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Sun Y, Sanders AM, Pashley DH, Alexander A, Bergeron BE, Gu L, Tay FR. Beyond hydrodynamics: The role of ion channels in dentine hypersensitivity. J Dent 2025; 157:105745. [PMID: 40216070 DOI: 10.1016/j.jdent.2025.105745] [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: 03/19/2025] [Revised: 04/06/2025] [Accepted: 04/09/2025] [Indexed: 04/25/2025] Open
Abstract
OBJECTIVES This review examined the roles of ion channels in dentine hypersensitivity (DH), highlighting their contributions to pain perception and intercellular communication between odontoblasts and afferent sensory neurons. BACKGROUND Dentine hypersensitivity is a prevalent condition resulting from the exposure of dentinal tubules to the oral environment, leading to sharp pain triggered by mechanical, thermal, chemical, and osmotic stimuli. The prevailing hypothesis integrates aspects of the hydrodynamic and odontoblast transducer theories. It suggests that rapid intratubular fluid movement activates specific ion channels in odontoblasts and trigeminal sensory neurons, converting external stimuli into electrical signals interpreted as pain by the central nervous system. DATA & SOURCES A comprehensive literature review was conducted on ion channels involved in DH, with a focus on transient receptor potential (TRP) channels, Piezo channels, acid-sensing ion channels (ASICs), as well as other voltage-gated ion channels. Particular emphasis was placed on their physiological roles, responsiveness to stimuli, and contributions to DH pain. RESULTS PIEZO, TRP, and ASICs respond to pressure, heat, acidic environments, and chemical irritants, all of which contribute to DH pain. Activation of odontoblastic ion channels results in the release of adenosine triphosphate and glutamate, which bind respectively to purinergic and glutamate receptors on sensory neurons. This interaction induces depolarization, generating action potentials that transmit pain signals to the brain. CONCLUSION The diverse ion channels involved in dentine hypersensitivity play a crucial role in intercellular communication that leads to pain perception. However, their widespread physiological functions make direct pharmacological targeting challenging due to potential systemic effects. CLINICAL SIGNIFICANCE The use of antagonists for targeting specific ion channels involved in dentine hypersensitivity is difficult because of their involvement in other important physiological processes. Hence, clinical management strategies focusing on dentinal tubule occlusion or dentine desensitisation remain the safest and most effective approaches.
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Affiliation(s)
- Yutong Sun
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China
| | | | | | | | | | - Lisha Gu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China.
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Shao C, Zhao M, Yang K. Spinal cord trunk preparation for analyzing cross-segmental primary afferent signal transmission and modulation. J Neurosci Methods 2025; 418:110440. [PMID: 40180159 DOI: 10.1016/j.jneumeth.2025.110440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/23/2025] [Accepted: 03/31/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND The spinal cord dorsal horn is pivotal for primary afferent signal transmission and modulation. Primary afferent fibers from each dorsal root arrive at the dorsal horn and travel 1-2 segments caudally and rostrally. Usually, in vitro spinal cord slices or in vivo preparations are employed for primary afferent stimulation and patch-clamp recordings to assess input signals. However, the spinal cord slices lose "intact" cross-segmental pathways, and in vivo studies are technically challenging. NEW METHOD Here, we describe the preparation of a spinal cord trunk for analyzing afferent signal cross-segmental transmission in adult rats. By combining patch-clamp recording, Lissauer's tract stimulation, and ambient temperature manipulation, our methods enable accessing primary afferent pathways within several segments. RESULTS Our present spinal trunk preparation can be maintained healthy for about 5 h. Lissauer's tract stimulation induced evoked excitatory postsynaptic currents (eEPSCs) recorded in 6-10 mm rostrally in the ipsilateral dorsal horn. The eEPSCs, spontaneous EPSCs (sEPSCs), and neural excitability can be modulated by ambient temperature rise. Neuropharmacological studies can also be conducted on this spinal trunk preparation. COMPARED WITH EXISTING METHODS Compared with conventional in vitro spinal cord slices, our present method maintains a relatively intact cross-segment pathway in the dorsal horn; compared with in vivo study, it avoids mechanical vibration and other technical challenges in living animals. CONCLUSION The rodent spinal cord trunk can be maintained for an extended period in a fully submerged chamber; combined with patch clamp recordings, our protocol facilitates the study of primary afferent transmission and modulation in the dorsal horn within adjacent segments.
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Affiliation(s)
- Caifeng Shao
- Department of Anesthesiology, Nantong Hospital of Traditional Chinese Medicine, Affiliated Traditional Chinese Medicine Hospital of Nantong University, Nantong, Jiangsu 226001, China; Department of Anatomy, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Mingwei Zhao
- Department of Anatomy, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Kun Yang
- Department of Anatomy, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China; Department of Anatomy, School of Life and Health Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong 266113, China; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Asimakopoulos T, Tsaroucha A, Kouri M, Pasqualucci A, Varrassi G, Leoni MLG, Rekatsina M. The Role of Biomarkers in Acute Pain: A Narrative Review. Pain Ther 2025; 14:775-789. [PMID: 40088258 PMCID: PMC12085431 DOI: 10.1007/s40122-025-00718-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/25/2025] [Indexed: 03/17/2025] Open
Abstract
Acute pain, a critical aspect of patient care, presents a challenge due to its subjective nature and complex biological underpinnings. Biomarkers for acute pain promise a paradigm shift in how pain is perceived, diagnosed, and managed. The study of genetic, inflammatory, and neurotransmission markers associated with pain experience may hold the key for the development of personalized and effective pain management strategies. This narrative review explores the neurobiological pathways of acute pain, encompassing inflammatory responses and neurotransmission mechanisms. It synthesizes current research on the identification and clinical application of biomarkers, emphasizing their potential to enhance diagnostic precision, treatment effectiveness, and risk prediction. We underscore the promising role of acute pain biomarkers in identifying patients at risk for developing acute and potentially chronic pain, predicting patients' response to pharmacological interventions, and aiding in the development of novel therapeutic and pain preventive strategies. The evolving landscape of biomarker research not only deepens our understanding of pain mechanisms but also lays the foundation for more tailored and patient-specific healthcare interventions.
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Affiliation(s)
- Thalis Asimakopoulos
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
- 1st Department of Anesthesiology and Pain Medicine, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Athanasia Tsaroucha
- 1st Department of Anesthesiology and Pain Medicine, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Kouri
- Department of Oral Medicine & Pathology and Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Alberto Pasqualucci
- Department of Anesthesia and Pain Medicine, University of Perugia, 06100, Perugia, Italy
| | | | - Matteo Luigi Giuseppe Leoni
- Department of Medical and Surgical Sciences and Translational Medicine, "La Sapienza" University of Rome, Rome, Italy
| | - Martina Rekatsina
- 1st Department of Anesthesiology and Pain Medicine, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
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Li C, Liu X, Hu C, Yan J, Qu Y, Li H, Zhou K, Li P. Genome-wide characterization of the TRP gene family and transcriptional expression profiles under different temperatures in gecko Hemiphyllodactylus yunnanensis. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101418. [PMID: 39809098 DOI: 10.1016/j.cbd.2025.101418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/07/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Temperature is closely linked to the life history of organisms, and thus thermoception is an important sensory mechanism. Transient receptor potential (TRP) ion channels are the key mediators of thermal sensation. In this study, we analyzed the sequence characteristics of TRPs in gecko Hemiphyllodactylus yunnanensis and compared the phylogenetic relationships of TRP family members among different Squamata species. In addition, we sequenced the transcriptome of skin and brain tissues of H. yunnanensis exposed to 12 °C (cold), 20 °C (cool), 28 °C (warm), and 36 °C (hot). The results showed that a total of 591 TRPs were identified in the genomes of 21 Squamate species, and these genes were classified into six subfamilies. Among them, 26 TRP genes were identified in H. yunnanensis and distributed on 13 chromosomes. Overall, TRP genes were conserved in squamates. Based on the transcriptome results, we found a total of 9 TRP genes expressed in the brain and skin of H. yunnanensis, of which six TRP genes were under positive selection. TRPP1L2, TRPP1L3, and TRPV1 were involved in heat-sensitive responses (> 36 °C), and TRPV3, TRPA1, and TRPM8 were involved in cold-sensitive responses (< 20 °C). TRPM8 and TRPP1L2 were important cold and heat sensors in H. yunnanensis, respectively.
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Affiliation(s)
- Chao Li
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Xiaoying Liu
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Chaochao Hu
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Jie Yan
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Yanfu Qu
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Hong Li
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Kaiya Zhou
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Peng Li
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China.
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Hou Y, Yang Y, Zhao Z, Wang S, Chen X, Xie Y, Chen H, Xu J. Capsazepine Inhibits Astrocyte Activation and Attenuates Neuroinflammation by Targeting Syntaxin 7. FASEB J 2025; 39:e70657. [PMID: 40386937 DOI: 10.1096/fj.202500523r] [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: 02/25/2025] [Revised: 04/22/2025] [Accepted: 05/09/2025] [Indexed: 05/20/2025]
Abstract
Astrocytic neuroinflammation contributes as a key player in neurodegenerative diseases. Capsazepine is a frequently used transient receptor potential vanilloid 1 (TRPV1) inhibitor; however, its effects, as well as the target, on inflammation remain controversial. This study examines the anti-inflammatory actions of capsazepine and explores mechanisms beyond TRPV1 inhibition. By assessing astrocytic inflammation in vitro and in vivo experiments, capsazepine was found to inhibit astrocyte activation and attenuate neuroinflammation, with reduced levels of interleukin-6 and complement 3. When utilizing TRPV1 deficient models, no significant decrease was observed in the anti-inflammatory effects of capsazepine, suggesting there could be alternative targets in addition to TRPV1. Further investigations used drug affinity responsive target stability analysis, siRNA knockdown, cellular thermal shift assay, and molecular docking to hunt for new targets. Syntaxin 7, a modulator in cytokine trafficking and phagosome maturation, was identified as a crucial target to interact with capsazepine in the inhibition of astrocytic inflammation. This study verifies the anti-inflammatory effects of capsazepine and identifies Syntaxin 7 as a potential novel therapeutic target for treating neuroinflammation.
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Affiliation(s)
- Yifei Hou
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuzhang Yang
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenzhen Zhao
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Sichen Wang
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xixiang Chen
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanyuan Xie
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongzhuan Chen
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianrong Xu
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Future Health Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Qin L, Zhang X, Li J. Mechanism of heat treatment on exercise pressor reflex in hindlimb ischemia-reperfusion: Does the temperature gradient matter? Auton Neurosci 2025; 259:103290. [PMID: 40382937 DOI: 10.1016/j.autneu.2025.103290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/11/2025] [Accepted: 05/09/2025] [Indexed: 05/20/2025]
Abstract
PURPOSE To examine the effect of heat treatment (HT) with two temperature gradients in skeletal muscle: 1.5 and 3 °C, on the exercise pressor reflex (EPR) responses following limb ischemia-reperfusion (IR). Specifically, the involvement role of the P2Xs (receptors of ATP) pathway in the muscle afferent neurons was accessed. METHODS An experimental IR model was induced by 6 h of ischemia followed by 18 h of reperfusion in rats (IR rats). For HT groups, three HT sessions (muscle temperature increased by 1.5 or 3 °C) lasted for 30 mins each were applied. EPR responses were evoked by static muscle contraction (30s). Protein expression of P2X3 receptor in dorsal root ganglions (DRGs) was evaluated by western blot. In addition, a calcium imaging study was applied to detect calcium influx induced by activation of P2X3 in the isolated muscle DRG neurons of studied animal groups. Data are presented as mean ± standard deviation (M ± SD). RESULTS The mean arterial pressure (MAP) response to the static muscle contraction was significantly exaggerated in rats of IR 18 h (vs. sham, p < 0.01). The exaggerated BP response was attenuated with increasing Tm by 1.5 and 3 °C (vs. IR, p < 0.05). The expression of the P2X3 receptor was significantly enhanced in the DRGs of IR 18 h rats (vs. sham, p < 0.01). The upregulated P2X3 was suppressed in the DRGs of IR 18 h rats +HT of 1.5 °C and 3 °C (vs. IR, p < 0.05). In the isolated muscle afferent neurons, the Ca2+ entry induced by extracellular application of α,β-Me-ATP (30 μM) were significantly increased in IR rats (vs. sham, p < 0.001). Both HT protocols suppressed the enhanced IR-induced Ca2+ entry (vs. IR, p < 0.001). There was no difference between the BP responses in HT1.5 °C and 3 °C groups, nor P2X3 expression in muscle afferent DRG, P2X-mediated Ca2+ entry in isolated muscle afferent neurons (all p > 0.05). CONCLUSION IR injury leads to upregulation of EPR responses, and HT attenuates this effect. The P2X3 signaling pathway was involved in the beneficial regulatory effect of HT on EPR in IR. The temperature gradient did not play a role in the extent of BP and muscle afferent P2X pathway activity attenuation in the present study.
