.org/)
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Yuping Wang
- Department of Obstetrics and Gynaecology, Louisiana State University, Shreveport, Louisiana, United States of America
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14
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Shang L, Zhao S, Shi H, Xing X, Zhang J, He Y. Nerve growth factor mediates activation of transient receptor potential vanilloid 1 in neurogenic pruritus of psoriasis. Int Immunopharmacol 2023; 118:110063. [PMID: 37004343 DOI: 10.1016/j.intimp.2023.110063] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/04/2023] [Accepted: 03/19/2023] [Indexed: 04/03/2023]
Abstract
Pruritus is a common and painful symptom in psoriasis with profoundly negative impacts on quality of life. The underlying mechanisms of pruritus are complex and multifactorial, and accumulating evidence suggests that pruritus induced by neurogenic inflammation predominates in psoriasis. Nerve growth factor (NGF) -mediated transient receptor potential vanilloid receptor 1(TRPV1) pathway has emerged as a crucial node in the regulation of neurogenic pruritus. TRPV1 appears coupled to most pruritus-specific molecules via the neuro-immune axis. While the modes of regulation differ for each axis, TRPV1 is involved in substantial biochemical crosstalk-causing feedback loops with significant effects on neurogenic pruritus. Therefore, TRPV1 has emerged as a target molecular in drug development for pruritus in psoriasis. However, no significant clinical progress occurred in the development of systemic TRPV1 antagonists due to elevated core temperature. Thus, topical application of TRPV1 antagonists and interference with mediators linked to the TRPV1 activation pathway may be promising therapeutic options to ameliorate pruritus. This Review focuses on recent advances in complicated regulation of NGF-mediated TRPV1 pathway in psoriatic neurogenic pruritus, as well as the therapeutic options that arise from the dissection of the pathway.
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15
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Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev 2023; 103:1565-1644. [PMID: 36454715 PMCID: PMC9988538 DOI: 10.1152/physrev.00059.2021] [Citation(s) in RCA: 128] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 11/23/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in sensory neurons as well as in other cell types, such as motor neurons and neuroendocrine cells. CGRP acts via at least two G protein-coupled receptors that form unusual complexes with receptor activity-modifying proteins. These are the CGRP receptor and the AMY1 receptor; in rodents, additional receptors come into play. Although CGRP is known to produce many effects, the precise molecular identity of the receptor(s) that mediates CGRP effects is seldom clear. Despite the many enigmas still in CGRP biology, therapeutics that target the CGRP axis to treat or prevent migraine are a bench-to-bedside success story. This review provides a contextual background on the regulation and sites of CGRP expression and CGRP receptor pharmacology. The physiological actions of CGRP in the nervous system are discussed, along with updates on CGRP actions in the cardiovascular, pulmonary, gastrointestinal, immune, hematopoietic, and reproductive systems and metabolic effects of CGRP in muscle and adipose tissues. We cover how CGRP in these systems is associated with disease states, most notably migraine. In this context, we discuss how CGRP actions in both the peripheral and central nervous systems provide a basis for therapeutic targeting of CGRP in migraine. Finally, we highlight potentially fertile ground for the development of additional therapeutics and combinatorial strategies that could be designed to modulate CGRP signaling for migraine and other diseases.
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Affiliation(s)
- Andrew F Russo
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa
- Department of Neurology, University of Iowa, Iowa City, Iowa
- Center for the Prevention and Treatment of Visual Loss, Department of Veterans Affairs Health Center, Iowa City, Iowa
| | - Debbie L Hay
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, The University of Auckland, Auckland, New Zealand
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16
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Girard BM, Campbell SE, Vizzard MA. Stress-induced symptom exacerbation: Stress increases voiding frequency, somatic sensitivity, and urinary bladder NGF and BDNF expression in mice with subthreshold cyclophosphamide (CYP). FRONTIERS IN UROLOGY 2023; 3:1079790. [PMID: 37811396 PMCID: PMC10558155 DOI: 10.3389/fruro.2023.1079790] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Symptom exacerbation due to stress is prevalent in many disease states, including functional disorders of the urinary bladder (e.g., overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS)); however, the mechanisms underlying the effects of stress on micturition reflex function are unclear. In this study we designed and evaluated a stress-induced symptom exacerbation (SISE) mouse model that demonstrates increased urinary frequency and somatic (pelvic and hindpaw) sensitivity. Cyclophosphamide (CYP) (35 mg/kg; i.p., every 48 hours for a total of 4 doses) or 7 days of repeated variate stress (RVS) did not alter urinary bladder function or somatic sensitivity; however, both CYP alone and RVS alone significantly (p ≤ 0.01) decreased weight gain and increased serum corticosterone. CYP treatment when combined with RVS for 7 days (CYP+RVS) significantly (p ≤ 0.01) increased serum corticosterone, urinary frequency and somatic sensitivity and decreased weight gain. CYP+RVS exposure in mice significantly (p ≤ 0.01) increased (2.6-fold) voiding frequency as we determined using conscious, open-outlet cystometry. CYP+RVS significantly (p ≤ 0.05) increased baseline, threshold, and peak micturition pressures. We also evaluated the expression of NGF, BDNF, CXC chemokines and IL-6 in urinary bladder in CYP alone, RVS alone and CYP+RVS mouse cohorts. Although all treatments or exposures increased urinary bladder NGF, BDNF, CXC and IL-6 content, CYP+RVS produced the largest increase in all inflammatory mediators examined. These results demonstrated that CYP alone or RVS alone creates a change in the inflammatory environment of the urinary bladder but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS). The SISE model of CYP+RVS will be useful to develop testable hypotheses addressing underlying mechanisms where psychological stress exacerbates symptoms in functional bladder disorders leading to identification of targets and potential treatments.
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Affiliation(s)
- Beatrice M Girard
- The Larner College of Medicine at The University of Vermont, Department of Neurological Sciences, Burlington, VT, 05405
| | - Susan E Campbell
- The Larner College of Medicine at The University of Vermont, Department of Neurological Sciences, Burlington, VT, 05405
| | - Margaret A Vizzard
- The Larner College of Medicine at The University of Vermont, Department of Neurological Sciences, Burlington, VT, 05405
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17
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Yu X, Yang Z, Zhang Y, Xia J, Zhang J, Han Q, Yu H, Wu C, Xu Y, Xu W, Yang W. Lipid Nanoparticle Delivery of Chemically Modified NGF R100W mRNA Alleviates Peripheral Neuropathy. Adv Healthc Mater 2023; 12:e2202127. [PMID: 36325948 DOI: 10.1002/adhm.202202127] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/26/2022] [Indexed: 11/06/2022]
Abstract
Messenger RNA (mRNA) carries genetic instructions to the cell machinery for the transient production of antigens or therapeutic proteins and shows enormous potential in vaccine development, cancer immunotherapy, protein replacement therapy, and genome engineering. Here, the synthesis of chemically modified nerve growth factor mutant (NGFR100W ) mRNA through in vitro transcription is described. After the replacement of the original signal peptide sequence with the Ig Kappa leader sequence, codon-optimized NGFR100W mRNA yielded high secretion of mature NGFR100W , which promotes axon growth in PC12 cells. Using lipid nanoparticle (LNP)-delivery of N1-methylpseudouridine-modified mRNA in mice, NGFR100W -mRNA-LNPs result in the successful expression of NGFR100W protein, which significantly reduces nociceptive activity compared to that of NGFWT . This indicates that NGFR100W derived from exogenous mRNA elicited "painless" neuroprotective activity. Additionally, the therapeutic value of NGFR100W mRNA is established in a paclitaxel-induced peripheral neuropathy model by demonstrating the rapid recovery of intraepidermal nerve fibers. The results show that in vitro-transcribed mRNA has significant flexibility in sequence design and fast in vivo functional validation of target proteins. Furthermore, the results highlight the therapeutic potential of mRNA as a supplement to beneficial proteins for preventing or reversing some chronic medical conditions, such as peripheral neuropathy.
