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1
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Motomura A, Inoue H, Ishii N, Horioka K, Okaba K, Moue C, Ohashi R, Yajima D. A suicide case of liquid nicotine intoxication. Leg Med (Tokyo) 2024; 68:102400. [PMID: 38237272 DOI: 10.1016/j.legalmed.2024.102400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/06/2023] [Accepted: 01/09/2024] [Indexed: 05/08/2024]
Abstract
A man in his 50 s, who was found vomiting and in a disturbed state when the emergency medical team arrived, then went into cardiopulmonary arrest during transport and died without responding to resuscitation. The hospital initially suspected that the death may have been caused by internal causes, but since the deceased had previously been transported to the hospital in a suicide attempt, the hospital called police regarding suspicions of unnatural death. The police investigation revealed two empty bottles of nicotine liquid for e-cigarettes in his house and a search history of "nicotine suicide" on his cellphone. In a forensic autopsy, he was found to be highly obese, and abundant fat deposits were observed in his organs. A stent was placed in the aorta, but no abnormality was found. There was no obvious stenosis or obstruction in the coronary arteries. Drug screening using liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on cardiac blood, urine, and stomach contents collected at autopsy, which revealed the presence of some medical products such as aripiprazole, nicotine, and cotinine. Further quantitative testing revealed high concentrations of nicotine in all samples. The left and right femoral venous blood concentrations were above the lethal dose, suggesting that arrhythmia or respiratory failure due to nicotine intoxication was the cause of death. With the widespread use of e-cigarettes, high concentrations of nicotine are readily available, and case reports of serious nicotine addiction are increasing. It is important to always consider addiction when conducting forensic evaluations in the medical field.
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Affiliation(s)
- Ayumi Motomura
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan; Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-o Ku, Chiba, Chiba 260-8670, Japan; Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ku, Tokyo 113-0033, Japan.
| | - Hiroyuki Inoue
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan
| | - Namiko Ishii
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan; Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-o Ku, Chiba, Chiba 260-8670, Japan
| | - Kie Horioka
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan; Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu, Aapistie 5A, Oulu 90220, Finland; Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Keisuke Okaba
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan; Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-o Ku, Chiba, Chiba 260-8670, Japan
| | - Chihiro Moue
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan
| | - Ryuto Ohashi
- School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan
| | - Daisuke Yajima
- Department of Forensic Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan; Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-o Ku, Chiba, Chiba 260-8670, Japan
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2
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Qi P, He Q, Zhang J, Lian Y, Xie T, Dong J, Zhangsun D, Wu Y, Luo S. Enhancing Stability and Albumin Binding Efficiency of α-Conotoxin GI through Fatty Acid Modification. Biochemistry 2023; 62:3373-3382. [PMID: 37967580 DOI: 10.1021/acs.biochem.3c00385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2023]
Abstract
α-Conotoxin GI is a competitive blocker of muscle-type acetylcholine receptors and holds the potential for being developed as a molecular probe or a lead compound for drug discovery. In this study, four fatty acid-modified α-conotoxin GI analogues of different lengths were synthesized by using a fatty acid modification strategy. Then, we performed a series of in vitro stability assays, albumin binding assays, and pharmacological activity assays to evaluate these modified mutants. The experimental results showed that the presence of fatty acids significantly enhanced the in vitro stability and albumin binding ability of α-conotoxin GI and that this effect was proportional to the length of the fatty acids used. Pharmacological activity tests showed that the modified mutants maintained a good acetylcholine receptor antagonistic activity. The present study shows that fatty acid modification can be an effective strategy to significantly improve conotoxin stability and albumin binding efficiency while maintaining the original targeting ion channel activity.
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Affiliation(s)
- Panpan Qi
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Quankuo He
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Junjie Zhang
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Yuanyuan Lian
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Ting Xie
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Jianying Dong
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Dongting Zhangsun
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
- Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China
| | - Yong Wu
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
| | - Sulan Luo
- School of Medicine, Guangxi University, Guangxi Key Laboratory of Special Biomedicine, Nanning 530004, China
- Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China
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3
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Zhang JJ, Fu H, Lin R, Zhou J, Haider A, Fang W, Elghazawy NH, Rong J, Chen J, Li Y, Ran C, Collier TL, Chen Z, Liang SH. Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography. J Med Chem 2023; 66:10889-10916. [PMID: 37583063 PMCID: PMC10461233 DOI: 10.1021/acs.jmedchem.3c00573] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Indexed: 08/17/2023]
Abstract
Cholinergic receptors represent a promising class of diagnostic and therapeutic targets due to their significant involvement in cognitive decline associated with neurological disorders and neurodegenerative diseases as well as cardiovascular impairment. Positron emission tomography (PET) is a noninvasive molecular imaging tool that has helped to shed light on the roles these receptors play in disease development and their diverse functions throughout the central nervous system (CNS). In recent years, there has been a notable advancement in the development of PET probes targeting cholinergic receptors. The purpose of this review is to provide a comprehensive overview of the recent progress in the development of these PET probes for cholinergic receptors with a specific focus on ligand structure, radiochemistry, and pharmacology as well as in vivo performance and applications in neuroimaging. The review covers the structural design, pharmacological properties, radiosynthesis approaches, and preclinical and clinical evaluations of current state-of-the-art PET probes for cholinergic receptors.
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Affiliation(s)
- Jing-Jing Zhang
- Jiangsu
Co-Innovation Center of Efficient Processing and Utilization of Forest
Resources, Jiangsu Provincial Key Lab for the Chemistry and Utilization
of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels
and Chemicals, International Innovation Center for Forest Chemicals
and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing, Jiangsu 210037, China
| | - Hualong Fu
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Key
Laboratory of Radiopharmaceuticals, Ministry of Education, College
of Chemistry, Beijing Normal University, Beijing 100875, China
| | - Ruofan Lin
- Jiangsu
Co-Innovation Center of Efficient Processing and Utilization of Forest
Resources, Jiangsu Provincial Key Lab for the Chemistry and Utilization
of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels
and Chemicals, International Innovation Center for Forest Chemicals
and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing, Jiangsu 210037, China
| | - Jingyin Zhou
- Key
Laboratory of Radiopharmaceuticals, Ministry of Education, College
of Chemistry, Beijing Normal University, Beijing 100875, China
| | - Ahmed Haider
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Department
of Radiology and Imaging Sciences, Emory
University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
| | - Weiwei Fang
- Jiangsu
Co-Innovation Center of Efficient Processing and Utilization of Forest
Resources, Jiangsu Provincial Key Lab for the Chemistry and Utilization
of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels
and Chemicals, International Innovation Center for Forest Chemicals
and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing, Jiangsu 210037, China
| | - Nehal H. Elghazawy
- Department
of Pharmaceutical, Chemistry, Faculty of Pharmacy & Biotechnology, German University in Cairo, 11835 Cairo, Egypt
| | - Jian Rong
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Department
of Radiology and Imaging Sciences, Emory
University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
| | - Jiahui Chen
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Department
of Radiology and Imaging Sciences, Emory
University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
| | - Yinlong Li
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Department
of Radiology and Imaging Sciences, Emory
University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
| | - Chongzhao Ran
- Athinoula
A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02114, United States
| | - Thomas L. Collier
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Department
of Radiology and Imaging Sciences, Emory
University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
| | - Zhen Chen
- Jiangsu
Co-Innovation Center of Efficient Processing and Utilization of Forest
Resources, Jiangsu Provincial Key Lab for the Chemistry and Utilization
of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels
and Chemicals, International Innovation Center for Forest Chemicals
and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing, Jiangsu 210037, China
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
| | - Steven H. Liang
- Division
of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital
& Department of Radiology, Harvard Medical
School, Boston, Massachusetts 02114, United States
- Department
of Radiology and Imaging Sciences, Emory
University, 1364 Clifton Road, Atlanta, Georgia 30322, United States
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Pechlivanidou M, Ninou E, Karagiorgou K, Tsantila A, Mantegazza R, Francesca A, Furlan R, Dudeck L, Steiner J, Tzartos J, Tzartos S. Autoimmunity to Neuronal Nicotinic Acetylcholine Receptors. Pharmacol Res 2023; 192:106790. [PMID: 37164280 DOI: 10.1016/j.phrs.2023.106790] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/30/2023] [Accepted: 05/05/2023] [Indexed: 05/12/2023]
Abstract
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in many and diverse cell types, participating in various functions of cells, tissues and systems. In this review, we focus on the autoimmunity against neuronal nAChRs, the specific autoantibodies and their mechanisms of pathological action in selected autoimmune diseases. We summarize the current relevant knowledge from human diseases as well as from experimental models of autoimmune neurological disorders related to antibodies against neuronal nAChR subunits. Despite the well-studied high immunogenicity of the muscle nAChRs where autoantibodies are the main pathogen of myasthenia gravis, autoimmunity to neuronal nAChRs seems infrequent, except for the autoantibodies to the ganglionic receptor, the α3 subunit containing nAChR (α3-nAChR), which are detected and are likely pathogenic in Autoimmune Autonomic Ganglionopathy (AAG). We describe the detection, presence and function of these antibodies and especially the recent development of a cell-based assay (CBA) which, contrary to until recently available assays, is highly specific for AAG. Rare reports of autoantibodies to the other neuronal nAChR subtypes include a few cases of antibodies to α7 and/or α4β2 nAChRs in Rasmussen encephalitis, schizophrenia, autoimmune meningoencephalomyelitis, and in some myasthenia gravis patients with concurrent CNS symptoms. Neuronal-type nAChRs are also present in several non-excitable tissues, however the presence and possible role of antibodies against them needs further verification. It is likely that the future development of more sensitive and disease-specific assays would reveal that neuronal nAChR autoantibodies are much more frequent and may explain the mechanisms of some seronegative autoimmune diseases.