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Affiliation(s)
- Lu Qin
- Heart and Vascular Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
| | - Xuexin Zhang
- Heart and Vascular Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Jianhua Li
- Heart and Vascular Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Li Y, Li C, Zhu H, Chu Y. TRPV1 in Dorsal Root Ganglion Contributed to Chronic Pancreatitis Pain. J Pain Palliat Care Pharmacother 2025:1-9. [PMID: 40371900 DOI: 10.1080/15360288.2025.2500984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 02/24/2025] [Accepted: 04/27/2025] [Indexed: 05/16/2025]
Abstract
Chronic pancreatitis presents a formidable challenge in pain management, often leading to significant suffering and reduced quality of life for affected individuals. The intricate interplay of factors contributing to this pain, including inflammation and neural sensitization, has garnered increasing attention in recent research. Among the key players in this scenario are the transient receptor potential vanilloid 1(TRPV1) channels located in dorsal root ganglion (DRG) neurons. These channels, known for their role in pain perception, exhibit heightened sensitivity and altered expression patterns in the context of chronic pancreatitis. Sensitization of TRPV1 channels amplifies their response to various pain triggers, exacerbating the perception of discomfort. Furthermore, dysregulated expression of TRPV1 within DRG neurons contributes to the chronic pain phenotype associated with pancreatitis. Understanding the nuanced mechanisms governing TRPV1 modulation in DRG neurons promises to unlock novel therapeutic avenues for managing chronic pancreatitis pain. By targeting TRPV1 channels specifically in DRG neurons, researchers aim to develop treatments that alleviate pain while minimizing adverse effects, ultimately offering hope for improved outcomes and enhanced well-being for individuals grappling with this debilitating condition.
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Affiliation(s)
- Yali Li
- Department of Intensive Care Unit, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Chenshuai Li
- Department of Pediatrics, Tianjin Beichen Hospital of Traditional Chinese Medicine, Tianjin, China
| | - Haiyun Zhu
- Department of Intensive Care Unit, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Yuru Chu
- Department of Intensive Care Unit, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
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Lansky S, Wang Z, Clarke OB, Chipot C, Scheuring S. Structural dynamics and permeability of the TRPV3 pentamer. Nat Commun 2025; 16:4520. [PMID: 40374654 PMCID: PMC12081643 DOI: 10.1038/s41467-025-59798-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 05/03/2025] [Indexed: 05/17/2025] Open
Abstract
TRPV3 belongs to the large superfamily of tetrameric transient receptor potential (TRP) ion channels. Recently, using high-speed atomic force microscopy (HS-AFM), we discovered a rare and transient pentameric state for TRPV3 that is in equilibrium with the tetrameric state, and, using cryo-EM, we solved a low-resolution structure of the TRPV3 pentamer, in which, however, many residues were unresolved. Here, we present a higher resolution and more complete structure of the pentamer, revealing a domain-swapped architecture, a collapsed vanilloid binding site, and a large pore. Molecular dynamics simulations and potential of mean force calculations of the pentamer establish high protein dynamics and permeability to large cations. Subunit interface analysis, together with thermal denaturation experiments, led us to propose a molecular mechanism of the tetramer-to-pentamer transition, backed experimentally by HS-AFM observations. Collectively, our data demonstrate that the TRPV3 pentamer is in a hyper-activated state with unique, highly permissive permeation properties.
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Affiliation(s)
- Shifra Lansky
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Zhaokun Wang
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA
| | - Oliver B Clarke
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA
| | - Christophe Chipot
- Laboratoire International Associé CNRS and University of Illinois at Urbana-Champaign, Université de Lorraine, Vandœuvre-lès-Nancy, France
- Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA
| | - Simon Scheuring
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
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Zhu Z, Zhu J, Gu S, Wang A, Chen P, Cao J, Li Y. Terahertz waves facilitate capsaicin expulsion from TRPV1. J Chem Phys 2025; 162:184301. [PMID: 40337933 DOI: 10.1063/5.0263609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Transient receptor potential vanilloid 1 (TRPV1) is a critical non-selective cation channel involved in various biological and physiological processes, making it a promising drug target for treating multiple diseases. Capsaicin, a TRPV1 agonist, is widely used to relieve pain by desensitizing the TRPV1 with persistent stimulation. However, the initially intolerable burning sensation due to TRPV1 activation necessitates the use of antagonists to deactivate TRPV1 and mitigate discomfort, which yet causes thermoregulation disorders. In this study, molecular dynamics simulations reveal that frequency-specific terahertz (THz) waves can promote capsaicin unbinding from TRPV1, suggesting a spatiotemporally controlled approach for TRPV1 deactivation. The THz wave resonates with the hydroxyl group in the capsaicin head, increasing its rotational kinetic energy and promoting its rotation. This disrupts the key hydrogen bond between the hydroxyl group and TRPV1 residue E570, significantly reducing capsaicin's affinity for TRPV1. Our findings suggest that THz waves could mimic TRPV1 antagonists in a more flexible way, offering temporal control over capsaicin recruitment and expulsion (i.e., TRPV1 activation, desensitization, and deactivation) for more comfortable pain relief. In addition, this work enlightens a THz-based, pill-free strategy to control the pain induced by inflammatory ligands activated TRPV1.
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Affiliation(s)
- Zhi Zhu
- School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Junquan Zhu
- School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Shiyu Gu
- School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Anqi Wang
- Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing 100071, China
| | - Peng Chen
- Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing 100071, China
| | - Jihua Cao
- The First College of Clinical Medical Science, China Three Gorges University, Yichang 443002, China
- Yichang Central People's Hospital, Yichang 443008, China
| | - Yangmei Li
- Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing 100071, China
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Qin Y, Fang S, Zhao Y, Liu H, Wang G, Lu W. Born with Silurian global warming: Defensive role of TRPV1 in caudal neurosecretory system (CNSS) in flounder. Int J Biol Macromol 2025; 312:144092. [PMID: 40350111 DOI: 10.1016/j.ijbiomac.2025.144092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/29/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
The caudal neurosecretory system (CNSS), unique to fish, emerged during the Silurian global warming period and appears to have an inevitable connection with "heat." Although TRPV1 is known to be a key molecule mediating high-temperature perception in fish, its role in CNSS remains unknown. Here, we found that TRPV1 located on Dahlgren cells in CNSS, is involved in sensing high-temperatures and helps flounder to respond correctly. Specifically, in the context of mild high-temperatures, Dahlgren cells expressing Urotensin I (UI) are the main active cell subpopulation. TRPV1 promotes the activation of the UI cell subpopulation by activating excitatory receptors, which in turn facilitates freezing behavior in flounder. When the accumulated temperature in the abdomen reaches avoidance high-temperatures, the firing activity of the UI cell subpopulation is inhibited, which is related to the TRPV1-mediated activation of NR3A. Accordingly, a subpopulation of Urotensin II (UII) cells was activated. Meanwhile, the expression of genes related to dopamine receptors and acetylcholine synthesis are significantly elevated, thereby mediating the avoidance behavior of flounder to escape from injury. Overall, these studies collectively elucidate the complex adaptive mechanisms employed by flounder in response to high-temperature fluctuations, with a special emphasis on the importance of CNSS temperature sensing.
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Affiliation(s)
- Yeyang Qin
- National Demonstration Center for Experimental Fisheries Science Education (Shanghai Ocean University), Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China
| | - Shilin Fang
- National Demonstration Center for Experimental Fisheries Science Education (Shanghai Ocean University), Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China
| | - Yinjie Zhao
- National Demonstration Center for Experimental Fisheries Science Education (Shanghai Ocean University), Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China
| | - Hao Liu
- National Demonstration Center for Experimental Fisheries Science Education (Shanghai Ocean University), Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China
| | - Guixing Wang
- The Experimental Station of Beidaihe Center, Chinese Academy of Fishery Sciences, Beidaihe, China
| | - Weiqun Lu
- National Demonstration Center for Experimental Fisheries Science Education (Shanghai Ocean University), Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China.
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Bunnell AA, Marshall EM, Estes SK, Deadmond MC, Loesgen S, Strother JA. Embryonic Zebrafish Irritant-evoked Hyperlocomotion (EZIH) as a high-throughput behavioral model for nociception. Behav Brain Res 2025; 485:115526. [PMID: 40057202 DOI: 10.1016/j.bbr.2025.115526] [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: 11/01/2024] [Revised: 02/25/2025] [Accepted: 03/03/2025] [Indexed: 03/16/2025]
Abstract
Behavioral models have served a key role in understanding nociception, the sensory system by which animals detect noxious stimuli in their environment. Developing zebrafish (Danio rerio) are a powerful study organism for examining nociceptive pathways, given the vast array of genetic, developmental, and neuroscience tools available for these animals. However, at present there are few widely-adopted behavioral models for nociception in developing zebrafish. This study examines the locomotor response of hatching-stage zebrafish embryos to dilute solutions of the noxious chemical and TRPA1 agonist allyl isothiocyanate (AITC). At this developmental stage, AITC exposure induces a robust uniphasic hyperlocomotion response. This behavior was thoroughly characterized by determining the effects of pre-treatment with an array of pharmacological agents, including anesthetics, TRPA1 agonists/antagonists, opioids, NSAIDs, benzodiazepines, SSRIs, and SNRIs. Anesthetics suppressed the response to AITC, pre-treatment with TRPA1 agonists induced hyperlocomotion and blunted the response to subsequent AITC exposures, and TRPA1 antagonists and the opioid buprenorphine tended to reduce the response to AITC. The behavioral responses of zebrafish embryos to a noxious chemical were minimally affected by the other pharmacological agents examined. The feasibility of using this behavioral model as a screening platform for drug discovery efforts was then evaluated by assaying a library of natural product mixtures from microbial extracts and fractions. Overall, our results indicate that irritant-evoked locomotion in embryonic zebrafish is a robust behavioral model for nociception with substantial potential for examining the molecular and cellular pathways associated with nociception and for drug discovery efforts.
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Affiliation(s)
- Amelia A Bunnell
- Whitney Laboratory for Marine Bioscience, University of Florida, Saint Augustine, FL, United States
| | - Erin M Marshall
- Whitney Laboratory for Marine Bioscience, University of Florida, Saint Augustine, FL, United States
| | | | - Monica C Deadmond
- Whitney Laboratory for Marine Bioscience, University of Florida, Saint Augustine, FL, United States
| | - Sandra Loesgen
- Whitney Laboratory for Marine Bioscience, University of Florida, Saint Augustine, FL, United States
| | - James A Strother
- Whitney Laboratory for Marine Bioscience, University of Florida, Saint Augustine, FL, United States; Oregon State University, Corvallis, OR, United States.
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12
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Wang J, Yu X, Zhao H, Xiong S, Guo H, Li Q. Specific and sensitive detection of capsaicin for edible oils authentication using fluorescent molecularly imprinted silica particles. Food Chem 2025; 486:144632. [PMID: 40345040 DOI: 10.1016/j.foodchem.2025.144632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/26/2025] [Accepted: 05/02/2025] [Indexed: 05/11/2025]
Abstract
In this study, we developed two fluorescent molecularly imprinted polymers (FMIPs) for sensitive detection of capsaicin to distinguish the recycled edible oils. Utilizing a catalyst-free molecular imprinting approach and N-vanillylnonanamide (capsaicin analog) as the template, two types of FMIPs were synthesized utilizing fluorescent monomers coupled with fluorescein isothiocyanate (FFMIP) and rhodamine B isothiocyanate (RFMIP). Both FFMIP and RFMIP showed high selectivity (imprinting factors of 2.9 and 10.6, respectively) and specificity (cross-reactivity factors ranging from of 2.4-3.8 and 1.9-16.4, respectively) to capsaicin, which were superior to their positive control polymers of FFMIP-N and RFMIP-N synthesized using an ammonia catalyst. The FMIP-based detection systems could quantitatively analyze spiked capsaicin in edible oil with detection limits of 22-38 nM and a detection time less than 10 min. Besides, these FMIPs are easy to be produced in mass and cost-effective, offering a powerful tool for rapid detection of capsaicin in food authentication.
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Affiliation(s)
- Jinjin Wang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China
| | - Xinping Yu
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China
| | - Haijuan Zhao
- Anyang Cigarette Factory, China Tobacco Henan Industrial Co., Ltd., Anyang 455000, Henan, China
| | - Shuqing Xiong
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China
| | - Hua Guo
- Institute of Public Health Surveillance and Evaluation, Guizhou Center for Disease Control and Prevention, Guiyang 550004, Guizhou, China.
| | - Qianjin Li
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China.