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Affiliation(s)
- Xiang Yu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Zheng Yang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Yu Zhang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Jia Xia
- Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Jiahui Zhang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Qi Han
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Hang Yu
- Shanghai RNACure Biopharma Co., Ltd., Shanghai, 200438, P. R. China
| | - Chengbiao Wu
- Department of Neurosciences, University of California San Diego, La Jolla, CA, 92037, USA
| | - Yingjie Xu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.,Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Wei Xu
- Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.,Department of Neurology, Ruijin Hospital, Zhoushan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, 316012, P. R. China
| | - Wen Yang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200025, P. R. China
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18
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Sun K, Jiang J, Wang Y, Sun X, Zhu J, Xu X, Sun J, Shi J. The role of nerve fibers and their neurotransmitters in regulating intervertebral disc degeneration. Ageing Res Rev 2022; 81:101733. [PMID: 36113765 DOI: 10.1016/j.arr.2022.101733] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/11/2022] [Accepted: 09/11/2022] [Indexed: 01/31/2023]
Abstract
Intervertebral disc degeneration (IVDD) has been the major contributor to chronic lower back pain (LBP). Abnormal apoptosis, senescence, and pyroptosis of IVD cells, extracellular matrix (ECM) degradation, and infiltration of immune cells are the major molecular alternations during IVDD. Changes at tissue level frequently occur at advanced IVD tissue. Ectopic ingrowth of nerves within inner annulus fibrosus (AF) and nucleus pulposus (NP) tissue has been considered as the primary cause for LBP. Innervation at IVD tissue mainly included sensory and sympathetic nerves, and many markers for these two types of nerves have been detected since 1940. In fact, in osteoarthritis (OA), beyond pain transmission, the direct regulation of neuropeptides on functions of chondrocytes have attracted researchers' great attention recently. Many physical and pathological similarities between joint and IVD have shed us the light on the neurogenic mechanism involved in IVDD. Here, an overview of the advances in the nervous system within IVD tissue will be performed, with a discussion on in the role of nerve fibers and their neurotransmitters in regulating IVDD. We hope this review can attract more research interest to address neuromodulation and IVDD itself, which will enhance our understanding of the contribution of neuromodulation to the structural changes within IVD tissue and inflammatory responses and will help identify novel therapeutic targets and enable the effective treatment of IVDD disease.
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Affiliation(s)
- Kaiqiang Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China; Department of Orthopedics, Naval Medical Center of PLA, China
| | - Jialin Jiang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Yuan Wang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Xiaofei Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jian Zhu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Ximing Xu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
| | - Jiangang Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
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Gil TH, Zheng H, Lee HG, Shin JW, Hwang SW, Jang KM, Jeon OH. Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis. Aging (Albany NY) 2022; 14:6006-6027. [PMID: 35951358 PMCID: PMC9417227 DOI: 10.18632/aging.204204] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/12/2022] [Indexed: 11/25/2022]
Abstract
Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from in vitro cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.
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Affiliation(s)
- Tae-Hwan Gil
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Haiyan Zheng
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea.,Department of Physiology, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Hyo Gyeong Lee
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Ji-Won Shin
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Sun Wook Hwang
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea.,Department of Physiology, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Ki-Mo Jang
- Department of Orthopaedic Surgery, Anam Hospital, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Ok Hee Jeon
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea
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20
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Capsoni S, Arisi I, Malerba F, D’Onofrio M, Cattaneo A, Cherubini E. Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer's Disease. Brain Sci 2022; 12:783. [PMID: 35741668 PMCID: PMC9221351 DOI: 10.3390/brainsci12060783] [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: 05/20/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 01/27/2023] Open
Abstract
GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration [Cl-]i due to the delayed expression of the chloride exporter KCC2 at birth. Depolarization-induced calcium rise via NMDA receptors and voltage-dependent calcium channels is instrumental in shaping neuronal circuits and in controlling the excitatory (E)/inhibitory (I) balance in selective brain areas. An E/I imbalance accounts for cognitive impairment observed in several neuropsychiatric disorders. The aim of this review is to summarize recent data on the mechanisms by which alterations of GABAergic signaling alter the E/I balance in cortical and hippocampal neurons in Alzheimer's disease (AD) and the role of cation-chloride co-transporters in this process. In particular, we discuss the NGF and AD relationship and how mice engineered to express recombinant neutralizing anti-NGF antibodies (AD11 mice), which develop a neurodegenerative pathology reminiscent of that observed in AD patients, exhibit a depolarizing action of GABA due to KCC2 impairment. Treating AD and other forms of dementia with bumetanide, a selective KCC2 antagonist, contributes to re-establishing a proper E/I balance in selective brain areas, leading to amelioration of AD symptoms and the slowing down of disease progression.
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Affiliation(s)
- Simona Capsoni
- Bio@SNS Laboratory of Biology, Scuola Normale Superiore, 56126 Pisa, Italy;
- Section of Physiology, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy
| | - Ivan Arisi
- Fondazione European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00161 Rome, Italy; (I.A.); (F.M.); (M.D.)
| | - Francesca Malerba
- Fondazione European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00161 Rome, Italy; (I.A.); (F.M.); (M.D.)
| | - Mara D’Onofrio
- Fondazione European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00161 Rome, Italy; (I.A.); (F.M.); (M.D.)
| | - Antonino Cattaneo
- Bio@SNS Laboratory of Biology, Scuola Normale Superiore, 56126 Pisa, Italy;
- Fondazione European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00161 Rome, Italy; (I.A.); (F.M.); (M.D.)
| | - Enrico Cherubini
- Fondazione European Brain Research Institute (EBRI) Rita Levi-Montalcini, 00161 Rome, Italy; (I.A.); (F.M.); (M.D.)
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21
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Tsanov M. Basal Forebrain Impairment: Understanding the Mnemonic Function of the Septal Region Translates in Therapeutic Advances. Front Neural Circuits 2022; 16:916499. [PMID: 35712645 PMCID: PMC9194835 DOI: 10.3389/fncir.2022.916499] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
The basal forebrain is one of the three major brain circuits involved in episodic memory formation together with the hippocampus and the diencephalon. The dysfunction of each of these regions is known to cause anterograde amnesia. While the hippocampal pyramidal neurons are known to encode episodic information and the diencephalic structures are known to provide idiothetic information, the contribution of the basal forebrain to memory formation has been exclusively associated with septo-hippocampal cholinergic signaling. Research data from the last decade broadened our understanding about the role of septal region in memory formation. Animal studies revealed that septal neurons process locomotor, rewarding and attentional stimuli. The integration of these signals results in a systems model for the mnemonic function of the medial septum that could guide new therapeutic strategies for basal forebrain impairment (BFI). BFI includes the disorders characterized with basal forebrain amnesia and neurodegenerative disorders that affect the basal forebrain. Here, we demonstrate how the updated model of septal mnemonic function can lead to innovative translational treatment approaches that include pharmacological, instrumental and behavioral techniques.
