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Beignon F, Notais M, Diochot S, Baron A, Fajloun Z, Tricoire-Leignel H, Lenaers G, Mattei C. Neurotoxins Acting on TRPV1-Building a Molecular Template for the Study of Pain and Thermal Dysfunctions. Toxins (Basel) 2025; 17:64. [PMID: 39998081 PMCID: PMC11861614 DOI: 10.3390/toxins17020064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/24/2025] [Accepted: 01/27/2025] [Indexed: 02/26/2025] Open
Abstract
Transient Receptor Potential (TRP) channels are ubiquitous proteins involved in a wide range of physiological functions. Some of them are expressed in nociceptors and play a major role in the transduction of painful stimuli of mechanical, thermal, or chemical origin. They have been described in both human and rodent systems. Among them, TRPV1 is a polymodal channel permeable to cations, with a highly conserved sequence throughout species and a homotetrameric structure. It is sensitive to temperature above 43 °C and to pH below 6 and involved in various functions such as thermoregulation, metabolism, and inflammatory pain. Several TRPV1 mutations have been associated with human channelopathies related to pain sensitivity or thermoregulation. TRPV1 is expressed in a large part of the peripheral and central nervous system, most notably in sensory C and Aδ fibers innervating the skin and internal organs. In this review, we discuss how the transduction of nociceptive messages is activated or impaired by natural compounds and peptides targeting TRPV1. From a pharmacological point of view, capsaicin-the spicy ingredient of chilli pepper-was the first agonist described to activate TRPV1, followed by numerous other natural molecules such as neurotoxins present in plants, microorganisms, and venomous animals. Paralleling their adaptive protective benefit and allowing venomous species to cause acute pain to repel or neutralize opponents, these toxins are very useful for characterizing sensory functions. They also provide crucial tools for understanding TRPV1 functions from a structural and pharmacological point of view as this channel has emerged as a potential therapeutic target in pain management. Therefore, the pharmacological characterization of TRPV1 using natural toxins is of key importance in the field of pain physiology and thermal regulation.
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Affiliation(s)
- Florian Beignon
- University of Angers, INSERM U1083, CNRS UMR6015, MITOVASC, SFR ICAT, F-49000 Angers, France; (F.B.); (M.N.); (H.T.-L.); (G.L.)
| | - Margaux Notais
- University of Angers, INSERM U1083, CNRS UMR6015, MITOVASC, SFR ICAT, F-49000 Angers, France; (F.B.); (M.N.); (H.T.-L.); (G.L.)
| | - Sylvie Diochot
- Université Côte d’Azur, CNRS U7275, INSERM U1323, IPMC (Institut de Pharmacologie Moléculaire et Cellulaire), LabEx ICST (Laboratory of Excellence in Ion Channel Science and Therapeutics), FHU InovPain (Fédération Hospitalo-Universitaire “Innovative Solutions in Refractory Chronic Pain”), 660 Route des Lucioles, Sophia-Antipolis, F-06560 Nice, France; (S.D.); (A.B.)
| | - Anne Baron
- Université Côte d’Azur, CNRS U7275, INSERM U1323, IPMC (Institut de Pharmacologie Moléculaire et Cellulaire), LabEx ICST (Laboratory of Excellence in Ion Channel Science and Therapeutics), FHU InovPain (Fédération Hospitalo-Universitaire “Innovative Solutions in Refractory Chronic Pain”), 660 Route des Lucioles, Sophia-Antipolis, F-06560 Nice, France; (S.D.); (A.B.)
| | - Ziad Fajloun
- Laboratory of Applied Biotechnology (LBA3B), Department of Cell Culture, Azm Center for Research in Biotechnology and Its Applications, EDST, Lebanese University, Tripoli 1300, Lebanon;
| | - Hélène Tricoire-Leignel
- University of Angers, INSERM U1083, CNRS UMR6015, MITOVASC, SFR ICAT, F-49000 Angers, France; (F.B.); (M.N.); (H.T.-L.); (G.L.)
| | - Guy Lenaers
- University of Angers, INSERM U1083, CNRS UMR6015, MITOVASC, SFR ICAT, F-49000 Angers, France; (F.B.); (M.N.); (H.T.-L.); (G.L.)
- Service de Neurologie, CHU d’Angers, F-49000 Angers, France
| | - César Mattei
- University of Angers, INSERM U1083, CNRS UMR6015, MITOVASC, SFR ICAT, F-49000 Angers, France; (F.B.); (M.N.); (H.T.-L.); (G.L.)
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Miura S, Nie M, Emoto K, Takeuchi S. Control of Tissue Strain Is Essential for Enhanced Dermal Innervation in the Three-Dimensional Skin Engineering. ACS Biomater Sci Eng 2025; 11:442-450. [PMID: 39694619 DOI: 10.1021/acsbiomaterials.4c01097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Engineered skin models with sensory innervation are a growing and challenging field of research aimed at applications in regenerative medicine, biosensing, and drug screening. Researchers are attempting to fabricate innervated skin tissues using collagen sponges, cell culture inserts, and microfluidic devices to partially mimic the layered structure of the skin. However, innervation of the full-thickness skin model has not yet been achieved. Here, using the anchoring culture device we previously reported, which is a powerful tool to construct a full-thickness three-dimensional (3D) skin model with balanced tissue contraction forces, we drastically improved dermal layer innervation using a composite hydrogel of collagen and Matrigel (Coll:MG). To determine the preferable hydrogel matrix for neurite extension in the 3D skin construct, DRG neural spheroids were placed at the bottom of the dermal layer composed of various hydrogel scaffold, including type I collagen from different origins (dermis or tendon) and Coll:MG composite hydrogel with different compositions. We showed that the Coll:MG (2:1) composite hydrogel significantly increased vertical neurite extension in the dermal layer, concomitant with the reduced tissue shrinkage during the culture. In contrast, in the collagen-only hydrogel, neurite extension occurred mostly in the horizontal direction, and tissues sometimes detached from the anchors due to significant shrinkage, indicating that tissue shrinkage may affect the direction of neurite extension. To exemplify this idea, 3D skin constructed in the device was partially detached from the anchors to comply with the cell-induced tissue shrinkage and reduce the strain on the tissue. The data showed that the partial allowance of in-plane tissue strain remarkably increased vertical neurite extension compared to the control cultures. Collectively, our results strongly suggest that neurite extension angles can be modulated by adjusting the tissue strain during the culture. Our findings highlight the importance of controlling tissue strain for the advancement of an innervated skin model.
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Affiliation(s)
- Shigenori Miura
- Department of Mechano-Informatics, Graduate School of Information Science and Technology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
- Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Minghao Nie
- Department of Mechano-Informatics, Graduate School of Information Science and Technology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Kazuo Emoto
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- International Research Center for Neurointelligence, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Shoji Takeuchi
- Department of Mechano-Informatics, Graduate School of Information Science and Technology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
- International Research Center for Neurointelligence, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Santos GX, dos Anjos-Garcia T, Vieira ACDJ, Galdino G. Spinal Involvement of TRPV1 and PI3K/AKT/mTOR Pathway During Chronic Postoperative Pain in Mice. Brain Sci 2025; 15:53. [PMID: 39851421 PMCID: PMC11763465 DOI: 10.3390/brainsci15010053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND Chronic postoperative pain (CPOP) is among the main consequences of surgical procedures, directly affecting the quality of life. Although many strategies have been used to treat this symptom, they are often ineffective. Thus, studies investigating CPOP-associated mechanisms may help to develop more effective treatment strategies. Therefore, the present study investigated the spinal participation of the transient potential receptor vanilloid type 1 (TRPV1) and PI3K/AKT/mTOR pathway activation during CPOP. METHODS In this study C57BL/6 male mice were used, and CPOP was induced by muscle retraction and incision. The nociceptive threshold was measured by the von Frey filament test. For pharmacological evaluation, TRPV1 and PI3K/AKT/mTOR inhibitors were administered intrathecally. TRPV1 and PI3K/AKT/mTOR protein levels were evaluated by Western blotting. RESULTS The results showed that CPOP increased TRPV1 and mTOR protein levels, and pretreatment with the specific inhibitors alleviated CPOP. In addition, pretreatment with the TRPV1 antagonist SB-366791 attenuated mTOR protein levels. CONCLUSIONS The results suggest that TRPV1 and the PI3K/AKT/mTOR pathway are involved in CPOP at the spinal level, and TRPV1 may activate mTOR during this process.
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Affiliation(s)
- Gabriela Xavier Santos
- Center for Experimental Biology, Laboratory of Neuroimmunobiology of Pain, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil
- Inapós College, Padre Gervásio National Institute of Higher Education and Postgraduate Studies, Pouso Alegre 37550-121, MG, Brazil
| | - Tayllon dos Anjos-Garcia
- Center for Experimental Biology, Laboratory of Neuroimmunobiology of Pain, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil
- Department of Animal Morphology and Physiology of the Faculty of Agricultural and Veterinary Sciences of São Paulo State University, Jaboticabal 14884-900, SP, Brazil
| | - Ana Carolina de Jesus Vieira
- Center for Experimental Biology, Laboratory of Neuroimmunobiology of Pain, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil
| | - Giovane Galdino
- Center for Experimental Biology, Laboratory of Neuroimmunobiology of Pain, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil
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Amawi T, Nmarneh A, Noy G, Ghantous M, Niv MY, Di Pizio A, Priel A. Identification of the TRPA1 cannabinoid-binding site. Pharmacol Res 2024; 209:107444. [PMID: 39368566 DOI: 10.1016/j.phrs.2024.107444] [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: 06/16/2024] [Revised: 09/29/2024] [Accepted: 09/29/2024] [Indexed: 10/07/2024]
Abstract
Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood. The principal phytocannabinoids, the psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors. Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies. Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations. Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.
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Affiliation(s)
- Tala Amawi
- The Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Alaa Nmarneh
- The Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Gilad Noy
- The Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Mariana Ghantous
- The Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Masha Y Niv
- The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Antonella Di Pizio
- Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising 85354, Germany; Proferssorship for Chemoinformatics and Protein Modelling, Department of Molecular Life Sciences, TUM School of Life Sciences, Technical University of Munich, Freising 85354, Germany
| | - Avi Priel
- The Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
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Asiri YI, Moni SS, Ramar M, Chidambaram K. Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings. Pharmaceuticals (Basel) 2024; 17:1439. [PMID: 39598351 PMCID: PMC11597627 DOI: 10.3390/ph17111439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024] Open
Abstract
Despite major advancements in our understanding of its fundamental causes, pain-both acute and chronic-remains a serious health concern. Various preclinical investigations utilizing diverse animal, cellular, and alternative models are required and frequently demanded by regulatory approval bodies to bridge the gap between the lab and the clinic. Investigating naturally occurring painful disorders can speed up medication development at the preclinical and clinical levels by illuminating molecular pathways. A wide range of animal models related to pain have been developed to elucidate pathophysiological mechanisms and aid in identifying novel targets for treatment. Pain sometimes drugs fail clinically, causing high translational costs due to poor selection and the use of preclinical tools and reporting. To improve the study of pain in a clinical context, researchers have been creating innovative models over the past few decades that better represent pathological pain conditions. In this paper, we provide a summary of traditional animal models, including rodents, cellular models, human volunteers, and alternative models, as well as the specific characteristics of pain diseases they model. However, a more rigorous approach to preclinical research and cutting-edge analgesic technologies may be necessary to successfully create novel analgesics. The research highlights from this review emphasize new opportunities to develop research that includes animals and non-animals using proven methods pertinent to comprehending and treating human suffering. This review highlights the value of using a variety of modern pain models in animals before human trials. These models can help us understand the different mechanisms behind various pain types. This will ultimately lead to the development of more effective pain medications.
