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Shimizu Y, Noguchi Y, Sasaki N, Matsuu-Matsuyama M, Kawashiri SY, Yamanashi H, Arima K, Nakamichi S, Nagata Y, Hayashida N, Maeda T. Association between anti-thyroid peroxidase antibody and insufficient sleep in euthyroid population. Int J Clin Health Psychol 2025; 25:100565. [PMID: 40248164 PMCID: PMC12001104 DOI: 10.1016/j.ijchp.2025.100565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 03/27/2025] [Indexed: 04/19/2025] Open
Abstract
Background Low sleep quality induces inflammation. Because anti-thyroid peroxidase antibody (TPO-Ab) is an autoantibody that induces inflammation in the thyroid, insufficient sleep may stimulate the production of TPO-Ab. However, the thyroid function is also associated with sleep. Therefore, to evaluate the association between TPO-Ab positivity and insufficient sleep, the target population should be limited to euthyroid individuals whose free triiodothyronine (T3), free thyroxine (T4), and thyroid-stimulating hormone (TSH) are within the normal ranges. Method This cross-sectional study recruited 1324 euthyroid individuals who participated in annual health checkups. Insufficient sleep was assessed by using a questionnaire. Individuals with free T3, free T4, and TSH levels within the normal ranges were defined as euthyroid. Results Among the study population, 406 had insufficient sleep, and 242 were TPO-Ab-positive. Insufficient sleep was associated with a higher likelihood of TPO-Ab positivity. Sex and age adjusted odd ratios (95 % confidence intervals, p) of TPO-Ab positive for insufficient sleep was 1.47 (1.08, 2.01, p = 0.014). These associations remained unchanged even after further adjustment for free T4 and TSH, status of body mass index, smoking status, drinking status, mental distress, and physical activity; 1.53 (1.11, 2.10, p = 0.009). Conclusion Euthyroid individuals with insufficient sleep may be at risk of autoimmune thyroiditis. Although further investigations are necessary, sleep disorder therapy might reduce the risk of the incidence of autoimmune thyroiditis.
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Affiliation(s)
- Yuji Shimizu
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
- Epidemiology Section, Division of Public Health, Osaka Institute of Public Health, Osaka 537-0025, Japan
| | - Yuko Noguchi
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Nagisa Sasaki
- Epidemiology Section, Division of Public Health, Osaka Institute of Public Health, Osaka 537-0025, Japan
| | - Mutsumi Matsuu-Matsuyama
- Division of Strategic Collaborative Research, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan
| | - Shin-Ya Kawashiri
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Hirotomo Yamanashi
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Kazuhiko Arima
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
- Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
| | - Seiko Nakamichi
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
- Nagasaki University Health Center, Nagasaki 852-8521, Japan
| | - Yasuhiro Nagata
- Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Naomi Hayashida
- Division of Strategic Collaborative Research, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Takahiro Maeda
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
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Wang Y, Fang F, Liu X. Targeting histamine in metabolic syndrome: Insights and therapeutic potential. Life Sci 2024; 358:123172. [PMID: 39461668 DOI: 10.1016/j.lfs.2024.123172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 10/29/2024]
Abstract
Metabolic syndrome is a complex disorder defined by a cluster of interconnected factors including obesity, insulin resistance, hypertension, hyperlipidemia and hyperglycemia which increase the risk of cardiovascular disease, non-alcoholic fatty liver disease, type 2 diabetes mellitus and other related diseases. Histamine, as a biogenic amine, participates in various physiological processes. Increasing evidence suggests histamine plays critical roles in Metabolic syndrome as well as its associated diseases by interacting with four histamine receptors. In this review, we summarize the functions and mechanisms of histamine in Metabolic syndrome, indicating histamine as a possible target in treating Metabolic syndrome and its associated diseases.
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Affiliation(s)
- Yiting Wang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Fude Fang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Xiaojun Liu
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
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Qian Y, Xiong S, Li L, Sun Z, Zhang L, Yuan W, Cai H, Feng G, Wang X, Yao H, Gao Y, Guo L, Wang Z. Spatial multiomics atlas reveals smooth muscle phenotypic transformation and metabolic reprogramming in diabetic macroangiopathy. Cardiovasc Diabetol 2024; 23:358. [PMID: 39395983 PMCID: PMC11471023 DOI: 10.1186/s12933-024-02458-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/25/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND Diabetic macroangiopathy has been the main cause of death and disability in diabetic patients. The mechanisms underlying smooth muscle cell transformation and metabolic reprogramming other than abnormal glucose and lipid metabolism remain to be further explored. METHOD Single-cell transcriptome, spatial transcriptome and spatial metabolome sequencing were performed on anterior tibial artery from 11 diabetic patients with amputation. Multi-omics integration, cell communication analysis, time series analysis, network analysis, enrichment analysis, and gene expression analysis were performed to elucidate the potential molecular features. RESULT We constructed a spatial multiomics map of diabetic blood vessels based on multiomics integration, indicating single-cell and spatial landscape of transcriptome and spatial landscape of metabolome. At the same time, the characteristics of cell composition and biological function of calcified regions were obtained by integrating spatial omics and single cell omics. On this basis, our study provides favorable evidence for the cellular fate of smooth muscle cells, which can be transformed into pro-inflammatory chemotactic smooth muscle cells, macrophage-like smooth muscle cells/foam-like smooth muscle cells, and fibroblast/chondroblast smooth muscle cells in the anterior tibial artery of diabetic patients. The smooth muscle cell phenotypic transformation is driven by transcription factors net including KDM5B, DDIT3, etc. In addition, in order to focus on metabolic reprogramming apart from abnormal glucose and lipid metabolism, we constructed a metabolic network of diabetic vascular activation, and found that HNMT and CYP27A1 participate in diabetic vascular metabolic reprogramming by combining public data. CONCLUSION This study constructs the spatial gene-metabolism map of the whole anterior tibial artery for the first time and reveals the characteristics of vascular calcification, the phenotypic transformation trend of SMCs, and the transcriptional driving network of SMCs phenotypic transformation of diabetic macrovascular disease. In the perspective of combining the transcriptome and metabolome, the study demonstrates the activated metabolic pathways in diabetic blood vessels and the key genes involved in diabetic metabolic reprogramming.
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Affiliation(s)
- Yongjiang Qian
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 212001, China
| | - Shizheng Xiong
- State Key Laboratory of Organic Electronics and Information Displays and Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing, 210023, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 212001, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 212001, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 212001, China
| | - Honghua Cai
- Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Guoquan Feng
- Department of Radiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Xiaoguang Wang
- Department of Joint Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Haipeng Yao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 212001, China
| | - Yun Gao
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Li Guo
- State Key Laboratory of Organic Electronics and Information Displays and Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing, 210023, China.
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 212001, China.
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Kimura S, Noguchi H, Yoshida K, Sato H, Nanbu U, Niino D, Shimajiri S, Nakayama T. Relationship of histamine expression with chemokine balance in the tumor microenvironment of squamous cell carcinoma of the tongue. Head Neck 2022; 44:1554-1562. [PMID: 35411649 DOI: 10.1002/hed.27056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 01/28/2022] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumor-associated macrophages in the tumor microenvironment (TME), as a factor affecting lymphocytes, have received much attention. Both lymphocytes and macrophages can switch the expression of histamine receptors. In this study, we investigated the role of histamine in the TME of tongue squamous cell carcinoma (SCC). METHODS Sixty-seven patients with stage I tongue SCC were studied. Histamine was evaluated by the expression of L-histidine decarboxylase (HDC). Macrophages, T lymphocytes, and lymph vessel density, as well as the Ki-67 labeling index (LI) and depth of invasion (DOI), were compared with HDC expression. RESULTS HDC expression was significantly affected by the TME. The DOI, worst pattern of invasion, and Ki-67 LI were associated with histamine expression. C-C motif chemokine ligand (CCL) 2 and CCL22 were co-expressed with histamine H1 and H2 receptors. Histamine expression was most affected by the DOI. CONCLUSIONS Tongue SCC expressing histamine affected the TME via histamine receptors and chemokines.