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Affiliation(s)
- Marian Tsanov
- UCD School of Medicine, University College Dublin, Dublin, Ireland
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22
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Kadowaki M, Yamamoto T, Hayashi S. Neuro-immune crosstalk and food allergy: Focus on enteric neurons and mucosal mast cells. Allergol Int 2022; 71:278-287. [PMID: 35410807 DOI: 10.1016/j.alit.2022.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
The nervous system and the immune system individually play important roles in regulating the processes necessary to maintain physiological homeostasis, respond to acute stress and protect against external threats. These two regulating systems for maintaining the living body had often been assumed to function independently. Allergies develop as a result of an overreaction of the immune system to substances that are relatively harmless to the body, such as food, pollen and dust mites. Therefore, it has been generally supposed that the development and pathogenesis of allergies can be explained through an immunological interpretation. Recently, however, neuro-immune crosstalk has attracted increasing attention. Consequently, it is becoming clear that there is close morphological proximity and physiological and pathophysiological interactions between neurons and immune cells in various peripheral tissues. Thus, researchers are now beginning to appreciate that neuro-immune interactions may play a role in tissue homeostasis and the pathophysiology of immune-mediated disease, but very little information is available on the molecular basis of these interactions. Mast cells are a part of the innate immune system implicated in allergic reactions and the regulation of host-pathogen interactions. Mast cells are ubiquitous in the body, and these cells are often found in close proximity to nerve fibers in various tissues, including the lamina propria of the intestine. Mast cells and neurons are thought to communicate bidirectionally to modulate neurophysiological effects and mast cell functions, which suggests that neuro-immune interactions may be involved in the pathology of allergic diseases.
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Zhou T, Lee A, Lo ACY, Kwok JSWJ. Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies. Front Pharmacol 2022; 13:816062. [PMID: 35281903 PMCID: PMC8905431 DOI: 10.3389/fphar.2022.816062] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/27/2022] [Indexed: 12/27/2022] Open
Abstract
Diabetes mellitus (DM) is a major global public health problem that can cause complications such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. Besides the reporting of reduction in corneal nerve density and decrease in corneal sensitivity in diabetic patients, there may be a subsequent result in delayed corneal wound healing and increased corneal infections. Despite being a potential cause of blindness, these corneal nerve changes have not gained enough attention. It has been proposed that corneal nerve changes may be an indicator for diabetic neuropathy, which can provide a window for early diagnosis and treatment. In this review, the authors aimed to give an overview of the relationship between corneal nerves and diabetic neuropathy as well as the underlying pathophysiological mechanisms of corneal nerve fiber changes caused by DM for improved prediction and prevention of diabetic neuropathy. In addition, the authors summarized current and novel therapeutic methods for delayed corneal wound healing, nerve protection and regeneration in the diabetic cornea.
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Affiliation(s)
- Ting Zhou
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Allie Lee
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Amy Cheuk Yin Lo
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Jeremy Sze Wai John Kwok
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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24
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Cyril AC, Jan RK, Radhakrishnan R. Pain in chronic prostatitis and the role of ion channels: a brief overview. Br J Pain 2022; 16:50-59. [PMID: 35111314 PMCID: PMC8801692 DOI: 10.1177/20494637211015265] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Prostatitis is the third most common urologic condition affecting more than half the male population at some point in their lives. There are different categories of prostatitis, of which approximately 90% of cases can be classified under the National Institute of Health (NIH) type III category (chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)) with no causative agents identified. CP/CPPS is associated with several symptoms, of which the most prominent being chronic pain. Despite its high incidence, pain management in patients with CP/CPPS has been poor, possibly due to the lack of understanding of aetiological factors and mechanisms underlying pain development. METHODS An extensive literature search of published articles on the molecular mechanisms of pain in CP/CPPS was conducted using PubMed and Google Scholar search engines (https://pubmed.ncbi.nlm.nih.gov and https://scholar.google.com). The terms used for the search were: prostatitis, pain mechanism in CP/CPPS, prostatitis pain models, acid-sensing ion channels (ASICs), transient receptor potential vanilloid type 1 (TRPVs), purinergic channels (P2X) in prostatitis pain mechanism and inflammatory mediators in CP/CPPS. The papers were identified based on the title and abstract, and after excluding the articles that did not emphasize the pain mechanism in CP/CPPS. Ninety-five articles (36 review and 59 original research papers) met our criteria and were included in the review. RESULTS A number of inflammatory mediator molecules and pain channels, including ASICs, transient receptor potential vanilloid channels (TRPVs) and P2Xs have been investigated for their role in prostatitis pain pathology using various animal models. CONCLUSION This review summarizes the pain mechanisms in CP/CPPS focusing on the inflammatory mediators, neurotransmitters, pain-transducing ion channels and small animal models developed for studying prostatitis.
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Affiliation(s)
| | | | - Rajan Radhakrishnan
- Rajan Radhakrishnan, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Building 14, Dubai Healthcare City, P.O Box 505055, Dubai, UAE.
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25
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Hanatleh OM, Kofahi NK, Aburahma SK, Bintareef EM, Al-Bashtawy M, Alkhawaldeh A, Ibnian AM. A 5-Year-Old Palestinian Bedouin Girl with Repeated Self-Induced Injuries to the Digits, a Diagnosis of Congenital Insensitivity to Pain, and Anhidrosis. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e933486. [PMID: 34732685 PMCID: PMC8579061 DOI: 10.12659/ajcr.933486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Congenital insensitivity to pain with anhidrosis (CIPA), also referred to as hereditary sensory and autonomic neuropathy type IV, is a rare autosomal recessive disease caused by mutations in the NTRK1 gene. The inability to feel pain and temperature often leads to repeated severe and unintentional self-inflicted injuries; these can result in severe complications, as patients heal slowly from skin and bone injuries. This case report describes a 5-year-old Palestinian girl with self-inflicted injury to the digits, a dislocated distal inter-phalangeal joint of the left big toe, and a diagnosis of CIPA. CASE REPORT A 5-year-old girl, a daughter of related Palestinian Bedouin parents, presented with a chronic unhealed wound over the planter surface of the left foot. Painless repetitive minor traumata over the same area badly affected wound healing and this led to wound dehiscence and dislocation of the distal inter-phalangeal joint of the left big toe. Surgical fixation of the dislocated joint along with intravenous antibiotics and close follow-up resulted in eventual improvement and near complete wound healing despite the obviously slow healing process. The girl also displayed evidence of unintentional self-inflicted injury, which within the overall clinical context warranted a clinical suspicion of CIPA. This was confirmed by genetic testing for the presence of a homozygous frameshift mutation in the NTRK1 gene (c.1842_1843insT; p.Pro615Serfs*12). CONCLUSIONS This case report shows that a physician should have a low threshold of suspicion to investigate for CIPA when managing children with multiple unintentional self-inflicted injuries, anhidrosis, and pain insensitivity, mainly through genetic testing to detect mutations in the NTRK1 gene.
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Affiliation(s)
- Omar M Hanatleh
- Department of Orthopedics, Al-Safa Specialized Hospital, Jarash, Jordan
| | - Noran K Kofahi
- Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Samah K Aburahma
- Department of Pediatrics, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | | | | | | | - Ali M Ibnian
- Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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26
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Music of metagenomics-a review of its applications, analysis pipeline, and associated tools. Funct Integr Genomics 2021; 22:3-26. [PMID: 34657989 DOI: 10.1007/s10142-021-00810-y] [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] [Received: 03/29/2021] [Revised: 09/25/2021] [Accepted: 10/03/2021] [Indexed: 10/20/2022]
Abstract
This humble effort highlights the intricate details of metagenomics in a simple, poetic, and rhythmic way. The paper enforces the significance of the research area, provides details about major analytical methods, examines the taxonomy and assembly of genomes, emphasizes some tools, and concludes by celebrating the richness of the ecosystem populated by the "metagenome."