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13
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Smith JD, Stillerová VT, Dračinský M, Popr M, Angermeier Gaustad HL, Lorenzi Q, Smrčková H, Reinhardt JK, Liénard MA, Bednárová L, Šácha P, Pluskal T. Discovery and isolation of novel capsaicinoids and their TRPV1-related activity. Eur J Pharmacol 2025; 999:177700. [PMID: 40320114 DOI: 10.1016/j.ejphar.2025.177700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 04/30/2025] [Accepted: 04/30/2025] [Indexed: 05/14/2025]
Abstract
Chilis contain capsaicin and other structurally related molecules known as capsaicinoids. Capsaicin's target protein, the transient receptor potential cation channel subfamily V member 1 (TRPV1), has been linked to many post-activation effects, including changes in metabolism and pain sensation. Capsaicinoids also bind to TRPV1, but current studies often disregard non-capsaicin interactions. To fill in these gaps, we screened 40 different chili varieties derived from four Capsicum species by means of untargeted metabolomics and a rat TRPV1 (rTRPV1) calcium influx activation assay. The resulting capsaicinoid profiles were specific to each variety but only partially corresponded with species delimitations. Based on rTRPV1 activation elicited by crude chili extracts, capsaicinoids act in an additive manner and a capsaicinoid profile can serve as a gauge of this activation. In addition, we isolated eighteen capsaicinoids, including five previously unreported ones, and confirmed their structure by NMR and MS/MS. We then tested rTRPV1 activation by 23 capsaicinoids and three related compounds. This testing revealed that even slight deviations from the structure of capsaicin reduce the ability to activate the target, with a mere single hydroxylation on the acyl tail reducing potency towards rTRPV1 by more than 100-fold. In addition, we tested how rTRPV1 activity changes in the presence of capsaicin together with non-activating capsaicin analogs and weakly activating capsaicinoids and found both classes of molecules to positively modulate the effects of capsaicin. This demonstrates that even such compounds have measurable pharmacological effects, making a case for the use and study of natural chili extracts.
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Affiliation(s)
- Joshua David Smith
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia; First Faculty of Medicine Charles University, Prague, Czechia
| | | | - Martin Dračinský
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
| | - Martin Popr
- CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | | | - Quentin Lorenzi
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
| | - Helena Smrčková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
| | - Jakob K Reinhardt
- Department of Pharmaceutical Sciences, University of Basel, Switzerland; Chemistry & Chemical Biology of Northeastern University, Boston, USA
| | | | - Lucie Bednárová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
| | - Pavel Šácha
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
| | - Tomáš Pluskal
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia.
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14
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Kornfield JM, Bright H, Drake MG. Touching a Nerve: Neuroimmune Interactions in Asthma. Immunol Rev 2025; 331:e70025. [PMID: 40186378 DOI: 10.1111/imr.70025] [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: 11/16/2024] [Revised: 03/04/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025]
Abstract
Asthma is an inflammatory airway disease characterized by excessive bronchoconstriction and airway hyperresponsiveness. Airway nerves play a crucial role in regulating these processes. In asthma, interactions between inflammatory cells and nerves result in nerve dysfunction, which worsens airway function. This review discusses new insights regarding the role of airway nerves in healthy lungs and examines how communication between nerves and leukocytes, including eosinophils, mast cells, dendritic cells, and innate lymphoid cells, contributes to nerve dysfunction and the worsening of airway disease. Clinical implications and therapeutic opportunities presented by neuroimmune interactions are also addressed.
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Affiliation(s)
- James M Kornfield
- Division of Pulmonary, Allergy, and Critical Care, Oregon Health and Science University, Portland, Oregon, USA
| | - Hoyt Bright
- Division of Pulmonary, Allergy, and Critical Care, Oregon Health and Science University, Portland, Oregon, USA
| | - Matthew G Drake
- Division of Pulmonary, Allergy, and Critical Care, Oregon Health and Science University, Portland, Oregon, USA
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15
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Reddy P, Narayan Prajapati J, Chaterji S, Varughese A, Chaudhary Y, Sathyamurthy A, Barik A. Converging inputs compete at the lateral parabrachial nuclei to dictate the affective-motivational responses to cold pain. Pain 2025; 166:1105-1117. [PMID: 39715193 DOI: 10.1097/j.pain.0000000000003468] [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: 04/08/2024] [Accepted: 09/05/2024] [Indexed: 12/25/2024]
Abstract
ABSTRACT The neural mechanisms of the affective-motivational symptoms of chronic pain are poorly understood. In chronic pain, our innate coping mechanisms fail to provide relief. Hence, these behaviors are manifested at higher frequencies. In laboratory animals, such as mice and rats, licking the affected areas is a behavioral coping mechanism and it is sensitized in chronic pain. Hence, we have focused on delineating the brain circuits mediating licking in mice with chemotherapy-induced peripheral neuropathy (CIPN). Mice with CIPN develop intense cold hypersensitivity and lick their paws upon contact with cold stimuli. We studied how the lateral parabrachial nucleus (LPBN) neurons facilitate licking behavior when mice are exposed to noxious thermal stimuli. Taking advantage of transsynaptic viral, optogenetic, and chemogenetic strategies, we observed that the LPBN neurons become hypersensitive to cold in mice with CIPN and facilitate licks. Furthermore, we found that the expression of licks depends on competing excitatory and inhibitory inputs from the spinal cord and lateral hypothalamus (LHA), respectively. We anatomically traced the postsynaptic targets of the spinal cord and LHA in the LPBN and found that they synapse onto overlapping populations. Activation of this LPBN population was sufficient to promote licking due to cold allodynia. In sum, our data indicate that the nociceptive inputs from the spinal cord and information on brain states from the hypothalamus impinge on overlapping LPBN populations to modulate their activity and, in turn, regulate the elevated affective-motivational responses in CIPN.
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Affiliation(s)
- Prannay Reddy
- Center for Neuroscience, Indian Institute of Science, Bengaluru, Karnataka, India
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16
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Devesa I, Fernández-Ballester G, Fernandez-Carvajal A, Ferrer-Montiel A. A review of the patent literature surrounding TRPV1 modulators. Expert Opin Ther Pat 2025; 35:477-491. [PMID: 39952645 DOI: 10.1080/13543776.2025.2467698] [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: 09/09/2024] [Revised: 12/25/2024] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
INTRODUCTION TRPV1, a pivotal therapeutic target for chronic pain and pruritus, has been validated in the pathogenesis of several pathologies from diabetes to cancer. Despite the constellation of chemical structures and strategies, none of these molecules has yet been clinically developed as a new drug application due to safety concerns, particularly in thermoregulation. Thus, clinical development of TRPV1 modulators remains a challenge. AREAS COVERED This review covers the patent literature on TRPV1 modulators (2019-2024, PubMed, Google Patents, and Espacenet), from orthosteric ligands to innovative compounds of biotechnological origin such as interfering RNAs or antibodies, and dual modulators that can act on TRPV1 and associated proteins in different tissues. EXPERT OPINION Therapeutic strategies that preferentially act on dysfunctional TRPV1 channels appear essential, along with a superior understanding of the underlying mechanisms affecting changes in core body temperature (CBT). Recent findings describing differential receptor interactions of antagonists that do not affect CBT may pave the way to the next generation of orally active TRPV1 inhibitors. Although we have thus far experienced a bitter feeling in TRPV1 drug development, the recent progress in different disciplines, including human-based preclinical models, will set an interdisciplinary approach to design and develop clinically relevant TRPV1 modulators.
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Affiliation(s)
- Isabel Devesa
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche, Universidad Miguel Hernández, Elche, Spain
| | - Gregorio Fernández-Ballester
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche, Universidad Miguel Hernández, Elche, Spain
| | - Asia Fernandez-Carvajal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche, Universidad Miguel Hernández, Elche, Spain
| | - Antonio Ferrer-Montiel
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche, Universidad Miguel Hernández, Elche, Spain
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17
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Roos S, Dahlgren A, Mao Y, Pallin A, Stanisz AM, Forsythe P, Kunze W, Hellström PM. Therapeutic Value of Lactobacillus gasseri 345A in Chronic Constipation. Neurogastroenterol Motil 2025; 37:e70012. [PMID: 40033155 PMCID: PMC11996050 DOI: 10.1111/nmo.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 12/16/2024] [Accepted: 02/08/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Chronic constipation is a prevalent, burdensome gastrointestinal disorder whose etiology and pathophysiology remain poorly understood. Differences in the composition of the intestinal microbiota have been shown between constipated patients and healthy people. Data indicate that these microbial differences contribute to the disorder. METHODS Preclinical studies in mice examined the effects of Lactobacillus gasseri on intestinal motility ex vivo, the reversal of motility inhibition by μ-opioid receptor agonists ex vivo and in vivo in mice, and the effects on capsaicin-stimulated transient receptor potential vanilloid 1 (TRPV1) in Jurkat cells. Thereafter, a clinical study of 40 women with functional constipation was conducted to investigate the effects of Lactobacillus gasseri with a randomized parallel design. After 14 days of baseline recording, treatment with Lactobacillus gasseri or placebo was given over 28 days, with 14 days of follow-up. Outcomes with complete spontaneous bowel movements (CSBM), spontaneous bowel movements, emptying frequency, abdominal pain, time spent for defecation, Bristol stool form scale, use of rescue laxatives, and impact on sex life were investigated. KEY RESULTS In preclinical studies, Lactobacillus gasseri increased intestinal motility in an ex vivo model, reversed the motility inhibition caused by μ-opioid receptor agonist ex vivo and in vivo in mice, and counteracted capsaicin-stimulated activity of TRPV1 in Jurkat cells. In the clinical trial, Lactobacillus gasseri showed a significant reduction in abdominal pain, along with a correlation and tendency for an increased number of CSBM. Few adverse events were encountered. CONCLUSIONS AND INFERENCES Treatment with Lactobacillus gasseri can alleviate pain sensations in functional constipation, possibly with an improved bowel-emptying function.
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Affiliation(s)
- Stefan Roos
- Department of Molecular Sciences, Uppsala BioCenterSwedish University of Agricultural SciencesUppsalaSweden
- BioGaia ABStockholmSweden
| | | | - Yu‐Kang Mao
- Brain‐Body InstituteMcMaster UniversityHamiltonOntarioCanada
| | - Anton Pallin
- Department of Molecular Sciences, Uppsala BioCenterSwedish University of Agricultural SciencesUppsalaSweden
| | | | - Paul Forsythe
- Brain‐Body InstituteMcMaster UniversityHamiltonOntarioCanada
| | - Wolfgang Kunze
- Brain‐Body InstituteMcMaster UniversityHamiltonOntarioCanada
- Department of PsychiatryMcMaster UniversityHamiltonOntarioCanada
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18
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Brice-Tutt AC, Murphy NP, Setlow B, Senetra AS, Malphurs W, Caudle RM, Bruijnzeel AW, Febo M, Sharma A, Neubert JK. Cannabidiol interactions with oxycodone analgesia in an operant orofacial cutaneous thermal pain assay following oral administration in rats. Pharmacol Biochem Behav 2025; 250:173968. [PMID: 39914591 DOI: 10.1016/j.pbb.2025.173968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/29/2025] [Accepted: 02/03/2025] [Indexed: 03/08/2025]
Abstract
Previous studies have driven the notion that the cannabis constituent cannabidiol could be an effective adjunct to opioid administration for managing pain. Most of these studies have used experimental rodents with routes of administration, such as subcutaneous and intraperitoneal, that do not correspond with the routes used in clinical practice. In response to this, we tested the ability of cannabidiol co-administration to augment opioid analgesia via the more clinically-relevant oral route of administration. To this end, male and female rats were orally gavaged with cannabidiol (25 mg/kg), oxycodone (1.4 mg/kg), or a combination of both, after which they were tested in an operant thermal orofacial pain assay in which they voluntarily exposed their faces to cutaneous thermal pain to receive a palatable reward. All three drug conditions produced analgesic effects of varying degrees, being most profound in the combination group where a statistically significant enhancement over oxycodone-induced analgesia alone was evident. Additionally, oxycodone administration decreased lick frequencies - a measure of motor coordination of rhythmic movements - which too was magnified by co-administration of cannabidiol. Together these studies provide further support of an ability of cannabidiol to augment opioid effects, particularly analgesia, when administered by a route relevant to human pain management. As such, they encourage the notion that cannabidiol could find utility as an opioid-sparing approach to treating pain.
