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1
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Gao X, Fu S, Liu Y, Yan A, Sun Y, Li X, Liu D, He D. TRPM8 activation inhibits neuroinflammation and ameliorates neurodegeneration by modulating Nrf2/HO-1 and NF-κB pathways in vivo and in vitro. Free Radic Biol Med 2025; 235:248-260. [PMID: 40320219 DOI: 10.1016/j.freeradbiomed.2025.04.049] [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: 03/04/2025] [Revised: 04/13/2025] [Accepted: 04/29/2025] [Indexed: 05/09/2025]
Abstract
Neuroinflammation plays a pivotal role in the progression of Parkinson's disease (PD), and molecules capable of inhibiting neuroinflammation hold significant promise as therapeutic targets for PD. The transient receptor potential melastatin 8 (TRPM8), a transmembrane protein with well-documented anti-inflammatory properties, is prominently expressed in macrophages. This study marks the first exploration of the anti-PD effects of TRPM8 activation and its underlying mechanisms. Experimental results demonstrate that Icilin, a small-molecule TRPM8 agonist, conferred beneficial effects in a PD mouse model, including improved motor function, reduced dopaminergic neuronal damage, and suppressed neuroinflammation. Mechanistically, Icilin alleviated neuroinflammation in microglia through TRPM8 activation, which modulated the Nrf2/HO-1 and NF-κB pathways, thereby shielding neurons from microglia-mediated inflammatory injury. These findings not only underscore the therapeutic potential of TRPM8 in PD but also highlight its relevance to functional food science, as TRPM8 activation could be harnessed to develop dietary interventions with neuroprotective and anti-inflammatory properties. In conclusion, our study identifies TRPM8 as a promising therapeutic target for PD by regulating neuroinflammation via the Nrf2/HO-1 and NF-κB pathways, offering novel insights for the development of functional foods aimed at mitigating neurodegenerative diseases.
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Affiliation(s)
- Xiyu Gao
- College of Animal Science, Jilin University, Changchun, China.
| | - Shoupeng Fu
- College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Yichen Liu
- College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Aohan Yan
- College of Animal Science, Jilin University, Changchun, China.
| | - Yue Sun
- College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Xinyi Li
- College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Dianfeng Liu
- College of Animal Science, Jilin University, Changchun, China; Chongqing Research Institute, Jilin University, Chongqing, China.
| | - Dewei He
- College of Veterinary Medicine, Jilin University, Changchun, China.
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2
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Cicia D, Biscu F, Iannotti FA, Miraglia M, Ferrante C, Iaccarino N, Cadenas de Miguel S, Chiavaroli A, Schiano Moriello A, De Cicco P, Nanì MF, Zanoletti L, Ke BJ, van Baarle L, Talavera K, Randazzo A, Elia I, Capasso R, Matteoli G, Pagano E, Izzo AA. Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity. Cell Death Dis 2025; 16:343. [PMID: 40280909 PMCID: PMC12032354 DOI: 10.1038/s41419-025-07553-9] [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] [Received: 06/27/2024] [Revised: 02/24/2025] [Accepted: 03/17/2025] [Indexed: 04/29/2025]
Abstract
The interplay between diet, host genetics, microbiota, and immune system has a key role in the pathogenesis of inflammatory bowel disease (IBD). Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity. Here, we proved that transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel, mediates LPS- evoked Ca2+ influx in macrophages leading to their activation. Additionally, we showed that TRPM8 is selectively blocked by the dietary flavonoid luteolin, which induced a pro-tolerogenic phenotype in pro-inflammatory macrophages. Accordingly, genetic deletion of Trpm8 in macrophages caused a deficit in the activation of pro-inflammatory metabolic and transcriptional reprogramming, leading to reduced production of key pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The TRPM8 anti-inflammatory effect was found to be dependent on lactate which in turn induces IL-10 gene expression. Adoptive transfer of TRPM8-deficient bone marrow in wild-type mice improved intestinal inflammation in a model of colitis. Accordingly, oral administration of luteolin protected mice against colitis through an impairment in the innate immune response. Our study reveals the potential of targeting TRPM8 through specific nutrient interventions to regulate immune function in sub-clinical scenarios or to treat inflammatory diseases, primarily driven by chronic immune responses, such as IBD.
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Affiliation(s)
- D Cicia
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - F Biscu
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - F A Iannotti
- Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy
| | - M Miraglia
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - C Ferrante
- Department of Pharmacy, Gabriele d'Annunzio University, Chieti, Italy
| | - N Iaccarino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - S Cadenas de Miguel
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
| | - A Chiavaroli
- Department of Pharmacy, Gabriele d'Annunzio University, Chieti, Italy
| | | | - P De Cicco
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - M F Nanì
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - L Zanoletti
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy
| | - B-J Ke
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - L van Baarle
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - K Talavera
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven and VIB Center for Brain and Disease Research, Leuven, Belgium
| | - A Randazzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - I Elia
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
| | - R Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
| | - G Matteoli
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
| | - E Pagano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
| | - A A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
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3
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Shikha D, Dalai R, Kumar S, Goswami C. Residues of TRPM8 at the Lipid-Water-Interface have Coevolved with Cholesterol Interaction and are Relevant for Diverse Health Disorders. J Membr Biol 2024; 257:345-364. [PMID: 39150496 PMCID: PMC11584472 DOI: 10.1007/s00232-024-00319-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: 05/05/2024] [Accepted: 07/15/2024] [Indexed: 08/17/2024]
Abstract
TRPM8 is a non-selective cation channel that is expressed in several tissues and cells and also has a unique property to be activated by low-temperature. In this work, we have analyzed the conservation of amino acids that are present in the lipid-water-interface (LWI) region of TRPM8, the region which experiences a microenvironment near the membrane surface. We demonstrate that the amino acids present in the LWI region are more conserved than the transmembrane or even full-length TRPM8, suggesting strong selection pressure in these residues. TRPM8 also has several conserved cholesterol-binding motifs where cholesterol can bind in different modes and energies. We suggest that mutations and/or physiological conditions can potentially alter these TRPM8-cholesterol complexes and can lead to physiological disorders or even apparently irreversible diseases such as cancer and neurodegeneration.
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Affiliation(s)
- Deep Shikha
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Ritesh Dalai
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Shamit Kumar
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Chandan Goswami
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India.
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Behrendt M. Implications of TRPM3 and TRPM8 for sensory neuron sensitisation. Biol Chem 2024; 405:583-599. [PMID: 39417661 DOI: 10.1515/hsz-2024-0045] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024]
Abstract
Sensory neurons serve to receive and transmit a wide range of information about the conditions of the world around us as well as the external and internal state of our body. Sensitisation of these nerve cells, i.e. becoming more sensitive to stimuli or the emergence or intensification of spontaneous activity, for example in the context of inflammation or nerve injury, can lead to chronic diseases such as neuropathic pain. For many of these disorders there are only very limited treatment options and in order to find and establish new therapeutic approaches, research into the exact causes of sensitisation with the elucidation of the underlying mechanisms and the identification of the molecular components is therefore essential. These components include plasma membrane receptors and ion channels that are involved in signal reception and transmission. Members of the transient receptor potential (TRP) channel family are also expressed in sensory neurons and some of them play a crucial role in temperature perception. This review article focuses on the heat-sensitive TRPM3 and the cold-sensitive TRPM8 (and TRPA1) channels and their importance in sensitisation of dorsal root ganglion sensory neurons is discussed based on studies related to inflammation and injury- as well as chemotherapy-induced neuropathy.
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Affiliation(s)
- Marc Behrendt
- Experimental Pain Research, Medical Faculty Mannheim, Heidelberg University, MCTN, Tridomus, Building C, Ludolf-Krehl-Straße 13-17, D-68167 Mannheim, Germany
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5
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Yu S, Wang S, Wang X, Xu X. The axis of tumor-associated macrophages, extracellular matrix proteins, and cancer-associated fibroblasts in oncogenesis. Cancer Cell Int 2024; 24:335. [PMID: 39375726 PMCID: PMC11459962 DOI: 10.1186/s12935-024-03518-8] [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: 02/22/2024] [Accepted: 09/29/2024] [Indexed: 10/09/2024] Open
Abstract
The extracellular matrix (ECM) is a complex, dynamic network of multiple macromolecules that serve as a crucial structural and physical scaffold for neighboring cells. In the tumor microenvironment (TME), ECM proteins play a significant role in mediating cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Revealing the ECM modification of the TME necessitates the intricate signaling cascades that transpire among diverse cell populations and ECM proteins. The advent of single-cell sequencing has enabled the identification and refinement of specific cellular subpopulations, which has substantially enhanced our comprehension of the intricate milieu and given us a high-resolution perspective on the diversity of ECM proteins. However, it is essential to integrate single-cell data and establish a coherent framework. In this regard, we present a comprehensive review of the relationships among ECM, TAMs, and CAFs. This encompasses insights into the ECM proteins released by TAMs and CAFs, signaling integration in the TAM-ECM-CAF axis, and the potential applications and limitations of targeted therapies for CAFs. This review serves as a reliable resource for focused therapeutic strategies while highlighting the crucial role of ECM proteins as intermediates in the TME.
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Affiliation(s)
- Shuhong Yu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Siyu Wang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xuanyu Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Shikha D, Chang YT, Goswami C. TRPM8 affects relative "cooling and heating" of subcellular organelles in microglia in a context-dependent manner. Int J Biochem Cell Biol 2024; 173:106615. [PMID: 38908471 DOI: 10.1016/j.biocel.2024.106615] [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: 02/23/2024] [Revised: 05/23/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Thermoregulation and thermal homeostasis at the cellular and subcellular organelle level are poorly understood events. In this work, we used BV2, a microglial cell line, and a series of thermo-sensitive subcellular organelle-specific probes to analyze the relative changes in the spatio-temporal temperatures of different subcellular organelles, both qualitatively and quantitatively. These methodologies allowed us to understand the thermal relationship of different subcellular organelles also. We modulated BV2 cells by pharmacological application of activator or inhibitor of TRPM8 ion channel (a cold-sensitive ion channel) and/or by treating the cells with LPS, a molecule that induces pathogen-associated molecular patterns (PAMPs) signaling. We demonstrate that the temperatures of individual organelles remain variable within a physiological range, yet vary in different conditions. We also demonstrate that treating BV2 cells by TRPM8 modulators and/or LPS alters the organelle temperatures in a specific and context-dependent manner. We show that TRPM8 modulation and/or LPS can alter the relationship of mitochondrial membrane potential to mitochondrial temperature. Our work suggests that mitochondrial temperature positively influences ER temperature and negatively influences Golgi temperature. Golgi temperature positively influences membrane temperature. This understanding of thermal relationships may be crucial for dissecting cellular structures, function, and stress signaling and may be relevant for different diseases.