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Affiliation(s)
- Satoshi Kimura
- Department of Clinical Pathology, Kitakyushu City Yahata Hospital, Kitakyushu, Japan.,Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hirotsugu Noguchi
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.,Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kosho Yoshida
- Department of Forensic Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hiroaki Sato
- Department of Forensic Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Uki Nanbu
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.,Department of Internal Medicine, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Daisuke Niino
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Shohei Shimajiri
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Toshiyuki Nakayama
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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Marichal-Cancino BA, González-Hernández A, Muñoz-Islas E, Villalón CM. Monoaminergic Receptors as Modulators of the Perivascular Sympathetic and Sensory CGRPergic Outflows. Curr Neuropharmacol 2021; 18:790-808. [PMID: 32364079 PMCID: PMC7569320 DOI: 10.2174/1570159x18666200503223240] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 03/02/2020] [Accepted: 04/24/2020] [Indexed: 12/27/2022] Open
Abstract
Blood pressure is a highly controlled cardiovascular parameter that normally guarantees an adequate blood supply to all body tissues. This parameter is mainly regulated by peripheral vascular resistance and is maintained by local mediators (i.e., autacoids), and by the nervous and endocrine systems. Regarding the nervous system, blood pressure can be modulated at the central level by regulating the autonomic output. However, at peripheral level, there exists a modulation by activation of prejunctional monoaminergic receptors in autonomic- or sensory-perivascular fibers. These modulatory mechanisms on resistance blood vessels exert an effect on the release of neuroactive substances from the autonomic or sensory fibers that modify blood pressure. Certainly, resistance blood vessels are innervated by perivascular: (i) autonomic sympathetic fibers (producing vasoconstriction mainly by noradrenaline release); and (ii) peptidergic sensory fibers [producing vasodilatation mainly by calcitonin gene-related peptide (CGRP) release]. In the last years, by using pithed rats, several monoaminergic mechanisms for controlling both the sympathetic and sensory perivascular outflows have been elucidated. Additionally, several studies have shown the functions of many monoaminergic auto-receptors and hetero-receptors expressed on perivascular fibers that modulate neurotransmitter release. On this basis, the present review: (i) summarizes the modulation of the peripheral vascular tone by adrenergic, serotoninergic, dopaminergic, and histaminergic receptors on perivascular autonomic (sympathetic) and sensory fibers, and (ii) highlights that these monoaminergic receptors are potential therapeutic targets for the development of novel medications to treat cardiovascular diseases (with some of them explored in clinical trials or already in clinical use).
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Affiliation(s)
- Bruno A Marichal-Cancino
- Departamento de Fisiologia y Farmacologia, Centro de Ciencias Basicas, Universidad Autonoma de Aguascalientes, Ciudad Universitaria, 20131 Aguascalientes, Ags., Mexico
| | | | - Enriqueta Muñoz-Islas
- Unidad Academica Multidisciplinaria Reynosa-Aztlan, Universidad Autonoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | - Carlos M Villalón
- Departamento de Farmacobiologia, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330 Mexico City, Mexico
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Weiler CR, Austen KF, Akin C, Barkoff MS, Bernstein JA, Bonadonna P, Butterfield JH, Carter M, Fox CC, Maitland A, Pongdee T, Mustafa SS, Ravi A, Tobin MC, Vliagoftis H, Schwartz LB. AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol 2019; 144:883-896. [DOI: 10.1016/j.jaci.2019.08.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/20/2019] [Accepted: 08/27/2019] [Indexed: 12/18/2022]
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Kimura S, Noguchi H, Nanbu U, Wang KY, Sasaguri Y, Nakayama T. Relationship between CCL22 Expression by Vascular Smooth Muscle Cells and Macrophage Histamine Receptors in Atherosclerosis. J Atheroscler Thromb 2018; 25:1240-1254. [PMID: 29794410 PMCID: PMC6249366 DOI: 10.5551/jat.44297] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
AIM CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines and is involved in monocyte migration and recruitment. We have previously investigated CCL22 and histamine in atherosclerosis. Here, we investigated the hypothesis that CCL22 is involved in atherosclerosis, which is influenced by the differentiation of macrophage phenotypes via histamine. METHODS CCL22 expression was investigated in human carotid arteries and coronary arteries with bare metal stents. Ligated carotid arteries of wild-type (C57BL/6J) and apolipoprotein E-deficient mice were also used as atherosclerotic models. The localization and expression of CCL22 and classical (M1)-like and M2-like macrophages in various human and mouse atherosclerotic lesions were investigated by immunohistochemical examination and quantitative real-time polymerase chain reaction. Histamine is expressed in atherosclerosis, and it induces inflammation and immunity. Human- and mice-derived monocytes and macrophages were used to examine the role of histamine in macrophage differentiation and CCL22-expression. Macrophages derived from histamine receptor 1 (H1R)- and 2 (H2R)-knockout (KO) mice were also examined. RESULTS Atherosclerotic lesions showed a distribution of heterogeneous macrophage phenotypes with M1-like and M2-like macrophage dominant sites. CCL22 was distributed in sparse areas of vascular smooth muscle cells (VSMCs) and associated with M2-like macrophages. Moreover, H2R stimulation was associated with CCL22 expression via M2-like macrophage dominant differentiation. CONCLUSION The expression of M1- or M2-like macrophages in atherosclerosis were observed to be dependent on the distribution of VSMCs owing to differences in causal stimuli and the switching of histamine receptors via Th1 or Th2 cytokines. These results suggest that CCL22 may control atherosclerosis.
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Affiliation(s)
- Satoshi Kimura
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health
| | - Hirotsugu Noguchi
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health
| | - Uki Nanbu
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health
| | - Ke-Yong Wang
- Shared-Use Research Center, University of Occupational and Environmental Health
| | - Yasuyuki Sasaguri
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health
| | - Toshiyuki Nakayama
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health
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Yamada S, Guo X. Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease. Pathol Int 2018; 68:91-101. [PMID: 29341349 DOI: 10.1111/pin.12634] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 12/13/2017] [Indexed: 01/07/2023]
Abstract
The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. We generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.