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Affiliation(s)
- Ariana C Brice-Tutt
- Department of Orthodontics, College of Dentistry, University of Florida, United States of America
| | - Niall P Murphy
- Department of Orthodontics, College of Dentistry, University of Florida, United States of America.
| | - Barry Setlow
- Department of Psychiatry, College of Medicine, University of Florida, United States of America; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, United States of America
| | - Alexandria S Senetra
- Department of Pharmaceutics, College of Pharmacy, University of Florida, United States of America
| | - Wendi Malphurs
- Department of Orthodontics, College of Dentistry, University of Florida, United States of America
| | - Robert M Caudle
- Department of Oral and Maxillofacial Surgery, College of Dentistry, University of Florida, United States of America; Department of Neuroscience, College of Medicine, University of Florida, United States of America
| | - Adriaan W Bruijnzeel
- Department of Neuroscience, College of Medicine, University of Florida, United States of America; Department of Psychiatry, College of Medicine, University of Florida, United States of America; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, United States of America
| | - Marcelo Febo
- Department of Neuroscience, College of Medicine, University of Florida, United States of America; Department of Psychiatry, College of Medicine, University of Florida, United States of America; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, United States of America
| | - Abhisheak Sharma
- Department of Pharmaceutics, College of Pharmacy, University of Florida, United States of America
| | - John K Neubert
- Department of Orthodontics, College of Dentistry, University of Florida, United States of America; Department of Neuroscience, College of Medicine, University of Florida, United States of America; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, United States of America
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19
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Varvel NH. Inflammation Emerges as a Sensitizer of a Heat-Responsive Cation Channel. Epilepsy Curr 2025:15357597251334101. [PMID: 40322487 PMCID: PMC12043651 DOI: 10.1177/15357597251334101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025] Open
Abstract
The Impact of Inflammation on Thermal Hyperpnea: Relevance for Heat Stress and Febrile Seizures . Barrett KT, Roy A, Ebdalla A, Pittman QJ, Wilson RJA, Scantlebury MH. Am J Respir Cell Mol Biol. 2024 Aug;71(2):195–206. doi: 10.1165/rcmb.2023-0451OC. PMID: 38597725; PMCID: PMC11299082. Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, in vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern too fast shallow breaths (tachypnea), making each breathless efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.
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Affiliation(s)
- Nicholas H Varvel
- Department of Pharmacology and Chemical Biology, Emory School of Medicine, Atlanta, GA, USA
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20
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Andrade ACM, Molina Esquivel N, Goldschmied Rossel F, Benso B. TRPV1-target drugs for the treatment of orofacial pain. Front Pharmacol 2025; 16:1568109. [PMID: 40343000 PMCID: PMC12058838 DOI: 10.3389/fphar.2025.1568109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 04/01/2025] [Indexed: 05/11/2025] Open
Abstract
Orofacial pain, encompassing sensory and emotional discomfort in the facial and oral regions, is a multifaceted condition that significantly impacts patients' quality of life. This review focuses on the role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in modulating orofacial pain and new ligands targeting this receptor. TRPV1 channels act as key mediators of nociception, responding to stimuli such as temperature, pH changes, and capsaicin molecules. Recent advancements in TRPV1-targeted therapeutics, including natural, synthetic, and protein-based molecules, offer promising strategies for pain management. This review analyzed studies related to TRPV1-mediated pain inhibition, including seven clinical trials and preclinical investigations. The compounds studied in these works demonstrated pain relief, although adverse effects were reported. TRPV1-targeted molecules represent a novel avenue for developing innovative pharmacological interventions, addressing the limitations of current therapies, and improving patient outcomes in managing orofacial pain.
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Affiliation(s)
| | | | | | - Bruna Benso
- School of Dentistry, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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21
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Su H, Dai Q, Teng F, Li Z, Qi Y, Lu Y. Expression profiles analysis and roles in immunity of transient receptor potential (TRP) channel genes in Spodoptera frugiperda. BMC Genomics 2025; 26:401. [PMID: 40275159 PMCID: PMC12023399 DOI: 10.1186/s12864-025-11599-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Transient receptor potential (TRP) ion channels play crucial roles in mediating responses to environmental stimuli, as well as regulating homeostasis and developmental processes in insects. Several members of the TRP superfamily are potential molecular targets for insecticides or repellents, indicating their research value in pest control. This study focuses on Spodoptera frugiperda, an important invasive pest in China known for its wide host range and strong reproductive capacity. Currently, there is a lack of molecular research on the TRP channels of the invasive pest S. frugiperda. RESULTS In this study, we identified 15 TRP family genes in S. frugiperda, which were classified into six subfamilies. The TRPP subfamily gene was not identified, whereas the TRPA subfamily contained the highest number of members in this insect. Real-time quantitative polymerase chain reaction (RT-qPCR) experiments revealed widespread expression of TRP channel genes across various developmental stages of S. frugiperda. However, TRPM and TRPML were highly expressed only in eggs. Transcripts of TRP channel genes were detected in the sensory organs of mature adults, including the mouthparts, antennae, compound eyes, legs, wings, harpagones, and ovipositors, as well as in tissues of 5th instar larvae (hemocytes, central nervous system, midgut, fat body, and Malpighian tubules). To explore the potential role of TRP channels in immunity, we detected their levels in larvae 24 h after infection with Serratia marcescens. The expression levels of TRPML, TRPL, and the Pain genes were significantly up-regulated, suggesting their important roles in immune responses to S. marcescens. CONCLUSIONS The results of this study extend our knowledge of these critical sensory channels in S. frugiperda. This knowledge provides a basis for the future development of insecticides that target these channels, thereby promoting the safe and effective control of this key pest.
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Affiliation(s)
- Hongai Su
- Department of Entomology, College of Plant Protection, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, 510642, China
| | - Qianxuan Dai
- Department of Entomology, College of Plant Protection, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, 510642, China
| | - Feiyue Teng
- Department of Entomology, College of Plant Protection, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, 510642, China
| | - Ziyuan Li
- Department of Entomology, College of Plant Protection, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, 510642, China
| | - Yixiang Qi
- Department of Entomology, College of Plant Protection, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, 510642, China.
| | - Yongyue Lu
- Department of Entomology, College of Plant Protection, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, 510642, China.
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22
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Ghitani N, von Buchholtz LJ, MacDonald DI, Falgairolle M, Nguyen MQ, Licholai JA, Ryba NJP, Chesler AT. A distributed coding logic for thermosensation and inflammatory pain. Nature 2025:10.1038/s41586-025-08875-6. [PMID: 40269164 DOI: 10.1038/s41586-025-08875-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 03/06/2025] [Indexed: 04/25/2025]
Abstract
Somatosensory neurons encode detailed information about touch and temperature and are the peripheral drivers of pain1,2. Here by combining functional imaging with multiplexed in situ hybridization3, we determined how heat and mechanical stimuli are encoded across neuronal classes and how inflammation transforms this representation to induce heat hypersensitivity, mechanical allodynia and continuing pain. Our data revealed that trigeminal neurons innervating the cheek exhibited complete segregation of responses to gentle touch and heat. By contrast, heat and noxious mechanical stimuli broadly activated nociceptor classes, including cell types proposed to trigger select percepts and behaviours4-6. Injection of the inflammatory mediator prostaglandin E2 caused long-lasting activity and thermal sensitization in select classes of nociceptors, providing a cellular basis for continuing inflammatory pain and heat hypersensitivity. We showed that the capsaicin receptor TRPV1 (ref. 7) has a central role in heat sensitization but not in spontaneous nociceptor activity. Unexpectedly, the responses to mechanical stimuli were minimally affected by inflammation, suggesting that tactile allodynia results from the continuing firing of nociceptors coincident with touch. Indeed, we have demonstrated that nociceptor activity is both necessary and sufficient for inflammatory tactile allodynia. Together, these findings refine models of sensory coding and discrimination at the cellular and molecular levels, demonstrate that touch and temperature are broadly but differentially encoded across transcriptomically distinct populations of sensory cells and provide insight into how cellular-level responses are reshaped by inflammation to trigger diverse aspects of pain.
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Affiliation(s)
- Nima Ghitani
- National Center for Complementary and Integrative Health, Bethesda, MD, USA
| | | | | | | | - Minh Q Nguyen
- National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
| | - Julia A Licholai
- National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
| | - Nicholas J P Ryba
- National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
| | - Alexander T Chesler
- National Center for Complementary and Integrative Health, Bethesda, MD, USA.
- National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
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Bhattacharyya A, Vasconcelos D, Spicarova D, Palecek J. 20:4-NAPE induced changes of mechanical sensitivity and DRG neurons excitability are concentration dependent and mediated via NAPE-PLD. Sci Rep 2025; 15:14131. [PMID: 40269193 PMCID: PMC12019079 DOI: 10.1038/s41598-025-98567-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/14/2025] [Indexed: 04/25/2025] Open
Abstract
Alterations in the excitability of dorsal root ganglion (DRG) neurons are critical in the pathogenesis of acute and chronic pain. Neurotransmitter release from the terminals of DRG neurons is regulated by cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both activated by anandamide (AEA). In our experiments, the AEA precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE) was used to study the modulation of nociceptive DRG neurons excitability using K+-evoked Ca2+ transients. Intrathecal administration was used to evaluate in vivo effects. Application of 20:4-NAPE at lower concentrations (10 nM - 1 µM) decreased the excitability of DRG neurons, whereas the higher (10 µM) increased it. Both effects of 20:4-NAPE were blocked by the N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. Similarly, lower concentrations of externally applied AEA (1 nM - 10 nM) inhibited DRG neurons, whereas higher concentration (100 nM) did not change it. High AEA concentration (10 µM) evoked Ca2+ transients dependent on TRPV1 activation in separate experiments. Inhibition of the CB1 receptor by PF514273 (400 nM) prevented the 20:4-NAPE- and AEA-induced inhibition, whereas TRPV1 inhibition by SB366791 (1 µM) prevented the increased DRG neuron excitability. In behavioral tests, lower 20:4-NAPE concentration caused hyposensitivity, while higher evoked mechanical allodynia. Intrathecal LEI-401 prevented both in vivo effects of 20:4-NAPE. These results highlight anti- and pro-nociceptive effects of 20:4-NAPE mediated by CB1 and TRPV1 in concentration-dependent manner. Our study underscores the complexity of endocannabinoid signaling in pain transmission modulation and highlights 20:4-NAPE as a potential therapeutic target, offering new insights for developing analgesic strategies.
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Affiliation(s)
- Anirban Bhattacharyya
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Daniel Vasconcelos
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Diana Spicarova
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jiri Palecek
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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24
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Lacroix E, Momchilova EA, Chandhok S, Padavu M, Zapf R, Audas TE. PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc. Cell Rep 2025; 44:115617. [PMID: 40272983 DOI: 10.1016/j.celrep.2025.115617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/17/2025] [Accepted: 04/04/2025] [Indexed: 04/26/2025] Open
Abstract
In response to environmental stress, eukaryotic cells reversibly form functional amyloid aggregates called amyloid bodies (A-bodies). While these solid-like biomolecular condensates share many biophysical characteristics with pathological amyloids, A-bodies are non-toxic, and they induce a protective state of cellular dormancy. As a recently identified structure, the modulators of A-body biogenesis remain uncharacterized, with the seeding noncoding RNA being the only known regulatory factor. Here, we use an image-based high-throughput screening approach to identify candidate pathways regulating A-body biogenesis. Our data demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling axis meditates A-body formation during stress exposure, with AKT activation repressing glycogen synthase kinase-3 (GSK3)-mediated degradation of c-Myc. This enhances c-Myc binding to regulatory elements of the seeding noncoding RNA, upregulating the transcripts that nucleate A-body formation. Identifying a link between PI3K/AKT signaling, c-Myc, and physiological amyloid aggregates extends the range of activity for these well-established regulators while providing insight into cellular components whose dysregulation could underly amyloidogenic disorders.
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Affiliation(s)
- Emma Lacroix
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Evgenia A Momchilova
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Sahil Chandhok
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Mythili Padavu
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Richard Zapf
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Timothy E Audas
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.
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25
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Kulkarni K, Walton RD, Chaigne S. Unlocking the potential of cardiac TRP channels using knockout mice models. Front Physiol 2025; 16:1585356. [PMID: 40313873 PMCID: PMC12043714 DOI: 10.3389/fphys.2025.1585356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 04/07/2025] [Indexed: 05/03/2025] Open
Affiliation(s)
- Kanchan Kulkarni
- IHU Liryc, INSERM, U1045, CRCTB, University Bordeaux, Bordeaux, France
| | - Richard D. Walton
- IHU Liryc, INSERM, U1045, CRCTB, University Bordeaux, Bordeaux, France
| | - Sebastien Chaigne
- IHU Liryc, INSERM, U1045, CRCTB, University Bordeaux, Bordeaux, France
- CHU de Bordeaux, Cardiology, INSERM, U1045, CRCTB, Bordeaux, France
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26
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Hole C, Dhamsania A, Brown C, Ryznar R. Immune Dysregulation in Depression and Anxiety: A Review of the Immune Response in Disease and Treatment. Cells 2025; 14:607. [PMID: 40277932 PMCID: PMC12025721 DOI: 10.3390/cells14080607] [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: 03/25/2025] [Revised: 04/13/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025] Open
Abstract
Rates of depression and anxiety have increased significantly in recent decades, with many patients experiencing treatment-resistant symptoms. Beyond psychiatric manifestations, these conditions are associated with heightened risks of suicide, cardiovascular disease, chronic pain, and fatigue. Emerging research suggests that neuroinflammation, immune dysregulation, and hypothalamic-pituitary-adrenal axis dysfunction contribute to their pathophysiology, often interacting bidirectionally with stress. While current first-line treatments primarily target neurotransmitter imbalances, many patients do not achieve symptom resolution, highlighting the need for novel approaches. This review explores the role of immune dysfunction, cytokine activity, and neurotransmitter interactions in depression and anxiety. Additionally, we examine how existing pharmacological and non-pharmacological interventions influence inflammation and immune responses. Understanding these mechanisms may pave the way for more integrative treatment strategies that combine immune modulation with traditional psychiatric therapies.