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Affiliation(s)
- Deep Shikha
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha 752050, India
| | - Young-Tae Chang
- Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
| | - Chandan Goswami
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha 752050, India.
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7
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Wu Z, Peng S, Huang W, Zhang Y, Liu Y, Yu X, Shen L. The Role and Function of TRPM8 in the Digestive System. Biomolecules 2024; 14:877. [PMID: 39062591 PMCID: PMC11275170 DOI: 10.3390/biom14070877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Transient receptor potential (TRP) melastatin member 8 (TRPM8) is a non-selective cation channel that can be activated by low temperatures (8-26 °C), cooling agents (including menthol analogs such as menthol, icilin, and WS-12), voltage, and extracellular osmotic pressure changes. TRPM8 expression has been identified in the digestive system by several research teams, demonstrating its significant involvement in tissue function and pathologies of the digestive system. Specifically, studies have implicated TRPM8 in various physiological and pathological processes of the esophagus, stomach, colorectal region, liver, and pancreas. This paper aims to comprehensively outline the distinct role of TRPM8 in different organs of the digestive system, offering insights for future mechanistic investigations of TRPM8. Additionally, it presents potential therapeutic targets for treating conditions such as digestive tract inflammation, tumors, sensory and functional disorders, and other related diseases. Furthermore, this paper addresses the limitations of existing studies and highlights the research prospects associated with TRPM8.
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Affiliation(s)
- Zunan Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.W.); (S.P.); (W.H.)
- Hubei Key Laboratory of Digestive Diseases, Wuhan 430060, China
| | - Shuai Peng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.W.); (S.P.); (W.H.)
- Hubei Key Laboratory of Digestive Diseases, Wuhan 430060, China
| | - Wensha Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.W.); (S.P.); (W.H.)
- Hubei Key Laboratory of Digestive Diseases, Wuhan 430060, China
| | - Yuling Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (Y.Z.); (Y.L.)
| | - Yashi Liu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (Y.Z.); (Y.L.)
| | - Xiaoyun Yu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (Y.Z.); (Y.L.)
| | - Lei Shen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.W.); (S.P.); (W.H.)
- Hubei Key Laboratory of Digestive Diseases, Wuhan 430060, China
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8
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Trif C, Banica AM, Manolache A, Anghel SA, Huţanu DE, Stratulat T, Badea R, Oprita G, Selescu T, Petrescu SM, Sisignano M, Offermanns S, Babes A, Tunaru S. Inhibition of TRPM8 function by prostacyclin receptor agonists requires coupling to Gq/11 proteins. Br J Pharmacol 2024; 181:1438-1451. [PMID: 38044577 DOI: 10.1111/bph.16295] [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: 04/18/2023] [Revised: 11/16/2023] [Accepted: 11/21/2023] [Indexed: 12/05/2023] Open
Abstract
BACKGROUND AND PURPOSE The TRPM8 ion channel is involved in innocuous cold sensing and has a potent anti-inflammatory action. Its activation by lower temperature or chemical agonists such as menthol and icilin induces analgesic effects, reversing hypersensitivity and reducing chronic pain. On the other hand, prostacyclin (PGI2) enhances pain and inflammation by activating the IP receptors. Due to the critical roles of TRPM8 and IP receptors in the regulation of inflammatory pain, and considering their overlapping expression pattern, we analysed the functional interaction between human TRPM8 and IP receptors. EXPERIMENTAL APPROACH We transiently expressed human TRPM8 channels and IP receptors in HEK293T cells and carried out intracellular calcium and cAMP measurements. Additionally, we cultured neurons from the dorsal root ganglia (DRGs) of mice and determined the increase in intracellular calcium triggered by the TRPM8 agonist, icilin, in the presence of the IP receptor agonist cicaprost, the IP receptor antagonist Cay10441, and the Gq/11 inhibitor YM254890. KEY RESULTS Activation of IP receptors by selective agonists (cicaprost, beraprost, and iloprost) inhibited TRPM8 channel function, independently of the Gs-cAMP pathway. The potent inhibition of TRPM8 channels by IP receptor agonists involved Gq/11 coupling. These effects were also observed in neurons isolated from murine DRGs. CONCLUSIONS AND IMPLICATIONS Our results demonstrate an unusual signalling pathway of IP receptors by coupling to Gq/11 proteins to inhibit TRPM8 channel function. This pathway may contribute to a better understanding of the role of TRPM8 channels and IP receptors in regulating pain and inflammation.
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Affiliation(s)
- Cosmin Trif
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Alexandra-Maria Banica
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Alexandra Manolache
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Sorina Andreea Anghel
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Debora-Elena Huţanu
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Teodora Stratulat
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Rodica Badea
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - George Oprita
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Tudor Selescu
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Stefana M Petrescu
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Marco Sisignano
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University, Frankfurt am Main, Germany
| | - Stefan Offermanns
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Alexandru Babes
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Sorin Tunaru
- Cell Signalling Research Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
- Prothanor Biotech S.R.L., Bucharest, Romania
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9
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Dvornikova KA, Platonova ON, Bystrova EY. The Role of TRP Channels in Sepsis and Colitis. Int J Mol Sci 2024; 25:4784. [PMID: 38731999 PMCID: PMC11084600 DOI: 10.3390/ijms25094784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/20/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
To date, several members of the transient receptor potential (TRP) channels which provide a wide array of roles have been found in the gastrointestinal tract (GI). The goal of earlier research was to comprehend the intricate signaling cascades that contribute to TRP channel activation as well as how these receptors' activity affects other systems. Moreover, there is a large volume of published studies describing the role of TRP channels in a number of pathological disorders, including inflammatory bowel disease (IBD) and sepsis. Nevertheless, the generalizability of these results is subject to certain limitations. For instance, the study of IBD relies on various animal models and experimental methods, which are unable to precisely imitate the multifactorial chronic disease. The diverse pathophysiological mechanisms and unique susceptibility of animals may account for the inconsistency of the experimental data collected. The main purpose of this study was to conduct a comprehensive review and analysis of existing studies on transient receptor potential (TRP) channels implicating specific models of colitis and sepsis, with particular emphasis on their involvement in pathological disorders such as IBD and sepsis. Furthermore, the text endeavors to evaluate the generalizability of experimental findings, taking into consideration the limitations posed by animal models and experimental methodologies. Finally, we also provide an updated schematic of the most important and possible molecular signaling pathways associated with TRP channels in IBD and sepsis.
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Affiliation(s)
| | | | - Elena Y. Bystrova
- I.P. Pavlov Institute of Physiology RAS, 199034 St. Petersburg, Russia; (K.A.D.); (O.N.P.)
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10
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Jiang Y, Shen L, Wang B. Non-electrophysiological techniques targeting transient receptor potential (TRP) gene of gastrointestinal tract. Int J Biol Macromol 2024; 262:129551. [PMID: 38367416 DOI: 10.1016/j.ijbiomac.2024.129551] [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: 10/25/2023] [Revised: 01/10/2024] [Accepted: 01/15/2024] [Indexed: 02/19/2024]
Abstract
Transient receptor potential (TRP) channels are cation channels related to a wide range of physical and chemical stimuli, they are expressed all along the gastrointestinal system, and a myriad of diseases are often associated with aberrant expression or mutation of the TRP gene, suggesting that TRPs are promising targets for drug therapy. Therefore, a better understanding of the information of TRPs in health and disease could facilitate the development of effective drugs for the treatment of gastrointestinal diseases like IBD. But there are very few generalizations about the experimental techniques studied in this field. In view of the promise of TRP as a therapeutic target, we discuss experimental methods that can be used for TRPs including their distribution, function and interaction with other proteins, as well as some promising emerging technologies to provide experimental methods for future studies.
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Affiliation(s)
- Yuting Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Lan Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Bing Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China.
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11
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Yan Q, Gao C, Li M, Lan R, Wei S, Fan R, Cheng W. TRP Ion Channels in Immune Cells and Their Implications for Inflammation. Int J Mol Sci 2024; 25:2719. [PMID: 38473965 DOI: 10.3390/ijms25052719] [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: 01/24/2024] [Revised: 02/16/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
The transient receptor potential (TRP) ion channels act as cellular sensors and mediate a plethora of physiological processes, including somatosensation, proliferation, apoptosis, and metabolism. Under specific conditions, certain TRP channels are involved in inflammation and immune responses. Thus, focusing on the role of TRPs in immune system cells may contribute to resolving inflammation. In this review, we discuss the distribution of five subfamilies of mammalian TRP ion channels in immune system cells and how these ion channels function in inflammatory mechanisms. This review provides an overview of the current understanding of TRP ion channels in mediating inflammation and may offer potential avenues for therapeutic intervention.
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Affiliation(s)
- Qiyue Yan
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Chuanzhou Gao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Mei Li
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Rui Lan
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Shaohan Wei
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Runsong Fan
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Wei Cheng
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
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Zhu W, Bai D, Ji W, Gao J. TRP channels associated with macrophages as targets for the treatment of obese asthma. Lipids Health Dis 2024; 23:49. [PMID: 38365763 PMCID: PMC10874053 DOI: 10.1186/s12944-024-02016-0] [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: 09/17/2023] [Accepted: 01/10/2024] [Indexed: 02/18/2024] Open
Abstract
Globally, obesity and asthma pose significant health challenges, with obesity being a key factor influencing asthma. Despite this, effective treatments for obese asthma, a distinct phenotype, remain elusive. Since the discovery of transient receptor potential (TRP) channels in 1969, their value as therapeutic targets for various diseases has been acknowledged. TRP channels, present in adipose tissue cells, influence fat cell heat production and the secretion of adipokines and cytokines, which are closely associated with asthma and obesity. This paper aims to investigate the mechanisms by which obesity exacerbates asthma-related inflammation and suggests that targeting TRP channels in adipose tissue could potentially suppress obese asthma and offer novel insights into its treatment.
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Affiliation(s)
- Wenzhao Zhu
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China
| | - Dinxi Bai
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China
| | - Wenting Ji
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China.
| | - Jing Gao
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China.