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Affiliation(s)
| | | | - Katerina Karagiorgou
- Tzartos NeuroDiagnostics, Athens, Greece; Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
| | | | - Renato Mantegazza
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, Italy
| | - Andreetta Francesca
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, Italy
| | - Raffaello Furlan
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Rozzano, Milan, Italy; Clinical and Research Center - IRCCS, Humanitas University, Rozzano, Milan, Italy
| | - Leon Dudeck
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Johann Steiner
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany; Center for Health and Medical Prevention (CHaMP), Magdeburg, Germany; German Center for Mental Health DZPG, Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health C-I-R-C, Halle-Jena-Magdeburg, Germany
| | - John Tzartos
- 2(nd) Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, "Attikon" University Hospital, Athens, Greece.
| | - Socrates Tzartos
- Tzartos NeuroDiagnostics, Athens, Greece; Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece; Department of Pharmacy, University of Patras, Patras, Greece.
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5
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Miyazaki Y, Sakushima K, Niino M, Takahashi E, Oiwa K, Naganuma R, Amino I, Akimoto S, Minami N, Yabe I, Kikuchi S. Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis. Immunol Med 2022; 46:77-83. [PMID: 36346077 DOI: 10.1080/25785826.2022.2143077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.
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Affiliation(s)
- Yusei Miyazaki
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Ken Sakushima
- Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masaaki Niino
- Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Eri Takahashi
- Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Kei Oiwa
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Ryoji Naganuma
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Itaru Amino
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Sachiko Akimoto
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Naoya Minami
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Ichiro Yabe
- Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Seiji Kikuchi
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
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Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
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Watson WH, Ritzenthaler JD, Torres-Gonzalez E, Arteel GE, Roman J. Mice lacking α4 nicotinic acetylcholine receptors are protected against alcohol-associated liver injury. Alcohol Clin Exp Res 2022; 46:1371-1383. [PMID: 35723023 PMCID: PMC9427714 DOI: 10.1111/acer.14893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND Chronic heavy alcohol consumption is a major risk factor for the development of liver steatosis, fibrosis, and cirrhosis, but the mechanisms by which alcohol causes liver damage remain incompletely elucidated. This group has reported that α4 nicotinic acetylcholine receptors (α4 nAChRs) act as sensors for alcohol in lung cells. This study tested the hypothesis that α4 nAChRs mediate the effects of alcohol in the liver. METHODS Expression of acetylcholine receptor subunits in mouse liver was determined by RNA sequencing (RNA-seq). α4 nAChR knockout (α4 KO) mice were generated in C57BL/6J mice by introducing a mutation encoding an early stop codon in exon 4 of Chrna4, the gene encoding the α4 subunit of the nAChR. The presence of the inactivating mutation was established by polymerase chain reaction and genomic sequencing, and the lack of α4 nAChR function was confirmed in primary fibroblasts isolated from the α4 KO mice. Wild-type (WT) and α4 KO mice were fed the Lieber-DeCarli diet (with 36% of calories from alcohol) or pair fed an isocaloric maltose-dextrin control diet for a 6-week period that included a ramping up phase of increasing dietary alcohol. RESULTS Chrna4 was the most abundantly expressed nAChR subunit gene in mouse livers. After 6 weeks of alcohol exposure, WT mice had elevated serum transaminases and their livers showed increased fat accumulation, decreased Sirt1 protein levels, and accumulation of markers of oxidative stress and inflammation including Cyp2E1, Nos2, Sod1, Slc7a11, TNFα, and PAI1. All these responses to alcohol were either absent or significantly attenuated in α4 KO animals. CONCLUSION Together, these observations support the conclusion that activation of α4 nAChRs by alcohol or one of its metabolites is one of the initial events promoting the accumulation of excess fat and expression of inflammatory mediators. Thus, α4 nAChRs may represent viable targets for intervention in chronic alcohol-related liver disease.
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Affiliation(s)
- Walter H. Watson
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY,Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY
| | - Jeffrey D. Ritzenthaler
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA
| | - Edilson Torres-Gonzalez
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA
| | - Gavin E. Arteel
- Department of Medicine, Division Gastroenterology, University of Pittsburgh, Pittsburgh, PA
| | - Jesse Roman
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA
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8
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Miyazaki Y, Niino M, Sakushima K, Takahashi E, Naganuma R, Amino I, Akimoto S, Minami N, Yabe I, Kikuchi S. Association of Smoking and Generalized Manifestations of Myasthenia Gravis. Intern Med 2022; 61:1693-1698. [PMID: 34744112 PMCID: PMC9259322 DOI: 10.2169/internalmedicine.8460-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.
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Affiliation(s)
- Yusei Miyazaki
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Japan
| | - Masaaki Niino
- Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Japan
| | - Ken Sakushima
- Department of Neurology, Hokkaido University Graduate School of Medicine, Japan
| | - Eri Takahashi
- Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Japan
| | - Ryoji Naganuma
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Japan
| | - Itaru Amino
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Japan
| | - Sachiko Akimoto
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Japan
| | - Naoya Minami
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Japan
| | - Ichiro Yabe
- Department of Neurology, Hokkaido University Graduate School of Medicine, Japan
| | - Seiji Kikuchi
- Department of Neurology, National Hospital Organization Hokkaido Medical Center, Japan
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9
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Sulforaphane Suppresses the Nicotine-Induced Expression of the Matrix Metalloproteinase-9 via Inhibiting ROS-Mediated AP-1 and NF-κB Signaling in Human Gastric Cancer Cells. Int J Mol Sci 2022; 23:ijms23095172. [PMID: 35563563 PMCID: PMC9099819 DOI: 10.3390/ijms23095172] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/28/2022] [Accepted: 05/02/2022] [Indexed: 02/01/2023] Open
Abstract
Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. Nicotine, a psychoactive alkaloid found in tobacco, is associated with the development of gastric cancer. Here, we found that sulforaphane suppresses the nicotine-mediated induction of MMP-9 in human gastric cancer cells. We discovered that reactive oxygen species (ROS) and MAPKs (p38 MAPK, Erk1/2) are involved in nicotine-induced MMP-9 expression. AP-1 and NF-κB are the critical transcription factors in MMP-9 expression. ROS/MAPK (p38 MAPK, Erk1/2) and ROS functioned as upstream signaling of AP-1 and NF-κB, respectively. Sulforaphane suppresses the nicotine-induced MMP-9 by inhibiting ROS-mediated MAPK (p38 MAPK, Erk1/2)/AP-1 and ROS-mediated NF-κB signaling axes, which in turn inhibit cell invasion in human gastric cancer AGS cells. Therefore, the current study provides valuable evidence for developing sulforaphane as a new anti-invasion strategy for human gastric cancer therapy.
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Zhang L, Yao LN, Liu W, Chen AQ, He SM, Wei ML, Fan ZX, Ren DL. N-acetylcholine receptors regulate cytokines expression and neutrophils recruitment via MAPK/ERK signaling in zebrafish. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 128:104328. [PMID: 34883109 DOI: 10.1016/j.dci.2021.104328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 06/13/2023]
Abstract
N-acetylcholine receptors (AChRs) are mainly distributed in the postsynaptic membrane and have been widely studied for their control of muscle contraction by regulating neural action potentials. However, the influences of AChRs on immune responses and potential mechanisms remain unclear. Here, we used the advantages of live imaging of zebrafish to explore the regulation process of AChRs on inflammatory responses. Pharmacologically activating of the receptor, we found that the expression of pro-inflammatory cytokines il-1β, il-6, tnf-α and il-8 was significantly up-regulated and neutrophil migration to injury sites was also significantly increased. However, these phenomena were reversed under antagonism of the receptor activity. Results showed that interfering with nAChRs functions did not significantly affect zebrafish motion behavior. Results also showed that activation and antagonism of nAChRs function could regulate the phosphorylation of ERK protein respectively. We further demonstrated that ERK participated in the regulation of AChRs in cytokines expression and neutrophils migration in zebrafish. This study preliminarily revealed the roles of AChRs in inflammatory processes and their potential mechanism, providing additional evidence of peripheral immune regulation by cholinergic receptors.
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Affiliation(s)
- Ling Zhang
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Li-Na Yao
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Wei Liu
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - An-Qi Chen
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Shi-Min He
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Mei-Li Wei
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Zi-Xuan Fan
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Da-Long Ren
- Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China.
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11
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Muderrisoglu A, Babaoglu E, Korkmaz ET, Kalkisim S, Karabulut E, Emri S, Babaoglu MO. Comparative Assessment of Outcomes in Drug Treatment for Smoking Cessation and Role of Genetic Polymorphisms of Human Nicotinic Acetylcholine Receptor Subunits. Front Genet 2022; 13:812715. [PMID: 35222535 PMCID: PMC8866864 DOI: 10.3389/fgene.2022.812715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/14/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: To investigate the effects of genetic polymorphisms of human nicotinic acetylcholine receptor subunits α3, α4 and α5, which are encoded by CHRNA3, CHRNA4 CHRNA5 genes, respectively, on nicotine addiction and outcomes of pharmacological treatments for smoking cessation.Methods: A total of 143 smokers and 130 non-smokers were included. Genotyping for CHRNA3 rs578776, CHRNA4 rs1044396-rs1044397, CNRNA5 rs16969968 polymorphisms was performed by PCR, flowed by RFLP. Clinical outcomes and success rates of pharmacological treatments for smoking cessation with nicotine replacement therapy (NRT), bupropion or varenicline were determined at the 12th week of the treatment.Results: Overall, 52 out of 143 (36.4%) smokers who received pharmacotherapy were able to quit smoking. Success rates for smoking cessation were similar for female (30.3%) and male (41.6%) subjects (p = 0.16). The success rate for smoking cessation treatment with varenicline (58.5%) was significantly higher as compared to other treatments with NRT (20.0%), bupropion (32.3%) or bupropion + NRT (40.0%) (chi-square test, p = 0.001). Smoker vs. non-smoker status and the clinical outcomes of drugs used for smoking cessation were found similar in subjects carrying wild-type and variant alleles of human nicotinic acetylcholine receptor α subunits.Conclusion: In this study, smoking cessation treatment with varenicline was significantly more effective than treatments with nicotine replacement or bupropion in a cohort of Turkish subjects. Smoker/non-smoker status and the clinical outcomes of treatment with pharmacological agents were similar in subjects with wild-type or variant alleles for human nicotinic acetylcholine receptor subunits α3 (CHRNA3), α4 (CHRNA4) and α5 (CHRNA5).