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Affiliation(s)
- Christopher Hole
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (C.H.); (A.D.); (R.R.)
| | - Akash Dhamsania
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (C.H.); (A.D.); (R.R.)
| | - Cassandra Brown
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (C.H.); (A.D.); (R.R.)
| | - Rebecca Ryznar
- College of Osteopathic Medicine, Rocky Vista University, Englewood, CO 80112, USA; (C.H.); (A.D.); (R.R.)
- Department of Biomedical Sciences, Rocky Vista University, Englewood, CO 80112, USA
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27
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Wang G. Pathway-dependent cold activation of heat-responsive TRPV channels. RESEARCH SQUARE 2025:rs.3.rs-6450204. [PMID: 40321781 PMCID: PMC12047967 DOI: 10.21203/rs.3.rs-6450204/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
The homotetrameric thermosensitive transient receptor potential vanilloid 1-4 (TRPV1-4) channels in sensory neurons are highly responsive to heat stimuli. However, their primary heat sensors or triggers for heat activation have not been examined for cold activation. In this study, cold activation of minimal TRPV1 without the pore turret was compared with that of full-length human TRPV3. The former followed a pathway from the putative heat activation starter, while the latter tracked a different pathway starting far from the assumed heat activation point. The results showed that the former shared temperature sensitivity with heat activation while the latter did not. Therefore, this mirrored thermosensitivity can be used to confirm the location of the primary thermal sensor for TRPV1 or TRPV3, and potentially define the primary thermal sensor of other thermosensitive proteins like TRPV2 or TRPV4 once the same heat capacity mechanism is applied.
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Affiliation(s)
- Guangyu Wang
- Department of Physiology and Membrane Biology, University of California School of Medicine, Davis, CA, USA
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28
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Pantke S, Steinberg JH, Weber LKH, Fricke TC, Carvalheira Arnaut Pombeiro Stein I, Oprita G, Herzog C, Leffler A. High Concentrations of the Antidepressant Amitriptyline Activate and Desensitize the Capsaicin Receptor TRPV1. Pharmaceuticals (Basel) 2025; 18:560. [PMID: 40283995 PMCID: PMC12030456 DOI: 10.3390/ph18040560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Background: A large number of patients suffer from neuropathic pain, and systemic therapy often remains ineffective while inducing severe side effects. Topical therapy with the TRPV1-agonist capsaicin is an established alternative, and the identification of co-therapeutics that modulate TRPV1 may be a promising approach to reduce the dose of capsaicin while maintaining efficacy. Here, we aimed to determine if the antidepressant amitriptyline displays properties rendering it a potential co-therapeutic agent. Methods: We performed patch clamp and calcium imaging experiments on HEK293T cells expressing human (h) TRPV1 as well as on dorsal root ganglion (DRG) neurons from adult mice. Results: Amitriptyline induced an increase in intracellular calcium in both HEK293T and mouse DRG neurons expressing TRPV1. Patch clamp experiments revealed a concentration-dependent activation of hTRPV1 by amitriptyline that was also evident in cell-free inside-out patches. When hTRPV1 was fully activated by capsaicin, amitriptyline induced concentration-dependent and partly reversible current inhibition. In contrast, amitriptyline potentiated small responses to capsaicin, heat and protons. We also found that amitriptyline desensitized hTRPV1 to capsaicin. This effect was reduced by the intracellular application of the strong calcium chelator BAPTA. Furthermore, the non-desensitizing mutant hTRPV1-Y672K displayed a reduced amitriptyline-induced desensitization. Conclusions: Our data showed that amitriptyline can activate, sensitize, desensitize and even inhibit TRPV1. Together with its property as a strong local anesthetic, our data suggest that amitriptyline may be a promising adjunct to topical capsaicin.
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Affiliation(s)
- Sebastian Pantke
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
- PRACTIS Clinician Scientist Program, Dean’s Office for Academic Career Development, Hannover Medical School, 30625 Hannover, Germany
| | - Johanna H. Steinberg
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
| | - Lucas K. H. Weber
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
| | - Tabea C. Fricke
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
- PRACTIS Clinician Scientist Program, Dean’s Office for Academic Career Development, Hannover Medical School, 30625 Hannover, Germany
| | - Inês Carvalheira Arnaut Pombeiro Stein
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
- PRACTIS Clinician Scientist Program, Dean’s Office for Academic Career Development, Hannover Medical School, 30625 Hannover, Germany
| | - George Oprita
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
| | - Christine Herzog
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
| | - Andreas Leffler
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany; (S.P.); (J.H.S.); (L.K.H.W.); (I.C.A.P.S.); (G.O.); (C.H.)
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29
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Abd El Hay MY, Kamm GB, Tlaie Boria A, Siemens J. Diverging roles of TRPV1 and TRPM2 in warm-temperature detection. eLife 2025; 13:RP95618. [PMID: 40215103 PMCID: PMC11991700 DOI: 10.7554/elife.95618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2025] Open
Abstract
The perception of innocuous temperatures is crucial for thermoregulation. The TRP ion channels TRPV1 and TRPM2 have been implicated in warmth detection, yet their precise roles remain unclear. A key challenge is the low prevalence of warmth-sensitive sensory neurons, comprising fewer than 10% of rodent dorsal root ganglion (DRG) neurons. Using calcium imaging of >20,000 cultured mouse DRG neurons, we uncovered distinct contributions of TRPV1 and TRPM2 to warmth sensitivity. TRPV1's absence - and to a lesser extent absence of TRPM2 - reduces the number of neurons responding to warmth. Additionally, TRPV1 mediates the rapid, dynamic response to a warmth challenge. Behavioural tracking in a whole-body thermal preference assay revealed that these cellular differences shape nuanced thermal behaviours. Drift diffusion modelling of decision-making in mice exposed to varying temperatures showed that TRPV1 deletion impairs evidence accumulation, reducing the precision of thermal choice, while TRPM2 deletion increases overall preference for warmer environments that wildtype mice avoid. It remains unclear whether TRPM2 in DRG sensory neurons or elsewhere mediates thermal preference. Our findings suggest that different aspects of thermal information, such as stimulation speed and temperature magnitude, are encoded by distinct TRP channel mechanisms.
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Affiliation(s)
- Muad Y Abd El Hay
- Department of Pharmacology, Heidelberg UniversityHeidelbergGermany
- Ernst Strüngmann Institute for Neuroscience in Cooperation with the Max Planck SocietyFrankfurt am MainGermany
| | - Gretel B Kamm
- Department of Pharmacology, Heidelberg UniversityHeidelbergGermany
| | - Alejandro Tlaie Boria
- Ernst Strüngmann Institute for Neuroscience in Cooperation with the Max Planck SocietyFrankfurt am MainGermany
| | - Jan Siemens
- Department of Pharmacology, Heidelberg UniversityHeidelbergGermany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL)HeidelbergGermany
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30
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Kim JI, Imaizumi K, Jurjuț O, Kelley KW, Wang D, Thete MV, Hudacova Z, Amin ND, Levy RJ, Scherrer G, Pașca SP. Human assembloid model of the ascending neural sensory pathway. Nature 2025:10.1038/s41586-025-08808-3. [PMID: 40205039 DOI: 10.1038/s41586-025-08808-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/19/2025] [Indexed: 04/11/2025]
Abstract
Somatosensory pathways convey crucial information about pain, touch, itch and body part movement from peripheral organs to the central nervous system1,2. Despite substantial needs to understand how these pathways assemble and to develop pain therapeutics, clinical translation remains challenging. This is probably related to species-specific features and the lack of in vitro models of the polysynaptic pathway. Here we established a human ascending somatosensory assembloid (hASA), a four-part assembloid generated from human pluripotent stem cells that integrates somatosensory, spinal, thalamic and cortical organoids to model the spinothalamic pathway. Transcriptomic profiling confirmed the presence of key cell types of this circuit. Rabies tracing and calcium imaging showed that sensory neurons connect to dorsal spinal cord neurons, which further connect to thalamic neurons. Following noxious chemical stimulation, calcium imaging of hASA demonstrated a coordinated response. In addition, extracellular recordings and imaging revealed synchronized activity across the assembloid. Notably, loss of the sodium channel NaV1.7, which causes pain insensitivity, disrupted synchrony across hASA. By contrast, a gain-of-function SCN9A variant associated with extreme pain disorder induced hypersynchrony. These experiments demonstrated the ability to functionally assemble the essential components of the human sensory pathway, which could accelerate our understanding of sensory circuits and facilitate therapeutic development.
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Affiliation(s)
- Ji-Il Kim
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Kent Imaizumi
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Ovidiu Jurjuț
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Kevin W Kelley
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Dong Wang
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Mayuri Vijay Thete
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Zuzana Hudacova
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Neal D Amin
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
| | - Rebecca J Levy
- Department of Neurology & Neurological Sciences, Division of Child Neurology, Stanford University, Stanford, CA, USA
| | - Grégory Scherrer
- Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA
| | - Sergiu P Pașca
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
- Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA.
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31
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Bryant GA, Smaldino PE. The cultural evolution of distortion in music (and other norms of mixed appeal). Philos Trans R Soc Lond B Biol Sci 2025; 380:20240014. [PMID: 40176525 PMCID: PMC11966159 DOI: 10.1098/rstb.2024.0014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/05/2025] [Accepted: 02/04/2025] [Indexed: 04/04/2025] Open
Abstract
Music traditions worldwide are subject to remarkable diversity but the origins of this variation are not well understood. Musical behaviour is the product of a multicomponent collection of abilities, some possibly evolved for music but most derived from traits serving nonmusical functions. Cultural evolution has stitched together these systems, generating variable normative practices across cultures and musical genres. Here, we describe the cultural evolution of musical distortion, a noisy manipulation of instrumental and vocal timbre that emulates nonlinear phenomena (NLP) present in the vocal signals of many animals. We suggest that listeners' sensitivity to NLP has facilitated technological developments for altering musical instruments and singing with distortion, which continues to evolve culturally via the need for groups to both coordinate internally and differentiate themselves from other groups. To support this idea, we present an agent-based model of norm evolution illustrating possible dynamics of continuous traits such as timbral distortion in music, dependent on (i) a functional optimum, (ii) intra-group cohesion and inter-group differentiation and (iii) groupishness for assortment and social learning. This account illustrates how cultural transmission dynamics can lead to diversity in musical sounds and genres, and also provides a more general explanation for the emergence of subgroup-differentiating norms.This article is part of the theme issue 'Nonlinear phenomena in vertebrate vocalizations: mechanisms and communicative functions'.
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Affiliation(s)
- Gregory A. Bryant
- Department of Communication, University of California, Los Angeles, CA90095-1563, USA
- UCLA Center for Behavior, Evolution, and Culture, Los Angeles, CA, USA
| | - Paul E. Smaldino
- Cognitive and Information Sciences, University of California, Merced, CA, USA
- Santa Fe Institute, Santa Fe, NM, USA
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32
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Chaweekulrat P, Kanokrungsee S, Viriyaskultorn N, Prasertsook S, Likittanasombat S, Boonchai W. Sensitive Skin in Thais: Prevalence, Clinical Characteristics, and Diagnostic Cutoff Scores. J Cosmet Dermatol 2025; 24:e70181. [PMID: 40211966 PMCID: PMC11986799 DOI: 10.1111/jocd.70181] [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: 08/24/2024] [Revised: 02/07/2025] [Accepted: 04/02/2025] [Indexed: 04/13/2025]
Abstract
BACKGROUND Sensitive skin is a dermatologic condition with variable prevalence. Universally established cutoff scores for the sensitive scale (SS) and burden of sensitive skin (BoSS) questionnaires are lacking in general populations. AIMS To determine the prevalence of and the associated risk factors for sensitive skin among Thais and to establish cutoff values for diagnosing mild, moderate, and severe cases of sensitive skin. PATIENTS/METHODS A cross-sectional study involving 621 participants aged ≥ 18 years was conducted using an online questionnaire disseminated via various social platforms. Participants completed the SS-14, SS-10, and BoSS questionnaires to assess sensitive skin severity. Cutoff scores for these instruments were determined. RESULTS Sensitive skin was reported by 86.9% of participants, with 57.5% indicating moderate to severe sensitive skin. Significant risk factors for sensitive skin included female sex, underlying dermatologic conditions, history of atopic dermatitis, and dry skin type. The following cutoff points for diagnosing mildly, moderately, and severely sensitive skin were established for each questionnaire: SS-14 (6/16/25), SS-10 (5/13/22), and BoSS (13/19/24), respectively. The SS-10 questionnaire demonstrated greater diagnostic accuracy than the BoSS questionnaire. CONCLUSIONS This pioneering study elucidated the prevalence of and risk factors for sensitive skin in Thais. The established cutoff values will facilitate sensitive skin diagnosis and guide patient management strategies.