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Alavi MS, Soheili V, Roohbakhsh A. The role of transient receptor potential (TRP) channels in phagocytosis: A comprehensive review. Eur J Pharmacol 2024; 964:176302. [PMID: 38154767 DOI: 10.1016/j.ejphar.2023.176302] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 12/30/2023]
Abstract
When host cells are exposed to foreign particles, dead cells, or cell hazards, a sophisticated process called phagocytosis begins. During this process, macrophages, dendritic cells, and neutrophils engulf the target by expanding their membranes. Phagocytosis of apoptotic cells is called efferocytosis. This process is of significant importance as billions of cells are eliminated daily without provoking inflammation. Both phagocytosis and efferocytosis depend on Ca2+ signaling. A big family of Ca2+ permeable channels is transient receptor potentials (TRPs) divided into nine subfamilies. We aimed to review their roles in phagocytosis. The present review article shows that various TRP channels such as TRPV1, 2, 3, 4, TRPM2, 4, 7, 8, TRPML1, TRPA1, TRPC1, 3, 5, 6 have roles at various stages of phagocytosis. They are involved in the phagocytosis of amyloid β, α-synuclein, myelin debris, bacteria, and apoptotic cells. In particular, TRPC3 and TRPM7 contribute to efferocytosis. These effects are mediated by changing Ca2+ signaling or targeting intracellular enzymes such as Akt. In addition, they contribute to the chemotaxis of phagocytic cells towards targets. Although a limited number of studies have assessed the role of TRP channels in phagocytosis and efferocytosis, their findings indicate that they have critical roles in these processes. In some cases, their ablation completely abolished the phagocytic function of the cells. As a result, TRP channels are potential targets for developing new therapeutics that modulate phagocytosis.
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Affiliation(s)
- Mohaddeseh Sadat Alavi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Soheili
- Pharmaceutical Control Department, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Roohbakhsh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhang Z, Yan X, Kang L, Leng Z, Ji Y, Yang S, Du X, Fang K, Wang Z, Li Z, Sun M, Zhao Z, Feng A, Chen Z, Zhang S, Wan D, Chen T, Xu M. TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis. Cell Death Dis 2024; 15:91. [PMID: 38280896 PMCID: PMC10821925 DOI: 10.1038/s41419-024-06480-5] [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: 09/19/2023] [Revised: 01/13/2024] [Accepted: 01/17/2024] [Indexed: 01/29/2024]
Abstract
Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3β from the Wnt/β-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven β-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3β, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.
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Affiliation(s)
- Zehua Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaohan Yan
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Le Kang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhuyun Leng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yingjie Ji
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shuangzhu Yang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaojing Du
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kang Fang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zeyu Wang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhaoxing Li
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Mingchuang Sun
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ziying Zhao
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Anqi Feng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhukai Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shihan Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dong Wan
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Meidong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
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Xiong J, Xiao R, Zhao J, Zhao Q, Luo M, Li F, Zhang W, Wu M. Matrix stiffness affects tumor-associated macrophage functional polarization and its potential in tumor therapy. J Transl Med 2024; 22:85. [PMID: 38246995 PMCID: PMC10800063 DOI: 10.1186/s12967-023-04810-3] [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: 11/08/2023] [Accepted: 12/17/2023] [Indexed: 01/23/2024] Open
Abstract
The extracellular matrix (ECM) plays critical roles in cytoskeletal support, biomechanical transduction and biochemical signal transformation. Tumor-associated macrophage (TAM) function is regulated by matrix stiffness in solid tumors and is often associated with poor prognosis. ECM stiffness-induced mechanical cues can activate cell membrane mechanoreceptors and corresponding mechanotransducers in the cytoplasm, modulating the phenotype of TAMs. Currently, tuning TAM polarization through matrix stiffness-induced mechanical stimulation has received increasing attention, whereas its effect on TAM fate has rarely been summarized. A better understanding of the relationship between matrix stiffness and macrophage function will contribute to the development of new strategies for cancer therapy. In this review, we first introduced the overall relationship between macrophage polarization and matrix stiffness, analyzed the changes in mechanoreceptors and mechanotransducers mediated by matrix stiffness on macrophage function and tumor progression, and finally summarized the effects of targeting ECM stiffness on tumor prognosis to provide insight into this new field.
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Affiliation(s)
- Jiaqiang Xiong
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Rourou Xiao
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jiahui Zhao
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Qiuyan Zhao
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Manwen Luo
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Feng Li
- Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
- Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan, 430071, China.
| | - Wei Zhang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430032, China.
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Feng J, Yang L, Ran L, Qi X, Wang X, Zhang Y, Zou Z, Liu T, Wang X, Yu Y, Sun X, Zhou Q. Loss of TRPM8 Exacerbate Herpes Simplex Keratitis Infection in Mice by Promoting the Infiltration of CD11b+ Ly6G+ Cells and Increasing the Viral Load in the Cornea. Invest Ophthalmol Vis Sci 2023; 64:24. [PMID: 38117245 PMCID: PMC10741096 DOI: 10.1167/iovs.64.15.24] [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: 04/14/2023] [Accepted: 10/30/2023] [Indexed: 12/21/2023] Open
Abstract
Purpose To reveal the role of transient receptor potential cation subfamily M member 8 (TRPM8) channels in herpes simplex keratitis (HSK). Methods HSK models were established using TRPM8 knockout (TRPM8-/-) mice and their wild-type (WT) littermates. The infected corneas were graded and harvested to evaluate the mRNA levels of inflammatory factors through quantitative real-time polymerase chain reaction (RT-PCR), as well as the infiltration of inflammatory cells through immunofluorescence staining and flow cytometry. Viral titers were determined by plaque assay and absolute quantitative method. RNA-sequencing was conducted to elucidate the transcriptome of corneal epithelium in response to TRPM8 knockout after infection. The anti-inflammatory effect of TRPM8 agonist menthol was documented via subconjunctival administration. Results Compared to their wild-type counterparts, TRPM8-deficient mice exhibited exacerbated infection symptoms and thicker corneas in HSK models. Infection in TRPM8-deficient mice resulted in significant lymphocyte infiltration, primarily consisting of Ly6G+ CD11b+ cells. Additionally, TRPM8-deficient mice displayed increased levels of corneal viral titers after infection, along with decreased expression of interferon-stimulated genes (ISGs). Subconjunctival administration of menthol effectively alleviated infection-induced symptoms and Ly6G+ CD11b+ cell infiltration in herpes simplex virus type 1 (HSV-1)-treated mice. Conclusions TRPM8 promoted host resistance to HSV-1 infection by suppressing the accumulation of Ly6G+ CD11b+ cells and virus replication. These findings suggest that targeting TRPM8 could be valuable for therapeutic interventions against HSV-1 infections.
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Affiliation(s)
- Jing Feng
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Lili Ran
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
- Qingdao University Medical College, Qingdao University, Qingdao, China
| | - Xia Qi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Xiaolei Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Yangyang Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Zongzheng Zou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Ting Liu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Xiaochuan Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Yang Yu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Xiaodong Sun
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Qingjun Zhou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
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Ustaoglu A, Daudali FA, D’afflitto M, Murtough S, Lee C, Moreno E, Blaydon DC, Kelsell DP, Sifrim D, Woodland P, Peiris M. Identification of novel immune cell signature in gastroesophageal reflux disease: altered mucosal mast cells and dendritic cell profile. Front Immunol 2023; 14:1282577. [PMID: 38098488 PMCID: PMC10720318 DOI: 10.3389/fimmu.2023.1282577] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/09/2023] [Indexed: 12/17/2023] Open
Abstract
Introduction Heartburn pathogenesis in GERD remains incompletely understood. We aimed to identify differences in the immune cell signature and sensory mucosal markers between reflux phenotypes and healthy asymptomatic subjects. Methods Thirty-seven patients with heartburn symptoms were phenotyped endoscopically and with objective reflux studies into erosive reflux disease (ERD) (N=10), nonerosive reflux disease (NERD) (N=9), functional heartburn (FH) (N=9), and Barrett's esophagus (BO) (N=9). Bulk mRNA-sequencing(RNA-seq) was conducted on RNA extracted from endoscopic biopsies, and immune cell deconvolution analysis was performed using CIBERSORT. RNA-seq findings were validated by immunofluorescent staining for CD1a, nerve growth factor (NGF), and mast cell tryptase in corresponding patient biopsies. Results Transcriptomic analysis detected higher mast cell abundance in BO, ERD, and NERD compared to healthy controls (p<0.05), with decreased dendritic cell infiltration in BO, ERD, and NERD patients compared to healthy controls and FH patients. CD1a-positive dendritic cell infiltration was significantly higher in the healthy esophageal mucosa at protein level compared to BO (p=0.0005), ERD (p=0.0004), and FH patients (p=0.0096). Moreover, NGF co-expression on mast cells in GERD patients was significantly higher than in healthy controls (p=0.0094). Discussion The mucosa in patients with GERD had a significant increase in NGF expression on mast cells, suggesting an upregulation of signalling for neuronal sprouting in GERD. Moreover, decreased dendritic cell abundance in GERD esophageal mucosa may play a role in reduced oral tolerance and development of subsequent immune responses which may participate in esophageal sensitivity.
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Affiliation(s)
- Ahsen Ustaoglu
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Fatema Arif Daudali
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Manfredi D’afflitto
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Stephen Murtough
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Chung Lee
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Estefania Moreno
- Royal London Hospital, Barts National Health Service (NHS) Health, London, United Kingdom
| | - Diana C. Blaydon
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - David P. Kelsell
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Daniel Sifrim
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Philip Woodland
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Madusha Peiris
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Shikha D, Mahish C, Sing R, Chattopadhyay S, Goswami C. Modulation of TRPM8 alters the phagocytic activity of microglia and induces changes in sub-cellular organelle functions. Biochem Biophys Res Commun 2023; 682:56-63. [PMID: 37801990 DOI: 10.1016/j.bbrc.2023.09.078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 09/25/2023] [Indexed: 10/08/2023]
Abstract
In this work, we investigated the presence and function of TRPM8, a non-selective and cold-sensitive Ca2+-permeable ion channel in the primary microglia cell as well as in microglia cell line BV2. We demonstrate that primary microglia as well as BV2 express TRPM8 endogenously. Both pharmacological activation or inhibition of TRPM8 causes enhanced uptake of bacterial particles at early time points of infection. In BV2, TRPM8 activation and/or LPS-signaling alters its surface expression and cytosolic ROS production. TRPM8 modulation in the absence and presence of LPS causes differential regulation of cytosolic pH and lysosomal pH. Notably, TRPM8 modulation also alters the correlation between lysosomal pH and cytosolic pH depending on TRPM8 modulation and the presence or absence of LPS. Collectively our data suggest that TRPM8 is involved in the regulation of subcellular organelle, i.e. mitochondrial and lysosomal functions. Data also suggest that primarily TRPM8 activation, but often deviation from endogenous TRPM8 function is linked with better innate immune function mediated by microglial cells. We suggest that TRPM8-mediated regulations of sub-cellular organelle functions are more context-dependent manner. Such understanding is relevant in the context of microglial cell functions and innate immunity.
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Affiliation(s)
- Deep Shikha
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Chandan Mahish
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Raima Sing
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Subhasis Chattopadhyay
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India
| | - Chandan Goswami
- School of Biological Sciences, National Institute of Science Education and Research, An OCC of Homi Bhabha National Institute, Khordha, Jatni, Odisha, 752050, India.