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Affiliation(s)
- Yahya I. Asiri
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia;
| | - Sivakumar S. Moni
- Health Research Centre, Jazan University, Jazan 45142, Saudi Arabia;
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Mohankumar Ramar
- Department of Pharmaceutical Sciences, UConn School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA;
| | - Kumarappan Chidambaram
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia;
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Dangi A, Sharma SS. Pharmacological agents targeting transient receptor potential (TRP) channels in neuropathic pain: Preclinical and clinical status. Eur J Pharmacol 2024; 980:176845. [PMID: 39067564 DOI: 10.1016/j.ejphar.2024.176845] [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: 04/19/2024] [Revised: 06/19/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
Neuropathic pain generally affects 7-10% population worldwide and an estimated ∼1 in every 20 individuals in western countries suffer and burden to society. The most limiting factor with existing therapies includes dose escalation issues, off-target side effects and poor translation of randomized trials into clinical practice. Neuropathic pain is a broad term that comprises direct injury/damage to the central and/or peripheral nervous system, leads to maladaptive changes in neuronal as well as in non-neuronal cells, which further contributes to the spontaneous pain, sensory and motor deficit along with altered sensitivity towards the noxious as well as non-noxious stimulus. Transient receptor potential (TRP) channels are polymodal, non-specific cation channels that operate as biosensors to various mechanical and chemical stimuli, including hyperosmolarity, shear stress, heat, mechanical stretch, extracellular ATP, and other products of inflammation. Modulation of these channels leads to various physiological and pathophysiological manifestations at molecular and cellular levels, leading to diseases including neuropathic pain. There are several molecules targeting TRP channels for neuropathic pain in pre-clinical studies, clinical trials and in the market. This review highlights the critical involvement of various pharmacological modulators for TRP channels targeting neuropathic pain and their possible outcomes to harness the therapeutic potential of TRP channels.
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Affiliation(s)
- Ashish Dangi
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India.
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Lötsch J, Gasimli K, Malkusch S, Hahnefeld L, Angioni C, Schreiber Y, Trautmann S, Wedel S, Thomas D, Ferreiros Bouzas N, Brandts CH, Schnappauf B, Solbach C, Geisslinger G, Sisignano M. Machine learning and biological validation identify sphingolipids as potential mediators of paclitaxel-induced neuropathy in cancer patients. eLife 2024; 13:RP91941. [PMID: 39347767 PMCID: PMC11444680 DOI: 10.7554/elife.91941] [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] [Indexed: 10/01/2024] Open
Abstract
Background Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy. Methods High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy. Results Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy. Conclusions Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects. Funding This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1).
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Affiliation(s)
- Jörn Lötsch
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Khayal Gasimli
- Goethe University, Department of Gynecology and Obstetrics, Frankfurt, Germany
| | - Sebastian Malkusch
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Lisa Hahnefeld
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Carlo Angioni
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
| | - Yannick Schreiber
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Sandra Trautmann
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Saskia Wedel
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
| | - Dominique Thomas
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Nerea Ferreiros Bouzas
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Christian H Brandts
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Goethe University, University Cancer Center Frankfurt (UCT), Goethe University Hospital, Frankfurt, Germany
| | | | - Christine Solbach
- Goethe University, Department of Gynecology and Obstetrics, Frankfurt, Germany
| | - Gerd Geisslinger
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
| | - Marco Sisignano
- Institute of Clinical Pharmacology, Goethe - University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt, Germany
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Kasuya K, Takahashi K, Hashimoto M, Ohta T. Nociceptive transient receptor potential ankyrin 1 (TRPA1) in sensory neurons are targets of the antifungal drug econazole. BMC Pharmacol Toxicol 2024; 25:53. [PMID: 39169383 PMCID: PMC11337588 DOI: 10.1186/s40360-024-00779-x] [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: 12/02/2023] [Accepted: 08/12/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants. METHODS We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(-/-) and TRPV1(-/-) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo. RESULTS Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(-/-) mouse DRG neurons but was not significant in the TRPV1(-/-) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(-/-) mice. CONCLUSIONS These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole.
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Affiliation(s)
- Kaoru Kasuya
- Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan
| | - Kenji Takahashi
- Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan
- Department of Veterinary Pharmacology, Joint Graduate School of Veterinary Sciences, Tottori University, Tottori, 680-8553, Japan
| | - Miho Hashimoto
- Department of Veterinary Pharmacology, Joint Graduate School of Veterinary Sciences, Tottori University, Tottori, 680-8553, Japan
| | - Toshio Ohta
- Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, 680-8553, Japan.
- Department of Veterinary Pharmacology, Joint Graduate School of Veterinary Sciences, Tottori University, Tottori, 680-8553, Japan.
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Roshni J, Sivakumar M, Alzahrani FM, Halawani IF, Alzahrani KJ, Patil S, Ahmed SSSJ. Virtual screening, molecular dynamics and density functional theory on pain inhibitors against TRPV1 associating inflammatory conditions. J Biomol Struct Dyn 2024; 42:6788-6798. [PMID: 37489910 DOI: 10.1080/07391102.2023.2237595] [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: 04/25/2023] [Accepted: 07/08/2023] [Indexed: 07/26/2023]
Abstract
Transient receptor potential vanilloid 1 protein (TRPV1) is expressed widely in skin and sensory neurons that contribute to pain/heat sensation in the human system. TRPV1 gene polymorphisms are susceptible to multiple diseases and it is considered a therapeutic target for various inflammatory conditions. Among the TRPV1 variants, rs8065080 (1911 A > G) plays a vital role in painful osteoarthritis and migraine. The presence of rs8065080 polymorphism may render drug efficacy. This study aimed to identify better antagonists against wild-type and variant TRPV1 that may help in the relief of pain/inflammation. We constructed suitable TRPV1 protein structures for wild-type and rs8065080 variant through a homology modelling approach. A total of 3363 anti-inflammatory compounds with high chemical diversity and good drug-like properties were collected and screened against the generated structures. Molecular docking showed that nobilamide B had the highest binding affinity (-5.83 kcal/mol) towards the wild-type. Whereas, isoquinoline analogue displayed highest binding potency with the variant TRPV1 (-11.65 kcal/mol). Besides those, C18H15F3N4O showed affinity towards both wild-type (-5.53 kcal/mol) and variant TRPV1 (-9.75 kcal/mol). Then, molecular dynamic simulation revealed stable conformation in wild-type and variant TRPV1 upon binding of nobilmaide B, isoquinoline analogue and C18H15F3N4O. Additionally, density functional theory (DFT) using B3LYP hybrid function showed high chemical reactiveness of nobilamie B, isoquinoline analogue and C18H15F3N4O. Overall, our systematic investigations provide, C18H15F3N4O could be a potential analgesic inhibiting both wild-type and variant TRPV1 against inflammatory conditions.
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Affiliation(s)
- Jency Roshni
- Drug discovery and Multi-omics Lab, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Mahema Sivakumar
- Drug discovery and Multi-omics Lab, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Fuad M Alzahrani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ibrahim F Halawani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Khalid J Alzahrani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Shankargouda Patil
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah, USA
| | - Shiek S S J Ahmed
- Drug discovery and Multi-omics Lab, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
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10
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Yang Z, Sa C, Yu T, Chen J, Zhang R, Zhang Y, Liu J, Zhang H, Sun J. Exploring the Analgesic Initiation Mechanism of Tuina in the Dorsal Root Ganglion of Minor CCI Rats via the TRPV1/TRPA1-cGMP Pathway. Pain Res Manag 2024; 2024:2437396. [PMID: 39104725 PMCID: PMC11300051 DOI: 10.1155/2024/2437396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 06/06/2024] [Accepted: 06/28/2024] [Indexed: 08/07/2024]
Abstract
Tuina is a treatment method in traditional Chinese medicine which has analgesic effects and effectively alleviates the symptoms of neuropathic pain (NP). Transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) play major roles in transmitting nociceptive sensory signals in the nociceptive primary sensory dorsal root ganglion (DRG) nerve. The nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate(cGMP) pathway exerts both nociceptive and antinociceptive effects in various chronic pain models. TRPV1 and TRPA1 mediate the influx of calcium, which stimulates the generation of NO. Subsequently, NO activates the NO/cGMP/protein kinase G (PKG) signaling pathway, thereby improving hyperalgesia. In the present study, oa rat model of NP with minor chronic constriction injury (CCI) of the right sciatic nerve of NP was established. The results of behavioral testing showed that, after a one-time tuina intervention, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were prolonged to varying degrees in the tuina group compared with the model group. Similarly, the expression of TRPV1, TRPA1, NO, soluble guanylate cyclase β (sGCβ), cGMP, and PKG1 was significantly decreased in the DRG of the tuina and tuina + TRPV1/TRPA1 antagonist group was significantly decreased. These findings suggest that the tuina intervention can effectively improve the symptoms of thermal and mechanical allodynia caused by peripheral nerve injuries. Tuina exerts immediate analgesic effects through the TRPV1/TRPA1-NO-cGMP-PKG signaling pathway.
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Affiliation(s)
- Zhenjie Yang
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Chula Sa
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Tianyuan Yu
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Jinping Chen
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Runlong Zhang
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Yingqi Zhang
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Jiayue Liu
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Hanyu Zhang
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
| | - Jiawei Sun
- School of Acupuncture-Moxibustion and TuinaBeijing University of Chinese Medicine, Beijing 102488, China
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11
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Howe CL, Icka-Araki D, Viray AEG, Garza S, Frank JA. Optical Control of TRPV1 Channels In Vitro with Tethered Photopharmacology. ACS Chem Biol 2024; 19:1466-1473. [PMID: 38904446 DOI: 10.1021/acschembio.4c00052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that is important for nociception and inflammatory pain and is activated by a variety of nociceptive stimuli─including lipids such as capsaicin (CAP) and endocannabinoids. TRPV1's role in physiological systems is often studied by activating it with externally perfused ligands; however, this approach is plagued by poor spatiotemporal resolution. Lipid agonists are insoluble in physiological buffers and can permeate membranes to accumulate nonselectively inside cells, where they can have off-target effects. To increase the spatiotemporal precision with which we can activate lipids on cells and tissues, we previously developed optically cleavable targeted (OCT) ligands, which use protein tags (SNAP-tags) to localize a photocaged ligand on a target cellular membrane. After enrichment, the active ligand is released on a flash of light to activate nearby receptors. In our previous work, we developed an OCT-ligand to control a cannabinoid-sensitive GPCR. Here, we expand the scope of OCT-ligand technology to target TRPV1 ion channels. We synthesize a probe, OCT-CAP, that tethers to membrane-bound SNAP-tags and releases a TRPV1 agonist when triggered by UV-A irradiation. Using Ca2+ imaging and electrophysiology in HEK293T cells expressing TRPV1, we demonstrate that OCT-CAP uncaging activates TRPV1 with superior spatiotemporal precision when compared to standard diffusible ligands or photocages. This study is the first example of an OCT-ligand designed to manipulate an ion-channel target. We anticipate that these tools will find many applications in controlling lipid signaling pathways in various cells and tissues.