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27
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Bimonte S, Cascella M, Forte CA, Esposito G, Cuomo A. The Role of Anti-Nerve Growth Factor Monoclonal Antibodies in the Control of Chronic Cancer and Non-Cancer Pain. J Pain Res 2021; 14:1959-1967. [PMID: 34234542 PMCID: PMC8253925 DOI: 10.2147/jpr.s302004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022] Open
Abstract
Nerve growth factor (NGF) belongs to the neurotrophin family and plays a fundamental role in the endurance of sensory and sympathetic neurons during embryogenesis. NGF, by interacting with tropomyosin receptor kinase A receptor (TrkA), modulates the pain pathway through the enhancement of the neurotrophic and nociceptor functions. Moreover, it has been demonstrated that NGF is upregulated in patients with chronic pain syndromes, which are difficult to treat. Thus, new non-pharmacological approaches, based on the use of different species-specific monoclonal antibodies (mAbs) targeting the NGF pathway, have been tested for the treatment of chronic pain in preclinical and clinical studies. With regard to preclinical investigations, anti-NGF mAbs have been used for the management of osteoarthritis (OA) and chronic low back pain animal models, with encouraging results. Moreover, anti-NGF mAb therapy is effective in animal models of neuropathic cancer pain. As regards patients with OA, although phase II and phase III clinical trials with tanezumab led to pain reduction, the safety was not observed in all these patients. Here, we review the preclinical and clinical studies on anti-NGF mAb therapy in chronic syndromes, dissect the role of NGF in pain transduction, and highlight the use of anti-NGF mAbs in humans.
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Affiliation(s)
- Sabrina Bimonte
- Division of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, Italy
| | - Marco Cascella
- Division of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, Italy
| | - Cira Antonietta Forte
- Division of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, Italy
| | - Gennaro Esposito
- Division of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, Italy
| | - Arturo Cuomo
- Division of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, Italy
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Guan M, Ying S, Wang Y. Increased expression of transient receptor potential channels and neurogenic factors associates with cough severity in a guinea pig model. BMC Pulm Med 2021; 21:187. [PMID: 34078339 PMCID: PMC8173754 DOI: 10.1186/s12890-021-01556-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 05/25/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies suggest that transient receptor potential (TRP) channels and neurogenic inflammation may be involved in idiopathic pulmonary fibrosis (IPF)-related high cough sensitivity, although the details of mechanism are largely unknown. Here, we aimed to further explore the potential mechanism involved in IPF-related high cough sensitivity to capsaicin challenge in a guinea pig model of pulmonary fibrosis induced by bleomycin. METHODS Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were employed to measure the expression of TRP channel subfamily A, member 1 (TRPA1) and TRP vanilloid 1 (TRPV1), which may be involved in the cough reflex pathway. Immunohistochemical analysis and RT-qPCR were used to detect the expression of neuropeptides substance P (SP), Neurokinin-1 receptor (NK1R), and calcitonin gene-related peptide (CGRP) in lung tissues. Concentrations of nerve growth factor (NGF), SP, neurokinin A (NKA), neurokinin B (NKB), and brain-derived neurotrophic factor (BDNF) in lung tissue homogenates were measured by ELISA. RESULTS Cough sensitivity to capsaicin was significantly higher in the model group than that of the sham group. RT-qPCR and immunohistochemical analysis showed that the expression of TRPA1 and TRPV1 in the jugular ganglion and nodal ganglion, and SP, NK1R, and CGRP in lung tissue was significantly higher in the model group than the control group. In addition, expression of TRP and neurogenic factors was positively correlated with cough sensitivity of the experimental animals. CONCLUSION Up-regulated expression of TRPA1 and TRPV1 in the cough reflex pathway and neurogenic inflammation might contribute to the IPF-related high cough sensitivity in guinea pig model.
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Affiliation(s)
- Mengyue Guan
- Department of Respiratory Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23rd Art Museum Backstreet, Dongcheng District, Beijing, 10010, China
| | - Sun Ying
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10th Xitoutiao, You'anmenwai Street, Fengtai District, Beijing, China
| | - Yuguang Wang
- Department of Respiratory Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23rd Art Museum Backstreet, Dongcheng District, Beijing, 10010, China.
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29
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Targeting Nerve Growth Factor for Pain Management in Osteoarthritis-Clinical Efficacy and Safety. Rheum Dis Clin North Am 2021; 47:181-195. [PMID: 33781489 DOI: 10.1016/j.rdc.2020.12.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Nerve growth factor (NGF) is a neurotrophin that mediates pain sensitization in pathologic states, including osteoarthritis. In clinical trials, antibodies to NGF reduce pain and improve physical function due to osteoarthritis of the knee or hip and have a long duration of action. Rapidly progressive osteoarthritis is a dose-dependent adverse event with these agents, and additional joint safety signals, such as subchondral insufficiency fractures and increased rates of total joint replacement, are reported. The effects on pain and potential mechanisms behind these joint events both are of considerable importance in the consideration of future use of anti-NGF therapies for osteoarthritis.
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30
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Moattari CR, Granstein RD. Neuropeptides and neurohormones in immune, inflammatory and cellular responses to ultraviolet radiation. Acta Physiol (Oxf) 2021; 232:e13644. [PMID: 33724698 DOI: 10.1111/apha.13644] [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: 12/06/2020] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/16/2022]
Abstract
Humans are exposed to varying amounts of ultraviolet radiation (UVR) through sunlight. UVR penetrates into human skin leading to release of neuropeptides, neurotransmitters and neuroendocrine hormones. These messengers released from local sensory nerves, keratinocytes, Langerhans cells (LCs), mast cells, melanocytes and endothelial cells (ECs) modulate local and systemic immune responses, mediate inflammation and promote differing cell biologic effects. In this review, we will focus on both animal and human studies that elucidate the roles of calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF), nitric oxide and proopiomelanocortin (POMC) derivatives in mediating immune and inflammatory effects of exposure to UVR as well as other cell biologic effects of UVR exposure.
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31
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Magadmi RM, Alsulaimani MA, Al-Rafiah AR, Ahmad MS, Esmat A. Carvedilol Exerts Neuroprotective Effect on Rat Model of Diabetic Neuropathy. Front Pharmacol 2021; 12:613634. [PMID: 33927613 PMCID: PMC8077026 DOI: 10.3389/fphar.2021.613634] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 02/24/2021] [Indexed: 11/13/2022] Open
Abstract
Diabetic neuropathy (DN) commonly occurs in diabetics, affecting approximately 50% of both type 1 and 2 diabetic patients. It is a leading cause of non-traumatic amputations. Oxidative stress could play a key role in the pathophysiology of DN. This study aimed to investigate the potential neuroprotective effect of carvedilol on STZ-induced DN in rats. Thirty male Sprague Dawley rats (weighing 200–250 g) were randomly divided into five groups (six/group), where group 1 (negative control) received only the vehicle (0.5% of carboxymethyl cellulose orally 1 ml/kg). DN was induced by a single injection of remaining rats with streptozotocin (STZ; 50 mg/kg, i.p.). After diabetes induction, group 2 served as the diabetic untreated animals; while groups 3 and 4 were treated with carvedilol (1 and 10 mg/kg/d, orally, respectively). Group 5 received a-lipoic acid as a reference neuroprotective (100 mg/kg/d, orally). All treatments were continued for 45 days after diabetes induction, followed by behavioural tests. After sacrificing the animals, dorsal root ganglia, and sciatic nerves were collected for histopathological examination and biochemical assessments. Briefly, STZ administration caused cold allodynia, induced oxidative stress, and increased nerve growth factor (NGF) concentration. Nevertheless, carvedilol improved the behavioural tests, ameliorated the oxidative imbalance as manifested by reducing malondialdehyde, restoring glutathione content, and superoxide dismutase activity. Carvedilol also decreased NGF concentration in DRG homogenate. In conclusion, this study demonstrates the neuroprotective effect of carvedilol in an experimentally induced DN rat model through–at least partly–its antioxidant effect and reduced NGF concentration in DRG.