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Liu S, Yan W, Lv Q, Yang L, Miao Y, Hu Y, Wei Z. 3, 3'-diindolylmethane, a natural aryl hydrocarbon receptor agonist, alleviates ulcerative colitis by enhancing "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation. Mol Immunol 2023; 163:147-162. [PMID: 37793204 DOI: 10.1016/j.molimm.2023.09.009] [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: 03/29/2023] [Revised: 07/26/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND Aryl hydrocarbon receptor (AhR) plays an important role in the occurrence and development of ulcerative colitis (UC). In this study, the effect and mechanism of 3, 3'-diindolylmethane (DIM), the classical AhR agonist, on UC was investigated from the angle of recovering the balance of Th17/Treg. METHODS The in vivo colitis model was established in mice by using dextran sulfate sodium, and CD4+ T cells were used to simulate the in vitro differentiation of Treg and Th17 cells. The proportions and related factors of Th17 and Treg cells were measured using flow cytometry, Q-PCR and western blotting. The glycolysis was evaluated by examining the glucose uptake, glucose consumption and lactate production using kits or immunofluorescence. The activation of AhR was detected by western blotting and the XRE-luciferase reporter gene. The co-immunoprecipitation, transfection or other methods were selected to investigate and identify the signaling molecular pathway. RESULTS DIM significantly attenuated symptoms of colitis mice by rebuilding the balance of Th17/Treg in anoxic colons. In hypoxia, a more potent promotion of Treg differentiation was showed by DIM relative to normoxia, and siFoxp3 prevented DIM-suppressed Th17 differentiation. DIM repressed the excessive glycolysis in hypoxia evidenced by down-regulated glucose uptake, lactate production, Glut1 and HK2 levels. Interestingly, IL-10, the function-related factor of Treg cells, showed the feedback effect of DIM-suppressed glycolysis. Besides, 2-deoxy-D-glucose, HK2 plasmid and IL-10 antibody prevented increase of DIM on the expression of Foxp3 at the transcriptional level and subsequent Treg differentiation through the lactate-STAT3 pathway, and reasons for the direct improvement of DIM on Foxp3 protein was attributed to promoting the formation of HIF-1α/TIP60 complexes as well as subsequent acetylation and protein stability. Finally, AhR dependence and mechanisms for DIM-improved Treg differentiation in vitro and in vivo were well confirmed by using plasmids or inhibitors. CONCLUSIONS DIM enhances activation of AhR and subsequent "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation.
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Affiliation(s)
- Shukun Liu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Wenxin Yan
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Qi Lv
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Ling Yang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Yumeng Miao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Yuxiao Hu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
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Zhang M, Ma Y, Ye X, Zhang N, Pan L, Wang B. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Signal Transduct Target Ther 2023; 8:261. [PMID: 37402746 DOI: 10.1038/s41392-023-01464-x] [Citation(s) in RCA: 164] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/26/2023] [Accepted: 04/25/2023] [Indexed: 07/06/2023] Open
Abstract
Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca2+, Mg2+, Na+, K+, and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.
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Affiliation(s)
- Miao Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- The Center for Microbes, Development and Health; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yueming Ma
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xianglu Ye
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ning Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lei Pan
- The Center for Microbes, Development and Health; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
- CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Bing Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, 201203, China.
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21
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Wu J, Li Z, Deng Y, Lu X, Luo C, Mu X, Zhang T, Liu Q, Tang S, Li J, An Q, Fan D, Xiang Y, Wu X, Hu Y, Du Q, Xu J, Xie R. Function of TRP channels in monocytes/macrophages. Front Immunol 2023; 14:1187890. [PMID: 37404813 PMCID: PMC10315479 DOI: 10.3389/fimmu.2023.1187890] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 06/02/2023] [Indexed: 07/06/2023] Open
Abstract
The transient receptor potential channel (TRP channel) family is a kind of non- specific cation channel widely distributed in various tissues and organs of the human body, including the respiratory system, cardiovascular system, immune system, etc. It has been reported that various TRP channels are expressed in mammalian macrophages. TRP channels may be involved in various signaling pathways in the development of various systemic diseases through changes in intracellular concentrations of cations such as calcium and magnesium. These TRP channels may also intermingle with macrophage activation signals to jointly regulate the occurrence and development of diseases. Here, we summarize recent findings on the expression and function of TRP channels in macrophages and discuss their role as modulators of macrophage activation and function. As research on TRP channels in health and disease progresses, it is anticipated that positive or negative modulators of TRP channels for treating specific diseases may be promising therapeutic options for the prevention and/or treatment of disease.
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Affiliation(s)
- Jiangbo Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Zhuo Li
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Ya Deng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xianmin Lu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Chen Luo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xingyi Mu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Ting Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qi Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Siqi Tang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jiajing Li
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qimin An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Dongdong Fan
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yiwei Xiang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Xianli Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Yanxia Hu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Qian Du
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Xie
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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22
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Millet A, Jendzjowsky N. Pathogen recognition by sensory neurons: hypotheses on the specificity of sensory neuron signaling. Front Immunol 2023; 14:1184000. [PMID: 37207232 PMCID: PMC10189129 DOI: 10.3389/fimmu.2023.1184000] [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] [Received: 03/10/2023] [Accepted: 04/19/2023] [Indexed: 05/21/2023] Open
Abstract
Sensory neurons cooperate with barrier tissues and resident immune cells to form a significant aspect of defensive strategies in concert with the immune system. This assembly of neuroimmune cellular units is exemplified across evolution from early metazoans to mammalian life. As such, sensory neurons possess the capability to detect pathogenic infiltrates at barrier surfaces. This capacity relies on mechanisms that unleash specific cell signaling, trafficking and defensive reflexes. These pathways exploit mechanisms to amplify and enhance the alerting response should pathogenic infiltration seep into other tissue compartments and/or systemic circulation. Here we explore two hypotheses: 1) that sensory neurons' potential cellular signaling pathways require the interaction of pathogen recognition receptors and ion channels specific to sensory neurons and; 2) mechanisms which amplify these sensing pathways require activation of multiple sensory neuron sites. Where possible, we provide references to other apt reviews which provide the reader more detail on specific aspects of the perspectives provided here.
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Affiliation(s)
- Antoine Millet
- Respiratory & Exercise Physiology, The Lundquist Institute for Biomedical Innovation at Harbor University of California Los Angeles (UCLA) Medical Center, Torrance, CA, United States
| | - Nicholas Jendzjowsky
- Respiratory & Exercise Physiology, The Lundquist Institute for Biomedical Innovation at Harbor University of California Los Angeles (UCLA) Medical Center, Torrance, CA, United States
- Division of Respiratory and Critical Care Medicine and Physiology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, United States
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23
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Cai Y, Zhou T, Chen J, Cai X, Fu Y. Uncovering the role of transient receptor potential channels in pterygium: a machine learning approach. Inflamm Res 2023; 72:589-602. [PMID: 36692516 DOI: 10.1007/s00011-023-01693-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 01/04/2023] [Accepted: 01/11/2023] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVES We aimed at identifying the role of transient receptor potential (TRP) channels in pterygium. METHODS Based on microarray data GSE83627 and GSE2513, differentially expressed genes (DEGs) were screened and 20 hub genes were selected. After gene correlation analysis, 5 TRP-related genes were obtained and functional analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed. Multifactor regulatory network including mRNA, microRNAs (miRNAs) and transcription factors (TFs) was constructed. The 5 gene TRP signature for pterygium was validated by multiple machine learning (ML) programs including support vector classifiers (SVC), random forest (RF), and k-nearest neighbors (KNN). Additionally, we outlined the immune microenvironment and analyzed the candidate drugs. Finally, in vitro experiments were performed using human conjunctival epithelial cells (CjECs) to confirm the bioinformatics results. RESULTS Five TRP-related genes (MCOLN1, MCOLN3, TRPM3, TRPM6, and TRPM8) were validated by ML algorithms. Functional analyses revealed the participation of lysosome and TRP-regulated inflammatory pathways. A comprehensive immune infiltration landscape and TFs-miRNAs-mRNAs network was studied, which indicated several therapeutic targets (LEF1 and hsa-miR-455-3p). Through correlation analysis, MCOLN3 was proposed as the most promising immune-related biomarker. In vitro experiments further verified the reliability of our in silico results and demonstrated that the 5 TRP-related genes could influence the proliferation and proinflammatory signaling in conjunctival tissue contributing to the pathogenesis of pterygium. CONCLUSIONS Our study suggested that TRP channels played an essential role in the pathogenesis of pterygium. The identified pivotal biomarkers (especially MCOLN3) and pathways provide novel directions for future mechanistic and therapeutic studies for pterygium.
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Affiliation(s)
- Yuchen Cai
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Tianyi Zhou
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jin Chen
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xueyao Cai
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, China.
| | - Yao Fu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
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24
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Pagano E, Romano B, Cicia D, Iannotti FA, Venneri T, Lucariello G, Nanì MF, Cattaneo F, De Cicco P, D'Armiento M, De Luca M, Lionetti R, Lama S, Stiuso P, Zoppoli P, Falco G, Marchianò S, Fiorucci S, Capasso R, Di Marzo V, Borrelli F, Izzo AA. TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β-catenin signalling. Br J Pharmacol 2023; 180:235-251. [PMID: 36168728 PMCID: PMC10092658 DOI: 10.1111/bph.15960] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/22/2022] [Accepted: 09/09/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC). EXPERIMENTAL APPROACH TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8-/- mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC. KEY RESULTS TRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt-Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β-catenin and its target oncogenes such as C-Myc and Cyclin D1. CONCLUSION AND IMPLICATIONS Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.