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Affiliation(s)
- Carmel L Howe
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - David Icka-Araki
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Alexander E G Viray
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Sarahi Garza
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon 97239, United States
- Neuroscience Graduate Program, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - James A Frank
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon 97239, United States
- Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, United States
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12
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Maciel JB, Liberato HR, da Silva AW, da Silva JPV, das Chagas L Pinto F, de Lima Rebouças E, da Silva FSH, Ferreira MKA, Marinho MM, Marinho ES, Pessoa ODL, de Barros Silva PG, Coelho-de-Souza AN, Guedes MIF, de Castro Gomes AF, de Menezes JESA, Dos Santos HS. Withanicandrin Isolated from Datura Ferox Promotes Antinociception by Modulating the Asics and TRPS Channels and Anti-Inflammation in Adult Zebrafish. Chem Biodivers 2024; 21:e202400538. [PMID: 38639566 DOI: 10.1002/cbdv.202400538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 04/20/2024]
Abstract
This is the first study to analyze the anti-inflammatory and antinociceptive effect of withanicandrin, isolated from Datura Ferox leaves, and the possible mechanism of action involved in adult zebrafish (ZFa). To this end, the animals were treated intraperitoneally (i. p.) with withanicandrin (4; 20 and 40 mg/kg; 20 μL) and subjected to locomotor activity and acute toxicity. Nociception tests were also carried out with chemical agents, in addition to tests to evaluate inflammatory processes induced by κ-Carrageenan 1.5 % and a Molecular Docking study. As a result, withanicandrin reduced nociceptive behavior by capsaicin at a dose of 40 mg/kg and by acid saline at doses of 4 and 40 mg/kg, through neuromodulation of TRPV1 channels and ASICs, identified through blocking the antinociceptive effect of withanicandrin by the antagonists capsazepine and naloxone. Furthermore, withanicandrin caused an anti-inflammatory effect through the reduction of abdominal edema, absence of leukocyte infiltrate in the liver tissue and reduction of ROS in thel liver tissue and presented better affinity energy compared to control morphine (TRPV1) and ibuprofen (COX-1 and COX-2).
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Affiliation(s)
- Jéssica Bezerra Maciel
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Hortência Ribeiro Liberato
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Antônio Wlisses da Silva
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - João Pedro Vieira da Silva
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Francisco das Chagas L Pinto
- Laboratório de Análise Fitoquímica de Plantas Medicinais II -, LAFIPLAM II Departamento de Química Orgânica e Inorgânica -, DQOI, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - Emanuela de Lima Rebouças
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Francisco Sydney Henrique da Silva
- Laboratório de Fisiologia Experimental -, LAFIEX, Programa de Pós-Graduação em Ciências Fisiológicas, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Maria Kueirislene Amâncio Ferreira
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | | | - Emmanuel Silva Marinho
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
- Grupo de Química Teórica e Eletroquímica -, GQTE, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Otília Deusdênia Loiola Pessoa
- Laboratório de Análise Fitoquímica de Plantas Medicinais II -, LAFIPLAM II Departamento de Química Orgânica e Inorgânica -, DQOI, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - Paulo Goberlânio de Barros Silva
- Laboratório de Patologia,Programa de Pós-Graduação em Odontologia, Ciências Odontológicas, Centro Universitário Unichristus, Fortaleza, Ceará, Brazil
| | - Andrelina Noronha Coelho-de-Souza
- Laboratório de Fisiologia Experimental -, LAFIEX, Programa de Pós-Graduação em Ciências Fisiológicas, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Maria Izabel Florindo Guedes
- Laboratório de Biotecnologia e Biologia Molecular -, LBBM, Centro de Ciências da Saúde, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | | | - Jane Eire Silva Alencar de Menezes
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
| | - Hélcio Silva Dos Santos
- Laboratório de Bioensaios Químicos-Farmacológicos e Ambiental - LabQFAm, Programa de Pós-Graduação em Ciências Naturais, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil
- Curso de Química, Universidade Estadual Vale do Acaraú, Sobral, Ceará, Brazil
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13
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Qiao S, Wu F, Wang H. Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation. Cancer Rep (Hoboken) 2024; 7:e2108. [PMID: 38837874 PMCID: PMC11150080 DOI: 10.1002/cnr2.2108] [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: 10/13/2023] [Revised: 03/26/2024] [Accepted: 04/30/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Pancreatic adenocarcinoma (PAAD), a member of highly lethal malignant tumors, has a poor outcome and extremely poor prognosis. The transient receptor potential (TRP) superfamily, a group of nonselective cation channels, is capable of influencing cellular functions by regulating calcium homeostasis. In addition, it has been shown that TRP channels can also affect various cellular phenotypes by regulating gene transcription levels and are involved in the development of a variety of malignant tumors. AIMS In order to find new therapeutic targets and biomarkers to improve the clinical prognosis of pancreatic cancer, we performed genetic and immunological characterization of TRP channels in PAAD, as well as related functional and prognostic analyses. METHODS AND RESULTS We investigated the expression, genetic alterations, methylation levels, and immune infiltration levels of TRP channels in PAAD, and further also analyzed the function of TRP channels in PAAD and their prognostic value for PAAD patients. Our results suggest that TRPM8 may contribute to tumor proliferation by controlling the PI3K-AKT-mTOR signaling pathway in PAAD. CONCLUSION After careful evaluation of the accumulated data, we concluded that TRPM8 has potential as a prognostic indicator and prospective therapeutic target in PAAD.
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Affiliation(s)
- Sen Qiao
- Assisted Reproduction CenterNorthwest Women's and Children's HospitalXi'anChina
| | - Fengming Wu
- School of MedicineSoutheast UniversityNanjingJiangsuChina
| | - Hongmei Wang
- School of MedicineSoutheast UniversityNanjingJiangsuChina
- Shaanxi University of Chinese MedicineXianyangChina
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14
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Vašek D, Fikarová N, Marková VN, Honc O, Pacáková L, Porubská B, Somova V, Novotný J, Melkes B, Krulová M. Lipopolysaccharide pretreatment increases the sensitivity of the TRPV1 channel and promotes an anti-inflammatory phenotype of capsaicin-activated macrophages. J Inflamm (Lond) 2024; 21:17. [PMID: 38790047 PMCID: PMC11127439 DOI: 10.1186/s12950-024-00391-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND The transient receptor potential vanilloid 1 (TRPV1) is well-established in neuronal function, yet its role in immune reactions remains enigmatic. The conflicting data on its inflammatory role, suggesting both pro-inflammatory and anti-inflammatory effects upon TRPV1 stimulation in immune cells, adds complexity. To unravel TRPV1 immunomodulatory mechanisms, we investigated how the TRPV1 agonist capsaicin influences lipopolysaccharide (LPS)-induced pro-inflammatory macrophage phenotypes. RESULTS Changes in the surface molecules, cytokine production, and signaling cascades linked to the phenotype of M1 or M2 macrophages of the J774 macrophage cell line and bone marrow-derived macrophages, treated with capsaicin before or after the LPS-induced inflammatory reaction were determined. The functional capacity of macrophages was also assessed by infecting the stimulated macrophages with the intracellular parasite Leishmania mexicana. CONCLUSION Our findings reveal that TRPV1 activation yields distinct macrophage responses influenced by the inflammatory context. LPS pre-treatment followed by capsaicin activation prompted increased calcium influx, accompanied by a shift toward an anti-inflammatory M2b-like polarization state.
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Affiliation(s)
- Daniel Vašek
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Natálie Fikarová
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Vendula Nagy Marková
- Department of Physiology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Ondřej Honc
- Department of Physiology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Lenka Pacáková
- Department of Parasitology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Bianka Porubská
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Veronika Somova
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Jiří Novotný
- Department of Physiology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Barbora Melkes
- Department of Physiology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic
| | - Magdaléna Krulová
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague, 2, 128 43, Czech Republic.
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15
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Fu X, Kim HS. Dentin Mechanobiology: Bridging the Gap between Architecture and Function. Int J Mol Sci 2024; 25:5642. [PMID: 38891829 PMCID: PMC11171917 DOI: 10.3390/ijms25115642] [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: 04/30/2024] [Revised: 05/20/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
It is remarkable how teeth maintain their healthy condition under exceptionally high levels of mechanical loading. This suggests the presence of inherent mechanical adaptation mechanisms within their structure to counter constant stress. Dentin, situated between enamel and pulp, plays a crucial role in mechanically supporting tooth function. Its intermediate stiffness and viscoelastic properties, attributed to its mineralized, nanofibrous extracellular matrix, provide flexibility, strength, and rigidity, enabling it to withstand mechanical loading without fracturing. Moreover, dentin's unique architectural features, such as odontoblast processes within dentinal tubules and spatial compartmentalization between odontoblasts in dentin and sensory neurons in pulp, contribute to a distinctive sensory perception of external stimuli while acting as a defensive barrier for the dentin-pulp complex. Since dentin's architecture governs its functions in nociception and repair in response to mechanical stimuli, understanding dentin mechanobiology is crucial for developing treatments for pain management in dentin-associated diseases and dentin-pulp regeneration. This review discusses how dentin's physical features regulate mechano-sensing, focusing on mechano-sensitive ion channels. Additionally, we explore advanced in vitro platforms that mimic dentin's physical features, providing deeper insights into fundamental mechanobiological phenomena and laying the groundwork for effective mechano-therapeutic strategies for dentinal diseases.
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Affiliation(s)
- Xiangting Fu
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea;
- Mechanobiology Dental Medicine Research Center, Cheonan 31116, Republic of Korea
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Hye Sung Kim
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea;
- Mechanobiology Dental Medicine Research Center, Cheonan 31116, Republic of Korea
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
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16
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He J, Zuo J, Fan X, Li Z. Electro-acupuncture modulated miR-214 expression to prevent chondrocyte apoptosis and reduce pain by targeting BAX and TRPV4 in osteoarthritis rats. Braz J Med Biol Res 2024; 57:e13238. [PMID: 38808885 PMCID: PMC11136484 DOI: 10.1590/1414-431x2024e13238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/15/2024] [Indexed: 05/30/2024] Open
Abstract
Osteoarthritis (OA) is a highly prevalent joint disorder characterized by progressive degeneration of articular cartilage, subchondral bone remodeling, osteophyte formation, synovial inflammation, and meniscal damage. Although the etiology of OA is multifactorial, pro-inflammatory processes appear to play a key role in disease pathogenesis. Previous studies indicate that electroacupuncture (EA) exerts chondroprotective, anti-inflammatory, and analgesic effects in preclinical models of OA, but the mechanisms underlying these potential therapeutic benefits remain incompletely defined. This study aimed to investigate the effects of EA on OA development in a rat model, as well as to explore associated molecular mechanisms modulated by EA treatment. Forty rats were divided into OA, EA, antagomiR-214, and control groups. Following intra-articular injection of monosodium iodoacetate to induce OA, EA and antagomiR-214 groups received daily EA stimulation at acupoints around the knee joint for 21 days. Functional pain behaviors and chondrocyte apoptosis were assessed as outcome measures. The expression of microRNA-214 (miR-214) and its downstream targets involved in apoptosis and nociception, BAX and TRPV4, were examined. Results demonstrated that EA treatment upregulated miR-214 expression in OA knee cartilage. By suppressing pro-apoptotic BAX and pro-nociceptive TRPV4, this EA-induced miR-214 upregulation ameliorated articular pain and prevented chondrocyte apoptosis. These findings suggested that miR-214 plays a key role mediating EA's therapeutic effects in OA pathophysiology, and represents a promising OA treatment target for modulation by acupuncture.