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Affiliation(s)
- Rania M Magadmi
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mujahid A Alsulaimani
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacy, Ministry of Health, Taif, Saudi Arabia
| | - Aziza R Al-Rafiah
- Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muhammad Saeed Ahmad
- King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed Esmat
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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32
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Wan Q, Qin W, Ma Y, Shen M, Li J, Zhang Z, Chen J, Tay FR, Niu L, Jiao K. Crosstalk between Bone and Nerves within Bone. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003390. [PMID: 33854888 PMCID: PMC8025013 DOI: 10.1002/advs.202003390] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/29/2020] [Indexed: 05/11/2023]
Abstract
For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve-resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress-related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.
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Affiliation(s)
- Qian‐Qian Wan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Wen‐Pin Qin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Yu‐Xuan Ma
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Min‐Juan Shen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Jing Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Zi‐Bin Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Ji‐Hua Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Franklin R. Tay
- College of Graduate StudiesAugusta UniversityAugustaGA30912USA
| | - Li‐Na Niu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Kai Jiao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
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Zhou X, Han X, Lyu SC, Bunning B, Kost L, Chang I, Cao S, Sampath V, Nadeau KC. Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy. JCI Insight 2021; 6:143058. [PMID: 33571165 PMCID: PMC8026193 DOI: 10.1172/jci.insight.143058] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 02/10/2021] [Indexed: 12/14/2022] Open
Abstract
DNA methylation (DNAm) has been shown to play a role in mediating food allergy; however, the mechanism by which it does so is poorly understood. In this study, we used targeted next-generation bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) versus nonallergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 potentially novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity), as well as DNAm signature combinations with superior diagnostic potential compared with serum peanut–specific IgE for PA versus NA. Furthermore, we found that, following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared with NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than those in randomly paired genetically unrelated individuals, suggesting that PA-related DNAm signatures may be associated with genetic factors.
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34
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Luo Y, Sun Y, Tian X, Zheng X, Wang X, Li W, Wu X, Shu B, Hou W. Deep Brain Stimulation for Alzheimer's Disease: Stimulation Parameters and Potential Mechanisms of Action. Front Aging Neurosci 2021; 13:619543. [PMID: 33776742 PMCID: PMC7990787 DOI: 10.3389/fnagi.2021.619543] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/19/2021] [Indexed: 12/19/2022] Open
Abstract
Deep brain stimulation (DBS) is a neurosurgical technique that regulates neuron activity by using internal pulse generators to electrodes in specific target areas of the brain. As a blind treatment, DBS is widely used in the field of mental and neurological diseases, although its mechanism of action is still unclear. In the past 10 years, DBS has shown a certain positive effect in animal models and patients with Alzheimer's disease (AD), but there are also different results that may be related to the stimulation parameters of DBS. Based on this, determining the optimal stimulation parameters for DBS in AD and understanding its mechanism of action are essential to promote the clinical application of DBS in AD. This review aims to explore the therapeutic effect of DBS in AD, and to analyze its stimulation parameters and potential mechanism of action. The keywords "Deep brain stimulation" and "Alzheimer's Disease" were used for systematic searches in the literature databases of Web of Science and PubMed (from 1900 to September 29, 2020). All human clinical studies and animal studies were reported in English, including individual case studies and long-term follow-up studies, were included. These studies described the therapeutic effects of DBS in AD. The results included 16 human clinical studies and 14 animal studies, of which 28 studies clearly demonstrated the positive effect of DBS in AD. We analyzed the current stimulation parameters of DBS in AD from stimulation target, stimulation frequency, stimulation start time, stimulation duration, unilateral/bilateral treatment and current intensity, etc., and we also discussed its potential mechanism of action from multiple aspects, including regulating related neural networks, promoting nerve oscillation, reducing β-amyloid and tau levels, reducing neuroinflammation, regulating the cholinergic system, inducing the synthesis of nerve growth factor.
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Affiliation(s)
- Yinpei Luo
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China
| | - Yuwei Sun
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China
| | - Xuelong Tian
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China.,Chongqing Medical Electronics Engineering Technology Research Center, Chongqing University, Chongqing, China
| | - Xiaolin Zheng
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China.,Chongqing Medical Electronics Engineering Technology Research Center, Chongqing University, Chongqing, China
| | - Xing Wang
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China.,Chongqing Medical Electronics Engineering Technology Research Center, Chongqing University, Chongqing, China
| | - Weina Li
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaoying Wu
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China.,Chongqing Medical Electronics Engineering Technology Research Center, Chongqing University, Chongqing, China
| | - Bin Shu
- Department of Rehabilitation Medicine, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Wensheng Hou
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing, China.,Chongqing Medical Electronics Engineering Technology Research Center, Chongqing University, Chongqing, China
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Tang M, Luo M, Lu W, Zhang R, Liang W, Gu J, Yu X, Zhang X, Hu C. Nerve growth factor is closely related to glucose metabolism, insulin sensitivity and insulin secretion in the second trimester: a case-control study in Chinese. Nutr Metab (Lond) 2020; 17:98. [PMID: 33292292 PMCID: PMC7678221 DOI: 10.1186/s12986-020-00523-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 11/10/2020] [Indexed: 01/31/2023] Open
Abstract
Objective Inflammation-related factors have been shown to play a significant role throughout pregnancy. In this study, we aimed to explore the relationships between selected inflammatory cytokines and gestational diabetes (GDM) in Chinese pregnant women.
Design and methods This was a 1:1 matched case–control study that included 200 pairs of subjects in the second trimester and 130 pairs of subjects in the third trimester. Serum levels of nerve growth factor (NGF), Interleukin-6 (IL-6), leptin, Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) were measured by enzyme immunoassay. The associations of these inflammatory factors with metabolic parameters were analysed. Results In the second trimester, GDM patients had higher NGF levels and lower IL-8 levels than did normal controls (P < 0.001 and P = 0.015, respectively). However, in the third trimester, only lower leptin levels were observed in the GDM group (P = 0.031). Additionally, in the second trimester, NGF levels were not only positively associated with fasting, 1-h and 2-h glucose levels and the area under curve of glucose, but also positively related to insulin sensitivity and secretion, as suggested by fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment index of β-cell secretion (HOMA-β) (all P < 0.05). Moreover, IL-6 and leptin levels were positively correlated with HOMA-IR and HOMA-β, and TNF-α levels were positively related to HOMA-IR (all P < 0.05). Except for the relationships between NGF and HOMA-β and TNF-α and HOMA-IR, the other correlations still existed even after adjusting for confounding factors (all P < 0.05). Conclusion In addition to the positive associations of IL-6 and leptin with insulin resistance and secretion, NGF was higher in the GDM patients and strongly linked to glucose metabolism, insulin resistance and pancreatic β cell function in Chinese pregnant women in the second trimester.