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Affiliation(s)
- Ester Pagano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Barbara Romano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Donatella Cicia
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabio A Iannotti
- Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy
| | - Tommaso Venneri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppe Lucariello
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria Francesca Nanì
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabio Cattaneo
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Paola De Cicco
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria D'Armiento
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Marcello De Luca
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Ruggiero Lionetti
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Stefania Lama
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Paola Stiuso
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pietro Zoppoli
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Geppino Falco
- Istituto di Ricerche Genetiche Gaetano Salvatore Biogem Scarl, Ariano Irpino, Italy.,Department of Biology, University of Naples Federico II, Naples, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
| | - Vincenzo Di Marzo
- Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy.,Institut sur la Nutrition et les Aliments Fonctionnels, Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, Canada.,Centre de Recherche de l'Institut de Pneumologie et Cardiologie de l'Université Laval, Faculté de Médecine, Université Laval, Québec, Canada.,Canada Research Excellence Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, Canada
| | - Francesca Borrelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
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25
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Zhang Z, Kang L, Yan X, Leng Z, Fang K, Chen T, Xu M. Global Trends and Hotspots of Transient Receptor Potential Melastatin 8 Research from 2002 to 2021: A Bibliometric Analysis. J Pain Res 2022; 15:3881-3892. [PMID: 36536695 PMCID: PMC9759117 DOI: 10.2147/jpr.s393582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/06/2022] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Transient receptor potential channels are the major temperature and nociceptive receptors in the human body and transient receptor potential melastatin 8 (TRPM8) is the cold-sensitive and non-selective cation channel. In our study, we performed a bibliometric analysis of TRPM8 from 2002 to 2021 to summarize the current research status and potential research direction in the future. METHODS The TRPM8-related publications were selected from the Web of Science Core Collection SCI-EXPANDED database from 2002 to 2021. The publication details, such as authors, titles, and author keywords, were used for bibliometric analysis and network visualization to present the current state of TRPM8 research. RESULTS A total of 1035 articles met the inclusion criteria. The number of TRPM8-related articles has grown rapidly over the past two decades. The USA has the largest number of publications, citations, and international collaborations. The TRPM8-related articles are mainly published and cited in neurological journals, such as the Journal of Neuroscience (41 publications and 2171 local citations). Prevarskaya N. has the most publications (26), and Patapoutian A. has been cited the most (1414 local citations). The popular disciplines in TRPM8 research include Neurosciences and Neurology, Pharmacology and Pharmacy, Biochemistry, and Molecular Biology. Research hotspots are mainly TRP channel, calcium, prostate cancer, proliferation, pain, cold, nociception, and inflammation. CONCLUSION Our bibliometric analysis demonstrates that the number of TRPM8 studies has increased from 2002 to 2021. The global research trends and hotspots include the activation mechanism of TRPM8 in neurons, the role of TRPM8 in neuronal and non-neuronal diseases, and therapeutic target research.
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Affiliation(s)
- Zehua Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Le Kang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Xiaohan Yan
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Zhuyun Leng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Kang Fang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Meidong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
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26
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Zong GF, Deng R, Yu SY, Wang AY, Wei ZH, Zhao Y, Lu Y. Thermo-Transient Receptor Potential Channels: Therapeutic Potential in Gastric Cancer. Int J Mol Sci 2022; 23:ijms232315289. [PMID: 36499622 PMCID: PMC9740781 DOI: 10.3390/ijms232315289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/08/2022] Open
Abstract
Over the last decade, researchers have found abnormal expression of transient receptor potential (TRP) channels. In particular, members of the thermally sensitive subclass (thermo-TRPs) are involved in many disease processes. Moreover, they have a vital role in the occurrence and development of gastric cancer (GC). Accordingly, thermo-TRPs constitute a major pharmacological target, and the elucidation of the mechanisms underlying their response to physiological stimuli or drugs is key for notable advances in GC treatment. Therefore, this paper summarizes the existing literature about thermo-TRP protein expression changes that are linked to the incidence and progression of GC. The review also discusses the implication of such association to pathology and cell physiology and identifies potential thermo-TRP protein targets for diagnosis and treatment of GC.
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Affiliation(s)
- Gang-Fan Zong
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Rui Deng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Su-Yun Yu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, No.138 Xianlin Avenue, Nanjing 210023, China
| | - Ai-Yun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhong-Hong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yang Zhao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, No.138 Xianlin Avenue, Nanjing 210023, China
- Correspondence: (Y.Z.); (Y.L.); Tel.: +86-025-13382098417 (Y.Z.); +86-02515605190001 (Y.L.)
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Correspondence: (Y.Z.); (Y.L.); Tel.: +86-025-13382098417 (Y.Z.); +86-02515605190001 (Y.L.)
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27
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Feng J, Xie Z, Hu H. Ion channel regulation of gut immunity. J Gen Physiol 2022; 155:213734. [PMID: 36459135 PMCID: PMC9723512 DOI: 10.1085/jgp.202113042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 08/15/2022] [Accepted: 11/17/2022] [Indexed: 12/03/2022] Open
Abstract
Mounting evidence indicates that gastrointestinal (GI) homeostasis hinges on communications among many cellular networks including the intestinal epithelium, the immune system, and both intrinsic and extrinsic nerves innervating the gut. The GI tract, especially the colon, is the home base for gut microbiome which dynamically regulates immune function. The gut's immune system also provides an effective defense against harmful pathogens entering the GI tract while maintaining immune homeostasis to avoid exaggerated immune reaction to innocuous food and commensal antigens which are important causes of inflammatory disorders such as coeliac disease and inflammatory bowel diseases (IBD). Various ion channels have been detected in multiple cell types throughout the GI tract. By regulating membrane properties and intracellular biochemical signaling, ion channels play a critical role in synchronized signaling among diverse cellular components in the gut that orchestrates the GI immune response. This work focuses on the role of ion channels in immune cells, non-immune resident cells, and neuroimmune interactions in the gut at the steady state and pathological conditions. Understanding the cellular and molecular basis of ion channel signaling in these immune-related pathways and initial testing of pharmacological intervention will facilitate the development of ion channel-based therapeutic approaches for the treatment of intestinal inflammation.
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Affiliation(s)
- Jing Feng
- Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO,Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China,Correspondence to Jing Feng:
| | - Zili Xie
- Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO
| | - Hongzhen Hu
- Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO,Hongzhen Hu:
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28
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Cheng H, An X. Cold stimuli, hot topic: An updated review on the biological activity of menthol in relation to inflammation. Front Immunol 2022; 13:1023746. [PMID: 36439160 PMCID: PMC9682018 DOI: 10.3389/fimmu.2022.1023746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/25/2022] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Rising incidence of inflammation-related diseases is an increasing concern nowadays. However, while menthol is a wildly-used and efficacious complementary medicine, its pharmacological mechanism still remains uncertain. Superimposed upon that, the aim of this review is to summarize the contemporary evidence of menthol's anti-inflammatory activity. METHODS Using the pharmacopeias and electronic databases, including Web of Science, PubMed, and CNKI, this study analyzed the relevant research articles and review articles from 2002 to 2022 and concluded those results and conjectures to finish this article. RESULTS The decrease in pro-inflammatory cytokines and related inflammatory markers, as well as associated pathway activation, was found to play the greatest role in the protective effects of menthol against inflammatory damage or association with protection against chronic inflammation. CONCLUSION This review mainly concludes the progress in menthol's anti-inflammatory activity. Further studies are needed to establish relationships between the mechanisms of action and to clarify the clinical relevance of any anti-inflammatory effects.
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Affiliation(s)
- Haojin Cheng
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xuemei An
- Nursing Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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29
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Horikawa R, Oe Y, Fujii R, Kasuga R, Yoshimura R, Miyata S. Effects of peripheral administration of lipopolysaccharide on chronic sickness responses in TRPM8-deficient mice. Neurosci Lett 2022; 790:136895. [PMID: 36191793 DOI: 10.1016/j.neulet.2022.136895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 10/31/2022]
Abstract
Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing thermoreceptor cation channel; however, its functional role in endotoxin-induced neuroinflammation remains unclear. In the present study, we investigated chronic sickness responses in TRPM8 knockout (KO) mice during lipopolysaccharide (LPS)-induced sepsis. The intraperitoneal administration of 5 mg/kg LPS generated longer-lasting hypothermia in TRPM8 KO mice than in wild-type (WT) mice. TRPM8 KO mice also exhibited longer-lasting declines in locomotor activity, body weight, and food and water intakes than WT mice upon LPS administration. In addition, LPS-induced decreases in the numbers of leucocytes and lymphocytes that persisted for a longer time in TRPM8 KO mice than in WT mice. The present results indicate TRPM8 attenuated chronic sickness responses in endotoxin-induced sepsis.
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Affiliation(s)
- Ririka Horikawa
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
| | - Yuzuki Oe
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
| | - Rena Fujii
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
| | - Rika Kasuga
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
| | - Ryoichi Yoshimura
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
| | - Seiji Miyata
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
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Selezneva A, Gibb AJ, Willis D. The contribution of ion channels to shaping macrophage behaviour. Front Pharmacol 2022; 13:970234. [PMID: 36160429 PMCID: PMC9490177 DOI: 10.3389/fphar.2022.970234] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
The expanding roles of macrophages in physiological and pathophysiological mechanisms now include normal tissue homeostasis, tissue repair and regeneration, including neuronal tissue; initiation, progression, and resolution of the inflammatory response and a diverse array of anti-microbial activities. Two hallmarks of macrophage activity which appear to be fundamental to their diverse cellular functionalities are cellular plasticity and phenotypic heterogeneity. Macrophage plasticity allows these cells to take on a broad spectrum of differing cellular phenotypes in response to local and possibly previous encountered environmental signals. Cellular plasticity also contributes to tissue- and stimulus-dependent macrophage heterogeneity, which manifests itself as different macrophage phenotypes being found at different tissue locations and/or after different cell stimuli. Together, plasticity and heterogeneity align macrophage phenotypes to their required local cellular functions and prevent inappropriate activation of the cell, which could lead to pathology. To execute the appropriate function, which must be regulated at the qualitative, quantitative, spatial and temporal levels, macrophages constantly monitor intracellular and extracellular parameters to initiate and control the appropriate cell signaling cascades. The sensors and signaling mechanisms which control macrophages are the focus of a considerable amount of research. Ion channels regulate the flow of ions between cellular membranes and are critical to cell signaling mechanisms in a variety of cellular functions. It is therefore surprising that the role of ion channels in the macrophage biology has been relatively overlooked. In this review we provide a summary of ion channel research in macrophages. We begin by giving a narrative-based explanation of the membrane potential and its importance in cell biology. We then report on research implicating different ion channel families in macrophage functions. Finally, we highlight some areas of ion channel research in macrophages which need to be addressed, future possible developments in this field and therapeutic potential.
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Matouk AI, El-Daly M, Habib HA, Senousy S, Naguib Abdel Hafez SM, Kasem AW, Almalki WH, Alzahrani A, Alshehri A, Ahmed ASF. Protective effects of menthol against sepsis-induced hepatic injury: Role of mediators of hepatic inflammation, apoptosis, and regeneration. Front Pharmacol 2022; 13:952337. [PMID: 36120368 PMCID: PMC9476320 DOI: 10.3389/fphar.2022.952337] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/01/2022] [Indexed: 11/22/2022] Open
Abstract
Liver dysfunction in sepsis is a major complication that amplifies multiple organ failure and increases the risk of death. Inflammation and oxidative stress are the main mediators in the pathophysiology of sepsis. Therefore, we investigated the role of menthol, a natural antioxidant, against sepsis-induced liver injury in female Wistar rats. Sepsis was induced by cecal ligation and puncture (CLP). Menthol (100 mg/kg) was given intragastric 2 h after CLP. Blood samples and liver tissues were collected 24 h after surgery. Menthol significantly (p < 0.05) attenuated the sepsis-induced elevation in serum liver enzymes and improved the hepatic histopathological changes. Menthol treatment significantly (p < 0.05) decreased hepatic levels of tumor necrosis factor-alpha, malondialdehyde, total nitrite, and cleaved caspase-3. It restored the hepatic levels of superoxide dismutase and reduced glutathione. Additionally, menthol significantly (p < 0.05) increased hepatic levels of B-cell lymphoma 2 (Bcl-2); an anti-apoptotic factor, and proliferating cell nuclear antigen (PCNA), a biomarker of regeneration and survival. Our results showed the therapeutic potential of menthol against liver injury induced by sepsis.