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Affiliation(s)
- Jia He
- Department of Traditional Chinese Medical Orthopedics, Xi'an Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jia Zuo
- Department of Acupuncture, Shaanxi Provincial Hospital of Chinese Medicine, Xi'an, Shaanxi, China
| | - Xiaochen Fan
- Department of Traditional Chinese Medical Orthopedics, Xi'an Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhe Li
- Department of Traditional Chinese Medical Orthopedics, Xi'an Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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17
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Kim H, Roh D, Oh SB. EGFR Tyrosine Kinase Inhibitor Lazertinib Activates a Subset of Mouse Sensory Neurons Via TRPA1. THE JOURNAL OF PAIN 2024; 25:104435. [PMID: 38008390 DOI: 10.1016/j.jpain.2023.11.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/21/2023] [Accepted: 11/20/2023] [Indexed: 11/28/2023]
Abstract
Lazertinib (JNJ-73841937, YH25448) is a mutant-selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor targeting both the T790M and activating mutation while sparing wild-type epidermal growth factor receptor. Paresthesia is one of the most common adverse events seen with lazertinib treatment, suggesting that lazertinib could affect the sensory nervous system. However, the mechanism of action for this paresthesia remains unclear. In this study, we investigated whether and how lazertinib affects peripheral sensory neurons. Through Fura-2-based calcium imaging and whole-cell patch clamp recording in primary-cultured dorsal root ganglion (DRG) neurons from adult mice, we found that application of lazertinib elicits spontaneous calcium responses in a subset of small-to-medium-sized neurons. Moreover, lazertinib induced spontaneous firings and hyperexcitability in a subset of transient receptor potential vanilloid 1-lineage DRG neurons and sensitized transient receptor potential ankyrin 1 (TRPA1) response, while sparing transient receptor potential vanilloid 1 response. Lazertinib-responsive neurons were also responsive to capsaicin, further supporting that lazertinib selectively activates nociceptive neurons. Lazertinib-induced calcium responses were pharmacologically blocked with HC-030031 (TRPA1 antagonist) and MDL-12330A (adenylyl cyclase inhibitor), suggesting that lazertinib activates sensory neurons through indirect activation of TRPA1. However, unlike vincristine which produces peripheral neuropathy by axonal degeneration, lazertinib did not cause neurite fragmentation in cultured DRG neurons. Finally, intraplantar injection of lazertinib induced TRPA1-dependent pain-like behaviors in vivo. Collectively, our data suggest a direct effect of lazertinib on nociceptive sensory neurons via TRPA1 selective mechanisms, which could be a putative mechanism of lazertinib-induced sensory abnormalities in clinical patients. PERSPECTIVE: This article presents a TRPA1-dependent, lazertinib-induced activation of mouse sensory neurons in vitro and lazertinib-induced pain-like behaviors in vivo. The same mechanisms may underlie the clinical condition, suggesting that TRPA1 could be a potential therapeutic target to manage lazertinib-induced paresthesia.
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Affiliation(s)
- Hayun Kim
- Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea
| | - Dahee Roh
- Department of Neurobiology and Physiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
| | - Seog Bae Oh
- Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea; Department of Neurobiology and Physiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
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18
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Grgić N, Tarle M, Perić A, Potočki S, Pašalić D, Perić B. THE IMPACT OF PREOPERATIVE SALIVARY UREA AND SUPEROXIDE DISMUTASE ACTIVITIES ON POSTOPERATIVE PAIN AFTER SURGICAL REMOVAL OF MANDIBULAR THIRD MOLARS. Acta Clin Croat 2024; 63:134-141. [PMID: 39959331 PMCID: PMC11827404 DOI: 10.20471/acc.2024.63.01.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 07/19/2022] [Indexed: 02/18/2025] Open
Abstract
The most frequent surgical procedure in oral surgery is extraction of mandibular third molars, which could be associated with postoperative complications such as pain, swelling, and trismus. We aimed to investigate the association of salivary urea and antioxidative enzyme activities with the intensity of postoperative pain after wisdom tooth extraction. This cross-sectional prospective study included 66 subjects (median age 25, range 17-47 years). Salivary urea and superoxide dismutase (SOD) were determined by enzymatic colorimetric tests. The questionnaire for study participants included demographic and history data, as well as data on personal experience of pain in grade 0-10 according to the visual analog scale (VAS). Grading 1-3 was considered as low (VAS-1), 4-6 mild (VAS-2) and 7-10 as severe pain (VAS-3). Moderate positive correlation was recorded between urea concentration and SOD activity in saliva (r=0.46). Moderate negative correlations were found between urea salivary concentration and VAS grading value reported after 12 hours (r=0.51). The concentrations of urea significantly differed among the three VAS categories (p<0.001), whereas salivary SOD activities did not differ among the categories. Preoperative salivary urea concentration and SOD activity might be associated with postsurgical pain after surgical removal of mandibular third molars.
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Affiliation(s)
- Nino Grgić
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, University of Zagreb, Dubrava University Hospital, Zagreb, Croatia
| | - Marko Tarle
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, University of Zagreb, Dubrava University Hospital, Zagreb, Croatia
| | - Ante Perić
- School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Slavica Potočki
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Daria Pašalić
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Berislav Perić
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, University of Zagreb, Dubrava University Hospital, Zagreb, Croatia
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19
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Tian J, Bavencoffe AG, Zhu MX, Walters ET. Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance. Pain 2024; 165:893-907. [PMID: 37862056 PMCID: PMC10950548 DOI: 10.1097/j.pain.0000000000003091] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/09/2023] [Indexed: 10/21/2023]
Abstract
ABSTRACT Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na + or Ca 2+ and that Ca 2+ -permeable channels are especially important for larger DSFs. Partial reduction of the amplitude or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca 2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na + or Ca 2+ produces DSFs that are poised to reach AP threshold if resting membrane potential depolarizes, AP threshold decreases, or DSFs become enhanced-all of which can occur under painful neuropathic and inflammatory conditions.
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Affiliation(s)
- Jinbin Tian
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston
| | - Alexis G. Bavencoffe
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston
| | - Michael X. Zhu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston
| | - Edgar T. Walters
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston
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20
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Hosseindoost S, Askari Rad M, Inanloo SH, Rahimi M, Dehghan S, Orandi A, Dehpour AR, Majedi H. The analgesic effects of botulinum neurotoxin by modulating pain-related receptors; A literature review. Mol Pain 2024; 20:17448069241275099. [PMID: 39093638 PMCID: PMC11339750 DOI: 10.1177/17448069241275099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/12/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024] Open
Abstract
Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs' analgesic effects is the inhibition of pain-related receptors' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.
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Affiliation(s)
- Saereh Hosseindoost
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziyar Askari Rad
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Hassan Inanloo
- Department of Urology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojgan Rahimi
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Dehghan
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Orandi
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Majedi
- Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- Anesthesia, Critical Care, and Pain Management Research Center, Tehran University of Medical Sciences, Tehran, Iran
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21
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Nakagawa T, Kaneko S. Role of TRPA1 in Painful Cold Hypersensitivity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1461:245-252. [PMID: 39289286 DOI: 10.1007/978-981-97-4584-5_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a polymodal cation channel that plays a pivotal role in pain generation after exposure to irritant chemicals and is involved in the sensation of a wide variety of pathological pain. TRPA1 was first reported to be sensitive to noxious cold, but its intrinsic cold sensitivity still remains under debate. To address this issue, we focused on cold hypersensitivity induced by oxaliplatin, a platinum-based chemotherapeutic drug, as a peculiar adverse symptom of acute peripheral neuropathy. We and other groups have shown that oxaliplatin enhances TRPA1 sensitivity to its chemical agonists and reactive oxygen species (ROS). Our in vitro and animal model studies revealed that oxaliplatin, or its metabolite oxalate, inhibits hydroxylation of a proline residue within the N-terminus of human TRPA1 (hTRPA1) via inhibition of prolyl hydroxylase domain-containing protein (PHD), which induces TRPA1 sensitization to ROS. Although hTRPA1 is insensitive to cold, PHD inhibition endows hTRPA1 with cold sensitivity through sensing the small amount of ROS produced after exposure to cold. Hence, we propose that PHD inhibition can unveil the cold sensitivity of hTRPA1 by converting ROS signaling into cold sensitivity. Furthermore, in this review, we summarize the role of TRPA1 in painful cold hypersensitivity during peripheral vascular impairment.
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Affiliation(s)
- Takayuki Nakagawa
- Department of Clinical Pharmacology and Pharmacotherapy, Wakayama Medical University, Wakayama, Japan.
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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22
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da Silva MDV, Piva M, Martelossi-Cebinelli G, Stinglin Rosa Ribas M, Hoffmann Salles Bianchini B, K Heintz O, Casagrande R, Verri WA. Stem cells and pain. World J Stem Cells 2023; 15:1035-1062. [PMID: 38179216 PMCID: PMC10762525 DOI: 10.4252/wjsc.v15.i12.1035] [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: 07/28/2023] [Revised: 11/06/2023] [Accepted: 11/30/2023] [Indexed: 12/26/2023] Open
Abstract
Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.
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Affiliation(s)
- Matheus Deroco Veloso da Silva
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Maiara Piva
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Geovana Martelossi-Cebinelli
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Mariana Stinglin Rosa Ribas
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Beatriz Hoffmann Salles Bianchini
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Olivia K Heintz
- Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, State University of Londrina, Londrina 86038-440, Paraná, Brazil
| | - Waldiceu A Verri
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, Center of Biological Sciences, State University of Londrina, Londrina 86057-970, Paraná, Brazil.