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Affiliation(s)
- Mengyang Tang
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China
| | - Mingjuan Luo
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China.,Department of Endocrinology and Metabolism, University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Wenqian Lu
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Liang
- Department of Endocrinology and Metabolism, University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Jianfen Gu
- Department of Endocrinology and Metabolism, University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Xuemei Yu
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China
| | - Xueli Zhang
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China
| | - Cheng Hu
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. .,Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China. .,Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
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William D. Willis, Jr, MD, PhD Memorial Lecture: The evolutionary history of nerve growth factor and nociception. Pain 2020; 161 Suppl 1:S36-S47. [PMID: 33090738 PMCID: PMC7434219 DOI: 10.1097/j.pain.0000000000001889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Alves CJ, Couto M, Sousa DM, Magalhães A, Neto E, Leitão L, Conceição F, Monteiro AC, Ribeiro-da-Silva M, Lamghari M. Nociceptive mechanisms driving pain in a post-traumatic osteoarthritis mouse model. Sci Rep 2020; 10:15271. [PMID: 32943744 PMCID: PMC7499425 DOI: 10.1038/s41598-020-72227-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 08/20/2020] [Indexed: 11/29/2022] Open
Abstract
In osteoarthritis (OA), pain is the dominant clinical symptom, yet the therapeutic approaches remain inadequate. The knowledge of the nociceptive mechanisms in OA, which will allow to develop effective therapies for OA pain, is of utmost need. In this study, we investigated the nociceptive mechanisms involved in post-traumatic OA pain, using the destabilization of the medial meniscus (DMM) mouse model. Our results revealed the development of peripheral pain sensitization, reflected by augmented mechanical allodynia. Along with the development of pain behaviour, we observed an increase in the expression of calcitonin gene-related peptide (CGRP) in both the sensory nerve fibers of the periosteum and the dorsal root ganglia. Interestingly, we also observed that other nociceptive mechanisms commonly described in non-traumatic OA phenotypes, such as infiltration of the synovium by immune cells, neuropathic mechanisms and also central sensitization were not present. Overall, our results suggest that CGRP in the sensory nervous system is underlying the peripheral sensitization observed after traumatic knee injury in the DMM model, highlighting the CGRP as a putative therapeutic target to treat pain in post-traumatic OA. Moreover, our findings suggest that the nociceptive mechanisms involved in driving pain in post-traumatic OA are considerably different from those in non-traumatic OA.
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Affiliation(s)
- C J Alves
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. .,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.
| | - M Couto
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - D M Sousa
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - A Magalhães
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal
| | - E Neto
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - L Leitão
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade de Porto, Porto, Portugal
| | - F Conceição
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade de Porto, Porto, Portugal
| | - A C Monteiro
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - M Ribeiro-da-Silva
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Faculdade de Medicina, Universidade do Porto (FMUP), Porto, Portugal.,Serviço de Ortopedia e Traumatologia, Centro Hospitalar São João, Porto, Portugal
| | - M Lamghari
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade de Porto, Porto, Portugal
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Abstract
Supplemental Digital Content is Available in the Text. A ligand-guided, light-activated photosensitizer tool targets TrkA-expressing nociceptors, reversing acute and chronic pain in mice. Nerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here, we describe novel technology to selectively photoablate TrkA-positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near-infrared illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic, and joint pain. To target peripheral nociceptors, we generated a SNAP-tagged NGF derivative NGFR121W that binds to TrkA/p75 receptors but does not provoke signaling in TrkA-positive cells or elicit pain behaviors in mice. NGFR121W-SNAP was coupled to the photosensitizer IRDye700DX phthalocyanine (IR700) and injected subcutaneously. After near-infrared illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic, and neuropathic pain, mechanical hypersensitivity was abolished for 3 weeks after a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then reinnervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGFR121W-SNAP-mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.
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O'Reilly ML, Tom VJ. Neuroimmune System as a Driving Force for Plasticity Following CNS Injury. Front Cell Neurosci 2020; 14:187. [PMID: 32792908 PMCID: PMC7390932 DOI: 10.3389/fncel.2020.00187] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/29/2020] [Indexed: 12/15/2022] Open
Abstract
Following an injury to the central nervous system (CNS), spontaneous plasticity is observed throughout the neuraxis and affects multiple key circuits. Much of this spontaneous plasticity can elicit beneficial and deleterious functional outcomes, depending on the context of plasticity and circuit affected. Injury-induced activation of the neuroimmune system has been proposed to be a major factor in driving this plasticity, as neuroimmune and inflammatory factors have been shown to influence cellular, synaptic, structural, and anatomical plasticity. Here, we will review the mechanisms through which the neuroimmune system mediates plasticity after CNS injury. Understanding the role of specific neuroimmune factors in driving adaptive and maladaptive plasticity may offer valuable therapeutic insight into how to promote adaptive plasticity and/or diminish maladaptive plasticity, respectively.
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Affiliation(s)
- Micaela L O'Reilly
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Veronica J Tom
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, United States
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40
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Sone PP, Kaneko T, Zaw SYM, Sueyama Y, Gu B, Murano H, Zaw ZCT, Okada Y, Han P, Katsube KI, Okiji T. Neural Regeneration/Remodeling in Engineered Coronal Pulp Tissue in the Rat Molar. J Endod 2020; 46:943-949. [DOI: 10.1016/j.joen.2020.04.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 03/10/2020] [Accepted: 04/03/2020] [Indexed: 12/25/2022]
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Ding XW, Li R, Geetha T, Tao YX, Babu JR. Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165858. [PMID: 32531260 DOI: 10.1016/j.bbadis.2020.165858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/11/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023]
Abstract
As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.
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Affiliation(s)
- Xiao-Wen Ding
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA
| | - Rongzi Li
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA
| | - Thangiah Geetha
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
| | - Jeganathan Ramesh Babu
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA.
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Oza MJ, Kulkarni YA. Formononetin Ameliorates Diabetic Neuropathy by Increasing Expression of SIRT1 and NGF. Chem Biodivers 2020; 17:e2000162. [PMID: 32459048 DOI: 10.1002/cbdv.202000162] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 04/17/2020] [Indexed: 12/13/2022]
Abstract
Diabetic neuropathy is commonly observed complication in more than 50 % of type 2 diabetic patients. Histone deacetylases including SIRT1 have significant role to protect neuron from hyperglycemia induced damage. Formononetin (FMNT) is known for its effect to control hyperglycemia and also activate SIRT1. In present study, we evaluated effect of FMNT as SIRT1 activator in type 2 diabetic neuropathy. Type 2 diabetic neuropathy was induced in rats by modification of diet for 15 days using high fat diet and administration of streptozotocin (35 mg/kg/day, i. p.). FMNT treatment was initiated after confirmation of type 2 diabetes. Treatment was given for 16 weeks at 10, 20 and 40 mg/kg/day dose orally. FMNT treatment-controlled hypoglycemia and reduced insulin resistance significantly in diabetic animals. FMNT treatment reduced oxidative stress in sciatic nerve tissue. FMNT treatment also reduced thermal hyperalgesia and mechanical allodynia significantly. It improved conduction velocity in nerve and unregulated SIRT1 and NGF expression in sciatic nerve tissue. Results of present study indicate that continuous administration of FMNT protected diabetic animals from hyperglycemia induced neuronal damage by controlling hyperglycemia and increasing SIRT1 and NGF expression in nerve tissue. Thus, FMNT can be an effective candidate for treatment of type 2 diabetic neuropathy.