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Affiliation(s)
- Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, Japan
| | - Xin Guo
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, Japan
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Hebei, China
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9
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Yamada S, Tanimoto A, Sasaguri Y. Critical in vivo roles of histamine and histamine receptor signaling in animal models of metabolic syndrome. Pathol Int 2016; 66:661-671. [PMID: 27860077 DOI: 10.1111/pin.12477] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 10/19/2016] [Accepted: 10/25/2016] [Indexed: 11/30/2022]
Abstract
Histamine, a classic low-molecular-weight amine, is synthesized from L-histidine by histidine decarboxylase (HDC), and histamine-specific receptors (HRs) are essential for its actions. Our serial in vivo studies have uniquely reported that expression of histamine/HRs is variably identified in atherosclerotic lesions, and that HDC-gene knockout mice without histamine/HRs signaling show a marked reduction of atherosclerotic progression. These data have convinced us that histamine plays a pivotal role in the pathogenesis of atherosclerosis. Among four subclasses of HRs, the expression profile of the main receptors (H1/2R) has been shown to be switched from H2R to H1R during monocyte to macrophage differentiation, and H1R is also predominant in smooth muscle and endothelial cells of atheromatous plaque. Using various animal models of H1/2R-gene knockout mice, H1R and H2R were found to reciprocally but critically regulate not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also hyperlipidemia-induced nonalcoholic fatty liver disease (NAFLD). Metabolic syndrome manifests obesity, dyslipidemia, insulin resistance, atherosclerosis, and/or NAFLD, i.e. the dysregulation of lipid/bile acid/glucose metabolism. Therefore, although its etiology is complicated and multifactorial, histamine/HRs signaling has a close relationship with the development of metabolic syndrome. We herein review diverse, key in vivo roles of histamine/HR signaling in the pathogenesis of metabolic syndrome.
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Affiliation(s)
- Sohsuke Yamada
- Department of Pathology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Akihide Tanimoto
- Department of Pathology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Lai TS, Lin CJ, Greenberg CS. Role of tissue transglutaminase-2 (TG2)-mediated aminylation in biological processes. Amino Acids 2016; 49:501-515. [PMID: 27270573 DOI: 10.1007/s00726-016-2270-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/31/2016] [Indexed: 01/08/2023]
Abstract
Post-translational modification (PTM) is an important mechanism in modulating a protein's structure and can lead to substantial diversity in biological function. Compared to other forms of PTMs such as phosphorylation, acetylation and glycosylation, the physiological significance of aminylation is limited. Aminylation refers to the covalent incorporation of biogenic/polyamines into target protein by calcium-dependent transglutaminases (TGs). The development of novel and more sensitive techniques has led to more proteins identified as tissue transglutaminase (TG2) substrates and potential targets for aminylation. Many of these substrate proteins play a role in cell signaling, cytoskeleton organization, muscle contraction, and inflammation. TG2 is well studied and widely expressed in a variety of tissues and will be the primary focus of this review on recent advance in transglutaminase-mediated aminylation.
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Affiliation(s)
- Thung-S Lai
- Graduate Institute of Biomedical Science, Mackay Medical College, No. 46, Sec. 3, Jhong-Jheng Rd., Sanzhi Dist, New Taipei City, 25200, Taiwan, ROC.
| | - Cheng-Jui Lin
- Nephrology/Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
- Nursing and Management, Mackay Junior College of Medicine, Taipei, Taiwan, ROC
| | - Charles S Greenberg
- Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA
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Adiponectin improves NF-κB-mediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice. Lipids Health Dis 2016; 15:33. [PMID: 26965176 PMCID: PMC4787184 DOI: 10.1186/s12944-016-0202-y] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 02/10/2016] [Indexed: 01/26/2023] Open
Abstract
Background Atherosclerosis is a common pathological basis of cardiovascular disease. Adiponectin (APN) has been shown to have an anti-atherosclerosis effect, and the underlying mechanisms, however, are largely unknown. Nuclear factor κB (NF-κB) has also been regarded as a proatherogenic factor, mainly because of its regulation of a variety of the proinflammatory genes linked to atherosclerosis. It was hypothesized that the inhibitory effects of adiponectin on the atherosclerosis is through the inhibition of NF-κB signaling pathway. Methods We injected adenovirus of Ad-eGFP virus (control group) or the same amount of Ad-APN-eGFP virus (APN group) in ApoE-/- mice tail-intravenously. Blood samples and aorta were executed at 0 day, 4, and 8 week of high-fat diet feeding. Histopathological changes of aortic arch root were detected. Levels of TC, TG, HDL-C, LDL-C were measured. Adiponectin and Matrix metalloproteinases-9 (MMP-9) concentration were detected by enzyme-linked immunosorbent assay. Gene and protein levels of adiponectin, eNOS, IL-6, MCP-1,VCAM-1, and other inflammatory factors were determined. Adiponectin, NF-κB p65 in aortic arch root were determined by immunofluorescence and western blot. Results Transduction of Ad-APN inhibited the formation of atherosclerotic plaque in aorta when compared with control group. The lesion formation in aortic arch root was inhibited significantly (P < 0.01). Lesion lumen ratio decreased significantly (P < 0.001). The expression of adiponectin attenuated the increases of serum TC (P < 0.001), TG (P < 0.001), and LDL-C (P < 0.001) induced by the high-fat diet, and the increase in body weight (P < 0.05). As increasing serum adiponectin, the levels of MMP-9 were significantly decreased (P < 0.05). The exogenous adiponectin increased the gene expression of the anti-inflammatory factors eNOS (P < 0.05) and IL-10 (P < 0.001), and reduced the gene expression of inflammatory factors tumor necrosis factor-α (TNF-α) (P < 0.001), IL-6 (P < 0.001), VCAM-1 (P < 0.05), respectively. Adiponectin effectively inhibited the activation of NF-κB pathway and the expression of NF-κB nuclear protein p65. Conclusions Adiponectin may protect the aorta from atherosclerotic injury by reducing inflammation. The molecular mechanism may involve inhibited the expression of downstream components of NF-κB and its transcription factors.
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12
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Kritikou E, Kuiper J, Kovanen PT, Bot I. The impact of mast cells on cardiovascular diseases. Eur J Pharmacol 2015; 778:103-15. [PMID: 25959384 DOI: 10.1016/j.ejphar.2015.04.050] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 04/10/2015] [Accepted: 04/21/2015] [Indexed: 12/30/2022]
Abstract
Mast cells comprise an innate immune cell population, which accumulates in tissues proximal to the outside environment and, upon activation, augments the progression of immunological reactions through the release and diffusion of either pre-formed or newly generated mediators. The released products of mast cells include histamine, proteases, as well as a variety of cytokines, chemokines and growth factors, which act on the surrounding microenvironment thereby shaping the immune responses triggered in various diseased states. Mast cells have also been detected in the arterial wall and are implicated in the onset and progression of numerous cardiovascular diseases. Notably, modulation of distinct mast cell actions using genetic and pharmacological approaches highlights the crucial role of this cell type in cardiovascular syndromes. The acquired evidence renders mast cells and their mediators as potential prognostic markers and therapeutic targets in a broad spectrum of pathophysiological conditions related to cardiovascular diseases.