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23
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Zhai R, Wang Q. Phylogenetic Analysis Provides Insight Into the Molecular Evolution of Nociception and Pain-Related Proteins. Evol Bioinform Online 2023; 19:11769343231216914. [PMID: 38107163 PMCID: PMC10725132 DOI: 10.1177/11769343231216914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 11/09/2023] [Indexed: 12/19/2023] Open
Abstract
Nociception and pain sensation are important neural processes in humans to avoid injury. Many proteins are involved in nociception and pain sensation in humans; however, the evolution of these proteins in animals is unknown. Here, we chose nociception- and pain-related proteins, including G protein-coupled receptors (GPCRs), ion channels (ICs), and neuropeptides (NPs), which are reportedly associated with nociception and pain in humans, and identified their homologs in various animals by BLAST, phylogenetic analysis and protein architecture comparison to reveal their evolution from protozoans to humans. We found that the homologs of transient receptor potential channel A 1 (TRPA1), TRAPM, acid-sensing IC (ASIC), and voltage-dependent calcium channel (VDCC) first appear in Porifera. Substance-P receptor 1 (TACR1) emerged from Coelenterata. Somatostatin receptor type 2 (SSTR2), TRPV1 and voltage-dependent sodium channels (VDSC) appear in Platyhelminthes. Calcitonin gene-related peptide receptor (CGRPR) was first identified in Nematoda. However, opioid receptors (OPRs) and most NPs were discovered only in vertebrates and exist from agnatha to humans. The results demonstrated that homologs of nociception and pain-related ICs exist from lower animal phyla to high animal phyla, and that most of the GPCRs originate from low to high phyla sequentially, whereas OPRs and NPs are newly evolved in vertebrates, which provides hints of the evolution of nociception and pain-related proteins in animals and humans.
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Affiliation(s)
- Rujun Zhai
- Department of Gastrointestinal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, P. R. China
| | - Qian Wang
- Changping Laboratory, Beijing, P. R. China
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24
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Xu J, Huang P, Bie B, Dai Y, Ben-Salem S, Borjini N, Zhang L, Chen J, Olman M, Cheng J, Lin F. Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1736-1746. [PMID: 37861348 PMCID: PMC10841827 DOI: 10.4049/jimmunol.2300252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 09/22/2023] [Indexed: 10/21/2023]
Abstract
Cancer chemotherapy-induced neuropathic pain is a devastating pain syndrome without effective therapies. We previously reported that rats deficient in complement C3, the central component of complement activation cascade, showed a reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of this model. However, the underlying mechanism was unclear. Complement activation leads to the production of C3a, which mediates inflammation through its receptor C3aR1. In this article, we report that the administration of paclitaxel induced a significantly higher expression level of C3aR1 on dorsal root ganglion (DRG) macrophages and expansion of these macrophages in DRGs in wild-type (WT) compared with in C3aR1 knockout (KO) mice. We also found that paclitaxel induced less severe PIMA, along with a reduced DRG expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4), an essential mediator for PIMA, in C3aR1 KO than in WT mice. Treating WT mice or rats with a C3aR1 antagonist markedly attenuated PIMA in association with downregulated DRG TRPV4 expression, reduced DRG macrophages expansion, suppressed DRG neuron hyperexcitability, and alleviated peripheral intraepidermal nerve fiber loss. Administration of C3aR1 antagonist to TRPV4 KO mice further protected them from PIMA. These results suggest that complement regulates PIMA development through C3aR1 to upregulate TRPV4 on DRG neurons and promote DRG macrophage expansion. Targeting C3aR1 could be a novel therapeutic approach to alleviate this debilitating pain syndrome.
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Affiliation(s)
- Jijun Xu
- Department of Pain Management, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Ping Huang
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Bihua Bie
- Department of Pain Management, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA
| | - Yang Dai
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Salma Ben-Salem
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Nozha Borjini
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Lingjun Zhang
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Jin Chen
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Mitchell Olman
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Jianguo Cheng
- Department of Pain Management, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA
- Department of Neurosciences, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
| | - Feng Lin
- Department of Inflammation and Immunity, 9500 Euclid Ave., Cleveland Clinic, Cleveland, OH 44195, USA
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25
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Hong JY, Kim H, Yeo C, Lee J, Jeon WJ, Lee YJ, Ha IH. Epidural Injection of Harpagoside for the Recovery of Rats with Lumbar Spinal Stenosis. Cells 2023; 12:2281. [PMID: 37759506 PMCID: PMC10526993 DOI: 10.3390/cells12182281] [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: 08/08/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Epidural administration is the leading therapeutic option for the management of pain associated with lumbar spinal stenosis (LSS), which is characterized by compression of the nerve root due to narrowing of the spinal canal. Corticosteroids are effective in alleviating LSS-related pain but can lead to complications with long-term use. Recent studies have focused on identifying promising medications administered epidurally to affected spinal regions. In this study, we aimed to investigate the effectiveness of harpagoside (HAS) as an epidural medication in rats with LSS. HAS at various concentrations was effective for neuroprotection against ferrous sulfate damage and consequent promotion of axonal outgrowth in primary spinal cord neurons. When two concentrations of HAS (100 and 200 μg/kg) were administered to the rat LSS model via the epidural space once a day for 4 weeks, the inflammatory responses around the silicone block used for LSS were substantially reduced. Consistently, pain-related factors were significantly suppressed by the epidural administration of HAS. The motor functions of rats with LSS significantly improved. These findings suggest that targeted delivery of HAS directly to the affected area via epidural injection holds promise as a potential treatment option for the recovery of patients with LSS.
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Affiliation(s)
| | | | | | | | | | | | - In-Hyuk Ha
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea; (J.Y.H.); (H.K.); (C.Y.); (J.L.); (W.-J.J.); (Y.J.L.)
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26
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Piciu F, Balas M, Badea MA, Cucu D. TRP Channels in Tumoral Processes Mediated by Oxidative Stress and Inflammation. Antioxidants (Basel) 2023; 12:1327. [PMID: 37507867 PMCID: PMC10376197 DOI: 10.3390/antiox12071327] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
The channels from the superfamily of transient receptor potential (TRP) activated by reactive oxygen species (ROS) can be defined as redox channels. Those with the best exposure of the cysteine residues and, hence, the most sensitive to oxidative stress are TRPC4, TRPC5, TRPV1, TRPV4, and TRPA1, while others, such as TRPC3, TRPM2, and TRPM7, are indirectly activated by ROS. Furthermore, activation by ROS has different effects on the tumorigenic process: some TRP channels may, upon activation, stimulate proliferation, apoptosis, or migration of cancer cells, while others inhibit these processes, depending on the cancer type, tumoral microenvironment, and, finally, on the methods used for evaluation. Therefore, using these polymodal proteins as therapeutic targets is still an unmet need, despite their draggability and modulation by simple and mostly unharmful compounds. This review intended to create some cellular models of the interaction between oxidative stress, TRP channels, and inflammation. Although somewhat crosstalk between the three actors was rather theoretical, we intended to gather the recently published data and proposed pathways of cancer inhibition using modulators of TRP proteins, hoping that the experimental data corroborated clinical information may finally bring the results from the bench to the bedside.
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Affiliation(s)
- Florentina Piciu
- Department of Anatomy, Animal Physiology and Biophysics (DAFAB), Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania
| | - Mihaela Balas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania
| | - Madalina Andreea Badea
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania
- Research Institute of the University of Bucharest (ICUB), University of Bucharest, 90-92 Sos. Panduri, 050663 Bucharest, Romania
| | - Dana Cucu
- Department of Anatomy, Animal Physiology and Biophysics (DAFAB), Faculty of Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania
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27
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Raman S, Ikutame D, Okura K, Matsuka Y. Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine. J Pers Med 2023; 13:jpm13030565. [PMID: 36983746 PMCID: PMC10057163 DOI: 10.3390/jpm13030565] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Orofacial pain (OFP) is a dental specialty that includes the diagnosis, management and treatment of disorders of the jaw, mouth, face, head and neck. Evidence-based understanding is critical in effectively treating OFPs as the pathophysiology of these conditions is multifactorial. Since OFP impacts the quality of life of the affected individuals, treating patients successfully is of the utmost significance. Despite the therapeutic choices available, treating OFP is still quite challenging, owing to inter-patient variations. The emerging trends in precision medicine could probably lead us to a paradigm shift in effectively managing the untreatable long-standing pain conditions. Precision medicine is designed based on the patient's genetic profile to meet their needs. Several significant relationships have been discovered based on the genetics and genomics of pain in the past, and some of the notable targets are discussed in this review. The scope of this review is to discuss preclinical and clinical trials that include approaches used in targeted therapy for orofacial pain. Future developments in pain medicine should benefit from current trends in research into novel therapeutic approaches.
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Affiliation(s)
- Swarnalakshmi Raman
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan
| | - Daisuke Ikutame
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan
| | - Kazuo Okura
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan
| | - Yoshizo Matsuka
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan
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28
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Hanč P, Messou MA, Wang Y, von Andrian UH. Control of myeloid cell functions by nociceptors. Front Immunol 2023; 14:1127571. [PMID: 37006298 PMCID: PMC10064072 DOI: 10.3389/fimmu.2023.1127571] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/23/2023] [Indexed: 03/19/2023] Open
Abstract
The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the primary function of the somatosensory branch of the peripheral nervous system is to collect and interpret sensory information about the environment, allowing the organism to react to or avoid situations that could otherwise have deleterious effects. Consequently, a teleological argument can be made that it is of advantage for the two systems to cooperate and form an “integrated defense system” that benefits from the unique strengths of both subsystems. Indeed, nociceptors, sensory neurons that detect noxious stimuli and elicit the sensation of pain or itch, exhibit potent immunomodulatory capabilities. Depending on the context and the cellular identity of their communication partners, nociceptors can play both pro- or anti-inflammatory roles, promote tissue repair or aggravate inflammatory damage, improve resistance to pathogens or impair their clearance. In light of such variability, it is not surprising that the full extent of interactions between nociceptors and the immune system remains to be established. Nonetheless, the field of peripheral neuroimmunology is advancing at a rapid pace, and general rules that appear to govern the outcomes of such neuroimmune interactions are beginning to emerge. Thus, in this review, we summarize our current understanding of the interaction between nociceptors and, specifically, the myeloid cells of the innate immune system, while pointing out some of the outstanding questions and unresolved controversies in the field. We focus on such interactions within the densely innervated barrier tissues, which can serve as points of entry for infectious agents and, where known, highlight the molecular mechanisms underlying these interactions.
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Affiliation(s)
- Pavel Hanč
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- *Correspondence: Pavel Hanč, ; Ulrich H. von Andrian,
| | - Marie-Angèle Messou
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Yidi Wang
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Ulrich H. von Andrian
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- *Correspondence: Pavel Hanč, ; Ulrich H. von Andrian,
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29
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Ramsay S, Zagorodnyuk V. Role of circadian rhythms and melatonin in bladder function in heath and diseases. Auton Neurosci 2023; 246:103083. [PMID: 36871511 DOI: 10.1016/j.autneu.2023.103083] [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: 12/20/2022] [Revised: 02/23/2023] [Accepted: 02/23/2023] [Indexed: 03/05/2023]
Abstract
The circadian system modulates all visceral organ physiological processes including urine storage and voiding. The "master clock" of the circadian system lies within suprachiasmatic nucleus of the hypothalamus while "peripheral clocks" are found in most peripheral tissue and organs, including the urinary bladder. Disruptions of circadian rhythms can cause organ malfunction and disorder or exacerbate pre-existing ones. It has been suggested that nocturia, which develops mostly in the elderly, could be a circadian-related disorder of the bladder. In the bladder, many types of gap junctions and ion channels in the detrusor, urothelium and sensory nerves are likely under strict local peripheral circadian control. The pineal hormone, melatonin, is a circadian rhythm synchroniser capable of controlling a variety of physiological processes in the body. Melatonin predominantly acts via the melatonin 1 and melatonin 2 G-protein coupled receptors expressed in the central nervous system, and many peripheral organs and tissues. Melatonin could be beneficial in the treatment of nocturia and other common bladder disorders. The ameliorating action of melatonin on bladder function is likely due to multiple mechanisms which include central effects on voiding and peripheral effects on the detrusor and bladder afferents. More studies are warranted to determine the precise mechanisms of circadian rhythm coordination of the bladder function and melatonin influences on the bladder in health and diseases.