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Affiliation(s)
- Asmaa I. Matouk
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Heba A. Habib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Shaymaa Senousy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | | | - AlShaimaa W. Kasem
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, Minya, Egypt
| | - Waleed Hassan Almalki
- Department of Pharmacology and Toxicology, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdulaziz Alzahrani
- Department of Pharmacology and Toxicology, College of Clinical Pharmacy, AlBaha University, Al Bahah, Saudi Arabia
| | - Ahmed Alshehri
- Department of Pharmacology and Toxicology, College of Clinical Pharmacy, AlBaha University, Al Bahah, Saudi Arabia
| | - Al-Shaimaa F. Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
- *Correspondence: Al-Shaimaa F. Ahmed,
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32
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Petitjean H, Héberlé E, Hilfiger L, Łapieś O, Rodrigue G, Charlet A. TRP channels and monoterpenes: Past and current leads on analgesic properties. Front Mol Neurosci 2022; 15:945450. [PMID: 35966017 PMCID: PMC9373873 DOI: 10.3389/fnmol.2022.945450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member 8 (TRPM8), the TRP vanilloid 1 (TRPV1), and the TRP ankyrin 1 (TRPA1) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia effects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, offer an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.
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Affiliation(s)
| | | | - Louis Hilfiger
- Benephyt, Strasbourg, France
- Centre National de la Recherche Scientifique, University of Strasbourg, Institute of Cellular and Integrative Neuroscience, INCI UPR3212, Strasbourg, France
| | - Olga Łapieś
- Centre National de la Recherche Scientifique, University of Strasbourg, Institute of Cellular and Integrative Neuroscience, INCI UPR3212, Strasbourg, France
| | | | - Alexandre Charlet
- Centre National de la Recherche Scientifique, University of Strasbourg, Institute of Cellular and Integrative Neuroscience, INCI UPR3212, Strasbourg, France
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Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation. Prog Retin Eye Res 2022; 91:101105. [PMID: 35868985 DOI: 10.1016/j.preteyeres.2022.101105] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/29/2022]
Abstract
In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4+ T cells, can be inhibitory to corneal re-innervation. Finally, this review considers the bidirectional interactions between corneal immune cells and corneal nerves, and how leveraging this interaction could represent a potential therapeutic approach for corneal neuropathy.
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Du Y, Chen J, Shen L, Wang B. TRP channels in inflammatory bowel disease: potential therapeutic targets. Biochem Pharmacol 2022; 203:115195. [DOI: 10.1016/j.bcp.2022.115195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 12/23/2022]
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Trusiano B, Tupik JD, Allen IC. Cold sensor, hot topic: TRPM8 plays a role in monocyte function and differentiation. J Leukoc Biol 2022; 112:361-363. [PMID: 35570407 PMCID: PMC9540614 DOI: 10.1002/jlb.3ce0222-099r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
Understanding the innate immune system and how aberrant activation or impaired inhibition leads to the development of hyperinflammatory conditions, including inflammatory bowel disease, is crucial for patient management and treatment. An emerging area of interest surrounding dysregulated inflammation focuses on membrane bound transient receptor potential (TRP) ion channels. These channels are permeable to calcium and other cations involved in the balance of leukocyte membrane potential and function, as well as afferent neuron signaling within the myenteric plexus of the GI tract, bladder, and skin. A particular channel, TRPM8, is an important cell surface marker for prostate cancer and participates in the function of cold sensing neurons. Specifically, this ion‐gated receptor is shown to be activated by agonists such as menthol and eucalyptus, which aid in the soothing, cooling effects of these agents. Furthermore, the TRPM8 channel is also identified on the surface of resident tissue Mϕs and is also linked to the protective role and release of calcitonin gene‐related peptide (CGRP) by sensory neurons.
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Affiliation(s)
- Brie Trusiano
- Department of Biomedical Sciences and Pathobiology Virginia‐Maryland College of Veterinary Medicine, Virginia Tech Blacksburg Virginia USA
| | - Juselyn D. Tupik
- Department of Biomedical Sciences and Pathobiology Virginia‐Maryland College of Veterinary Medicine, Virginia Tech Blacksburg Virginia USA
| | - Irving C. Allen
- Department of Biomedical Sciences and Pathobiology Virginia‐Maryland College of Veterinary Medicine, Virginia Tech Blacksburg Virginia USA
- Department of Basic Science Education Virginia Tech Carilion School of Medicine Roanoke Virginia USA
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Zhong T, Zhang W, Guo H, Pan X, Chen X, He Q, Yang B, Ding L. The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies. Acta Pharm Sin B 2022; 12:1761-1780. [PMID: 35847486 PMCID: PMC9279634 DOI: 10.1016/j.apsb.2021.11.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/11/2021] [Accepted: 10/19/2021] [Indexed: 02/08/2023] Open
Abstract
Transient receptor potential (TRP) channels are one primary type of calcium (Ca2+) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors' efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.
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Key Words
- 4α-PDD, 4α-phorbol-12,13-didecanoate
- ABCB, ATP-binding cassette B1
- AKT, protein kinase B
- ALA, alpha lipoic acid
- AMPK, AMP-activated protein kinase
- APB, aminoethoxydiphenyl borate
- ATP, adenosine triphosphate
- CBD, cannabidiol
- CRAC, Ca2+ release-activated Ca2+ channel
- CaR, calcium-sensing receptor
- CaSR, calcium sensing receptor
- Cancer progression
- DAG, diacylglycerol
- DBTRG, Denver Brain Tumor Research Group
- ECFC, endothelial colony-forming cells
- ECM, enhanced extracellular matrix
- EGF, epidermal growth factor
- EMT, epithelial–mesenchymal transition
- ER, endoplasmic reticulum
- ERK, extracellular signal-regulated kinase
- ETS, erythroblastosis virus E26 oncogene homolog
- FAK, focal adhesion kinase
- GADD, growth arrest and DNA damage-inducible gene
- GC, gastric cancer
- GPCR, G-protein coupled receptor
- GSC, glioma stem-like cells
- GSK, glycogen synthase kinase
- HCC, hepatocellular carcinoma
- HIF, hypoxia-induced factor
- HSC, hematopoietic stem cells
- IP3R, inositol triphosphate receptor
- Intracellular mechanism
- KO, knockout
- LOX, lipoxygenase
- LPS, lipopolysaccharide
- LRP, lipoprotein receptor-related protein
- MAPK, mitogen-activated protein kinase
- MLKL, mixed lineage kinase domain-like protein
- MMP, matrix metalloproteinases
- NEDD4, neural precursor cell expressed, developmentally down-regulated 4
- NFAT, nuclear factor of activated T-cells
- NLRP3, NLR family pyrin domain containing 3
- NO, nitro oxide
- NSCLC, non-small cell lung cancer
- Nrf2, nuclear factor erythroid 2-related factor 2
- P-gp, P-glycoprotein
- PCa, prostate cancer
- PDAC, pancreatic ductal adenocarcinoma
- PHD, prolyl hydroxylases
- PI3K, phosphoinositide 3-kinase
- PKC, protein kinase C
- PKD, polycystic kidney disease
- PLC, phospholipase C
- Programmed cancer cell death
- RNS/ROS, reactive nitrogen species/reactive oxygen species
- RTX, resiniferatoxin
- SMAD, Caenorhabditis elegans protein (Sma) and mothers against decapentaplegic (Mad)
- SOCE, store operated calcium entry
- SOR, soricimed
- STIM1, stromal interaction molecules 1
- TEC, tumor endothelial cells
- TGF, transforming growth factor-β
- TNF-α, tumor necrosis factor-α
- TRP channels
- TRPA/C/M/ML/N/P/V, transient receptor potential ankyrin/canonical/melastatin/mucolipon/NOMPC/polycystin/vanilloid
- Targeted tumor therapy
- Tumor microenvironment
- Tumor-associated immunocytes
- UPR, unfolded protein response
- VEGF, vascular endothelial growth factor
- VIP, vasoactive intestinal peptide
- VPAC, vasoactive intestinal peptide receptor subtype
- mTOR, mammalian target of rapamycin
- pFRG/RTN, parafacial respiratory group/retrotrapezoid nucleus
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Hornsby E, King HW, Peiris M, Buccafusca R, Lee WYJ, Wing ES, Blackshaw LA, Lindsay JO, Stagg AJ. The cation channel TRPM8 influences the differentiation and function of human monocytes. J Leukoc Biol 2022; 112:365-381. [PMID: 35233801 PMCID: PMC9543907 DOI: 10.1002/jlb.1hi0421-181r] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 01/20/2022] [Indexed: 12/24/2022] Open
Abstract
Monocytes are mononuclear phagocytes that can differentiate to a variety of cell fates under the influence of their microenvironment and hardwired commitment. We found that inhibition of TRPM8 in human blood CD14+ monocytes during a critical 3‐h window at the beginning of their differentiation into macrophages led to enhanced survival and LPS‐driven TNFα production after 24 h. TRPM8 antagonism also promoted LPS‐driven TNFα production in CD14+ monocytes derived from the intestinal mucosa. Macrophages that had been derived for 6 days under blockade of TRPM8 had impaired phagocytic capacity and were transcriptionally distinct. Most of the affected genes were altered in a way that opposed normal monocyte to macrophage differentiation indicating that TRPM8 activity promotes aspects of this differentiation programme. Thus, we reveal a novel role for TRPM8 in regulating human CD14+ monocyte fate and function.