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Affiliation(s)
- Pichanee Chaweekulrat
- Department of DermatologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Silada Kanokrungsee
- Department of DermatologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Noldtawat Viriyaskultorn
- Department of DermatologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | - Suthasanee Prasertsook
- Department of DermatologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
| | | | - Waranya Boonchai
- Department of DermatologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityBangkokThailand
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Raveh A, Pen Y, Silberman A, Peretz A, Attali B, Maile L, Davidson S, Brown AD, Kennedy JD, Belinson H. Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects. Pain 2025; 166:793-811. [PMID: 39324934 DOI: 10.1097/j.pain.0000000000003390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/04/2024] [Indexed: 09/27/2024]
Abstract
ABSTRACT Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.
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Affiliation(s)
- Adi Raveh
- Bsense Bio Therapeutics Ltd., Ness Ziona, Israel
| | - Yefim Pen
- Bsense Bio Therapeutics Ltd., Ness Ziona, Israel
| | | | - Asher Peretz
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel
| | - Bernard Attali
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel
| | - Laura Maile
- Department of Anesthesiology and Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Steve Davidson
- Department of Anesthesiology and Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Alan D Brown
- AD Brown Medchem Consulting Ltd., Deal, Kent, UK
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Abdullah NS, Bradaia A, Defaye M, Ohland C, Svendsen K, Dickemann A, Delanne-Cumenal M, Hassan A, Iftinca M, McCoy KD, Altier C. Early life microbiota colonization programs nociceptor sensitivity by regulating NGF production in mast cells. Mucosal Immunol 2025; 18:326-338. [PMID: 39662673 DOI: 10.1016/j.mucimm.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/02/2024] [Accepted: 12/05/2024] [Indexed: 12/13/2024]
Abstract
Recent evidence suggests that the gut microbiota can influence pain sensitivity, highlighting the potential for microbiota-targeted pain interventions. During early life, both the microbiota and nociceptors are fine-tuned and respond to environmental factors, however, little is known about how they interact with each other. Using germ-free and gnotobiotic models, we demonstrate that microbiota colonization controls nociceptor sensitivity, partly by modulating mast cell production of nerve growth factor (NGF). We report that germ-free mice respond less to thermal and capsaicin-induced stimulation, which correlates with reduced trafficking of TRPV1 to the cell membrane of nociceptors. In germ-free mice, mast cells express lower levels of NGF. Hyposensitivity to thermal and capsaicin-induced stimulation, reduced TRPV1 trafficking, and decreased NGF expression are reversed when mice are colonized at birth, but not when colonization occurs after weaning. Inhibition of mast cell degranulation and NGF signaling during the first weeks of life in colonized mice leads to a hyposensitive phenotype in adulthood, demonstrating a role for mast cells and NGF signaling in linking early life colonization with nociceptor sensitivity. These findings implicate the early life microbiota in shaping mast cell NGF production and nociceptor sensitivity later in life. SIGNIFICANCE STATEMENT: Nociceptors are specialized sensory neurons that detect and transduce painful stimuli. During the early postnatal period, nociceptors are influenced by sensory experiences and the environment. Our findings demonstrate that gut microbiota colonization is essential in setting the threshold of nociceptor responses to painful stimuli. We show that early-life bacterial colonization controls the production of nerve growth factor by mast cells, affecting our sensitivity to pain later in life. Our study highlights the potential for developing new pain treatments that target the gut microbiome.
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Affiliation(s)
- Nasser S Abdullah
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Amyaouch Bradaia
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Manon Defaye
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Christina Ohland
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Kristofer Svendsen
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Anabel Dickemann
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Melissa Delanne-Cumenal
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Ahmed Hassan
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Mircea Iftinca
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Christophe Altier
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Inflammation Research Network, Snyder institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, T2N4N1, Canada.
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Li L, Wu S, Wang L, Zhang X, Cui Y, Yan Z. Is gastroesophageal reflux disease a comorbidity of burning mouth syndrome? A cross-sectional, real-world study. Cephalalgia 2025; 45:3331024251336139. [PMID: 40266675 DOI: 10.1177/03331024251336139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
BackgroundThe etiology of burning mouth syndrome (BMS) patients remains unclear and systemic conditions concurrently with BMS are viewed with greater scrutiny. The present study aimed to reveal whether gastroesophageal reflux disease (GERD) is the possible comorbidity of BMS.MethodsIn our study, a real-world design was employed, enrolling BMS patients from an oral medicine clinic and capturing data in a non-interventional, cross-sectional setting. Endoscopy and the Gastroesophageal Reflux Disease Questionnaire (GERDQ) were used to assess the potential GERD patients. Demographics, clinical symptoms and signs were compared between both the GERD and non-GERD groups, and GERDQ ≥8 and <8 groups. Meanwhile, GERDQ items were assessed to determine predictive value.ResultsIn total, 124 BMS patients with GERDQ scores were enrolled, of whom 84 patients were screened by endoscopy. GERD were confirmed by endoscopy in 30.95% (26/84) of patients with BMS, whereas 69.05% (58/84) showed no definite evidence of GERD. When GERDQ with a cutoff score of 8 was utilized for screening all 124 BMS patients, 25.8% (32/124) had GERDQ scores ≥8. When considering the endoscopic diagnosis as the golden standard due to the low availability of 24-h pH monitoring, the specificity and sensitivity were 79.2% and 46.2% respectively. Clinically, altered taste (p = 0.022) and thickened tongue coating (p = 0.001) were significantly more common in the GERDQ ≥8 group, whereas no significant difference was revealed between endoscopy approved GERD and non-GERD groups.ConclusionsGERD may represent a potential systemic comorbidity in BMS patients and GERDQ might serve as the screening tool assisting healthcare professionals. Altered taste and thickened tongue coating might be suggestive for potential GERD symptoms in BMS patients. Further research is desired to elucidate the mechanisms linking such conditions.
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Affiliation(s)
- Linman Li
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Shuangshuang Wu
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Luling Wang
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Xinming Zhang
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Yajuan Cui
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Zhimin Yan
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
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Galosi E, Falco P, Di Pietro G, Esposito N, De Stefano G, Evangelisti E, Leone C, Litewczuk D, Tramontana L, Di Stefano G, Truini A. Epidermal Transient Receptor Potential Vanilloid 1 innervation is increased in patients with painful diabetic polyneuropathy experiencing ongoing burning pain. Pain 2025; 166:824-834. [PMID: 39968935 DOI: 10.1097/j.pain.0000000000003541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/17/2024] [Indexed: 02/20/2025]
Abstract
ABSTRACT Preclinical studies suggested that Transient Receptor Potential Vanilloid 1 (TRPV1) channels contribute to neuropathic pain in animal models of diabetic polyneuropathy. Patients with painful diabetic polyneuropathy commonly experience ongoing burning pain. This study aimed at evaluating the association between this specific type of pain and TRPV1 intraepidermal nerve fibers in patients with painful diabetic polyneuropathy. We consecutively enrolled 70 patients with diabetic polyneuropathy. Each patient completed the Neuropathic Pain Symptom Inventory (NPSI) to identify the various types of neuropathic pain. All patients underwent a distal leg skin biopsy, with immunostaining of skin nerve fibers using antibodies for the pan-axonal marker Protein Gene Product 9.5 (PGP9.5), TRPV1, Calcitonin Gene-Related Peptide (CGRP), and Substance P. We found that 57% of patients (n = 40) had neuropathic pain symptoms, with ongoing burning pain being the most frequently reported type of pain at the NPSI (70% of patients with pain, n = 28). Patients with ongoing burning pain had higher TRPV1 intraepidermal nerve fiber density and TRPV1/PGP9.5 ratio compared with those with painless polyneuropathy ( P = 0.014, P = 0.013) and painful polyneuropathy with other types of pain ( P < 0.0001, P = 0.024); they also had increased CGRP dermal nerve fiber density compared with patients with painless polyneuropathy ( P = 0.005). Our study showed that ongoing burning pain is associated with an increased expression of intraepidermal TRPV1 fibers, as well as an increased dermal representation of CGRP fibers. These findings suggest that TRPV1 contributes to ongoing burning pain, possibly in conjunction with elevated CGRP expression, highlighting its significance as a therapeutic target for patients with painful diabetic polyneuropathy.
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Affiliation(s)
- Eleonora Galosi
- Department of Human Neuroscience, Sapienza University, Rome, Italy
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37
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Wu Y, Xu Q, Chen Y, Li C, Wu Y, Yu X, Li H, Xu Z, Xu J, Ni Z, Ge Y, Yan T, Qi Z, Liu J. Mechanosensitive and pH-Gated Butterfly-Shaped Artificial Ion Channel for High-Selective K + Transport and Cancer Cell Apoptosis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2416852. [PMID: 39981913 DOI: 10.1002/adma.202416852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/10/2025] [Indexed: 02/22/2025]
Abstract
To advance the exploration of mechanisms underlying natural multi-gated ion channels, a novel butterfly-shaped biomimetic K+ channel GnC7 (n = 3, 4) is developed with dual mechanical and pH responsiveness, exhibiting unprecedented K+/Na+ selectivity (G3C7: 34.4; G4C7: 41.3). These channels constructed from poly(propylene imine) dendrimer and benzo-21-crown-7-ethers achieve high K+ transport activity (EC50: 0.72 µm for G3C7; 0.9 µm for G4C7) due to their arc-like mechanical rotation. The dynamic mode relies on butterfly-shaped topology derived from the highly symmetrical core and multiple intramolecular hydrogen bonds. GnC7 can sense mechanical stimulus applied to liposomes/cells and then adapt the K+ transport rate accordingly. Furthermore, reversible ON/OFF switching of K+ transport is realized through the pH-controllable host-guest complexation. G4C7-induced ultrafast cellular K+ efflux (70% within only 9 min) efficiently triggers mitochondrial-dependent apoptosis of cancer cells by provoking endoplasmic reticulum stress accompanied by drastic Ca2+ sparks. This work embodies a multi-dimensional regulation of channel functions; it will provide insights into the dynamic behaviors of biological analogs and promote the innovative design of artificial ion channels and therapeutic agents.
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Affiliation(s)
- Yaqi Wu
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Qiangqiang Xu
- Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Yaoxuan Chen
- Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Cong Li
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Yanliang Wu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Xiaoxuan Yu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
- Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Hui Li
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
- Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Zhengwei Xu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Jiayun Xu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Zhigang Ni
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Yan Ge
- Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Tengfei Yan
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Zhenhui Qi
- Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Junqiu Liu
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
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Wang J, Ma Y, Zhang H, Li N, Xu H, Liang Y, Luo M, Wang Y. Swallowing cortical network features under taste stimulation for patients with post stroke dysphagia-Insights from a fNIRS study. Brain Res Bull 2025; 223:111287. [PMID: 40049459 DOI: 10.1016/j.brainresbull.2025.111287] [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: 05/21/2024] [Revised: 10/17/2024] [Accepted: 02/28/2025] [Indexed: 03/18/2025]
Abstract
The alterations in the swallowing cortical network associated with taste stimulation in patients with post-stroke dysphagia remain unclear. The aim of the study was to investigate the alterations in brain functional activity among individuals with post-stroke dysphagia under taste stimuli using functional near-infrared spectroscopy (fNIRS). We recruited 28 patients with post-stroke dysphagia and 24 age-matched healthy controls in this study. Each of them completed swallowing evaluation, resting-state and swallowing task-related fNIRS test. We found that the brain activation of patients significantly decreased in the left and right supplemental motor area (SMA) for water swallowing task and the left SMA and right primary sensory area (S1) for salty water swallowing, compared with healthy controls, only the left SMA remained significant for salty water swallowing after False Discovery Rate (FDR) correction. Fourteen healthy controls and 13 patients were included in the subgroup analysis, to explore the influences of preferred taste on swallowing network, we observed that the brain activation in the right S1 was significantly reduced during water swallowing in patient group (p = 0.008, with FDR corrected), all channels showed similar strengths in the activation under preferred taste stimulus between the groups. Functional connectivity (FC) between hemispheric sensorimotor areas were significantly decreased in patients compared with healthy controls. Our investigation revealed a noteworthy reduction in the activation of the left SMA during the salty water swallowing task in patients with dysphagia when compared to the healthy control group. The dysphagic patients following stroke exhibited impaired interaction between hemispheric sensorimotor areas associated with swallowing. Sour, sweet, and preferred taste stimulation have the potential to enhance brain plasticity, which may offer new insights for developing novel strategies for post-stroke dysphagia.