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Affiliation(s)
- Ahmet Muderrisoglu
- Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
- *Correspondence: Ahmet Muderrisoglu, , orcid.org/0000-0003-2954-360X
| | - Elif Babaoglu
- Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Elif Tugce Korkmaz
- Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Said Kalkisim
- Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Erdem Karabulut
- Department of Biostatistics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Salih Emri
- Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Melih O. Babaoglu
- Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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12
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Lian S, Li S, Zhu J, Xia Y, Do Jung Y. Nicotine stimulates IL-8 expression via ROS/NF-κB and ROS/MAPK/AP-1 axis in human gastric cancer cells. Toxicology 2022; 466:153062. [PMID: 34890707 DOI: 10.1016/j.tox.2021.153062] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 02/04/2023]
Abstract
Nicotine, a major alkaloid found in tobacco, is a significant risk factor for gastric cancer. IL-8, a pleiotropic cytokine, plays a vital role in cancer cell metastasis. The role of nicotine in IL-8 expression and the underlying mechanism is currently unknown. Here, we examined the effects of nicotine on IL-8 expression and explored the potential mechanisms in gastric cancer cells. We found that nicotine increases IL-8 expression. Specific inhibitor and mutagenesis studies showed that ROS and MAPK (Erk1/2, p38) were involved in this process. Deletion and site-directed mutagenesis studies indicate the involvement of transcription factor NF-κB and AP-1. ROS and ROS/MAPK (Erk1/2, p38) functioned as the upstream signaling molecules in the activation of NF-κB and AP-1, respectively. AGS gastric cancer cells pretreated with nicotine stimulate angiogenesis in the tumor microenvironment, partially abrogated by silencing IL-8 in AGS cells. In this study, we found that nicotine induces IL-8 expression via ROS/NF-κB and ROS/MAPK (Erk1/2, p38)/AP-1 axis in gastric cancer cells, thus stimulating endothelial cell proliferation and angiogenesis in the tumor microenvironment.
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Affiliation(s)
- Sen Lian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China.
| | - Shinan Li
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jun Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Yong Xia
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, Shandong, 272067, China.
| | - Young Do Jung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
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13
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Kawasaki H, Hino H, Takayama F, Kitamura Y, Sendou T, Takatori S. Regulatory effects of nicotine on neurite outgrowth in rat superior cervical ganglia cells. J Pharmacol Sci 2021; 148:103-107. [PMID: 34924113 DOI: 10.1016/j.jphs.2021.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/21/2021] [Accepted: 10/24/2021] [Indexed: 11/28/2022] Open
Abstract
We have reported that nicotine has a neurotrophic action on peripheral adrenergic nerves in vivo, which is mediated by α7 nicotinic acetylcholine receptors (nAChRs). To clarify the possible mechanisms, the present study further investigated the effect of nicotine on neurite outgrowth in tyrosine hydroxylase (TH)-positive superior cervical ganglia (SCG) cells isolated from neonatal rats in vitro. Nicotine at low concentrations (0.01-0.3 mM) increased the number of neurite outgrowths in TH-immunopositive SCG cells, while high concentrations of nicotine (1-10 mM) gradually reduced it, and only 10 mM nicotine was markedly inhibited compared to the control. A 100 μM of nicotine-induced increase in neurite numbers depended on the exposure time and was inhibited by treatment with the nAChR antagonist hexamethonium (Hex) and α7 nAChR antagonist α-bungarotoxin (α-Bgtx). The nicotine (10 mM)-induced a significant decrease in neurite outgrowth in SCG, which was perfectly canceled by Hex to the control level but not by α-Bgtx. These results suggest that nicotine has a regulatory neurotrophic action mediated by both α7 nAChR and other subtypes in TH-positive SCG cells of rats.
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Affiliation(s)
- Hiromu Kawasaki
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
| | - Hayato Hino
- Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan; Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Fusako Takayama
- Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
| | - Yoshihisa Kitamura
- Department of Pharmacotherapy, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan
| | - Toshiaki Sendou
- Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Shingo Takatori
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
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14
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Maltan L, Najjar H, Tiffner A, Derler I. Deciphering Molecular Mechanisms and Intervening in Physiological and Pathophysiological Processes of Ca 2+ Signaling Mechanisms Using Optogenetic Tools. Cells 2021; 10:3340. [PMID: 34943850 PMCID: PMC8699489 DOI: 10.3390/cells10123340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 11/16/2022] Open
Abstract
Calcium ion channels are involved in numerous biological functions such as lymphocyte activation, muscle contraction, neurotransmission, excitation, hormone secretion, gene expression, cell migration, memory, and aging. Therefore, their dysfunction can lead to a wide range of cellular abnormalities and, subsequently, to diseases. To date various conventional techniques have provided valuable insights into the roles of Ca2+ signaling. However, their limited spatiotemporal resolution and lack of reversibility pose significant obstacles in the detailed understanding of the structure-function relationship of ion channels. These drawbacks could be partially overcome by the use of optogenetics, which allows for the remote and well-defined manipulation of Ca2+-signaling. Here, we review the various optogenetic tools that have been used to achieve precise control over different Ca2+-permeable ion channels and receptors and associated downstream signaling cascades. We highlight the achievements of optogenetics as well as the still-open questions regarding the resolution of ion channel working mechanisms. In addition, we summarize the successes of optogenetics in manipulating many Ca2+-dependent biological processes both in vitro and in vivo. In summary, optogenetics has significantly advanced our understanding of Ca2+ signaling proteins and the used tools provide an essential basis for potential future therapeutic application.
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Affiliation(s)
| | | | | | - Isabella Derler
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria; (L.M.); (H.N.); (A.T.)
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15
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Matta JA, Gu S, Davini WB, Bredt DS. Nicotinic acetylcholine receptor redux: Discovery of accessories opens therapeutic vistas. Science 2021; 373:373/6556/eabg6539. [PMID: 34385370 DOI: 10.1126/science.abg6539] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The neurotransmitter acetylcholine (ACh) acts in part through a family of nicotinic ACh receptors (nAChRs), which mediate diverse physiological processes including muscle contraction, neurotransmission, and sensory transduction. Pharmacologically, nAChRs are responsible for tobacco addiction and are targeted by medicines for hypertension and dementia. Nicotinic AChRs were the first ion channels to be isolated. Recent studies have identified molecules that control nAChR biogenesis, trafficking, and function. These nAChR accessories include protein and chemical chaperones as well as auxiliary subunits. Whereas some factors act on many nAChRs, others are receptor specific. Discovery of these regulatory mechanisms is transforming nAChR research in cells and tissues ranging from central neurons to spinal ganglia to cochlear hair cells. Nicotinic AChR-specific accessories also enable drug discovery on high-confidence targets for psychiatric, neurological, and auditory disorders.
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Affiliation(s)
| | | | - Weston B Davini
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA 92121, USA
| | - David S Bredt
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA 92121, USA.
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16
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Afrashteh Nour M, Hajiasgharzadeh K, Kheradmand F, Asadzadeh Z, Bolandi N, Baradaran B. Nicotinic acetylcholine receptors in chemotherapeutic drugs resistance: An emerging targeting candidate. Life Sci 2021; 278:119557. [PMID: 33930371 DOI: 10.1016/j.lfs.2021.119557] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/11/2021] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
There is no definitive cure for cancer, and most of the current chemotherapy drugs have limited effects due to the development of drug resistance and toxicity at high doses. Therefore, there is an ongoing need for identifying the causes of chemotherapeutic resistance, and it will be possible to develop innovative treatment approaches based on these novel targeting candidates. Cigarette smoking is known to be one of the main causes of resistance to chemotherapeutic agents. Nicotine as a component of cigarette smoke is an exogenous activator of nicotinic acetylcholine receptors (nAChRs). It can inhibit apoptosis, increase cell proliferation and cell survival, reducing the cytotoxic effects of chemotherapy drugs and cause a reduced therapeutic response. Recent studies have demonstrated that nAChRs and their downstream signaling pathways have considerable implications in different cancer's initiation, progression, and chemoresistance. In some previous studies, nAChRs have been targeted to obtain better efficacies for chemotherapeutics. Besides, nAChRs-based therapies have been used in combination with chemotherapy drugs to reduce the side effects. This strategy requires lower doses of chemotherapy drugs compared to the conditions that must be used alone. Here, we discussed the experimental and clinical studies that show the nAChRs involvement in response to chemotherapy agents. Also, controversies relating to the effects of nAChR on chemotherapy-induced apoptosis are in our focus in this review article. Delineating the complex influences of nAChRs would be of great interest in establishing new effective chemotherapy regimens.
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Affiliation(s)
- Mina Afrashteh Nour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Khalil Hajiasgharzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nadia Bolandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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17
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Sherafat Y, Bautista M, Fowler CD. Multidimensional Intersection of Nicotine, Gene Expression, and Behavior. Front Behav Neurosci 2021; 15:649129. [PMID: 33828466 PMCID: PMC8019722 DOI: 10.3389/fnbeh.2021.649129] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
The cholinergic system plays a crucial role in nervous system function with important effects on developmental processes, cognition, attention, motivation, reward, learning, and memory. Nicotine, the reinforcing component of tobacco and e-cigarettes, directly acts on the cholinergic system by targeting nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs leads to a multitude of immediate and long-lasting effects in specific cellular populations, thereby affecting the addictive properties of the drug. In addition to the direct actions of nicotine in binding to and opening nAChRs, the subsequent activation of circuits and downstream signaling cascades leads to a wide range of changes in gene expression, which can subsequently alter further behavioral expression. In this review, we provide an overview of the actions of nicotine that lead to changes in gene expression and further highlight evidence supporting how these changes can often be bidirectional, thereby inducing subsequent changes in behaviors associated with further drug intake.
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Affiliation(s)
- Yasmine Sherafat
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, Unites States
| | - Malia Bautista
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, Unites States
| | - Christie D Fowler
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, Unites States
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18
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Knowland D, Gu S, Eckert WA, Dawe GB, Matta JA, Limberis J, Wickenden AD, Bhattacharya A, Bredt DS. Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties. J Clin Invest 2021; 130:6158-6170. [PMID: 33074244 DOI: 10.1172/jci140311] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/06/2020] [Indexed: 01/25/2023] Open
Abstract
The α6β4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP's N-terminal region and IRE1α's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.