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Affiliation(s)
- Eve Hornsby
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Hamish W King
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Madusha Peiris
- Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Roberto Buccafusca
- School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, UK
| | - Wing-Yiu Jason Lee
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Elinor S Wing
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - L Ashley Blackshaw
- Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.,Department of Gastroenterology, Barts Health NHS Trust, The Royal London Hospital, Whitechapel, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology & Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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Li J, Pan X, Ren Z, Li B, Liu H, Wu C, Dong X, de Vos P, Pan LL, Sun J. Protein arginine methyltransferase 2 (PRMT2) promotes dextran sulfate sodium-induced colitis by inhibiting the SOCS3 promoter via histone H3R8 asymmetric dimethylation. Br J Pharmacol 2021; 179:141-158. [PMID: 34599829 DOI: 10.1111/bph.15695] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 07/12/2021] [Accepted: 07/16/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND AND PURPOSE There is emerging evidence for a critical role for epigenetic modifiers in the development of inflammatory bowel disease (IBD). Protein arginine methyltransferase 2 (PRMT2) is responsible for the methylation of arginine residues on histones and targets transcription factors involved in many cellular processes, including gene transcription, mRNA splicing, cell proliferation, and cell differentiation. In this study, the role and underlying mechanisms of PRMT2 in colitis were studied. EXPERIMENTAL APPROACH A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was used to study PRMT2 in colitis. Lentivirus-induced PRMT2 silencing or overexpression in vivo was applied to address the role of PRMT2 in colitis. Detailed western blot and expression analysis were done to understand epigenetic changes induced by PRMT2 in colitis. KEY RESULTS PRMT2 is highly expressed in inflammatory bowel disease patients, in inflamed murine colon and in TNF-α stimulated murine gut epithelial cells. PRMT2 overexpression aggravates, while knockdown alleviates DSS-induced colitis, suggesting that PRMT2 is a pivotal mediator of colitis in mice. Mechanistically, PRMT2 mediates colitis by increasing repressive histone mark H3R8 asymmetric methylation (H3R8me2a) at the promoter region of the suppressor of cytokine signalling 3 promoter (SOCS3). Resultant inhibition of SOCS3 expression and inhibition of SOCS3-mediated degradation of TNF receptor associated factor 5 (TRAF5) via ubiquitination led to elevated TRAF5 expression and TRAF5-mediated downstream NF-κB/MAPK activation. CONCLUSION AND IMPLICATIONS Our study demonstrates that PRMT2 acts as a transcriptional co-activator for proinflammatory genes during colitis. Hence, targeting PRMT2 may provide a novel therapeutic approach for colitis.
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Affiliation(s)
- Jiahong Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Xiaohua Pan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Zhengnan Ren
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Binbin Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - He Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Chengfei Wu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Xiaoliang Dong
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Li-Long Pan
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, P. R. China
| | - Jia Sun
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P. R. China
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Peiris M, Weerts ZZRM, Aktar R, Masclee AAM, Blackshaw A, Keszthelyi D. A putative anti-inflammatory role for TRPM8 in irritable bowel syndrome-An exploratory study. Neurogastroenterol Motil 2021; 33:e14170. [PMID: 34145938 DOI: 10.1111/nmo.14170] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/08/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic and recurring pain is a characteristic symptom in irritable bowel syndrome (IBS). Altered signaling between immune cells and sensory neurons within the gut may promote generation of pain symptoms. As transient receptor potential melastatin 8 (TRPM8) agonists, such as L-menthol in peppermint oil, have shown to attenuate IBS pain symptoms, we began investigating potential molecular mechanisms. METHODS Colonic biopsy tissues were collected from patients with IBS and controls, in two separate cohorts. Immunohistochemistry was performed to identify TRPM8 localization. Quantitative PCR was performed to measure mucosal mRNA levels of TRPM8. In addition, functional experiments with the TRPM8 agonist icilin were performed ex vivo to examine cytokine release from biopsies. Daily diaries were collected to ascertain pain symptoms. RESULTS In biopsy tissue from IBS patients, we showed that TRPM8 immunoreactivity is colocalized with immune cells predominantly of the dendritic cell lineage, in close approximation to nerve endings, and TRPM8 protein and mRNA expression was increased in IBS patients compared to controls (p < 0.001). TRPM8 mRNA expression showed a significant positive association with abdominal pain scores (p = 0.015). Treatment of IBS patient biopsies with icilin reduced release of inflammatory cytokines IL-1β, IL-6, and TNF-α (p < 0.05). CONCLUSIONS AND INFERENCES These data indicate TRPM8 may have important anti-inflammatory properties and by this virtue can impact neuro-immune disease mechanisms in IBS.
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Affiliation(s)
- Madusha Peiris
- Wingate Institute for Neurogastroenterology, Centre for Neuroscience, Trauma & Surgery, Blizard Institute, Queen Mary University of London, London, UK
| | - Zsa Zsa R M Weerts
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Rubina Aktar
- Wingate Institute for Neurogastroenterology, Centre for Neuroscience, Trauma & Surgery, Blizard Institute, Queen Mary University of London, London, UK
| | - Ad A M Masclee
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Ashley Blackshaw
- Wingate Institute for Neurogastroenterology, Centre for Neuroscience, Trauma & Surgery, Blizard Institute, Queen Mary University of London, London, UK
| | - Daniel Keszthelyi
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
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40
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Izquierdo C, Martín-Martínez M, Gómez-Monterrey I, González-Muñiz R. TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. Int J Mol Sci 2021; 22:ijms22168502. [PMID: 34445208 PMCID: PMC8395166 DOI: 10.3390/ijms22168502] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022] Open
Abstract
The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.
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Affiliation(s)
- Carolina Izquierdo
- Departamento de Biomiméticos, Instituto de Química Médica, Juan de la Cierva 3, 28006 Madrid, Spain; (C.I.); (M.M.-M.)
- Programa de Doctorado en Química Orgánica, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Mercedes Martín-Martínez
- Departamento de Biomiméticos, Instituto de Química Médica, Juan de la Cierva 3, 28006 Madrid, Spain; (C.I.); (M.M.-M.)
| | - Isabel Gómez-Monterrey
- Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, Via D. Montesano 49, 80131 Naples, Italy
- Correspondence: (I.G.-M.); (R.G.-M.)
| | - Rosario González-Muñiz
- Departamento de Biomiméticos, Instituto de Química Médica, Juan de la Cierva 3, 28006 Madrid, Spain; (C.I.); (M.M.-M.)
- Correspondence: (I.G.-M.); (R.G.-M.)
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Jiao H, Ivanusic JJ, McMenamin PG, Chinnery HR. Distribution of Corneal TRPV1 and Its Association With Immune Cells During Homeostasis and Injury. Invest Ophthalmol Vis Sci 2021; 62:6. [PMID: 34232260 PMCID: PMC8267209 DOI: 10.1167/iovs.62.9.6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Purpose Given the role of corneal sensory nerves during epithelial wound repair, we sought to examine the relationship between immune cells and polymodal nociceptors following corneal injury. Methods Young C57BL/6J mice received a 2 mm corneal epithelial injury. One week later, corneal wholemounts were immunostained using β-tubulin-488, TRPV1 (transient receptor potential ion channel subfamily V member-1, a nonselective cation channel) and immune cell (MHC-II, CD45 and CD68) antibodies. The sum length of TRPV1+ and TRPV1– nerve fibers, and their spatial association with immune cells, was quantified in intact and injured corneas. Results TRPV1+ nerves account for ∼40% of the nerve fiber length in the intact corneal epithelium and ∼80% in the stroma. In the superficial epithelial layers, TRPV1+ nerve terminal length was similar in injured and intact corneas. In intact corneas, the density (sum length) of basal epithelial TRPV1+ and TRPV1− nerve fibers was similar, however, in injured corneas, TRPV1+ nerve density was higher compared to TRPV1− nerves. The degree of physical association between TRPV1+ nerves and intraepithelial CD45+ MHC-II+ CD11c+ cells was similar in intact and injured corneas. Stromal leukocytes co-expressed TRPV1, which was partially localized to CD68+ lysosomes, and this expression pattern was lower in injured corneas. Conclusions TRPV1+ nerves accounted for a higher proportion of corneal nerves after injury, which may provide insights into the pathophysiology of neuropathic pain following corneal trauma. The close interactions of TRPV1+ nerves with intraepithelial immune cells and expression of TRPV1 by stromal macrophages provide evidence of neuroimmune interactions in the cornea.
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Affiliation(s)
- Haihan Jiao
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, Australia.,Department of Anatomy and Physiology, University of Melbourne, Parkville, Australia
| | - Jason J Ivanusic
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Australia
| | - Paul G McMenamin
- Department of Anatomy & Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, Australia
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42
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Ustaoglu A, Sawada A, Lee C, Lei WY, Chen CL, Hackett R, Sifrim D, Peiris M, Woodland P. Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors. Am J Physiol Gastrointest Liver Physiol 2021; 320:G804-G815. [PMID: 33655767 DOI: 10.1152/ajpgi.00013.2021] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.
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Affiliation(s)
- Ahsen Ustaoglu
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Akinari Sawada
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Chung Lee
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Richard Hackett
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Madusha Peiris
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Philip Woodland
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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43
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Hemida AS, Hammam MA, Heriz NAEM, Shehata WA. Expression of Transient Receptor Potential Channel of Melastatin number 8 (TRPM8) in Non- Melanoma Skin Cancer: A Clinical and Immunohistochemical study. J Immunoassay Immunochem 2021; 42:620-632. [PMID: 33896372 DOI: 10.1080/15321819.2021.1918709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Transient Receptor Potential Channel of Melastatin number 8 (TRPM8) is abnormally expressed in many cancers as lung, however little is known about TRPM8 expression in non-melanoma skin cancer (NMSC) including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). This work aimed to study TRPM8 expression in NMSC. It included 100 skin biopsies (50 normal skin as control group, 15 BCC and 35 SCC). Immunohistochemical staining for TRPM8 was done and results were correlated with clinicopathological characters. There was significant higher TRPM8 H-score in NMSC than control skin. On comparing SCC cases to control, there was significant positive TRPM8 expression, strong intensity, diffuse pattern, cytoplasmic and nucleo-cytoplasmic localization and higher range of H-score in SCC. In contrast, BCC showed significant lower TRPM8 positive expression when compared to control skin. Higher TRPM8 H-score in SCC showed significant positive correlation with large tumor size and poor tumor differentiation.TRPM8 may be implicated in pathogenesis of NMSC. Its association with bad prognostic characters; potentiates its role as prognostic biomarker and open new chances for therapeutic intervention in NMSC. TRPM8 antagonists may share in decreasing tumor growth and progression and may serve as potential target for tumor immunotherapy.