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Affiliation(s)
- Eva Kritikou
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Johan Kuiper
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | | | - Ilze Bot
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
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Murakami M, Yoshikawa T, Nakamura T, Ohba T, Matsuzaki Y, Sawamura D, Kuwasako K, Yanagisawa T, Ono K, Nakaji S, Yanai K. Involvement of the histamine H1 receptor in the regulation of sympathetic nerve activity. Biochem Biophys Res Commun 2015; 458:584-589. [DOI: 10.1016/j.bbrc.2015.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 02/02/2015] [Indexed: 10/24/2022]
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Kimura S, Wang KY, Yamada S, Guo X, Nabeshima A, Noguchi H, Watanabe T, Harada M, Sasaguri Y. CCL22/Macrophage-derived Chemokine Expression in Apolipoprotein E-deficient Mice and Effects of Histamine in the Setting of Atherosclerosis. J Atheroscler Thromb 2014; 22:599-609. [PMID: 25492567 DOI: 10.5551/jat.27417] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023] Open
Abstract
AIM Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines synthesized by monocyte-derived macrophages. Previous studies have reported a relationship between CCL22 and atherosclerosis and the role of histamine in this pathway. Histamine ncreases the CCL22 expression in human monocytes via the H2 receptor. In this study, we investigated the effects of CCL22 and the role of histamine in mouse monocytes with respect to atherosclerosis. METHODS AND RESULTS The expression of CCL22 was investigated in apolipoprotein E (apoE)-deficient mice. The mice had high serum concentrations of CCL22 and their atherosclerotic lesions contained abundant levels of CCL22. In addition, when the mouse monocyte cell line (J774A.1 cells) differentiated into macrophage-like cells, the cells showed a similar expression of CCL22 and reduced expression of H2 receptors. Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) in a single enzymatic step. HDC knockout mice were compared with apoE/HDC double knockout mice. The findings indicated that the expression of CCL22 in atherosclerosis models is under the influence of histamine. In addition, in vitro studies using J774A.1 cells and an in vivo study using histamine receptor knockout mice showed that histamine stimulates the CCL22 expression via the histamine H2 receptor. CONCLUSIONS The current results support our previous CCL22 studies in the setting of human atherosclerosis and suggest that this molecule is involved in the atherogenic processes in a mouse model of atherosclerosis.
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Affiliation(s)
- Satoshi Kimura
- Department of Laboratory and Transfusion Medicine, University of Occupational and Environmental Health
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15
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Wang X, Pu H, Ma C, Jiang T, Wei Q, Zhang C, Duan M, Shou X, Su L, Zhang J, Yang Y. Adiponectin abates atherosclerosis by reducing oxidative stress. Med Sci Monit 2014; 20:1792-800. [PMID: 25275545 PMCID: PMC4196893 DOI: 10.12659/msm.892299] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background We investigated whether the anti-atherosclerosis of adiponectin (APN) relates to the reduction of oxidative stress. We observed the overexpression of adiponectin gene with different titers on atherosclerosis (AS) models of high-fat apolipoprotein E-deficient (ApoE−/−) mice. Material/Methods We divided 48 male ApoE−/− mice into 4 groups: control group, high-fat diet group, low adiponectin group, and high adiponectin group. The low and high adiponectin group mice were treated with recombinant adenovirus expressing mice adiponectin (Ad-APN) with low-dose adiponectin 1.0×108 p.f.u. and high-dose adiponectin 5.0×108 p.f.u. via the tail every 2 weeks and given a high-fat diet for the last 8 weeks. On the 14th day after injection, blood samples were obtained from the vena cava. Results Along with increased serum adiponectin, serum superoxide dismutase (SOD) activity increased (P<0.05) and concentration of malondialdehyde (MDA) was decreased (P<0.05). Levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were decreased, especially TC and LDL-C (P<0.05). A real-time fluorescent quantitative polymerase chain reaction test was used to analyze levels of mRNA expression for endothelial nitric oxide synthase (eNOS) and adiponectin in the aorta. Along with increased adiponectin, the mRNA expression of eNOS in the aorta was increased significantly (P<0.05). The lesion formation in the aortic sinus was inhibited by 25% and 31% in the low-APN group and high-APN group, respectively (P<0.05). Along with the increase of adiponectin doses, the damage of atherosclerosis gradually eased. However, the differences between the low-APN group and high-APN group had no statistical significance. Conclusions Adiponectin may protect the aorta from atherosclerosis injury by reducing oxidative stress, reducing lesion formation size in the aortic root and reducing TC, TG, and LDL-C in serum. The molecular mechanism may involve preservation of SOD, reducing MDA in serum, and increasing eNOS and adiponectin mRNA expression in the aorta.
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Affiliation(s)
- Xuemei Wang
- Xinjiang Key Laboratory of Medical Animal Model Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Hongwei Pu
- Department of Science and Research Education Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Chuang Ma
- Department of Micro-Reconstructive Surgery of Orthopedics Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Tao Jiang
- Xinjiang Key Laboratory of Medical Animal Model Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Qin Wei
- Xinjiang Key Laboratory of Medical Animal Model Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Chun Zhang
- Xinjiang Key Laboratory of Medical Animal Model Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Mingjun Duan
- Xinjiang Key Laboratory of Medical animal Model Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Xi Shou
- Xinjiang Key Laboratory of Medical Animal Model Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
| | - Lipin Su
- College of Basic Medicine, Xinjiang Medical University, Urumqi, China (mainland)
| | - Jianlong Zhang
- College of Basic Medicine, Xinjiang Medical University, Urumqi, China (mainland)
| | - Yining Yang
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (mainland)
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Longhini R, Aparecida de Oliveira P, Sasso-Cerri E, Cerri PS. Cimetidine Reduces Alveolar Bone Loss in Induced Periodontitis in Rat Molars. J Periodontol 2014; 85:1115-25. [DOI: 10.1902/jop.2013.130453] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Effects of antidepressants on IP-10 production in LPS-activated THP-1 human monocytes. Int J Mol Sci 2014; 15:13223-35. [PMID: 25073092 PMCID: PMC4159790 DOI: 10.3390/ijms150813223] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/12/2014] [Accepted: 07/07/2014] [Indexed: 12/25/2022] Open
Abstract
Major depressive disorder and cardiovascular disease are common serious illnesses worldwide. Selective serotonin reuptake inhibitors and norepinephrine-dopamine reuptake inhibitors may reduce the mortality of cardiovascular disease patients with comorbid depression. Interferon-γ-inducible protein 10 (IP-10), a type 1 T helper cell (Th1)-related chemokine, contributes to manifestations of atherosclerosis during cardiovascular inflammations; however, the pathophysiological mechanisms linking cardiovascular disease and effective antidepressants have remained elusive. We investigated the in vitro effects of six different classes of antidepressants on the IP-10 chemokine expression in lipopolysaccharide (LPS)-stimulated monocytes, and their detailed intracellular mechanisms. The human monocytes were pretreated with antidepressants (10−8–10−5 M) before LPS-stimulation. IP-10 was measured by enzyme-linked immunosorbent assay (ELISA) and then intracellular signaling was investigated using Western blotting and chromatin immunoprecipitation. Fluoxetine and bupropion suppressed LPS-induced IP-10 expression in monocytes, and they had no cytotoxic effects. Furthermore, fluoxetine inhibited LPS-induced IP-10 expression via the mitogen-activated protein kinase (MAPK)-p38 pathway. Fluoxetine and bupropion could not only treat depression but also reduce Th1-related chemokine IP-10 production in human monocytes. Our results may indicate a possible mechanism related to how particular antidepressants reduce the risk of cardiovascular disease.
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Lai TS, Greenberg CS. Histaminylation of fibrinogen by tissue transglutaminase-2 (TGM-2): potential role in modulating inflammation. Amino Acids 2014; 45:857-64. [PMID: 23797785 DOI: 10.1007/s00726-013-1532-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 06/05/2013] [Indexed: 02/03/2023]
Abstract
Plasma fibrinogen plays an important role in hemostasis and inflammation. Fibrinogen is converted to fibrin to impede blood loss and serves as the provisional matrix that aids wound healing. Fibrinogen also binds to cytokine activated endothelial cells and promotes the binding and migration of leukocytes into tissues during inflammation. Tissue transglutaminase (TGM-2) released from injured cells could cross-link fibrinogen to form multivalent complexes that could promote adhesion of platelets and vascular cells to endothelium. Histamine released by mast cells is a potent biogenic amine that promotes inflammation. The covalent attachment of histamine to proteins (histaminylation) by TGM-2 could modify local inflammatory reactions. We investigated TGM-2 crosslinking of several biogenic amines (serotonin, histamine, dopamine and noradrenaline) to fibrinogen. We identified histaminylation of fibrinogen by TGM-2 as a preferred reaction in solid and solution phase transglutaminase assays. Histamine caused a concentration-dependent inhibition of fibrinogen cross-linking by TGM-2. Fibrinogen that was not TGM-2 crosslinked bound to unactivated endothelial cells with low affinity. However, the binding was increased by sevenfold when fibrinogen was cross-linked by TGM-2. Histaminylation of fibrinogen also inhibited TGM-2 crosslinking of fibrinogen and the binding to un-activated HUVEC cells by 75–90 %. In summary, the histaminylation of fibrinogen by TGM-2 could play a role in modifying inflammation by sequestering free histamine and by inhibiting TGM-2 crosslinking of fibrinogen.