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19
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Ho TNT, Abraham N, Lewis RJ. Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins. Front Neurosci 2020; 14:609005. [PMID: 33324158 PMCID: PMC7723979 DOI: 10.3389/fnins.2020.609005] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022] Open
Abstract
Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.
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Affiliation(s)
| | | | - Richard J. Lewis
- Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
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20
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Gaza JT, Sampaco ARB, Custodio KKS, Nellas RB. Conformational dynamics of
α
-conotoxin PnIB in complex solvent systems. Mol Divers 2020; 24:1291-1299. [PMID: 31502188 DOI: 10.1007/s11030-019-09993-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/03/2019] [Indexed: 01/13/2023]
Abstract
Cone snails are slow-moving animals that secure survival by injecting to their prey a concoction of highly potent and stable neurotoxic peptides called conotoxins. These small toxins (~ 10-30 AA) interact with ion channels and their diverse structures account for various variables such as the environment and the prey of preference. This study probed the conformational space of α-conotoxin PnIB from Conus pennaceus by performing all-atom molecular dynamics simulations on the conotoxin in complex solvent systems of water and octanol. Secondary structure analyses showed a uniform conformation for the pure (C100Oc, C100W) and minute (C95Oc, C5Oc) systems. In C50Oc, however, structural changes were observed. The original helices were converted to turns and were shown to happen simultaneously with the elongation of the helix and shortening of end-to-end distance. The transitions complement the orientation of the peptide at the interface. The shift to the broken helix conformation is marked by the rearrangement of solvent molecules to a framework that favors the accumulation of water molecules at residues 6-11 of the H2 region. This promotes specific protein-solvent interactions that facilitate secondary structure transitions. As PnIB has shown favorable binding toward neuronal nicotinic acetylcholine receptors, this study may provide insights on this conotoxin's therapeutic potential. Description: Structural changes in PnIB are accompanied by a simultaneous change in solvent density.
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Affiliation(s)
- Jokent T Gaza
- Institute of Chemistry, College of Science, University of the Philippines Diliman, Diliman, Quezon City, Philippines
| | - Abdul-Rashid B Sampaco
- Institute of Chemistry, College of Science, University of the Philippines Diliman, Diliman, Quezon City, Philippines
| | - Kenee Kaiser S Custodio
- Institute of Chemistry, College of Science, University of the Philippines Diliman, Diliman, Quezon City, Philippines
| | - Ricky B Nellas
- Institute of Chemistry, College of Science, University of the Philippines Diliman, Diliman, Quezon City, Philippines.
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21
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Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products. Proc Natl Acad Sci U S A 2020; 117:24534-24544. [PMID: 32929005 DOI: 10.1073/pnas.2013762117] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Auditory hair cells receive olivocochlear efferent innervation, which refines tonotopic mapping, improves sound discrimination, and mitigates acoustic trauma. The olivocochlear synapse involves α9α10 nicotinic acetylcholine receptors (nAChRs), which assemble in hair cells only coincident with cholinergic innervation and do not express in recombinant mammalian cell lines. Here, genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and retain α9α10-mediated transmission beyond the second postnatal week associated with abnormally persistent cholinergic innervation. Collectively, this study provides a mechanism to link cholinergic input with α9α10 assembly, identifies unexpected functions for human deafness genes TMIE/TMEM132e, and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders.
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Stegemann A, Böhm M. Targeting the α7 nicotinic acetylcholine receptor-A novel road towards the future treatment of skin diseases. Exp Dermatol 2020; 29:924-931. [PMID: 32780438 DOI: 10.1111/exd.14173] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022]
Abstract
Nicotinic acetylcholine receptors (nAChRs) are members of the superfamily of neurotransmitter-gated ion channels. The natural ligand for nAChRs is the endogenous neurotransmitter acetylcholine. Among the nAChRs is the α7nAChR. It is not only expressed by neural tissues but also in the skin. A number of different resident cutaneous cell types including epidermal keratinocytes, sebocytes and dermal fibroblasts express functional α7nAChR. Moreover, cells of the immune system such as lymphocytes, macrophages and monocytes, playing an important role in skin homeostasis, also express α7nAChR. Translational research focusing on the exploitation of the α7nAChR in dermatology has revealed that this neuroendocrine receptor could be promising target for the treatment of inflammatory skin diseases. For example, α7nAChR agonists can counteract transforming growth factor-β1-mediated responses in dermal fibroblasts, key effector cells in scleroderma. In accordance with this α7nAChR, agonists are effective in both inflammation and non-inflammation-driven models of experimentally induced skin fibrosis. Moreover, α7nAChR agonists can modulate expression of proinflammatory cytokines in epidermal keratinocytes that are crucially involved in the pathogenesis of psoriasis and other inflammatory skin diseases. Finally, the capability of α7nAChR agonists to suppress ultraviolet light A/B-induced responses, for example production of proinflammatory cytokines and oxidative stress, the latter crucially involved in dermal photoageing, points to a potential of such agents in the prevention of extrinsic skin ageing. Therefore, emphasis on translational research targeting the α7nAChR in skin may lead to the development of new treatment and prevention modalities against fibrosclerotic skin diseases, psoriasis vulgaris, atopic dermatitis, acne, photodermatoses and extrinsic skin ageing.
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Affiliation(s)
| | - Markus Böhm
- Dept. of Dermatology, University of Münster, Germany
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23
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NACHO Engages N-Glycosylation ER Chaperone Pathways for α7 Nicotinic Receptor Assembly. Cell Rep 2020; 32:108025. [DOI: 10.1016/j.celrep.2020.108025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/13/2020] [Accepted: 07/21/2020] [Indexed: 01/01/2023] Open
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24
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Abbasi F, Baradaran R, Khoshdel-Sarkarizi H, Kargozar S, Hami J, Mohammadipour A, Kheradmand H, Haghir H. Distribution pattern of nicotinic acetylcholine receptors in developing cerebellum of rat neonates born of diabetic mothers. J Chem Neuroanat 2020; 108:101819. [PMID: 32522497 DOI: 10.1016/j.jchemneu.2020.101819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 05/25/2020] [Accepted: 05/28/2020] [Indexed: 11/15/2022]
Affiliation(s)
- Faeze Abbasi
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Raheleh Baradaran
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Hoda Khoshdel-Sarkarizi
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Saeid Kargozar
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Hami
- Department of Anatomical Sciences, School of Medicine, BirjandUniversity of Medical Sciences, Birjand, Iran
| | - Abbas Mohammadipour
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Hamed Kheradmand
- Hazrat Rasoul Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Haghir
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran; Medical Genetic Research Center (MGRC), School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran.
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25
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Dhara M, Matta JA, Lei M, Knowland D, Yu H, Gu S, Bredt DS. Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology. Nat Commun 2020; 11:2799. [PMID: 32493979 PMCID: PMC7271128 DOI: 10.1038/s41467-020-16629-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/15/2020] [Indexed: 01/31/2023] Open
Abstract
Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology. Small molecule polyamines participate in diverse aspects of cell growth and differentiation and are known to regulate ion channel gating. Here authors reveal that cellular polyamines control nicotinic acetylcholine receptor (nAChR) biogenesis, and either catabolic degradation or inhibition of polyamine production augments nAChR assembly.
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Affiliation(s)
- Madhurima Dhara
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Jose A Matta
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Min Lei
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Daniel Knowland
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Hong Yu
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - Shenyan Gu
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA
| | - David S Bredt
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA.
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26
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Characterization of AN317, a novel selective agonist of α6β2-containing nicotinic acetylcholine receptors. Biochem Pharmacol 2020; 174:113786. [DOI: 10.1016/j.bcp.2019.113786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 12/23/2019] [Indexed: 11/23/2022]
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27
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Iarkov A, Barreto GE, Grizzell JA, Echeverria V. Strategies for the Treatment of Parkinson's Disease: Beyond Dopamine. Front Aging Neurosci 2020; 12:4. [PMID: 32076403 PMCID: PMC7006457 DOI: 10.3389/fnagi.2020.00004] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/09/2020] [Indexed: 12/11/2022] Open
Abstract
Parkinson’s disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.
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Affiliation(s)
- Alexandre Iarkov
- Laboratorio de Neurobiología, Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
| | - J Alex Grizzell
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO, United States
| | - Valentina Echeverria
- Laboratorio de Neurobiología, Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile.,Research & Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, United States
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28
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Associations between Environmental Tobacco Smoke Exposure in Early Life and Astigmatism among Chinese Preschool Children. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16193725. [PMID: 31623306 PMCID: PMC6801470 DOI: 10.3390/ijerph16193725] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 09/15/2019] [Accepted: 10/01/2019] [Indexed: 12/13/2022]
Abstract
This study aimed to investigate the association between environmental exposure to tobacco smoke (ETS) during early life and astigmatism in Chinese preschool children. In this cross-sectional study, information concerning prenatal and postnatal ETS exposure at three stages of early life (during pregnancy, from birth to one year and from one to three years), visual problems of children and parents (including a confirmed diagnosis of astigmatism), socio-demographics and perinatal characteristics were obtained from 27,890 parent-reported questionnaires. Logistic regression analyses were undertaken to yield adjusted odds ratios (OR) for assessing their associations. After adjusting for the potential confounders, children were more likely to exhibit astigmatism when they were exposed to ETS during pregnancy + from one to three years [OR (95% CI) = 1.37 (1.02, 1.84)], or from birth to one year + from one to three years [OR (95% CI) = 1.36 (1.11, 1.66)], or during pregnancy + from birth to one year + from one to three years old [OR (95% CI) = 1.29 (1.16, 1.45)], compared to children without ETS exposure at any stage of early life. In Chinese preschool children, prenatal and postnatal astigmatism was associated with ETS exposure; the greater the ETS dose, the greater the astigmatism risk.