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Affiliation(s)
- Aiat Shaban Hemida
- Pathology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Mostafa Ahmed Hammam
- Dermatology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | | | - Wafaa Ahmed Shehata
- Dermatology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
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44
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Detection of Vascular Reactive Oxygen Species in Experimental Atherosclerosis by High-Resolution Near-Infrared Fluorescence Imaging Using VCAM-1-Targeted Liposomes Entrapping a Fluorogenic Redox-Sensitive Probe. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6685612. [PMID: 33763173 PMCID: PMC7963910 DOI: 10.1155/2021/6685612] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/28/2021] [Accepted: 02/05/2021] [Indexed: 01/06/2023]
Abstract
Excessive production of reactive oxygen species (ROS) and the ensuing oxidative stress are instrumental in all phases of atherosclerosis. Despite the major achievements in understanding the regulatory pathways and molecular sources of ROS in the vasculature, the specific detection and quantification of ROS in experimental models of disease remain a challenge. We aimed to develop a reliable and straightforward imaging procedure to interrogate the ROS overproduction in the vasculature and in various organs/tissues in atherosclerosis. To this purpose, the cell-impermeant ROS Brite™ 700 (RB700) probe that produces bright near-infrared fluorescence upon ROS oxidation was encapsulated into VCAM-1-targeted, sterically stabilized liposomes (VLp). Cultured human endothelial cells (EC) and macrophages (Mac) were used for in vitro experiments. C57BL6/J and ApoE-/- mice were randomized to receive normal or high-fat, cholesterol-rich diet for 10 or 32 weeks. The mice received a retroorbital injection with fluorescent tagged VLp incorporating RB700 (VLp-RB700). After two hours, the specific signals of the oxidized RB700 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) (NBD-DSPE), inserted into liposome bilayers, were measured ex vivo in the mouse aorta and various organs by high-resolution fluorescent imaging. VLp-RB700 was efficiently taken up by cultured human EC and Mac, as confirmed by fluorescence microscopy and spectrofluorimetry. After systemic administration in atherosclerotic ApoE-/- mice, VLp-RB700 were efficiently concentrated at the sites of aortic lesions, as indicated by the augmented NBD fluorescence. Significant increases in oxidized RB700 signal were detected in the aorta and in the liver and kidney of atherosclerotic ApoE-/- mice. RB700 encapsulation into sterically stabilized VCAM-1-sensitive Lp could be a novel strategy for the qualitative and quantitative detection of ROS in the vasculature and various organs and tissues in animal models of disease. The accurate and precise detection of ROS in experimental models of disease could ease the translation of the results to human pathologies.
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45
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Zhang FX, Li M, Yuan YLL, Cui SS, Qiu ZC, Li RM. Dissection of the potential pharmacological mechanism of Rhizoma coptidis water extract against inflammation in diabetes mellitus via chemical profiling, network pharmacology and experimental validation. NEW J CHEM 2021. [DOI: 10.1039/d1nj02812j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Elucidating the therapeutical basis and functional mechanism of traditional Chinese medicine (TCM) is still a challenge faced by researchers since the effects of TCM are always achieved by the interactions of multiple components and multiple targets.
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Affiliation(s)
- Feng-xiang Zhang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Min Li
- Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Yu-lin-lan Yuan
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Shuang-Shuang Cui
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Zuo-cheng Qiu
- Guangzhou Key Laboratory of FormulaPattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China
| | - Rui-man Li
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
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46
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Acharya TK, Tiwari A, Majhi RK, Goswami C. TRPM8 channel augments T-cell activation and proliferation. Cell Biol Int 2020; 45:198-210. [PMID: 33090595 DOI: 10.1002/cbin.11483] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 09/21/2020] [Accepted: 10/10/2020] [Indexed: 12/25/2022]
Abstract
The transient receptor potential melastatin 8 (TRPM8) is an ion channel that has been widely studied as a cold-sensitive nociceptor. However, its importance in nonneuronal cells is mostly unexplored. Here, we describe the presence and functional significance of endogenous TRPM8, a nonselective Ca2+ -channel in T cell functions. The major pool of TRPM8 resides at the T cell surface and its surface accumulation significantly increases in activated T cells. TRPM8 activation synergizes with T-cell receptor (TCR) stimulation to increase CD25, CD69 levels and enhances secretion of proinflammatory cytokine tumor necrosis factor. However, TRPM8 inhibition does not restrict TCR stimulation mediated activation of T cells, indicating that unlike the heat-sensitive TRPV1 and TRPV4 channels, the cold-sensitive TRPM8 channel may be dispensable during T-cell activation, at least in mice. In this study, we demonstrate that TRPM8 promotes TCR-induced intracellular calcium increase. TRPM8 activation is beneficial for T-cell activation and differentiation into effector cells. TRPM8 inhibition during the T-cell activation process may lead to altered phenotype and reduced proliferation, without affecting cell viability. These results collectively establish TRPM8 as a functional calcium channel whose activation may be utilized for mounting an effective immune response. The findings of this study will be relevant to the regulation and response of T cells during cell-mediated immunity. These results will likely further our understanding on the role of ion channels in T-cell activation.
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Affiliation(s)
- Tusar K Acharya
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Odisha, India.,Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Ankit Tiwari
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Odisha, India
| | - Rakesh K Majhi
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Odisha, India.,Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Chandan Goswami
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Odisha, India.,Homi Bhabha National Institute, Mumbai, Maharashtra, India
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47
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Zhang Z, Engel MA, Koch E, Reeh PW, Khalil M. Menthacarin induces calcium ion influx in sensory neurons, macrophages and colonic organoids of mice. Life Sci 2020; 264:118682. [PMID: 33127519 DOI: 10.1016/j.lfs.2020.118682] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/19/2020] [Accepted: 10/24/2020] [Indexed: 02/08/2023]
Abstract
AIMS Menthacarin is a herbal combination that is clinically used for the treatment of functional gastrointestinal disorders (FGIDs). In several clinical studies, Menthacarin reduced visceral hypersensitivity-related symptoms. Pathogenesis of visceral hypersensitivity is multifactorial. This involves several cell types and different transient receptor potential ion channels (TRPs); these ion channels are highly conductive for calcium ions. Since transient changes in cytosolic calcium levels are crucial for many functions of living cells, we investigated if Menthacarin can induce calcium influx in sensory, largely nociceptive, neurons from dorsal root ganglia (DRG), peritoneal macrophages (PMs) and colonic organoids. MAIN METHODS We employed the calcium imaging technique on sensory neurons from DRG, PMs and colonic organoids isolated from mice. All cells were superfused by Menthacarin at several concentrations (600, 1200, 1800 μg/ml) during the experiments, followed by calcium ionophor ionomycin (Iono., 1 μM) as a positive control. KEY FINDINGS Menthacarin induced concentration-dependent calcium ion influx in all investigated cell types. Furthermore, repeated applications of Menthacarin induced tachyphylaxis (desensitisation) of calcium responses in sensory neurons and colonic organoids. SIGNIFICANCE Menthacarin-induced calcium influx into sensory neurons, macrophages and colonic organoids is probably related to its clinical desensitising effects in patients with FGIDs.
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Affiliation(s)
- Z Zhang
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
| | - M A Engel
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.
| | - E Koch
- Preclinical Research, Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany
| | - P W Reeh
- Institute of Physiology und Pathophysiology, Friedrich-Alexander-Universität Erlangen, Erlangen, Germany
| | - M Khalil
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
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48
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Silverman HA, Chen A, Kravatz NL, Chavan SS, Chang EH. Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation. Front Immunol 2020; 11:590261. [PMID: 33193423 PMCID: PMC7645044 DOI: 10.3389/fimmu.2020.590261] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022] Open
Abstract
Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body’s immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.
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Affiliation(s)
- Harold A Silverman
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Adrian Chen
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Nigel L Kravatz
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Sangeeta S Chavan
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, United States
| | - Eric H Chang
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, United States
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49
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Alliger K, Khalil M, König B, Weisenburger S, Koch E, Engel M. Menthacarin attenuates experimental colitis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 77:153212. [PMID: 32711288 DOI: 10.1016/j.phymed.2020.153212] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 03/10/2020] [Accepted: 03/19/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Peppermint oil and caraway oil are established remedies in gastroenterological medicine because of their spasmolytic/analgesic effects. PURPOSE We investigated whether Menthacarin, a combination of both oils, exerted anti-inflammatory effects in a dextran sodium sulphate (DSS, 2%) murine model of colitis. STUDY DESIGN AND METHODS C57BL/6 mice were orally administered Menthacarin in doses of 10, 30, 60, and 120 µg/g body weight (BW), and control mice received 0.2% agar, 10 µl/g BW, during 8 days of DSS-induced colitis. Colitis was monitored by BW measurements and colonoscopies. Colons of euthanised mice were excised for histological staining and ELISA measurements of the cytokines TNFα, IL-6, IL-10, IL-1β, and TGF-β. RESULTS Menthacarin-treated mice compared to controls showed improved macroscopical and microscopical parameters and lower BW loss during the course of colitis. Menthacarin changed the colonic cytokine profile towards a regulatory/anti-inflammatory phenotype. CONCLUSION Menthacarin attenuates experimental colitis and may be a promising add-on therapy for the treatment of IBD.
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Affiliation(s)
- Korina Alliger
- Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
| | - Mohammad Khalil
- Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany; Institute of Physiology and Pathophysiology, Universitätsstraße 17, 91054 Erlangen, Germany
| | - Beatrix König
- Dr. Willmar Schwabe Pharmaceuticals, Preclinical Research, Willmar-Schwabe-Straße 4, 76227 Karlsruhe, Germany
| | - Sabrina Weisenburger
- Dr. Willmar Schwabe Pharmaceuticals, Preclinical Research, Willmar-Schwabe-Straße 4, 76227 Karlsruhe, Germany
| | - Egon Koch
- Dr. Willmar Schwabe Pharmaceuticals, Preclinical Research, Willmar-Schwabe-Straße 4, 76227 Karlsruhe, Germany
| | - Matthias Engel
- Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
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50
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Ramirez V, Swain S, Murray K, Reardon C. Neural Immune Communication in the Control of Host-Bacterial Pathogen Interactions in the Gastrointestinal Tract. Infect Immun 2020; 88:e00928-19. [PMID: 32341116 PMCID: PMC7440759 DOI: 10.1128/iai.00928-19] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The orchestration of host immune responses to enteric bacterial pathogens is a complex process involving the integration of numerous signals, including from the nervous system. Despite the recent progress in understanding the contribution of neuroimmune interactions in the regulation of inflammation, the mechanisms and effects of this communication during enteric bacterial infection are only beginning to be characterized. As part of this neuroimmune communication, neurons specialized to detect painful or otherwise noxious stimuli can respond to bacterial pathogens. Highlighting the complexity of these systems, the immunological consequences of sensory neuron activation can be either host adaptive or maladaptive, depending on the pathogen and organ system. These are but one of many types of neuroimmune circuits, with the vagus nerve and sympathetic innervation of numerous organs now known to modulate immune cell function and therefore dictate immunological outcomes during health and disease. Here, we review the evidence for neuroimmune communication in response to bacterial pathogens, and then discuss the consequences to host morbidity and mortality during infection of the gastrointestinal tract.
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Affiliation(s)
- Valerie Ramirez
- Department. of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, Davis, California, USA
| | - Samantha Swain
- Department. of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, Davis, California, USA
| | - Kaitlin Murray
- Department. of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, Davis, California, USA
| | - Colin Reardon
- Department. of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, Davis, California, USA
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