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Takahashi H, Sadamori H, Teshigawara K, Niwa A, Liu K, Wake H, Mori S, Yoshino T, Nishibori M. Histamine inhibits high mobility group box 1-induced adhesion molecule expression on human monocytes. Eur J Pharmacol 2013; 718:305-13. [PMID: 24012904 DOI: 10.1016/j.ejphar.2013.08.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2013] [Revised: 08/28/2013] [Accepted: 08/29/2013] [Indexed: 10/26/2022]
Abstract
Cell-cell interaction through binding of adhesion molecules on monocytes to their ligands on T-cells plays roles in cytokine production and lymphocyte proliferation. High mobility group box 1 (HMGB1), an abundant and conserved nuclear protein, acts in the extracellular environment as a primary pro-inflammatory signal. HMGB1 induces expression of intercellular adhesion molecule (ICAM), B7.1, B7.2 and CD40 on monocytes, resulting in production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and lymphocyte proliferation in human peripheral blood mononuclear cells (PBMCs). Histamine inhibits pro-inflammatory cytokine production via histamine H2-receptors; however, it is not known whether histamine inhibits HMGB1 activity. This study was designed to study the inhibitory effect of histamine on HMGB1 activity. We examined the effect of histamine on HMGB1-induced expression of ICAM-1, B7.1, B7.2 and CD40 on monocytes, production of IFN-γ and TNF-α and lymphocyte proliferation in PBMCs. Histamine inhibited HMGB1 activity in a concentration-dependent manner. The effects of histamine were partially ablated by the H2-receptor antagonist, famotidine, and mimicked by the H2/H4-receptor agonists, dimaprit and 4-methylhistamine. Histamine induced cyclic adenosine monophosphate (cAMP) production in the presence and absence of HMGB1. The effects of histamine were reversed by the protein kinase A (PKA) inhibitor, H89, and mimicked by the membrane-permeable cAMP analog, dibutyryl cAMP (dbcAMP), and the adenylate cyclase activator, forskolin. These results together indicated that histamine inhibited HMGB1 activity.
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Affiliation(s)
- Hideo Takahashi
- Department of Pharmacology, Kinki University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
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20
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Purification of novel anti-inflammatory peptides from enzymatic hydrolysate of the edible microalgal Spirulina maxima. J Funct Foods 2013. [DOI: 10.1016/j.jff.2013.05.001] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Abstract
Mast cells are increasingly being recognized as effector cells in many cardiovascular conditions. Many mast-cell-derived products such as tryptase and chymase can, through their enzymic action, have detrimental effects on blood vessel structure while mast cell-derived mediators such as cytokines and chemokines can perpetuate vascular inflammation. Mice lacking mast cells have been developed and these are providing an insight into how mast cells are involved in cardiovascular diseases and, as knowledge increase, mast cells may become a viable therapeutic target to slow progression of cardiovascular disease.
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Kimura S, Tanimoto A, Wang KY, Shimajiri S, Guo X, Tasaki T, Yamada S, Sasaguri Y. Expression of macrophage-derived chemokine (CCL22) in atherosclerosis and regulation by histamine via the H2 receptor. Pathol Int 2012; 62:675-683. [PMID: 23005594 DOI: 10.1111/j.1440-1827.2012.02854.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines and is synthesized by monocyte-derived macrophages and dendritic cells (DCs). In this study, we investigate the relationship between monocytes/macrophages and histamine in atherosclerosis and discover that histamine levels regulate various immunologically important molecules and influences atherosclerotic progression. Immunohistochemical analysis of human atherosclerotic lesions revealed that macrophages and DCs express CCL22. The human acute monocytic leukemia cell line (THP-1) adhered to culture plates and morphologically changed to macrophage-like cells when treated with tetradecanoylphorbol-13-acetate (TPA). Macrophage-like cells derived from THP-1 cells and cultivated peripheral blood mononuclear cells (PBMCs) show similar expression of CCL22. Gene expression of CCL22 was also detected in THP-1 cells treated with histamine and the expression of the protein produced by the CCL22 gene is similar in PBMCs and THP-1 cells. In addition, the histamine H2 receptor mediated these reactions. Our results suggest that CCL22 expression in monocytes is regulated by histamine, and that CCL22 is involved centrally in the development of human atherosclerotic lesions. In conclusion, CCL22 is a marker that is a characteristic of the monocytes/ macrophages migrating into atherosclerotic lesions and histamine plays a role in regulating its expression.
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Affiliation(s)
- Satoshi Kimura
- Department of Laboratory and Transfusion Medicine, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyusyu, Japan.
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Nagashima Y, Kako K, Kim JD, Fukamizu A. Enhanced histamine production through the induction of histidine decarboxylase expression by phorbol ester in Jurkat cells. Mol Med Rep 2012; 6:944-8. [PMID: 22940786 PMCID: PMC3493046 DOI: 10.3892/mmr.2012.1049] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 07/07/2012] [Indexed: 11/16/2022] Open
Abstract
Histamine (HA), a mediator of inflammation, type I allergic responses and neurotransmission, is synthesized from L-histidine, the reaction of which is catalyzed by histidine decarboxylase (HDC). HDC has been reported to be induced by various stimuli, not only in mast cells and basophils, but also in T lymphocytes and macrophages. Although its mRNA has been shown to be increased in Jurkat cells when treated with phorbol 12-myristate 13-acetate (TPA), little is known concerning the induced production of HA by HDC. The present study quantified the trace amounts of intracellular HA using ultra-high liquid chromatography in combination with the 6-aminoquinoline carbamate-derivatization technique. To test whether the cellular level of HA is elevated by the induction of HDC in Jurkat cells treated with TPA, the peak corresponding to authentic HA in the cell lysate was fractioned and its molecular weight determined by matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry. The results of this study show that the HA level is increased by the induction of HDC expression by TPA in Jurkat cells. Therefore, this method is useful in elucidating the physiological significance of HA production.
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Affiliation(s)
- Yusuke Nagashima
- Graduate School of Life and Environmental Sciences, Faculty of Life and Environmental Sciences, Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
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Bruserud Ø. Bidirectional crosstalk between platelets and monocytes initiated by Toll-like receptor: an important step in the early defense against fungal infections? Platelets 2012; 24:85-97. [PMID: 22646762 DOI: 10.3109/09537104.2012.678426] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Monocytes are important in the defense against fungal infections due to their phagocytic and immunoregulatory functions. Platelets also contribute in such immune responses through their release of soluble mediators, including chemokines as well as several other soluble mediators. Both monocytes and platelets express several Toll-like receptors (TLRs) that can recognize fungal molecules and thus initiate intracellular signaling events. TLR ligation on monocytes and platelets may thereby be an early immunological event and function as an initiator of a local proinflammatory crosstalk between platelets and monocytes resulting in (i) monocyte-induced increase of platelet activation and (ii) platelet-associated enhancement of the monocyte activation/function. These effects may have clinical implications both for the efficiency of antifungal treatment and for the predisposition to fungal infections, for example, increased predisposition in patients with thrombocytopenia/monocytopenia due to chemotherapy- or disease-induced bone marrow failure.