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29
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Sallam MY, El-Gowilly SM, Fouda MA, Abd-Alhaseeb MM, El-Mas MM. Brainstem cholinergic pathways diminish cardiovascular and neuroinflammatory actions of endotoxemia in rats: Role of NFκB/α7/α4β2AChRs signaling. Neuropharmacology 2019; 157:107683. [DOI: 10.1016/j.neuropharm.2019.107683] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/16/2019] [Accepted: 06/23/2019] [Indexed: 12/20/2022]
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30
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Hajiasgharzadeh K, Sadigh-Eteghad S, Mansoori B, Mokhtarzadeh A, Shanehbandi D, Doustvandi MA, Asadzadeh Z, Baradaran B. Alpha7 nicotinic acetylcholine receptors in lung inflammation and carcinogenesis: Friends or foes? J Cell Physiol 2019; 234:14666-14679. [PMID: 30701535 DOI: 10.1002/jcp.28220] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 01/24/2023]
Abstract
The lung tissue expresses the cholinergic system including nicotinic acetylcholine receptors (nAChRs) which included in many physiologic and pathologic processes. Mounting evidence revealed that these receptors have important roles in lung carcinogenesis via modulating either stimulatory or inhibitory signaling pathways. Among different members of nicotinic receptors family, alpha7-subtype of nAChR (α7nAChR) is a critical mediator involved in both inflammatory responses and cancers. Several studies have shown that this receptor is the most powerful regulator of responses that stimulate lung cancer processes such as proliferation, angiogenesis, metastasis, and inhibition of apoptosis. Moreover, aside from its roles in the regulation of cancer pathways, there is growing evidence indicating that α7nAChR has profound impacts on lung inflammation through the cholinergic anti-inflammatory pathway. Regarding such diverse effects as well as the critical roles of nicotine as an activator of α7nAChR on lung cancer pathogenesis, its modulation has emerged as a promising target for drug developments. In this review, we aim to highlight the detrimental as well as the possible beneficial influences of α7nAChR downstream signaling cascades in the control of lung inflammation and cancer-associated properties. Consequently, by considering the significant global burden of lung cancer, delineating the complex influences of α7 receptors would be of great interest in designing novel anticancer and anti-inflammatory strategies for the patients suffering from lung cancer.
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Affiliation(s)
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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31
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Sow AS, Ndiaye JM, Wane AM, Kane H, Ka AM, Diagne JP, Nguer M, Quenum MED, Ba EA, Ndoye Roth PA, Ndiaye PA. [Ametropia among senegalese children in a hospital setting]. J Fr Ophtalmol 2019; 42:959-961. [PMID: 31235321 DOI: 10.1016/j.jfo.2019.05.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 05/12/2019] [Accepted: 05/16/2019] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Ametropia is common in children and cause strabismus and amblyopia. The goal was to establish its prevalence in a hospital setting among Senegalese children. PATIENTS AND METHODS This was a retrospective study of patients under 15 years of age with clear ocular media. The marital status, circumstances of discovery, and results of cycloplegic refraction were recorded. RESULTS Of 1506 children, 175 demonstrated ametropia. The mean age was 8 years, and the male : female ratio was 0.68. Family history of ametropia was present in 8.5 %. Decreased VA was present in 39.66 %, headache 10.06 %, and strabismus 4.47 %. Automated refraction in 109 patients and skiascopy in one patient showed 58.18 % cases of myopia, 18.18 % of hyperopia and 36.57 % of astigmatism. DISCUSSION The most common ametropia was myopia. Patients were referred for symptomatic ametropia. CONCLUSION Screening for ametropia might occur earlier if it is associated with pediatric monitoring in our regions.
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Affiliation(s)
- A S Sow
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal.
| | - J M Ndiaye
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal
| | - A M Wane
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal
| | - H Kane
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal
| | - A M Ka
- Clinique ophtalmologique, CHU Abass Ndao Dakar Gueule Tapée, Sénégal
| | - J P Diagne
- Clinique ophtalmologique, CHU Abass Ndao Dakar Gueule Tapée, Sénégal
| | - M Nguer
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal
| | - M E D Quenum
- Clinique ophtalmologique, CHU Abass Ndao Dakar Gueule Tapée, Sénégal
| | - E A Ba
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal
| | - P A Ndoye Roth
- Clinique ophtalmologique, CHU Aristide Le Dantec, Dakar, Sénégal
| | - P A Ndiaye
- Clinique ophtalmologique, CHU Abass Ndao Dakar Gueule Tapée, Sénégal
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32
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Aoki Y, Ikeda T, Tani N, Shida A, Oritani S, Ishikawa T. Evaluation of the distribution of nicotine intravenous injection: an adult autopsy case report with a review of literature. Int J Legal Med 2019; 134:243-249. [PMID: 30955048 PMCID: PMC6949309 DOI: 10.1007/s00414-019-02035-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 02/27/2019] [Indexed: 11/24/2022]
Abstract
We reported the first comprehensive autopsy case of death due to intravenous injection of nicotine. We examined the distribution of nicotine in the body tissues and fluid and exposed the pathophysiology of nicotine poisoning. A 19-year-old woman was rushed to the hospital in cardiorespiratory arrest and was confirmed dead upon arrival. Liquid nicotine, hydrogen peroxide water, and a syringe were found in the hotel room where she stayed. On autopsy, nicotine concentration was the highest (15,023 μg/mg) in the tissue around the injection mark on the right upper arm. Among the body fluids, the intraperitoneal fluid had the highest, whereas the pericardial fluid had the lowest (0.736 μg/mL) nicotine concentration. Among the organs, the brain had the highest (11.637 μg/mg), whereas the fat tissue had the lowest (1.307 μg/mg) nicotine concentration. The concentration of cotinine, which is the metabolite of nicotine, was the highest in the tissue around the injection mark on the right arm (5.495 μg/mg) and was almost the same among the other body fluids and organs. The respective concentrations of nicotine and cotinine were 1.529 μg/mL and 0.019 μg/mL in the left heart blood and 3.157 μg/mL and 0.002 μg/mL in right heart blood. In this case, the nicotine concentrations in blood reached the lethal level. The distributions of nicotine and cotinine, as indicated by the intravenous injection, were related to the distribution of organs that metabolize nicotine and the distribution of nicotinic acetylcholine receptors.
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Affiliation(s)
- Yayoi Aoki
- Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan.
| | - Tomoya Ikeda
- Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
- Forensic Autopsy Section, Medico-legal Consultation and Postmortem Investigation Support Center, c/o Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
| | - Naoto Tani
- Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
- Forensic Autopsy Section, Medico-legal Consultation and Postmortem Investigation Support Center, c/o Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
| | - Alissa Shida
- Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
| | - Shigeki Oritani
- Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
| | - Takaki Ishikawa
- Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
- Forensic Autopsy Section, Medico-legal Consultation and Postmortem Investigation Support Center, c/o Department of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, Japan
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Friedman JR, Richbart SD, Merritt JC, Brown KC, Nolan NA, Akers AT, Lau JK, Robateau ZR, Miles SL, Dasgupta P. Acetylcholine signaling system in progression of lung cancers. Pharmacol Ther 2019; 194:222-254. [PMID: 30291908 PMCID: PMC6348061 DOI: 10.1016/j.pharmthera.2018.10.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The neurotransmitter acetylcholine (ACh) acts as an autocrine growth factor for human lung cancer. Several lines of evidence show that lung cancer cells express all of the proteins required for the uptake of choline (choline transporter 1, choline transporter-like proteins) synthesis of ACh (choline acetyltransferase, carnitine acetyltransferase), transport of ACh (vesicular acetylcholine transport, OCTs, OCTNs) and degradation of ACh (acetylcholinesterase, butyrylcholinesterase). The released ACh binds back to nicotinic (nAChRs) and muscarinic receptors on lung cancer cells to accelerate their proliferation, migration and invasion. Out of all components of the cholinergic pathway, the nAChR-signaling has been studied the most intensely. The reason for this trend is due to genome-wide data studies showing that nicotinic receptor subtypes are involved in lung cancer risk, the relationship between cigarette smoke and lung cancer risk as well as the rising popularity of electronic cigarettes considered by many as a "safe" alternative to smoking. There are a small number of articles which review the contribution of the other cholinergic proteins in the pathophysiology of lung cancer. The primary objective of this review article is to discuss the function of the acetylcholine-signaling proteins in the progression of lung cancer. The investigation of the role of cholinergic network in lung cancer will pave the way to novel molecular targets and drugs in this lethal malignancy.
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Affiliation(s)
- Jamie R Friedman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Stephen D Richbart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Justin C Merritt
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Kathleen C Brown
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Nicholas A Nolan
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Austin T Akers
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Jamie K Lau
- Biology Department, Center for the Sciences, Box 6931, Radford University, Radford, Virginia 24142
| | - Zachary R Robateau
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Sarah L Miles
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755.
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Gu S, Matta JA, Davini WB, Dawe GB, Lord B, Bredt DS. α6-Containing Nicotinic Acetylcholine Receptor Reconstitution Involves Mechanistically Distinct Accessory Components. Cell Rep 2019; 26:866-874.e3. [PMID: 30673609 DOI: 10.1016/j.celrep.2018.12.103] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 09/26/2018] [Accepted: 12/21/2018] [Indexed: 01/29/2023] Open
Abstract
Acetylcholine gates a large family of nicotinic receptor cation channels that control neuronal excitation and neurotransmitter release. These receptors are key targets for neuropsychiatric disorders; however, difficulties in expressing nicotinic acetylcholine (nACh) receptors hamper elaboration of their pharmacology and obscure elucidation of their biological functions. Particularly intriguing are α6-containing nACh receptors, which mediate nicotine-induced dopamine release in striatum-nucleus accumbens. Using genome-wide cDNA screening, we identify three accessory proteins, β-anchoring and -regulatory protein (BARP), lysosomal-associated membrane protein 5 (LAMP5), and SULT2B1, that complement the nACh receptor chaperone NACHO to reconstitute α6β2β3 channel function. Whereas NACHO mediates α6β2β3 assembly, BARP primarily enhances channel gating and LAMP5 and SULT2B1 promote receptor surface trafficking. BARP knockout mice show perturbations in presynaptic striatal nACh receptors that are consistent with BARP modulation of receptor desensitization. These studies unravel the molecular complexity of α6β2β3 biogenesis and enable physiological studies of this crucial neuropharmacological target.