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Affiliation(s)
- Stewart Ramsay
- Discipline of Human Physiology, Flinders Health & Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Vladimir Zagorodnyuk
- Discipline of Human Physiology, Flinders Health & Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia.
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Yang F, Sivils A, Cegielski V, Singh S, Chu XP. Transient Receptor Potential (TRP) Channels in Pain, Neuropsychiatric Disorders, and Epilepsy. Int J Mol Sci 2023; 24:ijms24054714. [PMID: 36902145 PMCID: PMC10003176 DOI: 10.3390/ijms24054714] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/05/2023] Open
Abstract
Pharmacomodulation of membrane channels is an essential topic in the study of physiological conditions and disease status. Transient receptor potential (TRP) channels are one such family of nonselective cation channels that have an important influence. In mammals, TRP channels consist of seven subfamilies with a total of twenty-eight members. Evidence shows that TRP channels mediate cation transduction in neuronal signaling, but the full implication and potential therapeutic applications of this are not entirely clear. In this review, we aim to highlight several TRP channels which have been shown to mediate pain sensation, neuropsychiatric disorders, and epilepsy. Recent findings suggest that TRPM (melastatin), TRPV (vanilloid), and TRPC (canonical) are of particular relevance to these phenomena. The research reviewed in this paper validates these TRP channels as potential targets of future clinical treatment and offers patients hope for more effective care.
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Gallardo VJ, Gómez-Galván JB, Asskour L, Torres-Ferrús M, Alpuente A, Caronna E, Pozo-Rosich P. A study of differential microRNA expression profile in migraine: the microMIG exploratory study. J Headache Pain 2023; 24:11. [PMID: 36797674 PMCID: PMC9936672 DOI: 10.1186/s10194-023-01542-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/27/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Several studies have described potential microRNA (miRNA) biomarkers associated with migraine, but studies are scarcely reproducible primarily due to the heterogeneous variability of participants. Increasing evidence shows that disease-related intrinsic factors together with lifestyle (environmental factors), influence epigenetic mechanisms and in turn, diseases. Hence, the main objective of this exploratory study was to find differentially expressed miRNAs (DE miRNA) in peripheral blood mononuclear cells (PBMC) of patients with migraine compared to healthy controls in a well-controlled homogeneous cohort of non-menopausal women. METHODS Patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) and healthy controls without familial history of headache disorders were recruited. All participants completed a very thorough questionnaire and structured-interview in order to control for environmental factors. RNA was extracted from PBMC and a microarray system (GeneChip miRNA 4.1 Array chip, Affymetrix) was used to determine the miRNA profiles between study groups. Principal components analysis and hierarchical clustering analysis were performed to study samples distribution and random forest (RF) algorithms were computed for the classification task. To evaluate the stability of the results and the prediction error rate, a bootstrap (.632 + rule) was run through all the procedure. Finally, a functional enrichment analysis of selected targets was computed through protein-protein interaction networks. RESULTS After RF classification, three DE miRNA distinguished study groups in a very homogeneous female cohort, controlled by factors such as demographics (age and BMI), life-habits (physical activity, caffeine and alcohol consumptions), comorbidities and clinical features associated to the disease: miR-342-3p, miR-532-3p and miR-758-5p. Sixty-eight target genes were predicted which were linked mainly to enriched ion channels and signaling pathways, neurotransmitter and hormone homeostasis, infectious diseases and circadian entrainment. CONCLUSIONS A 3-miRNA (miR-342-3p, miR-532-3p and miR-758-5p) novel signature has been found differentially expressed between controls and patients with migraine. Enrichment analysis showed that these pathways are closely associated with known migraine pathophysiology, which could lead to the first reliable epigenetic biomarker set. Further studies should be performed to validate these findings in a larger and more heterogeneous sample.
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Affiliation(s)
- V. J. Gallardo
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J. B. Gómez-Galván
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - L. Asskour
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M. Torres-Ferrús
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain ,grid.411083.f0000 0001 0675 8654Neurology Department, Headache Unit, Vall d’Hebron University Hospital, Barcelona, Spain
| | - A. Alpuente
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain ,grid.411083.f0000 0001 0675 8654Neurology Department, Headache Unit, Vall d’Hebron University Hospital, Barcelona, Spain
| | - E. Caronna
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain ,grid.411083.f0000 0001 0675 8654Neurology Department, Headache Unit, Vall d’Hebron University Hospital, Barcelona, Spain
| | - P. Pozo-Rosich
- grid.430994.30000 0004 1763 0287Headache and Neurological Pain Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain ,grid.411083.f0000 0001 0675 8654Neurology Department, Headache Unit, Vall d’Hebron University Hospital, Barcelona, Spain
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Kumar PS, Radhakrishnan A, Mukherjee T, Khamaru S, Chattopadhyay S, Chattopadhyay S. Understanding the role of Ca 2+ via transient receptor potential (TRP) channel in viral infection: Implications in developing future antiviral strategies. Virus Res 2023; 323:198992. [PMID: 36309316 PMCID: PMC10194134 DOI: 10.1016/j.virusres.2022.198992] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022]
Abstract
Transient receptor potential (TRP) channels are a superfamily of cation-specific permeable channels primarily conducting Ca2+ions across various membranes of the cell. The perturbation of the Ca2+ homeostasis is the hallmark of viral infection. Viruses hijack the host cell Ca2+ signaling, employing tailored Ca2+ requirements via TRP channels to meet their own cellular demands. This review summarizes the importance of Ca2+ across diverse viruses based on the Baltimore classification and focuses on the associated role of Ca2+-conducting TRP channels in viral pathophysiology. More emphasis has been given to the role of the TRP channel in viral life-cycle events such as viral fusion, viral entry, viral replication, virion maturation, and egress. Additionally, this review highlights the TRP channel as a store-operated channel which has been discussed vividly. The TRP channels form an essential aspect of host-virus interaction by virtue of its Ca2+ permeability. These channels are directly involved in regulating the viral calcium dynamics in host cells and thereby affect the viral infection. Considering its immense potential in regulating viral infection, the TRP channels may act as a target for antiviral therapeutics.
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Affiliation(s)
- P Sanjai Kumar
- School of Biological Sciences, National Institute of Science Education & Research, an OCC of Homi Bhabha National Institute, Bhubaneswar, Jatni, Khurda, Odisha 752050, India; Infectious Disease Biology, Institute of Life Sciences, Autonomous Institute of Department of Biotechnology, Government of India, Nalco Square, Bhubaneswar, Odisha 751023, India
| | - Anukrishna Radhakrishnan
- School of Biological Sciences, National Institute of Science Education & Research, an OCC of Homi Bhabha National Institute, Bhubaneswar, Jatni, Khurda, Odisha 752050, India
| | - Tathagata Mukherjee
- School of Biological Sciences, National Institute of Science Education & Research, an OCC of Homi Bhabha National Institute, Bhubaneswar, Jatni, Khurda, Odisha 752050, India
| | - Somlata Khamaru
- School of Biological Sciences, National Institute of Science Education & Research, an OCC of Homi Bhabha National Institute, Bhubaneswar, Jatni, Khurda, Odisha 752050, India
| | - Soma Chattopadhyay
- Infectious Disease Biology, Institute of Life Sciences, Autonomous Institute of Department of Biotechnology, Government of India, Nalco Square, Bhubaneswar, Odisha 751023, India.
| | - Subhasis Chattopadhyay
- School of Biological Sciences, National Institute of Science Education & Research, an OCC of Homi Bhabha National Institute, Bhubaneswar, Jatni, Khurda, Odisha 752050, India.
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Blanes-Mira C, Fernández-Aguado P, de Andrés-López J, Fernández-Carvajal A, Ferrer-Montiel A, Fernández-Ballester G. Comprehensive Survey of Consensus Docking for High-Throughput Virtual Screening. Molecules 2022; 28:molecules28010175. [PMID: 36615367 PMCID: PMC9821981 DOI: 10.3390/molecules28010175] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/19/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
The rapid advances of 3D techniques for the structural determination of proteins and the development of numerous computational methods and strategies have led to identifying highly active compounds in computer drug design. Molecular docking is a method widely used in high-throughput virtual screening campaigns to filter potential ligands targeted to proteins. A great variety of docking programs are currently available, which differ in the algorithms and approaches used to predict the binding mode and the affinity of the ligand. All programs heavily rely on scoring functions to accurately predict ligand binding affinity, and despite differences in performance, none of these docking programs is preferable to the others. To overcome this problem, consensus scoring methods improve the outcome of virtual screening by averaging the rank or score of individual molecules obtained from different docking programs. The successful application of consensus docking in high-throughput virtual screening highlights the need to optimize the predictive power of molecular docking methods.
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Caballero J. A new era for the design of TRPV1 antagonists and agonists with the use of structural information and molecular docking of capsaicin-like compounds. J Enzyme Inhib Med Chem 2022; 37:2169-2178. [PMID: 35975286 PMCID: PMC9387342 DOI: 10.1080/14756366.2022.2110089] [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] [Indexed: 11/20/2022] Open
Abstract
The design of TRPV1 antagonists and agonists has reached a new era since TRPV1 structures at near-atomic resolution are available. Today, the ligand-binding forms of several classical antagonists and agonists are known; therefore, the specific role of key TRPV1’s residues in binding of ligands can be elucidated. It is possible to place the well-defined pharmacophore of TRPV1 ligands, conformed by head, neck, and tail groups, in the right pocket regions of TRPV1. It will allow a more thorough use of molecular modelling methods to conduct more effective rational drug design protocols. In this work, important points about the interactions between TRPV1 and capsaicin-like compounds are spelled out, based on the known pharmacophore of the ligands and the already available TRPV1 structures. These points must be addressed to generate reliable poses of novel candidates and should be considered during the design of novel TRPV1 antagonists and agonists.
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Affiliation(s)
- Julio Caballero
- Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca, Chile
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Shang Y, Li Y, Yang Z, Zhou Z. Upregulation of TACAN in the trigeminal ganglion affects pain transduction in acute pulpitis. Arch Oral Biol 2022; 143:105530. [PMID: 36088852 DOI: 10.1016/j.archoralbio.2022.105530] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/28/2022] [Accepted: 08/23/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVE Acute pulpitis is one of the common causes of tooth pain. TACAN (Tmem120a) is a newly identified ion channel that senses mechanical pain. In this experiment, we studied the expression of the TACAN ion channel in the trigeminal ganglia in a rat model of pulpitis to explore the correlation between the expression of this ion channel and inflammatory pain. DESIGN Lipopolysaccharide was used to induce acute pulpitis in rats, and pulpitis was assessed histologically. The facial pain threshold of the rats was measured by the von Frey test. TACAN mRNA expression in rat dental pulp and the trigeminal nerve was measured by qPCR, and TACAN protein expression in the trigeminal ganglia was evaluated by western blot analysis and immunofluorescence. Antisense oligonucleotides were used to reduce TACAN protein expression in the trigeminal ganglia, and the change in the pain threshold in the rats with acute pulpitis was determined. RESULTS The results showed that the TACAN transcript level in rat pulp tissue increased under inflammatory conditions, and we proved that pulpitis increased TACAN protein expression in the rat ipsilateral trigeminal ganglia. The facial pain threshold was decreased in rats with pulpitis. A short-term decrease in TACAN protein expression could improve the pain threshold. CONCLUSIONS With the development of pulpitis after bacterial infection, the upregulation of TACAN expression in the trigeminal ganglia promoted pain sensitivity. A short-term reduction in TACAN expression relieved pain. Therefore, this study indicated that TACAN is a potential target channel for new analgesics.