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Affiliation(s)
- Øyvind Bruserud
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
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He G, Hu J, Li T, Ma X, Meng J, Jia M, Lu J, Ohtsu H, Chen Z, Luo X. Arrhythmogenic effect of sympathetic histamine in mouse hearts subjected to acute ischemia. Mol Med 2012; 18:1-9. [PMID: 21989948 PMCID: PMC3269646 DOI: 10.2119/molmed.2011.00225] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2011] [Accepted: 10/04/2011] [Indexed: 11/06/2022] Open
Abstract
The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout (HDC(-/-)) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC(-/-) mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H(2) receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H(2) receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.
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Affiliation(s)
- Gonghao He
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
- Department of Pharmacy, Kunming General Hospital of Chengdu Military Region, Kunming, China
| | - Jing Hu
- Department of Histology and Embryology, The Fourth Military Medical University, Xi’an, China
| | - Teng Li
- Department of Histology and Embryology, The Fourth Military Medical University, Xi’an, China
| | - Xue Ma
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
| | - Jingru Meng
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
| | - Min Jia
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
| | - Jun Lu
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
| | - Hiroshi Ohtsu
- Department of Engineering, School of Medicine, Tohoku University, Aoba-ku, Sendai, Japan
| | - Zhong Chen
- Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaoxing Luo
- Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
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Raveendran VV, Tan X, Sweeney ME, Levant B, Slusser J, Stechschulte DJ, Dileepan KN. Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. Immunology 2011; 132:578-88. [PMID: 21255012 DOI: 10.1111/j.1365-2567.2010.03403.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll-like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC.
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Affiliation(s)
- Vineesh V Raveendran
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Rozenberg I, Sluka SHM, Rohrer L, Hofmann J, Becher B, Akhmedov A, Soliz J, Mocharla P, Borén J, Johansen P, Steffel J, Watanabe T, Lüscher TF, Tanner FC. Histamine H1 receptor promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins. Arterioscler Thromb Vasc Biol 2010; 30:923-30. [PMID: 20203300 DOI: 10.1161/atvbaha.109.201079] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive. METHODS AND RESULTS Apolipoprotein E-null (ApoE(-/-)) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE(-/-) controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. CONCLUSION These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease.
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Affiliation(s)
- Izabela Rozenberg
- Cardiovascular Research, Institute of Physiology, University of Zurich, Switzerland
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Schneider E, Leite-de-Moraes M, Dy M. Histamine, Immune Cells and Autoimmunity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 709:81-94. [DOI: 10.1007/978-1-4419-8056-4_9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Sakurai-Komada N, A. Koike K, Kaku Y, Hiraki M, Cui R, Sankai T, Kikuchi S, Date C, Tamakoshi A, Iso H. Chlamydia pneumoniae Infection was Associated with Risk of Mortality from Coronary Heart Disease in Japanese Women but not Men: the JACC Study. J Atheroscler Thromb 2010; 17:510-6. [DOI: 10.5551/jat.2725] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Biosse-Duplan M, Baroukh B, Dy M, de Vernejoul MC, Saffar JL. Histamine promotes osteoclastogenesis through the differential expression of histamine receptors on osteoclasts and osteoblasts. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:1426-34. [PMID: 19264900 DOI: 10.2353/ajpath.2009.080871] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
In addition to the numerous roles of histamine in both the immune and nervous systems, previous studies have suggested that this bioamine might also be involved in bone metabolism. Following our observations of impaired bone resorption in ovariectomized rats after histamine receptor antagonist treatment, we focused in this study on osteoclasts and osteoclast precursors. We looked for a direct action of histamine on these cells using both in vivo and in vitro approaches. In vivo, we triggered a remodeling sequence in rat mandibular bone and treated the animals with either histamine or histamine receptor antagonists. Histamine was shown to increase the number of osteoclasts and osteoclast precursors whereas antagonists of histamine receptor-1 and -2 decreased both osteoclast recruitment and resorption. In vitro, spleen cells from histamine-deficient mice were treated with receptor activator for nuclear factor kappa B ligand and macrophage colony stimulating factor, giving rise to both reduced numbers of osteoclasts and decreased resorption on dentin slices. Histamine enhanced resorption in these cultures in a dose-dependent manner. In addition, we identified osteoclast precursors as a source of histamine. In contrast, histamine increased the receptor activator for nuclear factor kappa B ligand/osteoprotegerin ratio in primary osteoblasts that did not secrete histamine. We observed a differential expression of histamine receptor-1 and -2 mRNAs in both primary osteoclasts and osteoblasts, confirming their functional roles with selective antagonists. Thus, histamine acts directly on osteoclasts, osteoclast precursors, and osteoblasts, promoting osteoclastogenesis through autocrine/paracrine mechanisms.
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Carralot JP, Kim TK, Lenseigne B, Boese AS, Sommer P, Genovesio A, Brodin P. Automated High-Throughput siRNA Transfection in Raw 264.7 Macrophages: A Case Study for Optimization Procedure. ACTA ACUST UNITED AC 2009; 14:151-60. [DOI: 10.1177/1087057108328762] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
RNAi using siRNA is a very powerful tool for functional genomics to identify new drug targets and biological pathways. Although their use in epithelial cells is relatively easy and straightforward, transfection in other cell types is still challenging. The authors report the optimization of transfection conditions for Raw 267.4 macrophage cells. The herein described procedure makes use of automated confocal microscopy, enhanced green fluorescent protein (EGFP)—expressing macrophages, and fluorescently labeled siRNAs to simultaneously quantify both siRNA uptake and silencing efficiency. A comparison of 10 commercial transfectants was performed, leading to the selection of the transfectant giving the highest reproducible knock-down effect without inducing cell toxicity or cell activation. Several buffers used for siRNA/lipid complex assembly were tested, and such a study revealed the crucial importance of this parameter. In addition, a kinetics study led to the determination of the optimal siRNA concentration and the best time window for the assay. In an original approach aimed at simultaneously optimizing both the high-throughput screening process and biological factors, optimal reagent volumes and a process flowchart were defined to ensure robust silencing efficiencies during screening. Such an account should pave the way for future genome-wide RNAi research in macrophages and present an optimization procedure for other “hard-totransfect” cell lines. ( Journal of Biomolecular Screening 2009:151-160)
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Affiliation(s)
| | - Tae-Kyu Kim
- Biology of Intracellular Pathogens Équipe Avenir Inserm
| | | | - Annette S. Boese
- Cell Biology of Retroviruses, Institut Pasteur Korea, Seoul, South Korea
| | - Peter Sommer
- Cell Biology of Retroviruses, Institut Pasteur Korea, Seoul, South Korea
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Induction of histidine decarboxylase in macrophages inhibited by the novel NF-κB inhibitor (−)-DHMEQ. Biochem Biophys Res Commun 2009; 379:379-83. [DOI: 10.1016/j.bbrc.2008.12.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2008] [Accepted: 12/12/2008] [Indexed: 12/18/2022]