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Affiliation(s)
- Manisha J Oza
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, 400056, India.,SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, 400056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, 400056, India
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43
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Barker PA, Mantyh P, Arendt-Nielsen L, Viktrup L, Tive L. Nerve Growth Factor Signaling and Its Contribution to Pain. J Pain Res 2020; 13:1223-1241. [PMID: 32547184 PMCID: PMC7266393 DOI: 10.2147/jpr.s247472] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Nerve growth factor (NGF) is a neurotrophic protein essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development. A substantial body of evidence, based on both animal and human studies, demonstrates that NGF plays a pivotal role in modulation of nociception in adulthood. This has spurred development of a variety of novel analgesics that target the NGF signaling pathway. Here, we present a narrative review designed to summarize how NGF receptor activation and downstream signaling alters nociception through direct sensitization of nociceptors at the site of injury and changes in gene expression in the dorsal root ganglion that collectively increase nociceptive signaling from the periphery to the central nervous system. This review illustrates that NGF has a well-known and multifunctional role in nociceptive processing, although the precise signaling pathways downstream of NGF receptor activation that mediate nociception are complex and not completely understood. Additionally, much of the existing knowledge derives from studies performed in animal models and may not accurately represent the human condition. However, available data establish a role for NGF in the modulation of nociception through effects on the release of inflammatory mediators, nociceptive ion channel/receptor activity, nociceptive gene expression, and local neuronal sprouting. The role of NGF in nociception and the generation and/or maintenance of chronic pain has led to it becoming a novel and attractive target of pain therapeutics for the treatment of chronic pain conditions.
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Affiliation(s)
- Philip A Barker
- Department of Biology, University of British Columbia, Kelowna, BC, Canada
| | - Patrick Mantyh
- Department of Pharmacology, University of Arizona, Tucson, AZ, USA
| | - Lars Arendt-Nielsen
- Department of Health Science and Technology and the Center for Sensory-Motor Interaction/Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
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Lebold KM, Drake MG, Hales-Beck LB, Fryer AD, Jacoby DB. IL-5 Exposure In Utero Increases Lung Nerve Density and Airway Reactivity in Adult Offspring. Am J Respir Cell Mol Biol 2020; 62:493-502. [PMID: 31821769 PMCID: PMC7110978 DOI: 10.1165/rcmb.2019-0214oc] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 12/10/2019] [Indexed: 12/12/2022] Open
Abstract
Asthma is characterized by airway hyperreactivity and inflammation. In the lungs, parasympathetic and sensory nerves control airway tone and induce bronchoconstriction. Dysregulation of these nerves results in airway hyperreactivity. Humans with eosinophilic asthma have significantly increased sensory nerve density in airway epithelium, suggesting that type 2 cytokines and inflammatory cells promote nerve growth. Similarly, mice with congenital airway eosinophilia also have airway hyperreactivity and increased airway sensory nerve density. Here, we tested whether this occurs during development. We show that transgenic mice that overexpress IL-5, a cytokine required for eosinophil hematopoiesis, give birth to wild-type offspring that have significantly increased airway epithelial nerve density and airway hyperreactivity that persists into adulthood. These effects are caused by in utero exposure to maternal IL-5 and resulting fetal eosinophilia. Allergen exposure of these adult wild-type offspring results in severe airway hyperreactivity, leading to fatal reflex bronchoconstriction. Our results demonstrate that fetal exposure to IL-5 is a developmental origin of airway hyperreactivity, mediated by hyperinnervation of airway epithelium.
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Affiliation(s)
- Katie M Lebold
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon
| | - Matthew G Drake
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon
| | - Lauren B Hales-Beck
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon
| | - Allison D Fryer
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon
| | - David B Jacoby
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon
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Ayasse MT, Buddenkotte J, Alam M, Steinhoff M. Role of neuroimmune circuits and pruritus in psoriasis. Exp Dermatol 2020; 29:414-426. [PMID: 31954075 DOI: 10.1111/exd.14071] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 12/09/2019] [Accepted: 12/31/2019] [Indexed: 12/19/2022]
Abstract
Psoriasis is a chronic inflammatory skin disease presenting with an array of clinical phenotypes, often associated with pruritus. Environmental and psychological stressors can exacerbate psoriasis symptoms and provoke flares. Recent studies suggest a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis in some patients with psoriasis that can result in immune dysregulation. The immune system, in turn, can communicate with the nervous system to induce, maintain or aggravate psoriasis. In the skin, peripheral sensory as well as autonomic nerves control release of inflammatory mediators from dendritic cells, mast cells, T cells or keratinocytes, thereby modulating inflammatory responses and, in case of sensory nerves, pruritus. In response to the environment or stress, cytokines, chemokines, proteases, and neuropeptides fluctuate in psoriasis and influence immune responses as well as nerve activity. Furthermore, immune cells communicate with sensory nerves which control release of cytokines, such as IL-23, that are ultimately involved in psoriasis pathogenesis. Nerves also communicate with keratinocytes to induce epidermal proliferation. Notably, in contrast to recent years the debilitating problem of pruritus in psoriasis has been increasingly appreciated. Thus, investigating neuroimmune communication in psoriasis will not only expand our knowledge about the impact of sensory nerves in inflammation and pruritus and give new insights into the impact of environmental factors activating neuroimmune circuits or of stress in psoriasis, but may also lead to novel therapies. This review summarizes the relevant literature on the role of neuroimmune circuits, stress and how the central HPA axis and its peripheral equivalent in the skin, impact psoriasis.
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Affiliation(s)
- Marissa T Ayasse
- Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Jörg Buddenkotte
- Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA.,Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar.,Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Majid Alam
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar.,Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Martin Steinhoff
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar.,Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.,Weill Cornell Medicine-Qatar, Doha, Qatar.,Medical School, Qatar University, Doha, Qatar.,School of Medicine, Weill Cornell University, New York, NY, USA
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Sandoval-Talamantes AK, Gómez-González BA, Uriarte-Mayorga DF, Martínez-Guzman MA, Wheber-Hidalgo KA, Alvarado-Navarro A. Neurotransmitters, neuropeptides and their receptors interact with immune response in healthy and psoriatic skin. Neuropeptides 2020; 79:102004. [PMID: 31902596 DOI: 10.1016/j.npep.2019.102004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 12/22/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023]
Abstract
Psoriasis is a chronic inflammatory disease with a multifactorial origin that affects the skin. It is characterized by keratinocyte hyperproliferation, which results in erythemato-squamous plaques. Just as the immune system plays a fundamental role in psoriasis physiopathology, the nervous system maintains the inflammatory process through the neuropeptides and neurotransmitters synthesis, as histamine, serotonin, calcitonin gene-related peptide, nerve growth factor, vasoactive intestinal peptide, substance P, adenosine, glucagon-like peptide, somatostatin and pituitary adenylate cyclase polypeptide. In patients with psoriasis, the systemic or in situ expression of these chemical mediators and their receptors are altered, which affects the clinical activity of patients due to its link to the immune system, provoking neurogenic inflammation. It is important to establish the role of the nervous system since it could represent a therapeutic alternative for psoriasis patients. The aim of this review is to offer a detailed review of the current literature about the neuropeptides and neurotransmitters involved in the physiopathology of psoriasis.
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Affiliation(s)
- Ana Karen Sandoval-Talamantes
- Centro de Reabilitación Infantil Teletón de Occidente, Copal 4575, Col. Arboledas del Sur, 44980 Guadalajara, Jalisco, México
| | - B A Gómez-González
- Instituto Dermatológico de Jalisco "Dr. José Barba Rubio", Av. Federalismo Norte 3102, Col. Atemajac del Valle, 45190 Zapopan, Jalisco, México
| | - D F Uriarte-Mayorga
- Instituto Dermatológico de Jalisco "Dr. José Barba Rubio", Av. Federalismo Norte 3102, Col. Atemajac del Valle, 45190 Zapopan, Jalisco, México
| | - M A Martínez-Guzman
- Unima Diagnósticos de México, Paseo de los Mosqueteros 4181, Col. Villa Universitaria, 45110 Zapopan, Jalisco, México
| | - Katia Alejandra Wheber-Hidalgo
- Instituto Dermatológico de Jalisco "Dr. José Barba Rubio", Av. Federalismo Norte 3102, Col. Atemajac del Valle, 45190 Zapopan, Jalisco, México
| | - Anabell Alvarado-Navarro
- Centro de Investigación en Inmunología y dermatología, Universidad de Guadalajara, México, Sierra Mojada 950, Col. Independencia, 44340, Guadalajara, Jalisco, México.