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Affiliation(s)
- Yicong Shang
- College of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Yueheng Li
- College of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Zhengyan Yang
- College of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.
| | - Zhi Zhou
- College of Stomatology, Chongqing Medical University, Chongqing, China.
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Jennings EM, Sullivan LC, Jamshidi RJ, LoCoco PM, Smith HR, Chavera TS, Berg KA, Clarke WP. Age-related changes in peripheral nociceptor function. Neuropharmacology 2022; 216:109187. [PMID: 35835212 DOI: 10.1016/j.neuropharm.2022.109187] [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] [Received: 12/30/2021] [Revised: 06/21/2022] [Accepted: 07/03/2022] [Indexed: 01/05/2023]
Abstract
Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels. Unlike other senses that decrease in sensitivity with age, sensitivity of hindpaw nociceptors to thermal and mechanical stimulation was not different between young and aged F344xBN rats. Intraplantar injection of bradykinin (BK) produced greater thermal and mechanical allodynia in aged versus young rats, whereas only mechanical allodynia was greater in aged rats following injection of prostaglandin E2 (PGE2). Intraplantar injection of TRP channel activators, capsaicin (TRPV1), mustard oil (TRPA1) and menthol (TRPM8) each resulted in greater mechanical allodynia in aged versus young rats and capsaicin-induced heat allodynia was also greater in aged rats. A treatment-induced allodynia that was greater in young rats was never observed. The anti-allodynic effects of intraplantar injection of kappa and delta opioid receptor agonists, salvinorin-A and D-Pen2,D-Pen5]enkephalin (DPDPE), respectively, were greater in aged than young rats, whereas mu opioid receptor agonists, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and morphine, were not effective in aged rats. Consistent with these observations, in primary cultures of peripheral sensory neurons, inhibition of cAMP signaling in response to delta and kappa receptor agonists was greater in cultures derived from aged rats. By contrast, mu receptor agonists did not inhibit cAMP signaling in aged rats. Thus, age-related changes in nociceptors generally favor increased pain signaling in aged versus young rats, suggesting that changes in nociceptor sensitivity may play a role in the increased incidence of pain in the elderly population. These results also suggest that development of peripherally-restricted kappa or delta opioid receptor agonists may provide safer and effective pain relief for the elderly.
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Affiliation(s)
- Elaine M Jennings
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - Laura C Sullivan
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - Raehannah J Jamshidi
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - Peter M LoCoco
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - Hudson R Smith
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - Teresa S Chavera
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - Kelly A Berg
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA
| | - William P Clarke
- Department of Pharmacology, The University of Texas Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229-3900, USA.
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Fernández-Carvajal A, Fernández-Ballester G, Ferrer-Montiel A. TRPV1 in chronic pruritus and pain: Soft modulation as a therapeutic strategy. Front Mol Neurosci 2022; 15:930964. [PMID: 36117910 PMCID: PMC9478410 DOI: 10.3389/fnmol.2022.930964] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic pain and pruritus are highly disabling pathologies that still lack appropriate therapeutic intervention. At cellular level the transduction and transmission of pain and pruritogenic signals are closely intertwined, negatively modulating each other. The molecular and cellular pathways involved are multifactorial and complex, including peripheral and central components. Peripherally, pain and itch are produced by subpopulations of specialized nociceptors that recognize and transduce algesic and pruritogenic signals. Although still under intense investigation, cumulative evidence is pointing to the thermosensory channel TRPV1 as a hub for a large number of pro-algesic and itchy agents. TRPV1 appears metabolically coupled to most neural receptors that recognize algesic and pruritic molecules. Thus, targeting TRPV1 function appears as a valuable and reasonable therapeutic strategy. In support of this tenet, capsaicin, a desensitizing TRPV1 agonist, has been shown to exhibit clinically relevant analgesic, anti-inflammatory, and anti-pruritic activities. However, potent TRPV1 antagonists have been questioned due to an hyperthermic secondary effect that prevented their clinical development. Thus, softer strategies directed to modulate peripheral TRPV1 function appear warranted to alleviate chronic pain and itch. In this regard, soft, deactivatable TRPV1 antagonists for topical or local application appear as an innovative approach for improving the distressing painful and itchy symptoms of patients suffering chronic pain or pruritus. Here, we review the data on these compounds and propose that this strategy could be used to target other peripheral therapeutic targets.
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Jawaid S, Herring AI, Getsy PM, Lewis SJ, Watanabe M, Kolesova H. Differential immunostaining patterns of transient receptor potential (TRP) ion channels in the rat nodose ganglion. J Anat 2022; 241:230-244. [PMID: 35396708 PMCID: PMC9296033 DOI: 10.1111/joa.13656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 01/26/2022] [Accepted: 03/07/2022] [Indexed: 11/27/2022] Open
Abstract
Vagal afferents regulate numerous physiological functions including arterial blood pressure, heart rate, breathing, and nociception. Cell bodies of vagal afferents reside in the inferior vagal (nodose) ganglia and their stimulation by various means is being considered as a way to regulate cardiorespiratory responses and control pain sensations. Stimulation of the nodose by exposure to infrared light is recently being considered as a precise way to elicit responses. These responses would likely involve the activity of temperature-sensitive membrane-bound channels. While papers have been published to track the expression of these transient receptor potential ion channels (TRPs), further studies are warranted to determine the in situ expression of the endogenous TRP proteins in the nodose ganglia to fully understand their pattern of expression, subcellular locations, and functions in this animal model. TRP ion channels are a superfamily of Na+ /Ca2+ -channels whose members are temperature- and/or mechano-sensitive and therefore represent a potential set of proteins that will be activated directly or indirectly by infrared light. Here, we report the spatial localization of six TRP channels, TRPV1, TRPV4, TRPM3, TRPM8, TRPA1, and TRPC1, from nodose ganglia taken from juvenile male Sprague-Dawley rats. The channels were detected using immunohistology with fluorescent tags on cryosections and imaged using confocal microscopy. All six TRP channels were detected with different levels of intensity in neuronal cell bodies and some were also detected in axonal fibers and blood vessels. The TRP receptors differed in their prevalence, in their patterns of expression, and in subcellular expression/localization. More specifically, TRPV1, TRPV4, TRPA1, TRPM8, TRPC1, and TRPM3 were found in vagal afferent cell bodies with a wide range of immunostaining intensity from neuron to neuron. Immunostaining for TRPV1, TRPV4, and TRPA1 appeared as fine particles scattered throughout the cytoplasm of the cell body. Intense TRPV1 immunostaining was also evident in a subset of axonal fibers. TRPM8 and TRPC1 were expressed in courser particles suggesting different subcellular compartments than for TRPV1. The localization of TRPM3 differed markedly from the other TRP channels with an immunostaining pattern that was localized to the periphery of a subset of cell bodies, whereas a scattering or no immunostaining was detected within the bulk of the cytoplasm. TRPV4 and TRPC1 were also expressed on the walls of blood vessels. The finding that all six TRP channels (representing four subfamilies) were present in the nodose ganglia provides the basis for studies designed to understand the roles of these channels in sensory transmission within vagal afferent fibers and in the responses elicited by exposure of nodose ganglia to infrared light and other stimuli. Depending on the location and functionality of the TRP channels, they may regulate the flux of Na+ /Ca2+ -across the membranes of cell bodies and axons of sensory afferents, efferent (motor) fibers coursing through the ganglia, and in vascular smooth muscle.
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Affiliation(s)
- Safdar Jawaid
- Divisions of Pediatric CardiologyCase Western Reserve University School of MedicineClevelandOHUSA
| | - Amanda I. Herring
- Divisions of Pediatric CardiologyCase Western Reserve University School of MedicineClevelandOHUSA
| | - Paulina M. Getsy
- Pediatric Pulmonology, Department of PediatricsCase Western Reserve University School of MedicineClevelandOHUSA
| | - Stephen J. Lewis
- Pediatric Pulmonology, Department of PediatricsCase Western Reserve University School of MedicineClevelandOHUSA
| | - Michiko Watanabe
- Divisions of Pediatric CardiologyCase Western Reserve University School of MedicineClevelandOHUSA
| | - Hana Kolesova
- Department of Anatomy, First Faculty of MedicineCharles UniversityPragueCzech Republic
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Gupta S, Gautam S, Kumar U, Arora T, Dada R. Potential Role of Yoga Intervention in the Management of Chronic Non-malignant Pain. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:5448671. [PMID: 35668780 PMCID: PMC9167073 DOI: 10.1155/2022/5448671] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/18/2022] [Accepted: 05/13/2022] [Indexed: 12/22/2022]
Abstract
Pain is an unpleasant and upsetting experience. Persistent pain has an impact on an individual's quality of life which causes stress and mood disorders. There are currently no pain-relieving techniques available that can eliminate pain and offer relief without causing any adverse effects. These factors draw attention to traditional treatments like yoga and meditation, which can reduce biological stress and hence increase immunity, as well as alleviate the psychological and emotional suffering produced by pain. Yoga reduces the stress response and the pain cascade via the downregulation of the hypothalamus-pituitary-adrenal (HPA) axis and vagal stimulation. Yoga is a cost-effective growing health practice that, unlike pharmaceuticals, has no side effects and can help patients stay in remission for longer periods of time with fewer relapses. Yoga not only reduces stress and depression severity but also improves functional status and reduces pain perception. This article highlights the impact of yoga on pain management and on a malfunctioning immune system, which leads to improved health, pain reduction, disease management, and improvement in overall quality of life.
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Affiliation(s)
- Shivani Gupta
- Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gautam
- Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
| | - Uma Kumar
- Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India
| | - Taruna Arora
- Division of Reproductive Biology, Maternal & Child Health, Indian Council of Medical Research, New Delhi, India
| | - Rima Dada
- Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
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Apoptosis and (in) Pain—Potential Clinical Implications. Biomedicines 2022; 10:biomedicines10061255. [PMID: 35740277 PMCID: PMC9219669 DOI: 10.3390/biomedicines10061255] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 02/06/2023] Open
Abstract
The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.