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Affiliation(s)
- Shenyan Gu
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Jose A Matta
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Weston B Davini
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - G Brent Dawe
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Brian Lord
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - David S Bredt
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
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35
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Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5. Arch Biochem Biophys 2018; 657:65-73. [PMID: 30222954 DOI: 10.1016/j.abb.2018.09.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/28/2018] [Accepted: 09/14/2018] [Indexed: 01/03/2023]
Abstract
Tobacco and alcohol are often co-abused. Nicotine can enhance alcoholic fatty liver, and CYP2A6 (CYP2A5 in mice), a major metabolism enzyme for nicotine, can be induced by alcohol. CYP2A5 knockout (cyp2a5-/-) mice and their littermates (cyp2a5+/+) were used to test whether CYP2A5 has an effect on nicotine-enhanced alcoholic fatty liver. The results showed that alcoholic fatty liver was enhanced by nicotine in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Combination of ethanol and nicotine increased serum triglyceride in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Cotinine, a major metabolite of nicotine, also enhanced alcoholic fatty liver, which was also observed in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Nitrotyrosine and malondialdehyde (MDA), markers of oxidative/nitrosative stress, were induced by alcohol and were further increased by nicotine and cotinine in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Reactive oxygen species (ROS) production during microsomal metabolism of nicotine and cotinine was increased in microsomes from cyp2a5+/+ mice but not in microsomes from cyp2a5-/- mice. These results suggest that nicotine enhances alcoholic fatty liver in a CYP2A5-dependent manner, which is related to ROS produced during the process of CYP2A5-dependent nicotine metabolism.
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Badanavalu MP, Srivatsan M. Nicotine is neuroprotective to neonatal neurons of sympathetic ganglion in rat. Auton Neurosci 2018; 216:25-32. [PMID: 30206032 DOI: 10.1016/j.autneu.2018.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/13/2018] [Accepted: 08/31/2018] [Indexed: 01/04/2023]
Abstract
Sympathetic neurons of SCG are dependent on availability of nerve growth factor (NGF) for their survival. SCG neurons express nicotinic receptors (nAChR) whose expression levels are modulated by nicotine. Nicotine exerts multiple effects on neurons, including neuroprotection, through nAChR binding. Although sympathetic neurons express robust levels of nAChR, a possible neuroprotective role for nicotine in these neurons is not well-understood. Therefore we determined the effect of nicotine exposure on survival of SCG neurons during NGF withdrawal in a well-established cell culture system. NGF was withdrawn in rat neonatal SCG neuron cultures which were then treated with either 10 μM nicotine alone or with nAChR antagonists 0.1 μM α-bungarotoxin (antagonist for α7 subunit bearing nAChR) and 10 μM mecamylamine (non-specific antagonist for ganglionic nAChR) for 48 h. Apoptotic death was determined by TUNEL staining. Cell survival was also determined by MTS assay. Western blot analysis of ERK1/2 was also performed. Our results showed that exposure to 10 μM nicotine significantly reduced apoptotic cell death in SCG neurons resulting from NGF withdrawal as shown by fewer TUNEL positive cells. The MTS assay results also revealed that 10 μM nicotine concentration significantly increased cell survival thus indicating neuroprotective effect of nicotine against cell death resulting from NGF withdrawal. Nicotinic receptor antagonists (bungarotoxin & mecamylamine) attenuated the effect of nicotine's action of neuroprotection. Western blot analysis showed an increased expression of ERK1/2 in nicotine treated cultures suggesting nicotine provided neuroprotection in SCG neurons by increasing the expression of ERK1/2 through nicotinic receptor dependent mechanisms.
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Affiliation(s)
- Mahadevappa P Badanavalu
- Department of Biological Sciences, Arkansas State University, Jonesboro, AR 72401, United States
| | - Malathi Srivatsan
- Department of Biological Sciences, Arkansas State University, Jonesboro, AR 72401, United States.
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Eom S, Kim YS, Lee SB, Noh S, Yeom HD, Bae H, Lee JH. Molecular Determinants of α3β4 Nicotinic Acetylcholine Receptors Inhibition by Triterpenoids. Biol Pharm Bull 2018; 41:65-72. [PMID: 29311484 DOI: 10.1248/bpb.b17-00576] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In a previous work, we reported the regulatory role of the triterpenoids on 5-hydroxytryptamine (5-HT)3A receptors activity in Xenopus laevis oocytes (Eur. J. Pharmacol., 615, 2009, Lee et al.). In the present report, we studied the modulation of triterpenoids on the activity of the human nicotinic acetylcholine receptor type α3β4. Two-electrode voltage clamp experiments were used to test acetylcholine mediated inward current (IACh). Treatment with triterpenoids (dehydroeburicoic acid, 6α-hydroxypolyporenic acid C and pachymic acid) inhibited IACh in a concentration dependent and reversible manner. The IC50 values for pachymic acid, dehydroeburicoic acid, and 6α-hydroxypolyporenic acid C were 14.9, 37.7, and 20.9 µM, respectively. The inhibitory regulation of IACh by each triterpenoid showed in a non-competitive manner on the activity of α3β4 nicotinic acetylcholine receptors. These results show that triterpenoids (pachymic acid, dehydroeburicoic acid, 6α-hydroxypolyporenic acid C) can be used as agents to modulate the activity of nicotinic acetylcholine receptor type α3β4. Furthermore, molecular docking studies of 6α-hydroxypolyporenic acid C on α3β4 nicotinic acetylcholine receptors in silico showed that this molecule interacted predominantly with residues at cavities in the α3 subunit and β4 subunit. This docking assays indicated four potential binding sites for this ligand in the extracellular region at sensor domain of α3β4 nicotinic acetylcholine receptors. In point mutagenesis of those whose alanine substitution, 6α-hydroxypolyporenic acid C potency decreased on W25A of α3 subunit or N109A of β4 subunit in both mutants. The double mutation of W25A of α3 subunit and N109A of β4 subunit was significantly attenuated inhibitory effects by 6α-hydroxypolyporenic acid C. All taken together, this study revealed that molecular basis of α3β4 nicotinic acetylcholine receptors by triterpenoids and provides a novel potent interaction ligand.
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Affiliation(s)
- Sanung Eom
- Department of Biotechnology, Chonnam National University
| | - Yoon Suh Kim
- Department of Biotechnology, Chonnam National University
| | - Sung Bae Lee
- Department of Biotechnology, Chonnam National University
| | - Shinhwa Noh
- Department of Biotechnology, Chonnam National University
| | - Hye Duck Yeom
- Department of Biotechnology, Chonnam National University
| | - Hyunsu Bae
- College of Korean Medicine, Kyung Hee University
| | - Jun-Ho Lee
- Department of Biotechnology, Chonnam National University
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Zarezin DP, Kabylda AM, Vinogradova VI, Dorovatovskii PV, Khrustalev VN, Nenajdenko VG. Efficient synthesis of tetrazole derivatives of cytisine using the azido-Ugi reaction. Tetrahedron 2018. [DOI: 10.1016/j.tet.2018.06.045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Torrealba D, Balasch JC, Criado M, Tort L, Mackenzie S, Roher N. Functional evidence for the inflammatory reflex in teleosts: A novel α7 nicotinic acetylcholine receptor modulates the macrophage response to dsRNA. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2018; 84:279-291. [PMID: 29501534 DOI: 10.1016/j.dci.2018.02.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/28/2018] [Accepted: 02/28/2018] [Indexed: 06/08/2023]
Abstract
The inflammatory reflex modulates the innate immune system, keeping in check the detrimental consequences of overstimulation. A key player controlling the inflammatory reflex is the alpha 7 acetylcholine receptor (α7nAChR). This receptor is one of the signalling molecules regulating cytokine expression in macrophages. In this study, we characterize a novel teleost α7nAChR. Protein sequence analysis shows a high degree of conservation with mammalian orthologs and trout α7nAChR has all the features and essential amino acids to form a fully functional receptor. We demonstrate that trout macrophages can bind α-bungarotoxin (α-BTX), a competitive antagonist for α7nAChRs. Moreover, nicotine stimulation produces a decrease in pro-inflammatory cytokine expression after stimulation with poly(I:C). These results suggest the presence of a functional α7nAChR in the macrophage plasma membrane. Further, in vivo injection of poly(I:C) induced an increase in serum ACh levels in rainbow trout. Our results manifest for the first time the functional conservation of the inflammatory reflex in teleosts.
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Affiliation(s)
- Débora Torrealba
- Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; Departament de Biologia Cel·lular, Fisiologia Animal i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Joan Carles Balasch
- Departament de Biologia Cel·lular, Fisiologia Animal i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Manuel Criado
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, 03550 Sant Joan d'Alacant, Spain
| | - Lluís Tort
- Departament de Biologia Cel·lular, Fisiologia Animal i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Simon Mackenzie
- Institute of Aquaculture, University of Stirling, Stirling, FK9 4LA, United Kingdom.
| | - Nerea Roher
- Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; Departament de Biologia Cel·lular, Fisiologia Animal i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
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Kiguchi N, Kobayashi D, Saika F, Matsuzaki S, Kishioka S. Inhibition of peripheral macrophages by nicotinic acetylcholine receptor agonists suppresses spinal microglial activation and neuropathic pain in mice with peripheral nerve injury. J Neuroinflammation 2018; 15:96. [PMID: 29587798 PMCID: PMC5872578 DOI: 10.1186/s12974-018-1133-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 03/15/2018] [Indexed: 12/24/2022] Open
Abstract
Background Neuro–immune interaction underlies chronic neuroinflammation and aberrant sensory processing resulting in neuropathic pain. Despite the pathological significance of both neuroinflammation-driven peripheral sensitization and spinal sensitization, the functional relationship between these two distinct events has not been understood. Methods In this study, we determined whether inhibition of inflammatory macrophages by administration of α4β2 nicotinic acetylcholine receptor (nAChR) agonists improves neuropathic pain and affects microglial activation in the spinal dorsal horn (SDH) in mice following partial sciatic nerve ligation (PSL). Expression levels of neuroinflammatory molecules were evaluated by RT-qPCR and immunohistochemistry, and PSL-induced mechanical allodynia was defined by the von Frey test. Results Flow cytometry revealed that CD11b+ F4/80+ macrophages were accumulated in the injured sciatic nerve (SCN) after PSL. TC-2559, a full agonist for α4β2 nAChR, suppressed the upregulation of interleukin-1β (IL-1β) in the injured SCN after PSL and attenuated lipopolysaccharide-induced upregulation of IL-1β in cultured macrophages. Systemic (subcutaneous, s.c.) administration of TC-2559 during either the early (days 0–3) or middle/late (days 7–10) phase of PSL improved mechanical allodynia. Moreover, local (perineural, p.n.) administration of TC-2559 and sazetidine A, a partial agonist for α4β2 nAChR, during either the early or middle phase of PSL improved mechanical allodynia. However, p.n. administration of sazetidine A during the late (days 21–24) phase did not show the attenuating effect, whereas p.n. administration of TC-2559 during this phase relieved mechanical allodynia. Most importantly, p.n. administration of TC-2559 significantly suppressed morphological activation of Iba1+ microglia and decreased the upregulation of inflammatory microglia-dominant molecules, such as CD68, interferon regulatory factor 5, and IL-1β in the SDH after PSL. Conclusion These findings support the notion that pharmacological inhibition of inflammatory macrophages using an α4β2 nAChR agonist exhibit a wide therapeutic window on neuropathic pain after nerve injury, and it could be nominated as a novel pharmacotherapy to relieve intractable pain. Electronic supplementary material The online version of this article (10.1186/s12974-018-1133-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Norikazu Kiguchi
- Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama city, Wakayama, 641-0012, Japan.