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Li FXZ, Xu F, Lin X, Wu F, Zhong JY, Wang Y, Guo B, Zheng MH, Shan SK, Yuan LQ. The Role of Substance P in the Regulation of Bone and Cartilage Metabolic Activity. Front Endocrinol (Lausanne) 2020; 11:77. [PMID: 32180759 PMCID: PMC7059306 DOI: 10.3389/fendo.2020.00077] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 02/05/2020] [Indexed: 01/06/2023] Open
Abstract
Substance P (SP) is a neuropeptide that is released from sensory nerve endings and is widely present in nerve fibers. It acts on bones and related tissues by binding to receptors, thereby regulating bone metabolism, cartilage metabolism, and fracture healing. SP has attracted widespread attention as a signaling substance that can be recognized by both the immune system and the nervous system. Previous studies have shown that bone and chondrocytes can synthesize and secrete sensory neuropeptides and express their receptors, and can promote proliferation, differentiation, apoptosis, matrix synthesis, and the degradation of target cells through autocrine/paracrine modes. In this paper, we review the research progress made in this field in recent years in order to provide a reference for further understanding the regulatory mechanism of bone and cartilage physiology and pathological metabolism.
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Affiliation(s)
- Fu-Xing-Zi Li
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Feng Xu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Feng Wu
- Department of Pathology, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Jia-Yu Zhong
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Yi Wang
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Bei Guo
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan
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Kim BY, Park J, Kim E, Kim B. Olfactory Ensheathing Cells Mediate Neuroplastic Mechanisms After Olfactory Training in Mouse Model. Am J Rhinol Allergy 2019; 34:217-229. [PMID: 31680531 DOI: 10.1177/1945892419885036] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Several studies have reported beneficial effects of olfactory training (OT) on the olfactory nervous system. However, the mechanisms underlying the regeneration of the olfactory system induced by OT are still under investigation. Objectives To determine the key mechanisms involved in the olfactory system recovery and to assess the neuroplastic effects of OT. Methods Thirty healthy female C57BL/6 mice were randomly allocated to 4 groups: control, n = 6; anosmia (no treatment), n = 8; OT, n = 8; and steroid treatment; n = 8. Except for the control group, mice were administered 3-methylindole. Anosmia was assessed using a food-finding test (FFT). The olfactory neuroepithelium was for histological examinations, gene ontology with pathway analyses, RNA, and protein studies. Results FFT was significantly reduced at 3 weeks in the OT mice versus steroids (78.27 s vs 156.83 s, P < .008) and controls (78.27 s vs 13.14 s, P < .003), although final outcome in the FFT was similar in these groups. Expression of olfactory and neurogenesis marker was higher in the olfactory neuroepithelium of the OT group than in the anosmia group without treatment. The mechanisms underlying olfactory regeneration might be related to early olfactory receptor stimulation, followed by neurotrophic factor stimulation of neuronal plasticity. Conclusion OT can improve olfactory function and accelerate olfactory recovery. The mechanisms underlying olfactory regeneration might be related to an initial stimulation of olfactory receptors followed by neurogenesis. Olfactory ensheathing cells might play an important role in olfactory regeneration following OT, based on the observed changes in messenger ribonucleic acid (mRNA) and protein expression, as well as the findings of the gene analysis.
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Affiliation(s)
- Boo-Young Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - JuYeon Park
- Department of Clinical Laboratory, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - EuiJin Kim
- Department of Clinical Laboratory, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - ByungGuk Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, St. Paul Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Can Botulinum Toxin A Still Have a Role in Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia Through Inhibition of Chronic Prostatic Inflammation? Toxins (Basel) 2019; 11:toxins11090547. [PMID: 31546892 PMCID: PMC6784075 DOI: 10.3390/toxins11090547] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/12/2019] [Accepted: 09/17/2019] [Indexed: 11/16/2022] Open
Abstract
Patients with benign prostatic hyperplasia (BPH) can exhibit various lower urinary tract symptoms (LUTS) owing to bladder outlet obstruction (BOO), prostatic inflammation, and bladder response to BOO. The pathogenesis of BPH involves an imbalance of internal hormones and chronic prostatic inflammation, possibly triggered by prostatic infection, autoimmune responses, neurogenic inflammation, oxidative stress, and autonomic dysfunction. Botulinum toxin A (BoNT-A) is well recognized for its ability to block acetylcholine release at the neuromuscular junction by cleaving synaptosomal-associated proteins. Although current large clinical trials have shown no clinical benefits of BoNT-A for the management of LUTS due to BPH, BoNT-A has demonstrated beneficial effects in certain subsets of BPH patients with LUTS, especially in males with concomitant chronic prostatitis/chronic pelvic pain syndrome and smaller prostate. We conducted a review of published literature in Pubmed, using Botulinum toxin, BPH, BOO, inflammation, LUTS, and prostatitis as the key words. This article reviewed the mechanisms of BPH pathogenesis and anti-inflammatory effects of BoNT-A. The results suggested that to achieve effectiveness, the treatment of BPH with BoNT-A should be tailored according to more detailed clinical information and reliable biomarkers.
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Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in Bone: Evolving Concepts in Pain and Anabolism. J Bone Miner Res 2019; 34:1393-1406. [PMID: 31247122 PMCID: PMC6697229 DOI: 10.1002/jbmr.3822] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/28/2019] [Accepted: 06/18/2019] [Indexed: 12/21/2022]
Abstract
The innervation of bone has been described for centuries, and our understanding of its function has rapidly evolved over the past several decades to encompass roles of subtype-specific neurons in skeletal homeostasis. Current research has been largely focused on the distribution and function of specific neuronal populations within bone, as well as their cellular and molecular relationships with target cells in the bone microenvironment. This review provides a historical perspective of the field of skeletal neurobiology that highlights the diverse yet interconnected nature of nerves and skeletal health, particularly in the context of bone anabolism and pain. We explore what is known regarding the neuronal subtypes found in the skeleton, their distribution within bone compartments, and their central projection pathways. This neuroskeletal map then serves as a foundation for a comprehensive discussion of the neural control of skeletal development, homeostasis, repair, and bone pain. Active synthesis of this research recently led to the first biotherapeutic success story in the field. Specifically, the ongoing clinical trials of anti-nerve growth factor therapeutics have been optimized to titrated doses that effectively alleviate pain while maintaining bone and joint health. Continued collaborations between neuroscientists and bone biologists are needed to build on this progress, leading to a more complete understanding of neural regulation of the skeleton and development of novel therapeutics. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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Affiliation(s)
- Jennifer M Brazill
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University, St. Louis, MO, USA
| | - Alec T Beeve
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University, St. Louis, MO, USA.,Department of Biomedical Engineering, Washington University, St. Louis, MO, USA
| | - Clarissa S Craft
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University, St. Louis, MO, USA.,Department of Cell Biology and Physiology, Washington University, St. Louis, MO, USA
| | - Jason J Ivanusic
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Erica L Scheller
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University, St. Louis, MO, USA.,Department of Cell Biology and Physiology, Washington University, St. Louis, MO, USA
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