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Hwang SM, Jo YY, Cohen CF, Kim YH, Berta T, Park CK. Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development. Int J Mol Sci 2022; 23:ijms23105772. [PMID: 35628583 PMCID: PMC9147560 DOI: 10.3390/ijms23105772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/02/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023] Open
Abstract
The transient receptor potential vanilloid 1 (TRPV1) ion channel plays an important role in the peripheral nociceptive pathway. TRPV1 is a polymodal receptor that can be activated by multiple types of ligands and painful stimuli, such as noxious heat and protons, and contributes to various acute and chronic pain conditions. Therefore, TRPV1 is emerging as a novel therapeutic target for the treatment of various pain conditions. Notably, various peptides isolated from venomous animals potently and selectively control the activation and inhibition of TRPV1 by binding to its outer pore region. This review will focus on the mechanisms by which venom-derived peptides interact with this portion of TRPV1 to control receptor functions and how these mechanisms can drive the development of new types of analgesics.
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Affiliation(s)
- Sung-Min Hwang
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Korea; (S.-M.H.); (Y.-H.K.)
| | - Youn-Yi Jo
- Gil Medical Center, Department of Anesthesiology and Pain Medicine, Gachon University, Incheon 21565, Korea;
| | - Cinder Faith Cohen
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH 45242, USA;
| | - Yong-Ho Kim
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Korea; (S.-M.H.); (Y.-H.K.)
| | - Temugin Berta
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH 45242, USA;
- Correspondence: (T.B.); (C.-K.P.)
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Korea; (S.-M.H.); (Y.-H.K.)
- Correspondence: (T.B.); (C.-K.P.)
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42
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Anticancer Activity of Natural and Semi-Synthetic Drimane and Coloratane Sesquiterpenoids. Molecules 2022; 27:molecules27082501. [PMID: 35458699 PMCID: PMC9031474 DOI: 10.3390/molecules27082501] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 12/12/2022] Open
Abstract
Drimane and coloratane sesquiterpenoids are present in several plants, microorganisms, and marine life. Because of their cytotoxic activity, these sesquiterpenoids have received increasing attention as a source for new anticancer drugs and pharmacophores. Natural drimanes and coloratanes, as well as their semi-synthetic derivatives, showed promising results against cancer cell lines with in vitro activities in the low micro- and nanomolar range. Despite their high potential as novel anticancer agents, the mode of action and structure–activity relationships of drimanes and coloratanes have not been completely enlightened nor systematically reviewed. Our review aims to give an overview of known structures and derivatizations of this class of sesquiterpenoids, as well as their activity against cancer cells and potential modes-of-action. The cytotoxic activities of about 40 natural and 25 semi-synthetic drimanes and coloratanes are discussed. In addition to that, we give a summary about the clinical significance of drimane and coloratane sesquiterpenoids.
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43
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Jesus CHA, Scarante FF, Schreiber AK, Gasparin AT, Redivo DDB, Rosa ES, Cunha JMD. Comparative study of cold hyperalgesia and mechanical allodynia in two animal models of neuropathic pain: different etiologies and distinct pathophysiological mechanisms. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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44
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Ahluwalia P, Gupta B. Quest ignited for newer analgesics. INDIAN JOURNAL OF PAIN 2022. [DOI: 10.4103/ijpn.ijpn_96_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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45
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da Silva JF, Binda NS, Pereira EMR, de Lavor MSL, Vieira LB, de Souza AH, Rigo FK, Ferrer HT, de Castro CJ, Ferreira J, Gomez MV. Analgesic effects of Phα1β toxin: a review of mechanisms of action involving pain pathways. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20210001. [PMID: 34868281 PMCID: PMC8610172 DOI: 10.1590/1678-9199-jvatitd-2021-0001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/26/2021] [Indexed: 01/01/2023] Open
Abstract
Phα1β is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1β to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1β (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1β antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.
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Affiliation(s)
- Juliana Figueira da Silva
- Laboratory of Pharmacology, Department of Pharmacy, Federal
University of Ouro Preto, Ouro Preto, MG, Brazil
| | - Nancy Scardua Binda
- Laboratory of Pharmacology, Department of Pharmacy, Federal
University of Ouro Preto, Ouro Preto, MG, Brazil
| | - Elizete Maria Rita Pereira
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | | | - Luciene Bruno Vieira
- Department of Pharmacology, Institute of Biological Sciences (ICB),
Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Alessandra Hubner de Souza
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Flávia Karine Rigo
- Graduate Program in Health Sciences, University of the Extreme South
of Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Hèlia Tenza Ferrer
- Center of Technology in Molecular Medicine, School of Medicine,
Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Célio José de Castro
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Juliano Ferreira
- Department of Pharmacology, Federal University of Santa Catarina,
Florianópolis, SC, Brazil
| | - Marcus Vinicius Gomez
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
- Center of Technology in Molecular Medicine, School of Medicine,
Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
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46
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Go EJ, Ji J, Kim YH, Berta T, Park CK. Transient Receptor Potential Channels and Botulinum Neurotoxins in Chronic Pain. Front Mol Neurosci 2021; 14:772719. [PMID: 34776867 PMCID: PMC8586451 DOI: 10.3389/fnmol.2021.772719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/30/2022] Open
Abstract
Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.
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Affiliation(s)
- Eun Jin Go
- Department of Physiology, Gachon Pain Center, Gachon University College of Medicine, Incheon, South Korea
| | - Jeongkyu Ji
- Gachon University College of Medicine, Incheon, South Korea
| | - Yong Ho Kim
- Department of Physiology, Gachon Pain Center, Gachon University College of Medicine, Incheon, South Korea
| | - Temugin Berta
- Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, OH, United States
| | - Chul-Kyu Park
- Department of Physiology, Gachon Pain Center, Gachon University College of Medicine, Incheon, South Korea
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47
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Leuti A, Fava M, Pellegrini N, Maccarrone M. Role of Specialized Pro-Resolving Mediators in Neuropathic Pain. Front Pharmacol 2021; 12:717993. [PMID: 34456731 PMCID: PMC8385637 DOI: 10.3389/fphar.2021.717993] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/27/2021] [Indexed: 12/17/2022] Open
Abstract
Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)-i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the "resolution of inflammation"-has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.
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Affiliation(s)
- Alessandro Leuti
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy
| | - Marina Fava
- European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy.,Faculty of Biosciences and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Niccolò Pellegrini
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Mauro Maccarrone
- European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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48
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Neurocosmetics in Skincare—The Fascinating World of Skin–Brain Connection: A Review to Explore Ingredients, Commercial Products for Skin Aging, and Cosmetic Regulation. COSMETICS 2021. [DOI: 10.3390/cosmetics8030066] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The “modern” cosmetology industry is focusing on research devoted to discovering novel neurocosmetic functional ingredients that could improve the interactions between the skin and the nervous system. Many cosmetic companies have started to formulate neurocosmetic products that exhibit their activity on the cutaneous nervous system by affecting the skin’s neuromediators through different mechanisms of action. This review aims to clarify the definition of neurocosmetics, and to describe the features of some functional ingredients and products available on the market, with a look at the regulatory aspect. The attention is devoted to neurocosmetic ingredients for combating skin stress, explaining the stress pathways, which are also correlated with skin aging. “Neuro-relaxing” anti-aging ingredients derived from plant extracts and neurocosmetic strategies to combat inflammatory responses related to skin stress are presented. Afterwards, the molecular basis of sensitive skin and the suitable neurocosmetic ingredients to improve this problem are discussed. With the aim of presenting the major application of Botox-like ingredients as the first neurocosmetics on the market, skin aging is also introduced, and its theory is presented. To confirm the efficacy of the cosmetic products on the market, the concept of cosmetic claims is discussed.
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49
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Val‐Blasco A, Gil‐Fernández M, Rueda A, Pereira L, Delgado C, Smani T, Ruiz Hurtado G, Fernández‐Velasco M. Ca 2+ mishandling in heart failure: Potential targets. Acta Physiol (Oxf) 2021; 232:e13691. [PMID: 34022101 DOI: 10.1111/apha.13691] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022]
Abstract
Ca2+ mishandling is a common feature in several cardiovascular diseases such as heart failure (HF). In many cases, impairment of key players in intracellular Ca2+ homeostasis has been identified as the underlying mechanism of cardiac dysfunction and cardiac arrhythmias associated with HF. In this review, we summarize primary novel findings related to Ca2+ mishandling in HF progression. HF research has increasingly focused on the identification of new targets and the contribution of their role in Ca2+ handling to the progression of the disease. Recent research studies have identified potential targets in three major emerging areas implicated in regulation of Ca2+ handling: the innate immune system, bone metabolism factors and post-translational modification of key proteins involved in regulation of Ca2+ handling. Here, we describe their possible contributions to the progression of HF.
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Affiliation(s)
| | | | - Angélica Rueda
- Department of Biochemistry Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV‐IPN) México City Mexico
| | - Laetitia Pereira
- INSERM UMR‐S 1180 Laboratory of Ca Signaling and Cardiovascular Physiopathology University Paris‐Saclay Châtenay‐Malabry France
| | - Carmen Delgado
- Instituto de Investigaciones Biomédicas Alberto Sols Madrid Spain
- Department of Metabolism and Cell Signalling Biomedical Research Institute "Alberto Sols" CSIC‐UAM Madrid Spain
| | - Tarik Smani
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV) Madrid Spain
- Department of Medical Physiology and Biophysics University of Seville Seville Spain
- Group of Cardiovascular Pathophysiology Institute of Biomedicine of Seville University Hospital of Virgen del Rocío, University of Seville, CSIC Seville Spain
| | - Gema Ruiz Hurtado
- Cardiorenal Translational Laboratory Institute of Research i+12 University Hospital 12 de Octubre Madrid Spain
- CIBER‐CV University Hospita1 12 de Octubre Madrid Spain
| | - Maria Fernández‐Velasco
- La Paz University Hospital Health Research Institute IdiPAZ Madrid Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV) Madrid Spain
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50
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Borges JP, Mekhail K, Fairn GD, Antonescu CN, Steinberg BE. Modulation of Pathological Pain by Epidermal Growth Factor Receptor. Front Pharmacol 2021; 12:642820. [PMID: 34054523 PMCID: PMC8149758 DOI: 10.3389/fphar.2021.642820] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 04/26/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of people suffering from this devastating disease. To this end, recent clinical and preclinical studies have implicated the epidermal growth factor receptor signaling pathway in chronic pain states. EGFR is one of four members of the ErbB family of receptor tyrosine kinases that have key roles in development and the progression of many cancers. EGFR functions by activating many intracellular signaling pathways following binding of various ligands to the receptor. Several of these signaling pathways, such as phosphatidylinositol 3-kinase, are known mediators of pain. EGFR inhibitors are known for their use as cancer therapeutics but given recent evidence in pilot clinical and preclinical investigations, may have clinical use for treating chronic pain. Here, we review the clinical and preclinical evidence implicating EGFR in pathological pain states and provide an overview of EGFR signaling highlighting how EGFR and its ligands drive pain hypersensitivity and interact with important pain pathways such as the opioid system.
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Affiliation(s)
- Jazlyn P Borges
- Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Katrina Mekhail
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.,Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Gregory D Fairn
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.,Department of Biochemistry, University of Toronto, Toronto, ON, Canada.,Department of Surgery, University of Toronto, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada
| | - Costin N Antonescu
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.,Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada
| | - Benjamin E Steinberg
- Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Physiology, University of Toronto, Toronto, ON, Canada.,Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, ON, Canada
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