| | - Daichi Kobayashi
- Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama city, Wakayama, 641-0012, Japan
| | - Fumihiro Saika
- Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama city, Wakayama, 641-0012, Japan
| | - Shinsuke Matsuzaki
- Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama city, Wakayama, 641-0012, Japan
| | - Shiroh Kishioka
- Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama city, Wakayama, 641-0012, Japan
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Mocanu V, Horhat R. Prevalence and Risk Factors of Amblyopia among Refractive Errors in an Eastern European Population. ACTA ACUST UNITED AC 2018; 54:medicina54010006. [PMID: 30344237 PMCID: PMC6037249 DOI: 10.3390/medicina54010006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 03/09/2018] [Accepted: 03/17/2018] [Indexed: 12/18/2022]
Abstract
Background and objective: Amblyopia is the leading cause of visual impairment in children and adults and is very common during childhood. The aim of this study was to identify the prevalence and the risk factors of amblyopia in a pediatric population with refractive errors from an Eastern European country. Materials and methods: A total of 1231 children aged 5–16 years, who had refractive errors and were examined from January to August 2017, were enrolled in a cross-sectional population-based study. Every child underwent a complete ophthalmological exam. Amblyopia was defined as a visual acuity (VA) of less than 0.63. The study respected the Multi-Ethnic Pediatric Eye Disease Study (MEPEDS) criteria for defining amblyopia (MEPEDS, 2008). Parents participated in a face-to-face interview. The questionnaire contained details about their family history of amblyopia; the child’s maternal nutritional status in the preconception period; their history of maternal smoking or work in a toxic environment; the child’s birth, and the child’s history of congenital naso-lacrimal duct obstruction (CNLDO). Results: Amblyopia was identified in 2.8% of the participants. The ocular conditions hyperopia (p = 0.0079), astigmatism (p = 0.046), anisometropia (p < 0.001), esotropia (p < 0.001), exotropia (p = 0.0195), and CNLDO (p < 0.001), as well as a family history of amblyopia (p < 0.001), were associated with amblyopia. The non-ocular risk factors for amblyopia that were found in the study included low birth weight (p < 0.0009), prematurity (p < 0.001), an Apgar score under 7 (p = 0.0008), maternal age, maternal smoking history or work in toxic environment (p < 0.001), and maternal body mass index in the preconception period (p < 0.003). Conclusions: Some of the risk factors we identified for amblyopia are modifiable factors. This is an important observation as an adequate health education program can provide the relevant information for future mothers that will allow for a better management of the condition. We also wanted to highlight the need for amblyopia screening starting from the age of 3 years in case of significant parental refractive errors, strabismus, prematurity, and maternal risk factors.
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Affiliation(s)
- Valeria Mocanu
- Department of Ophthalmology, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania.
- Clinic of Paediatric Surgery, Emergency Children's Hospital Louis Turcanu, 300011 Timisoara, Romania.
| | - Raluca Horhat
- Clinic of Paediatric Surgery, Emergency Children's Hospital Louis Turcanu, 300011 Timisoara, Romania.
- Department of Biophysics, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania.
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Machaalani R, Chen H. Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine. Neurotoxicology 2018; 65:186-195. [DOI: 10.1016/j.neuro.2018.02.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 02/21/2018] [Accepted: 02/25/2018] [Indexed: 02/07/2023]
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Matta JA, Gu S, Davini WB, Lord B, Siuda ER, Harrington AW, Bredt DS. NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain. Cell Rep 2018; 19:688-696. [PMID: 28445721 DOI: 10.1016/j.celrep.2017.04.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 02/22/2017] [Accepted: 04/03/2017] [Indexed: 12/30/2022] Open
Abstract
Neuronal nicotinic acetylcholine receptors (nAChRs) participate in diverse aspects of brain function and mediate behavioral and addictive properties of nicotine. Neuronal nAChRs derive from combinations of α and β subunits, whose assembly is tightly regulated. NACHO was recently identified as a chaperone for α7-type nAChRs. Here, we find NACHO mediates assembly of all major classes of presynaptic and postsynaptic nAChR tested. NACHO acts at early intracellular stages of nAChR subunit assembly and then synergizes with RIC-3 for receptor surface expression. NACHO knockout mice show profound deficits in binding sites for α-bungarotoxin, epibatidine, and conotoxin MII, illustrating essential roles for NACHO in proper assembly of α7-, α4β2-, and α6-containing nAChRs, respectively. By contrast, GABAA receptors are unaffected consistent with NACHO specifically modulating nAChRs. NACHO knockout mice show abnormalities in locomotor and cognitive behaviors compatible with nAChR deficiency and underscore the importance of this chaperone for physiology and disease associated with nAChRs.
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Affiliation(s)
- Jose A Matta
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Shenyan Gu
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Weston B Davini
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Brian Lord
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Edward R Siuda
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Anthony W Harrington
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - David S Bredt
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
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Maher MP, Matta JA, Gu S, Seierstad M, Bredt DS. Getting a Handle on Neuropharmacology by Targeting Receptor-Associated Proteins. Neuron 2017; 96:989-1001. [PMID: 29216460 DOI: 10.1016/j.neuron.2017.10.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/28/2017] [Accepted: 10/02/2017] [Indexed: 12/13/2022]
Abstract
Targeted therapy for neuropsychiatric disorders requires selective modulation of dysfunctional neuronal pathways. Receptors relevant to CNS disorders typically have associated proteins discretely expressed in specific neuronal pathways; these accessory proteins provide a new dimension for drug discovery. Recent studies show that targeting a TARP auxiliary subunit of AMPA receptors selectively modulates neuronal excitability in specific forebrain pathways relevant to epilepsy. Other medicinally important ion channels, gated by glutamate, γ-aminobutyric acid (GABA), and acetylcholine, also have associated proteins, which may be druggable. This emerging pharmacology of receptor-associated proteins provides a new approach for improving drug efficacy while mitigating side effects.
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Affiliation(s)
- Michael P Maher
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Jose A Matta
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Shenyan Gu
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - Mark Seierstad
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
| | - David S Bredt
- Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
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Pandey N, Pal S, Sharma LK, Guleria R, Mohan A, Srivastava T. SNP rs16969968 as a Strong Predictor of Nicotine Dependence and Lung Cancer Risk in a North Indian Population. ASIAN PACIFIC JOURNAL OF CANCER PREVENTION : APJCP 2017; 18:3073-3079. [PMID: 29172281 PMCID: PMC5773793 DOI: 10.22034/apjcp.2017.18.11.3073] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Background: The 15q24-25 loci contain genes (CHRNA5 and CHRNA3) encoding nicotinic acetylcholine receptor subunits. We here determined for the first time the association of genetic variants rs16969968 and rs3743074 in CHRNA5 and CHRNA3, respectively, on nicotine dependence and lung cancer risk in a North Indian population by a case-control approach. Methods: Venous blood samples were obtained from 324 participants (108 lung cancer patients and 216 healthy individuals). DNA was extracted and PCR amplified with primers flanking the SNPs rs16969968 and rs3743074. Amplicons were subjected to sequencing and logistic regression was used to analyze association between variables. Results: The risk variant SNP rs16969968 in both heterozygous and homozygous forms appeared to exert a significant effect on nicotine dependence [GA (OR=2.77) and AA (OR=2.53)]. As expected, smoking was strongly associated with lung cancer (OR= 2.62). Risk allele rs16969968 in CHRNA5 also showed a significant association with increased lung cancer risk in our cohort, alone (OR= 4.99) and with smoking as a co-variable (OR= 4.28). Comparison of our analysis with other populations suggested that individuals with rs16969968 risk allele in the Indian population are more susceptible to lung cancer. Conclusion: Overall, the results strongly indicated that, in our cohort North Indian population, the genetic variant rs16969968, but not rs3743074, is significantly associated with both nicotine dependence and increased risk of lung cancer. While the results are significant, there is further need to increase the sample size and improve precision of our risk prediction.
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Affiliation(s)
- Namita Pandey
- Department of Genetics, University of Delhi South Campus, New Delhi Delhi, India.
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Kiguchi N, Kobayashi D, Saika F, Matsuzaki S, Kishioka S. Pharmacological Regulation of Neuropathic Pain Driven by Inflammatory Macrophages. Int J Mol Sci 2017; 18:ijms18112296. [PMID: 29104252 PMCID: PMC5713266 DOI: 10.3390/ijms18112296] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 10/27/2017] [Accepted: 10/31/2017] [Indexed: 12/16/2022] Open
Abstract
Neuropathic pain can have a major effect on quality of life but current therapies are often inadequate. Growing evidence suggests that neuropathic pain induced by nerve damage is caused by chronic inflammation. Upon nerve injury, damaged cells secrete pro-inflammatory molecules that activate cells in the surrounding tissue and recruit circulating leukocytes to the site of injury. Among these, the most abundant cell type is macrophages, which produce several key molecules involved in pain enhancement, including cytokines and chemokines. Given their central role in the regulation of peripheral sensitization, macrophage-derived cytokines and chemokines could be useful targets for the development of novel therapeutics. Inhibition of key pro-inflammatory cytokines and chemokines prevents neuroinflammation and neuropathic pain; moreover, recent studies have demonstrated the effectiveness of pharmacological inhibition of inflammatory (M1) macrophages. Nicotinic acetylcholine receptor ligands and T helper type 2 cytokines that reduce M1 macrophages are able to relieve neuropathic pain. Future translational studies in non-human primates will be crucial for determining the regulatory mechanisms underlying neuroinflammation-associated neuropathic pain. In turn, this knowledge will assist in the development of novel pharmacotherapies targeting macrophage-driven neuroinflammation for the treatment of intractable neuropathic pain.