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Sánchez-Patán F, Anchuelo R, Aller MA, Vara E, García C, Nava MP, Arias J. Chronic prehepatic portal hypertension in the rat: is it a type of metabolic inflammatory syndrome? Lipids Health Dis 2008; 7:4. [PMID: 18271959 PMCID: PMC2262079 DOI: 10.1186/1476-511x-7-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Accepted: 02/13/2008] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND A progressive development of hepatic steatosis with an increase in the lipid hepatocyte content and the formation of megamitochondria have been demonstrated in rats with prehepatic portal hypertension. The aim of this study is to verify the existence of liver and serum lipid metabolism impairments in rats with long-term (2 years) portal hypertension. METHODS Male Wistar rats: Control (n = 10) and with prehepatic portal hypertension by triple partial portal vein ligation (n = 9) were used. Liver content of Triglycerides (TG), phospholipids (PL) and cholesterol and serum cholesterol, lipoproteins (HDL and LDL), TG, glucose and Lipid Binding Protein (LBP) were assayed with specific colorimetric commercial kits. Serum levels of insulin and somatostatin were assayed by RIA. RESULTS The liver content of TG (6.30 +/- 1.95 vs. 4.17 +/- 0.59 microg/ml; p < 0.01) and cholesterol (1.48 +/- 0.15 vs. 1.10 +/- 0.13 microg/ml; p < 0.001) increased in rats with portal hypertension. The serum levels of cholesterol (97.00+26.02 vs. 114.78 +/- 37.72 mg/dl), TG (153.41 +/- 80.39 vs. 324.39 +/- 134.9 mg/dl; p < 0.01), HDL (20.45 +/- 5.14 vs. 55.15 +/- 17.47 mg/dl; p < 0.001) and somatostatin (1.32 +/- 0.31 vs. 1.59 +0.37 mg/dl) decreased, whereas LDL (37.83 +/- 15.39 vs. 16.77 +/- 6.81 mg/dl; p < 0.001) and LBP (308.47 +/- 194.53 vs. 60.27 +/- 42.96 ng/ml; p < 0.001) increased. CONCLUSION Portal hypertension in the rat presents changes in the lipid and carbohydrate metabolisms similar to those produced in chronic inflammatory conditions and sepsis in humans. These underlying alterations could be involved in the development of hepatic steatosis and, therefore, in those described in the metabolic syndrome in humans.
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Affiliation(s)
| | - Raquel Anchuelo
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
| | - Maria-Angeles Aller
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
| | - Elena Vara
- Biochemistry and Molecular Biology III Department, School of Medicine, Complutense University of Madrid, Spain
| | - Cruz García
- Biochemistry and Molecular Biology III Department, School of Medicine, Complutense University of Madrid, Spain
| | - Maria-Paz Nava
- Department of Physiology (Animal Physiology II), School of Biology, Complutense University of Madrid, Spain
| | - Jaime Arias
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
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Adlesic M, Verdrengh M, Bokarewa M, Dahlberg L, Foster SJ, Tarkowski A. Histamine in Rheumatoid Arthritis. Scand J Immunol 2007; 65:530-7. [PMID: 17523945 DOI: 10.1111/j.1365-3083.2007.01938.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent inflammation of the synovium, leading to the erosion of articular cartilage and bone. Synovial mast cells and their effector molecule, histamine, receive increased attention as mediators of joint inflammation. The aim of our study was to analyse levels of free histamine in serum and joint fluid of RA patients and to evaluate the potential inflammatogenic properties of histamine in vivo and in vitro. Histamine levels were measured by an ELISA in synovial fluid and sera of RA patients and of healthy controls. Histamine levels were also assessed in plasma of RA patients undergoing anti-TNF-alpha treatment. In the murine part of the study, histamine was injected intra-articularly in the knee joint of mice and the joints were subsequently analysed with respect to induction of inflammation. RA patients displayed significantly lower levels of histamine in circulation (0.93 +/- 0.16 ng/ml) compared with the healthy controls (1.89 +/- 0.45 ng/ml, P < 0.001). Locally, in synovial fluid the levels of histamine were even lower (0.37 +/- 0.16 ng/ml, P < 0.0006). Long-term anti-TNF-alpha treatment significantly increased circulating levels of histamine in RA patients. Our experiments on animals show that histamine on its own neither induces inflammation in the joint cavity nor influences the course of HMGB1 and peptidoglycan-induced joint inflammation. Based on our experimental and clinical studies we suggest that histamine lacks harmful properties in RA.
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Affiliation(s)
- M Adlesic
- Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden
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Aller MA, Vara E, García C, Nava MP, Angulo A, Sánchez-Patán F, Calderón A, Vergara P, Arias J. Hepatic lipid metabolism changes in short- and long-term prehepatic portal hypertensive rats. World J Gastroenterol 2006; 12:6828-34. [PMID: 17106932 PMCID: PMC4087438 DOI: 10.3748/wjg.v12.i42.6828] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To verify the impairment of the hepatic lipid metabolism in prehepatic portal hypertension.
METHODS: The concentrations of free fatty acids, diacylglycerol, triglycerides, and phospholipids were assayed by using D-[U-14C] glucose incorporation in the different lipid fractions and thin-layer chromatography and cholesterol was measured by spectrophotometry, in liver samples of Wistar rats with partial portal vein ligation at short- (1 mo) and long-term (1 year) (i.e. portal hypertensive rats) and the control rats.
RESULTS: In the portal hypertensive rats, liver phospholipid synthesis significantly decreased (7.42 ± 0.50 vs 4.70 ± 0.44 nCi/g protein; P < 0.01) and was associated with an increased synthesis of free fatty acids (2.08 ± 0.14 vs 3.36 ± 0.33 nCi/g protein; P < 0.05), diacylglycerol (1.93 ± 0.2 vs 2.26 ± 0.28 nCi/g protein), triglycerides (2.40 ± 0.30 vs 4.49 ± 0.15 nCi/g protein) and cholesterol (24.28 ± 2.12 vs 57.66 ± 3.26 mg/g protein; P < 0.01).
CONCLUSION: Prehepatic portal hypertension in rats impairs the liver lipid metabolism. This impairment consists in an increase in lipid deposits (triglycerides, diacylglycerol and cholesterol) in the liver, accompanied by a decrease in phospholipid synthesis.
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Affiliation(s)
- Maria-Angeles Aller
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain.
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Abstract
Statins have been shown to have pleiotropic effects apart from serum lipid-lowering effect in human. One of the major target organs for the effects of statins is the vascular endothelium, which plays an important role in the development of atherosclerosis and angiogenesis. Recent numerous studies have shown that the statins' cholesterol-independent vascular effects appear to involve directly restoring or improving endothelial function by increasing NO production, promoting re-endothelialization after arterial injury, and inhibiting inflammatory responses within the vessel wall that are thought to contribute to atherosclerosis. This review provides an update of the unique effects of statins on endothelial cells including endothelial progenitor cells as well as highlighting the therapeutic potential of statins beyond their established lipid-lowering effects.
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Affiliation(s)
- Masaaki Ii
- Stem Cell Translational Research, RIKEN Center for Developmental Biology, 2-2 Minatojima, Minamimachi, Kobe, Japan.
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Abstract
The pathogenesis of atherosclerosis remains incompletely understood. Accumulation of oxidized lipoproteins (oxLDL) within the vascular wall drives a related immune response very early during the disease course. Such an immune response is self-amplified and eventually escapes from physiologic control mechanisms. Certain lymphocytes may become pathogenic. B cells play a protective role by producing antibodies able to neutralize oxLDL. Elucidation of the immune control mechanisms in atherosclerosis will open the way to new therapeutic perspectives.