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Affiliation(s)
- Jie Wang
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Yanping Ma
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Haiping Zhang
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Na Li
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Hangrui Xu
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Yanan Liang
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Meiling Luo
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China
| | - Yonghui Wang
- Rehabilitation Center, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong 250012, China.
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Palomino SM, Gabriel KA, Mwirigi JM, Cervantes A, Horton P, Funk G, Moutal A, Martin LF, Khanna R, Price TJ, Patwardhan A. Genetic editing of primary human dorsal root ganglion neurons using CRISPR-Cas9. Sci Rep 2025; 15:11116. [PMID: 40169710 PMCID: PMC11961745 DOI: 10.1038/s41598-025-91153-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/18/2025] [Indexed: 04/03/2025] Open
Abstract
CRISPR-Cas9 is now the leading method for genome editing and is advancing for the treatment of human disease. CRIPSR has promise in treating neurological diseases, but traditional viral-vector-delivery approaches have neurotoxicity limiting their use. Here we describe a simple method for non-viral transfection of primary human DRG (hDRG) neurons for CRISPR-Cas9 editing. We edited TRPV1, NTSR2, and CACNA1E using a lipofection method with CRISPR-Cas9 plasmids containing reporter tags (GFP or mCherry). Transfection was successfully demonstrated by the expression of the reporters two days post-administration. CRISPR-Cas9 editing was confirmed at the genome level with a T7-endonuclease-I assay; protein level with immunocytochemistry and Western blot; and functional level through capsaicin-induced Ca2+ accumulation in a high-throughput compatible fluorescent imaging plate reader (FLIPR) system. This work establishes a reliable, target specific, non-viral CRISPR-Cas9-mediated genetic editing in primary human neurons with potential for future clinical application for sensory diseases.
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Affiliation(s)
- Seph M Palomino
- Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 6202 Harry Hines Blvd., 9th Floor, Dallas, 75235, TX, USA
| | - Katherin A Gabriel
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Juliet M Mwirigi
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Anna Cervantes
- Southwest Transplant Alliance, Manderville Ln, Dallas, TX, 8190, 75231, USA
| | - Peter Horton
- Southwest Transplant Alliance, Manderville Ln, Dallas, TX, 8190, 75231, USA
| | - Geoffrey Funk
- Southwest Transplant Alliance, Manderville Ln, Dallas, TX, 8190, 75231, USA
| | - Aubin Moutal
- Department of Pharmacology and Physiology, Saint Louis University, 1402 S. Grand Blvd, St. Louis, Mo, 63104, USA
| | - Laurent F Martin
- Department of Pharmacology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ, 85721, USA
| | - Rajesh Khanna
- Department of Pharmacology and Therapeutics, University of Florida, 1200 Newell Drive, Gainesville, FL, ARB R5-234, 32610-0267, USA
| | - Theodore J Price
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX, 75080, USA.
| | - Amol Patwardhan
- Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 6202 Harry Hines Blvd., 9th Floor, Dallas, 75235, TX, USA.
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Lozinšek M. Single-crystal structure of the spicy capsaicin. Acta Crystallogr C Struct Chem 2025; 81:188-192. [PMID: 40052876 PMCID: PMC11970115 DOI: 10.1107/s2053229625001706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/23/2025] [Indexed: 04/05/2025] Open
Abstract
The crystal structure of capsaicin (C18H27NO3), or trans-8-methyl-N-vanillylnon-6-enamide, the natural product responsible for the spiciness of chilli peppers, was determined using low-temperature single-crystal X-ray diffraction. The reported crystal structure is in good agreement with previous determinations based on powder X-ray diffraction data. The localization and free refinement of all H atoms revealed that each capsaicin molecule is hydrogen bonded to four other molecules, with the O-H and N-H groups acting as hydrogen-bond donors, and the C=O group serving as a bifurcated hydrogen-bond acceptor.
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Affiliation(s)
- Matic Lozinšek
- Jožef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia
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41
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Zhang S, Huang Y, Wang G, Zhang X, Xia L, Cao Y, Mou C, Chen Z, Bao W. Capsaicin inhibits porcine enteric coronaviruses replication through blocking TRPV4-mediated calcium ion influx. Int J Biol Macromol 2025; 302:140495. [PMID: 39894121 DOI: 10.1016/j.ijbiomac.2025.140495] [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: 09/30/2024] [Revised: 12/10/2024] [Accepted: 01/28/2025] [Indexed: 02/04/2025]
Abstract
Porcine enteric coronaviruses, including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV), have caused enormous economic losses to the global pig industry. Unfortunately, new variants emerge of these viruses will make it difficult for pigs vaccinated with the appropriate vaccine to develop protective immunity. Hence, it is urgent to explore effective therapeutic agents and targets against these viruses. Capsaicin is an active compound found in plants of the Capsicum genus (prevention and/or treatment of pain, hypertension and inflammation), but little is known about its effects on enterovirus infections. Herein, we used porcine enteric coronavirus TGEV as a model to evaluate the antiviral activity of capsaicin and discovered that capsaicin inhibited the replication phase of TGEV. Mechanistically, calcium signaling pathway participates in the capsaicin-mediated antiviral function. Importantly, capsaicin treatment impaired the viral replication by attenuating cytosolic calcium, and supplementation with CaCl2 reduced the inhibitory effect of capsaicin on TGEV infection. Finally, we revealed that TRPV4 plays an essential role in modulating calcium ion influx in IPEC-J2 cells, and capsaicin inhibits TGEV replication by decreasing calcium ion influx through inhibition of TRPV4. Overall, our data suggest that capsaicin is a promising small molecular drug candidate for strengthening host resistance to porcine enteric coronavirus infection.
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Affiliation(s)
- Shuai Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yanjie Huang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Guangzheng Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xueli Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Liangxing Xia
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yanan Cao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Chunxiao Mou
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
| | - Zhenhai Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
| | - Wenbin Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
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42
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Liu L, Yang S, Chai L, Zhang S, Liu D, Xu H, Zhao Y, Chen S, Jiang G, Li B. Nicotinic acetylcholine receptors regulate growth hormone in pituitary somatotrophs of tigers. Commun Biol 2025; 8:526. [PMID: 40164859 PMCID: PMC11958662 DOI: 10.1038/s42003-025-07980-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 03/21/2025] [Indexed: 04/02/2025] Open
Abstract
The Felidae exhibits remarkable diversity in body size, with lengths ranging from 50 to 370 cm and weights from 1.1 to 423 kg. However, the underlying mechanisms driving this variation remain poorly understood. Here, we focused on the Siberian tiger (Panthera tigris altaica), the largest of the six extant tiger subspecies, and revealed the surprising expression of nicotinic acetylcholine receptors (nAChRs) in pituitary somatotrophs, which are crucial for regulating growth hormone (GH) secretion. Single-nucleus RNA sequencing of Siberian tiger pituitary cells exhibited the coexpression of CHRNA3, CHRNB4, and CHRNA5 genes in somatotrophs, a finding confirmed by electrophysiological experiments demonstrating the formation of functional nAChRs. Activation of these receptors elevated intracellular Ca2+ levels, thereby enhancing GH secretion in somatotrophs. Notably, nAChRs were absent in the pituitary glands of mice, domestic cats, and rats, both in early life and adulthood, despite high acetylcholine levels during early life. These results suggest that nAChRs in Siberian tiger somatotrophs play a pivotal role in GH release, offering new insights into the molecular mechanisms regulating body size in these terrestrial giants.
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Affiliation(s)
- Lulu Liu
- College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin, China
| | - Shilong Yang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Longhui Chai
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Shipei Zhang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Dan Liu
- Siberian Tiger Park, Harbin, Heilongjiang, China
| | - Haitao Xu
- Siberian Tiger Park, Harbin, Heilongjiang, China
| | - Yue Zhao
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Shiyu Chen
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China.
| | - Guangshun Jiang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China.
| | - Bin Li
- College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin, China.
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43
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Ayakannu T, Taylor AH, Konje JC. Expression, Distribution and Function of the Transient Receptor Potential Vanilloid Type 1 (TRPV1) in Endometrial Cancer. Int J Mol Sci 2025; 26:3104. [PMID: 40243844 PMCID: PMC11988754 DOI: 10.3390/ijms26073104] [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: 10/23/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 04/18/2025] Open
Abstract
The transient receptor potential vanilloid 1 receptor (TRPV1) is a calcium-sensitive membrane receptor activated by capsaicin and the endocannabinoid, anandamide (AEA). Once activated in vitro, endometrial cancer (EC) cell growth appears to be inhibited through increased apoptosis, but the mechanism remains unclear. Our aim was to investigate the expression and distribution of TRPV1 in normal and cancerous endometria and to determine the precise in vitro mechanism of decreased EC cellular growth. TRPV1 expression in patients with endometrial carcinoma (15 Type 1 EC, six Type 2 EC) and six normal patients (atrophic endometria) was assessed using quantitative RT-PCR and immunohistochemistry (IHC). Additionally, immunohistochemical staining for the proliferation marker Ki-67, the pro-apoptotic marker BAX and the anti-apoptotic marker Bcl-2 were explored. TRPV1 transcript (p = 0.0054) and immunoreactive protein (p < 0.0001) levels were significantly reduced in all EC tissues when compared to control (atrophic) endometria. The almost 50% reduction in TRPV1 transcript levels was mirrored by an almost complete loss of immunoreactive TRPV1 protein. The increased proliferation (Ki-67) of EC tissues correlated with the expression of mutated BAX and inversely correlated to Bcl-2, but only in Type 2 EC samples. In vitro, AEA caused a decrease in Ishikawa cell numbers, whilst capsaicin did not, suggesting the anti-proliferative effect of AEA in EC cells is not via the TRPV1 receptor. In conclusion, the loss of TRPV1 expression in vivo plays a role in the aetiopathogenesis of EC. Activation of cells by AEA also probably promotes EC cell loss through a pro-apoptotic mechanism not involving TRPV1.
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Affiliation(s)
- Thangesweran Ayakannu
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK; (A.H.T.); (J.C.K.)
- Obstetrics & Gynaecology Centre of Excellence, Sunway Medical Centre, Petaling Jaya 47500, Malaysia
- Division of Obstetrics & Gynaecology, Department of Clinical Medicine and Surgery, Sunway University, Petaling Jaya 47500, Malaysia
| | - Anthony H. Taylor
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK; (A.H.T.); (J.C.K.)
- Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Justin C. Konje
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK; (A.H.T.); (J.C.K.)
- Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK
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Enders JD, Prodoehl EK, Penn SM, Sriram A, Stucky CL. Episodic pain in Fabry disease is mediated by a heat shock protein-TRPA1 axis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.20.639340. [PMID: 40060522 PMCID: PMC11888165 DOI: 10.1101/2025.02.20.639340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/18/2025]
Abstract
Two-thirds of patients with Fabry disease suffer debilitating pain attacks triggered by exercise, fever, and exposure to environmental heat. These patients face an even greater risk of heat-related episodic pain in the face of global climate change. Almost nothing is known about the biological mechanisms underlying heat-induced pain crises in Fabry disease, and there is no preclinical model available to study Fabry crises. Here, we established the first model of heat-induced pain attacks in Fabry disease by exposing transgenic Fabry rats to environmental heat. Heat exposure precipitated robust mechanical hypersensitivity, closely matching temporal features reported by patients with Fabry disease. At the cellular level, heat exposure sensitized Fabry dorsal root ganglia (DRG) neurons to agonists for transient receptor potential cation channel A1 (TRPA1), but not TRPV1. The heat shock response, which normally confers heat-resilience, was impaired in Fabry disease, and we demonstrated that heat shock proteins (HSP70 and HSP90) regulate TRPA1. Strikingly, pharmacologically inhibiting HSP90 completely prevented cellular and behavioral sensitization by environmental heat in Fabry disease. Together, this work establishes the first model of episodic pain in Fabry disease, implicates the heat shock response in heat-evoked pain episodes, and identifies a novel heat shock protein-TRPA1 regulatory axis.
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Affiliation(s)
- Jonathan D Enders
- Department of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin, Milwaukee, WI
| | - Eve K Prodoehl
- Department of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin, Milwaukee, WI
| | - Signe M Penn
- Department of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin, Milwaukee, WI
| | - Anvitha Sriram
- Department of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin, Milwaukee, WI
| | - Cheryl L Stucky
- Department of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin, Milwaukee, WI
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45
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Takayama Y. Interaction between thermosensitive TRP channels and anoctamin 1. J Physiol Sci 2025; 75:100015. [PMID: 40184917 PMCID: PMC11999596 DOI: 10.1016/j.jphyss.2025.100015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 04/07/2025]
Abstract
Some thermosensitive transient receptor potential (TRP) channels form a protein complex with anoctamin 1 (ANO1, also called TMEM16A). TRP channels have high calcium permeability, and the calcium entering cells through TRP channel activation activates ANO1, a calcium-activated chloride channel, involved in many physiological and pathological conditions. The physiological significance of TRP channels is often mediated by their ability to activate ANO1, which controls chloride flux across the plasma membrane. This review summarizes the latest understanding on the interactions between ANO1 and thermosensitive TRP channels, including TRPV1, TRPV3, and TRPV4, which are involved in pain sensitization in primary sensory neurons, proliferation and migration of human keratinocytes, and fluid secretion such as sweat, respectively.