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Affiliation(s)
- Norikazu Kiguchi
- Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan.
| | - Daichi Kobayashi
- Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan.
| | - Fumihiro Saika
- Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan.
| | - Shinsuke Matsuzaki
- Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan.
| | - Shiroh Kishioka
- Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan.
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Connor DA, Kutlu MG, Gould TJ. Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus. J Psychopharmacol 2017; 31:934-944. [PMID: 28675115 PMCID: PMC5755391 DOI: 10.1177/0269881117695861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS- (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning.
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Affiliation(s)
- David A Connor
- Department of Psychology, Neuroscience Program, Temple University, Philadelphia, PA, USA
| | - Munir G Kutlu
- Department of Psychology, Neuroscience Program, Temple University, Philadelphia, PA, USA
| | - Thomas J Gould
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, USA
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Cuny H, Yu R, Tae HS, Kompella SN, Adams DJ. α-Conotoxins active at α3-containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition. Br J Pharmacol 2017; 175:1855-1868. [PMID: 28477355 DOI: 10.1111/bph.13852] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 04/13/2017] [Accepted: 04/24/2017] [Indexed: 01/22/2023] Open
Abstract
Neuronal α3-containing nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (PNS) and non-neuronal tissues are implicated in a number of severe disease conditions ranging from cancer to cardiovascular diseases and chronic pain. However, despite the physiological characterization of mouse models and cell lines, the precise pathophysiology of nAChRs outside the CNS remains not well understood, in part because there is a lack of subtype-selective antagonists. α-Conotoxins isolated from cone snail venom exhibit characteristic individual selectivity profiles for nAChRs and, therefore, are excellent tools to study the determinants for nAChR-antagonist interactions. Given that human α3β4 subtype selective α-conotoxins are scarce and this is a major nAChR subtype in the PNS, the design of new peptides targeting this nAChR subtype is desirable. Recent studies using α-conotoxins RegIIA and AuIB, in combination with nAChR site-directed mutagenesis and computational modelling, have shed light onto specific nAChR residues, which determine the selectivity of the α-conotoxins for the human α3β2 and α3β4 subtypes. Publications describing the selectivity profile and binding sites of other α-conotoxins confirm that subtype-selective nAChR antagonists often work through common mechanisms by interacting with the same structural components and sites on the receptor. LINKED ARTICLES This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.
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Affiliation(s)
- Hartmut Cuny
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia.,Victor Chang Cardiac Research Institute, Developmental and Stem Cell Biology Division, Sydney, NSW, Australia
| | - Rilei Yu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Han-Shen Tae
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia
| | - Shiva N Kompella
- Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia
| | - David J Adams
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia
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Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Crit Care Med 2017; 44:2079-2103. [PMID: 27755068 DOI: 10.1097/ccm.0000000000002027] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To update the 2002 version of "Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient." DESIGN A Task Force comprising 17 members of the Society of Critical Medicine with particular expertise in the use of neuromuscular-blocking agents; a Grading of Recommendations Assessment, Development, and Evaluation expert; and a medical writer met via teleconference and three face-to-face meetings and communicated via e-mail to examine the evidence and develop these practice guidelines. Annually, all members completed conflict of interest statements; no conflicts were identified. This activity was funded by the Society for Critical Care Medicine, and no industry support was provided. METHODS Using the Grading of Recommendations Assessment, Development, and Evaluation system, the Grading of Recommendations Assessment, Development, and Evaluation expert on the Task Force created profiles for the evidence related to six of the 21 questions and assigned quality-of-evidence scores to these and the additional 15 questions for which insufficient evidence was available to create a profile. Task Force members reviewed this material and all available evidence and provided recommendations, suggestions, or good practice statements for these 21 questions. RESULTS The Task Force developed a single strong recommendation: we recommend scheduled eye care that includes lubricating drops or gel and eyelid closure for patients receiving continuous infusions of neuromuscular-blocking agents. The Task Force developed 10 weak recommendations. 1) We suggest that a neuromuscular-blocking agent be administered by continuous intravenous infusion early in the course of acute respiratory distress syndrome for patients with a PaO2/FIO2 less than 150. 2) We suggest against the routine administration of an neuromuscular-blocking agents to mechanically ventilated patients with status asthmaticus. 3) We suggest a trial of a neuromuscular-blocking agents in life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise. 4) We suggest that neuromuscular-blocking agents may be used to manage overt shivering in therapeutic hypothermia. 5) We suggest that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment. 6) We suggest against the use of peripheral nerve stimulation with train of four alone for monitoring the depth of neuromuscular blockade in patients receiving continuous infusion of neuromuscular-blocking agents. 7) We suggest that patients receiving a continuous infusion of neuromuscular-blocking agent receive a structured physiotherapy regimen. 8) We suggest that clinicians target a blood glucose level of less than 180 mg/dL in patients receiving neuromuscular-blocking agents. 9) We suggest that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular-blocking agents doses for obese patients. 10) We suggest that neuromuscular-blocking agents be discontinued at the end of life or when life support is withdrawn. In situations in which evidence was lacking or insufficient and the study results were equivocal or optimal clinical practice varies, the Task Force made no recommendations for nine of the topics. 1) We make no recommendation as to whether neuromuscular blockade is beneficial or harmful when used in patients with acute brain injury and raised intracranial pressure. 2) We make no recommendation on the routine use of neuromuscular-blocking agents for patients undergoing therapeutic hypothermia following cardiac arrest. 3) We make no recommendation on the use of peripheral nerve stimulation to monitor degree of block in patients undergoing therapeutic hypothermia. 4) We make no recommendation on the use of neuromuscular blockade to improve the accuracy of intravascular-volume assessment in mechanically ventilated patients. 5) We make no recommendation concerning the use of electroencephalogram-derived parameters as a measure of sedation during continuous administration of neuromuscular-blocking agents. 6) We make no recommendation regarding nutritional requirements specific to patients receiving infusions of neuromuscular-blocking agents. 7) We make no recommendation concerning the use of one measure of consistent weight over another when calculating neuromuscular-blocking agent doses in obese patients. 8) We make no recommendation on the use of neuromuscular-blocking agents in pregnant patients. 9) We make no recommendation on which muscle group should be monitored in patients with myasthenia gravis receiving neuromuscular-blocking agents. Finally, in situations in which evidence was lacking or insufficient but expert consensus was unanimous, the Task Force developed six good practice statements. 1) If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia. 2) Optimal clinical practice suggests that a protocol should include guidance on neuromuscular-blocking agent administration in patients undergoing therapeutic hypothermia. 3) Optimal clinical practice suggests that analgesic and sedative drugs should be used prior to and during neuromuscular blockade, with the goal of achieving deep sedation. 4) Optimal clinical practice suggests that clinicians at the bedside implement measure to attenuate the risk of unintended extubation in patients receiving neuromuscular-blocking agents. 5) Optimal clinical practice suggests that a reduced dose of an neuromuscular-blocking agent be used for patients with myasthenia gravis and that the dose should be based on peripheral nerve stimulation with train-of-four monitoring. 6) Optimal clinical practice suggests that neuromuscular-blocking agents be discontinued prior to the clinical determination of brain death.
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Llopis-Lorente A, Díez P, de la Torre C, Sánchez A, Sancenón F, Aznar E, Marcos MD, Martínez-Ruíz P, Martínez-Máñez R, Villalonga R. Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles. Chemistry 2017; 23:4276-4281. [DOI: 10.1002/chem.201700603] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Antoni Llopis-Lorente
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universidat Politécnica de Valencia; Universitat de Valencia; Spain
- Departamento de Química; Universidad Politécnica de Valencia; Camino de Vera s/n 46022 Valencia Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain
| | - Paula Díez
- Department of Analytical Chemistry; Faculty of Chemistry, Complutense University of Madrid; 28040 Madrid Spain
| | - Cristina de la Torre
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universidat Politécnica de Valencia; Universitat de Valencia; Spain
- Departamento de Química; Universidad Politécnica de Valencia; Camino de Vera s/n 46022 Valencia Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain
| | - Alfredo Sánchez
- Department of Analytical Chemistry; Faculty of Chemistry, Complutense University of Madrid; 28040 Madrid Spain
- IMDEA Nanoscience Cantoblanco University City; 28049 Madrid Spain
| | - Félix Sancenón
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universidat Politécnica de Valencia; Universitat de Valencia; Spain
- Departamento de Química; Universidad Politécnica de Valencia; Camino de Vera s/n 46022 Valencia Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain
| | - Elena Aznar
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universidat Politécnica de Valencia; Universitat de Valencia; Spain
- Departamento de Química; Universidad Politécnica de Valencia; Camino de Vera s/n 46022 Valencia Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain
| | - María D. Marcos
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universidat Politécnica de Valencia; Universitat de Valencia; Spain
- Departamento de Química; Universidad Politécnica de Valencia; Camino de Vera s/n 46022 Valencia Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain
| | - Paloma Martínez-Ruíz
- Department of Organic Chemistry I, Faculty of Chemistry; Complutense University of Madrid; 28040 Madrid Spain
| | - Ramón Martínez-Máñez
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universidat Politécnica de Valencia; Universitat de Valencia; Spain
- Departamento de Química; Universidad Politécnica de Valencia; Camino de Vera s/n 46022 Valencia Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain
| | - Reynaldo Villalonga
- Department of Analytical Chemistry; Faculty of Chemistry, Complutense University of Madrid; 28040 Madrid Spain
- IMDEA Nanoscience Cantoblanco University City; 28049 Madrid Spain
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