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Affiliation(s)
- Emilie Groyer
- Inserm U681, Université Pierre et Marie Curie - Paris VI, Institut des Cordeliers
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Hasturk H, Kantarci A, Ebrahimi N, Andry C, Holick M, Jones VL, Van Dyke TE. Topical H2 antagonist prevents periodontitis in a rabbit model. Infect Immun 2006; 74:2402-14. [PMID: 16552070 PMCID: PMC1418940 DOI: 10.1128/iai.74.4.2402-2414.2006] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cimetidine is a powerful H2 receptor antagonist that eliminates histamine's effects on chemotaxis, phagocytosis, and superoxide anion production by phagocytes. The purpose of this study was to analyze the clinical and histopathological changes associated with experimental periodontitis in rabbits in response to topically applied cimetidine. Experimental periodontitis was induced in 21 New Zealand White rabbits using Porphyromonas gingivalis (10(9) CFU) topically applied three times a week for a 6-week period to previously ligatured teeth. Topical application of cimetidine in a liposome carrier for the prevention of periodontitis was evaluated in four groups of four animals each: 1, 10, and 100 mg/ml and no treatment (positive control). In addition, there was a vehicle group (n = 3) that received liposome preparation (carrier) only, and two animals with ligature application alone served as negative controls. Periodontal disease was quantified by direct visualization and radiographical evaluation of bone loss on defleshed skulls and by histological analyses of sections stained with hematoxylin-eosin and tartrate-resistant acid phosphatase. In the no-treatment (positive control) and liposome (vehicle) groups, direct visualization and radiological measurements revealed statistically significant bone loss compared to the negative control. Application of cimetidine at all concentrations tested inhibited inflammation and bone loss by >90%. Histological findings revealed that ligated sites of the positive control and vehicle groups showed significant reduction in bone level (P < 0.05) compared to the three cimetidine groups, with a marked decrease in inflammation. The findings of this study provide morphological and histological evidence that topically active cimetidine is a potent inhibitor of P. gingivalis-elicited periodontal inflammation, arresting and/or preventing tissue destruction and influencing cell populations present in the inflammatory cell infiltrate.
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Affiliation(s)
- H Hasturk
- Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, 100 East Newton Street, Suite 108, Boston, MA 02118, USA
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Ashida K, Miyazaki K, Takayama E, Tsujimoto H, Ayaori M, Yakushiji T, Iwamoto N, Yonemura A, Isoda K, Mochizuki H, Hiraide H, Kusuhara M, Ohsuzu F. Characterization of the expression of TLR2 (toll-like receptor 2) and TLR4 on circulating monocytes in coronary artery disease. J Atheroscler Thromb 2005; 12:53-60. [PMID: 15725697 DOI: 10.5551/jat.12.53] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
TLRs are receptors involved in the recognition of pathogens by the innate immune system, and TLR2 and TLR4 play important roles in the activation of monocytes. A total of 105 consecutive patients who underwent coronary angiography comprised of 46 with stable effort angina (SA), 41 with unstable angina (UA), and 18 with no significant CAD (CNT) were enrolled. The baseline expression levels of TLR2 and TLR4 on monocytes in peripheral blood mononuclear cells (PBMCs) were determined by flow-cytometric analysis. Since TLR2 expression has been reported to be regulated by TLR4 signaling, we cultured PBMCs with or without lipopolysaccharide (LPS, 1 microg/ml). At baseline, TLR4 levels (mean of fluorescence intensity ) in SA (145 +/- 58, p < 0.05) and UA (164 +/- 65, p < 0.01) were higher than those in CNT (107 +/- 37). As for TLR2, levels were higher in UA (108 +/- 36, p < 0.05) than in SA (94 +/- 18) and CNT (87 +/- 22). After stimulation with LPS, TLR2 levels increased in SA but decreased in UA. In conclusions, TLR4 levels increased in both SA and UA. Monocytes in UA were characterized by elevated TLR2 levels and unresponsiveness of the TLR2 levels to TLR4 stimulation.
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Affiliation(s)
- Kazuhiro Ashida
- Internal Medicine I, National Defense Medical College, Saitama, Japan.
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Liu YZ, Dvornyk V, Lu Y, Shen H, Lappe JM, Recker RR, Deng HW. A Novel Pathophysiological Mechanism for Osteoporosis Suggested by an in Vivo Gene Expression Study of Circulating Monocytes. J Biol Chem 2005; 280:29011-6. [PMID: 15965235 DOI: 10.1074/jbc.m501164200] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Bone mineral density (BMD) is a major risk factor for osteoporosis. Circulating monocytes may serve as early progenitors of osteoclasts and produce a wide variety of factors important to bone metabolism. However, little is known about the roles of circulating monocytes in relation to the pathophysiology of osteoporosis. Using the Affymetrix HG-U133A GeneChip(R) array, we performed a comparative gene expression study of circulating monocytes in subjects with high and low BMD. We identified in total 66 differentially expressed genes including some novel as well as some already known to be relevant to bone metabolism. Three genes potentially contributing to bone metabolism, CCR3 (chemokine receptor 3), HDC (histidine decarboxylase, i.e. the histamine synthesis enzyme), and GCR (glucocorticoid receptor), were confirmed by quantitative real-time reverse transcriptase-PCR as up-regulated in subjects with lower BMD. In addition, significant negative correlation was observed between expression levels of the genes and BMD Z-scores. These three genes and/or their products mediate monocyte chemotaxis, histamine production, and/or sensitivity to glucocorticoids. Our results suggest a novel pathophysiological mechanism for osteoporosis that is characterized by increased recruitment of circulating monocyte into bone, enhanced monocyte differentiation into osteoclasts, as well as osteoclast stimulation via monocyte functional changes. This is the first in vivo microarray study of osteoporosis in humans. The results may contribute to identification of new genes and their functions for osteoporosis and suggest genetic markers to discern individuals at higher risk to osteoporosis with an aim for preventive intervention and treatment.
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Affiliation(s)
- Yao-Zhong Liu
- Osteoporosis Research Center, Creighton University Medical Center,Creighton University, Omaha, NE 68131, USA
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Pedro-Botet J, Jericó C. Etiopatogenia de la arteriosclerosis. Aspectos celulares y moleculares del daño vascular. Aten Primaria 2005. [DOI: 10.1016/s0212-6567(05)70579-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Vanderlaan PA, Reardon CA. Thematic review series: the immune system and atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis. J Lipid Res 2005; 46:829-38. [PMID: 15772419 DOI: 10.1194/jlr.r500003-jlr200] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Atherosclerosis is a complex inflammatory disease process involving an array of cell types and interactions. Although macrophage foam cells and vascular smooth muscle cells constitute the bulk of the atherosclerotic lesion, other cell types have been implicated in this disease process as well. These cellular components of both innate and adaptive immunity are involved in modulating the response of macrophage foam cells and vascular smooth muscle cells to the retained and modified lipids in the vessel wall as well as in driving the chronic vascular inflammation that characterizes this disease. In this review, the involvement of a number of less prominent leukocyte populations in the pathogenesis of atherosclerosis is discussed. More specifically, the roles of natural killer cells, mast cells, neutrophils, dendritic cells, gammadelta T-cells, natural killer T-cells, regulatory T-cells, and B-cells are addressed.
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Affiliation(s)
- Paul A Vanderlaan
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
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