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Affiliation(s)
- Yasunori Takayama
- Department of Physiology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan.
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46
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Ovechkina VS, Andrianova SK, Shimanskaia IO, Suvorova PS, Ryabinina AY, Blagonravov ML, Belousov VV, Mozhaev AA. Advances in Optogenetics and Thermogenetics for Control of Non-Neuronal Cells and Tissues in Biomedical Research. ACS Chem Biol 2025; 20:553-572. [PMID: 40056098 DOI: 10.1021/acschembio.4c00842] [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: 03/22/2025]
Abstract
Optogenetics and chemogenetics are relatively new biomedical technologies that emerged 20 years ago and have been evolving rapidly since then. This has been made possible by the combined use of genetic engineering, optics, and electrophysiology. With the development of optogenetics and thermogenetics, the molecular tools for cellular control are continuously being optimized, studied, and modified, expanding both their applications and their biomedical uses. The most notable changes have occurred in the basic life sciences, especially in neurobiology and the activation of neurons to control behavior. Currently, these methods of activation have gone far beyond neurobiology and are being used in cardiovascular research, for potential cancer therapy, to control metabolism, etc. In this review, we provide brief information on the types of molecular tools for optogenetic and thermogenetic methods─microbial rhodopsins and proteins of the TRP superfamily─and also consider their applications in the field of activation of non-neuronal tissues and mammalian cells. We also consider the potential of these technologies and the prospects for the use of optogenetics and thermogenetics in biomedical research.
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Affiliation(s)
- Vera S Ovechkina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, 117997, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
| | - Sofya K Andrianova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- National Research University Higher School of Economics, Moscow, 101000, Russia
| | - Iana O Shimanskaia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- National Research University Higher School of Economics, Moscow, 101000, Russia
| | - Polina S Suvorova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- National Research University Higher School of Economics, Moscow, 101000, Russia
| | - Anna Y Ryabinina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- V.A. Frolov Department of General Pathology and Pathological Physiology, Institute of Medicine, Peoples' Friendship University of Russia (RUDN University), Moscow, 117198, Russia
| | - Mikhail L Blagonravov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- V.A. Frolov Department of General Pathology and Pathological Physiology, Institute of Medicine, Peoples' Friendship University of Russia (RUDN University), Moscow, 117198, Russia
| | - Vsevolod V Belousov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, 117997, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow, 117513, Russia
- Life Improvement by Future Technologies (LIFT) Center, Moscow, 121205, Russia
| | - Andrey A Mozhaev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, 117997, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- National Research University Higher School of Economics, Moscow, 101000, Russia
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47
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Meng TK, Han RL, Ma P, Chen SX, Qi BH, Wang ZX, Li XY, Deng HS. Microemulsion-based drug delivery system identifies pepper alkaloids as anti-obesity compounds. Acta Pharmacol Sin 2025:10.1038/s41401-025-01521-x. [PMID: 40113987 DOI: 10.1038/s41401-025-01521-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/23/2025] [Indexed: 03/22/2025]
Abstract
Obesity is a significant contributor to various metabolic diseases such as heart disease and diabetes. Due to the adverse effects of synthetic anti-obesity drugs, natural products from functional food plants, which mimic the effects of synthetic chemicals, present promising alternatives. However, many natural plant-derived compounds are poorly soluble in water, resulting in low bioavailability within the gastrointestinal tract, a key limitation for the effectiveness of many hydrophobic substances. In this study we developed a microemulsion-based drug delivery system in Drosophila, which effectively enhanced the solubility of hydrophobic compounds without noticeable effects on food intake or survival in fruit flies. This system consisted of cremophor EL, ethanol and ethyl oleate (7:6:1), which enabled the establishment of an emulsion-based liquid high-fat diet (LHFD) model, followed by a pilot screening of 161 standard substances from traditional Chinese medicine. We found that piperine (PIP), an alkaloid derived from black pepper, significantly decreased triacylglycerol (TAG) levels in both the intestine and in whole flies. We demonstrated that piperine (1 mg/ml) significantly elevated cytosolic Ca2+ levels in enterocytes by activating Transient receptor potential (TRP) channels. TRPV1 agonists such as capsaicin and evodiamine (another alkaloid identified during the screening) also exhibited anti-obesity effects. Increased Ca2+ levels resulted in the suppression of dietary lipase Magro expression through the activation of the transcription factor cAMP response element binding protein (CREB). Furthermore, hydrophobic compounds in the microemulsion were successfully delivered to distal tissues including liver and brain blood vessels in mice, and PIP in the microemulsion was sufficient to reduce body weight in mice. In conclusion, we have developed a microemulsion-based U-GLAD platform for drug delivery, and piperine is identified as a weight-controlling compound, providing a novel approach to the treatment of obesity and its associated symptoms.
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Affiliation(s)
- Tian-Kai Meng
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Ruo-Lei Han
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Peng Ma
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Shu-Xin Chen
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Bo-Han Qi
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Zi-Xuan Wang
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xiao-Yu Li
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Han-Song Deng
- Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
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48
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Schiano Moriello A, Bossoni A, Mattoteia D, Caprioglio D, Minassi A, Appendino G, De Petrocellis L, Amodeo P, Vitale RM. The Impact of a Quinone Scaffold on Thermo-TRPs Modulation by Dimethylheptyl Phytocannabinoids. Int J Mol Sci 2025; 26:2682. [PMID: 40141324 PMCID: PMC11942486 DOI: 10.3390/ijms26062682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 03/10/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Phytocannabinoids (pCBs) from Cannabis sativa represent an important class of bioactive molecules, potentially useful for the treatment of a wide range of diseases. Their efficacy is due to their ability to interact with multiple targets of the endocannabinoid system, including the thermosensitive transient receptor potential (Thermo-TRPs), namely TRPV1-4, TRPA1, and TRPM8 channels. Previously, we demonstrated a shift in selectivity toward TRPA1 in the activity profile of the main pCBs, that is, CBD, ∆8-THC, CBG, CBC, and CBN, by swapping the pentyl chain with the α,α-dimethylheptyl (DMH) one. Using these derivatives as a starting point, here we investigate the effects on the thermo-TRPs activity profile of the integration of a quinone group into the resorcinol scaffold. We found that, while the activity on TRPA1 is substantially retained, an increase in potency/efficacy on the TRPV3 modulation is observed. Docking studies were used to elucidate the binding modes of the most active compounds toward this receptor, providing a rationale for this biological activity. In summary, we show that the quinone derivatives of DMH-pCBs are endowed with a TRPA1/TRPV3 desensitizing activity, potentially useful for the treatment of skin diseases sustained by inflammatory conditions.
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Affiliation(s)
- Aniello Schiano Moriello
- Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy; (A.S.M.); (L.D.P.); (P.A.)
- Epitech Group SpA, Via Leonardo Da Vinci 3, 35030 Saccolongo, PD, Italy
| | - Aurora Bossoni
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, NO, Italy; (A.B.); (D.M.); (D.C.); (A.M.); (G.A.)
| | - Daiana Mattoteia
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, NO, Italy; (A.B.); (D.M.); (D.C.); (A.M.); (G.A.)
| | - Diego Caprioglio
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, NO, Italy; (A.B.); (D.M.); (D.C.); (A.M.); (G.A.)
| | - Alberto Minassi
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, NO, Italy; (A.B.); (D.M.); (D.C.); (A.M.); (G.A.)
| | - Giovanni Appendino
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, NO, Italy; (A.B.); (D.M.); (D.C.); (A.M.); (G.A.)
| | - Luciano De Petrocellis
- Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy; (A.S.M.); (L.D.P.); (P.A.)
| | - Pietro Amodeo
- Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy; (A.S.M.); (L.D.P.); (P.A.)
| | - Rosa Maria Vitale
- Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy; (A.S.M.); (L.D.P.); (P.A.)
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49
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Ehmsen JF, Nikolova N, Christensen DE, Banellis L, Böhme RA, Brændholt M, Courtin AS, Krænge CE, Mitchell AG, Sardeto Deolindo C, Steenkjær CH, Vejlø M, Mathys C, Allen MG, Fardo F. Thermosensory predictive coding underpins an illusion of pain. SCIENCE ADVANCES 2025; 11:eadq0261. [PMID: 40073134 PMCID: PMC11900864 DOI: 10.1126/sciadv.adq0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 02/05/2025] [Indexed: 03/15/2025]
Abstract
The human brain has a remarkable ability to learn and update its beliefs about the world. Here, we investigate how thermosensory learning shapes our subjective experience of temperature and the misperception of pain in response to harmless thermal stimuli. Through computational modeling, we demonstrate that the brain uses a probabilistic predictive coding scheme to update beliefs about temperature changes based on their uncertainty. We find that these expectations directly modulate the perception of pain in the thermal grill illusion. Quantitative microstructural brain imaging further revealed that individual variability in computational parameters related to uncertainty-driven learning and decision-making is reflected in the microstructure of brain regions such as the precuneus, posterior cingulate gyrus, cerebellum, as well as basal ganglia and brainstem. These findings provide a framework to understand how the brain infers pain from innocuous thermal inputs, with important implications for the etiology of thermosensory symptoms under chronic pain conditions.
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Affiliation(s)
- Jesper Fischer Ehmsen
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Niia Nikolova
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Daniel Elmstrøm Christensen
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Leah Banellis
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rebecca A. Böhme
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Malthe Brændholt
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- BioMedical Design, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Arthur S. Courtin
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Institute of Neuroscience (IoNS), Université catholique de Louvain, Brussels, Belgium
| | - Camilla E. Krænge
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Alexandra G. Mitchell
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Camila Sardeto Deolindo
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christian Holm Steenkjær
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Neurology, Aalborg University Hospital, Aalborg, Denmark
| | - Melina Vejlø
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christoph Mathys
- Interacting Minds Center (IMC), Aarhus University, Aarhus, Denmark
| | - Micah G. Allen
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Cambridge Psychiatry, University of Cambridge, Cambridge, UK
| | - Francesca Fardo
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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50
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Wang J, Xu X, Huang X, Zhai L, Li Z, Sun G, Jiang R, Sun L. Coptis cream ethanol extract regulates degranulation caused by allergic reactions through MGPRB3/PLC/TRPV1 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 343:119473. [PMID: 39954829 DOI: 10.1016/j.jep.2025.119473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 02/17/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The classic formulation, Coptis cream, is widely used in clinical practice to treat allergic skin conditions, including eczema and urticaria. Through extraction screening, Coptis cream extract obtained with 75% ethanol (referred to as RPTCA) demonstrated optimal anti-allergic effects. However, the underlying mechanism of its anti-allergic action remains unexplored. AIM OF THE STUDY To investigate the anti-allergic effects of RPTCA and to explore its possible mechanism of action. METHODS The anti-allergic effects of RPTCA were investigated in C48/80-induced allergy models, namely, RBL-2H3 cells in vitro and foot-swelling mouse models in vivo. The underlying mechanisms and the monomer composition of RPTCA were explored. RESULTS Results demonstrated that RPTCA significantly reduced C48/80-induced foot swelling, vascular permeability, mast cell count, and cytokine secretion in mice. Mechanistic analysis revealed that C48/80 activated TRPV1 and TRPV4, with TRPV1 inhibition suppressing cell degranulation. RPTCA downregulated MRGPRB3 overexpression and degranulation levels, while MRGPRB3 inhibition markedly suppressed C48/80 activation and degranulation. RPTCA also decreased PLC phosphorylation through MRGPRB3, reduced intracellular Ca2+ and CaMKII phosphorylation, inhibited PKC phosphorylation, suppressed TRPV1 activation, and ultimately limited mast cell degranulation. Furthermore, RPTCA downregulated NF-κB and ERK/JNK signaling pathways, inhibiting inflammatory factor release. The component analysis identified nine main components in RPTCA, each capable of inhibiting cell degranulation. CONCLUSIONS RPTCA inhibits TRPV1 activation and reduces cell degranulation through the PLC/Ca2+/PKC pathway, while also suppressing the secretion of inflammatory factors through the NF-κB signaling pathway and ERK/JNK proteins.
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Affiliation(s)
- Jing Wang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Xiaohao Xu
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Xiaolin Huang
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Lu Zhai
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Zhenzhuo Li
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Guang Sun
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Rui Jiang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China.
| | - Liwei Sun
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Changchun University of Chinese Medicine, Changchun, Jilin Province, 130021, China.
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