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Histamine-Related Molecules as Therapeutic Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 97349

Special Issue Editors

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Tohoku University, Sendai, Japan
Department of Molecular Studies for Incurable Diseases, Tokushima University, Tokushima 770-0855, Japan
Interests: molecular pharmacology; anti-allergic; natural medicines; pathological mechanism of allergy; histamine h1 receptor

Special Issue Information

Dear Colleagues,

Histamine is known to mediate the induction of various allergic responses via the histamine H1 receptor and gastric acid secretion via H2 receptor. The histamine H3 and H4 receptors also regulate various pathological and physiological responses; consequently, the antagonists/agonists of these receptors are expected to be new medicines. Furthermore, recent basic studies have indicated that various histamine-related molecules, which are involved in histamine production, release, and clearance, adjust the concentration and activity of histamine. These molecules include the histamine-producing enzyme, histidine decarboxylase; the metabolizing enzyme, histamine N-methyltransferase; and the transporters, monoamine transporter and organic cation transporter 3. In addition, a novel G protein-coupled receptor on mast cells, MAS-related G protein-coupled receptor X2 (MRGPRX2), was reported to be involved in IgE-independent histamine release from mast cells. These molecules will be the therapeutic targets. This special issue of IJMS addresses the current topics in the study of these molecules in basic and clinical research to drive the development of new medicines.

Prof. Dr. Noriyasu Hirasawa
Prof. Dr. Hiroyuki Fukui
Guest Editors

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Keywords

  • histamine
  • histamine receptor
  • histidine decarboxylase
  • histamine clearance
  • mast cells
  • drug discovery

Published Papers (11 papers)

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Research

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15 pages, 9171 KiB  
Article
Effect of Bilastine on Diabetic Nephropathy in DBA2/J Mice
by Roberta Verta, Cristina Grange, Maura Gurrieri, Sara Borga, Patrizia Nardini, Monica Argenziano, Corrado Ghè, Roberta Cavalli, Elisa Benetti, Gianluca Miglio, Benedetta Bussolati, Alessandro Pini and Arianna Carolina Rosa
Int. J. Mol. Sci. 2019, 20(10), 2554; https://doi.org/10.3390/ijms20102554 - 24 May 2019
Cited by 6 | Viewed by 5450
Abstract
Diabetic nephropathy is an unmet therapeutic need, and the search for new therapeutic strategies is warranted. Previous data point to histamine H1 receptor as a possible target for glomerular dysfunction associated with long term hyperglycaemia. Therefore, this study investigated the effects of [...] Read more.
Diabetic nephropathy is an unmet therapeutic need, and the search for new therapeutic strategies is warranted. Previous data point to histamine H1 receptor as a possible target for glomerular dysfunction associated with long term hyperglycaemia. Therefore, this study investigated the effects of the H1 receptor antagonist bilastine on renal morphology and function in a murine model of streptozotocin-induced diabetes. Diabetes was induced in DBA2/J male mice and, from diabetes onset (glycaemia ≥200 mg/dL), mice received bilastine (1–30 mg/kg/day) by oral gavage for 14 consecutive weeks. At the end of the experimental protocol, diabetic mice showed polyuria (+195.5%), increase in Albumin-to-Creatine Ratio (ACR, +284.7%), and a significant drop in creatinine clearance (p < 0.05). Bilastine prevented ACR increase and restored creatinine clearance in a dose-dependent manner, suggesting a positive effect on glomerular filtration. The ultrastructural analysis showed a preserved junctional integrity. Preservation of the basal nephrin, P-cadherin, and synaptopodin expression could explain this effect. In conclusion, the H1 receptor could contribute to the glomerular damage occurring in diabetic nephropathy. Bilastine preserved the glomerular junctional integrity, leading to the hypothesis of anti-H1 antihistamines as a possible add-on therapy for diabetic nephropathy. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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15 pages, 3542 KiB  
Article
Role of Histamine H3 Receptor Antagonists on Intraocular Pressure Reduction in Rabbit Models of Transient Ocular Hypertension and Glaucoma
by Cecilia Lanzi, Laura Lucarini, Mariaconcetta Durante, Silvia Sgambellone, Alessandro Pini, Stefano Catarinicchia, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Holger Stark and Emanuela Masini
Int. J. Mol. Sci. 2019, 20(4), 981; https://doi.org/10.3390/ijms20040981 - 24 Feb 2019
Cited by 19 | Viewed by 5044
Abstract
Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term [...] Read more.
Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term IOP fluctuation and glaucoma progression; however, it has not yet been determined whether histamine plays a role in IOP fluctuations. The aim of this research was to establish the distribution of the histamine receptor proteins and respective mRNAs in the eye by western blot, immunohistochemistry and RT-PCR in New Zealand rabbits. Furthermore, we used a transient ocular hypertension (OHT) model induced by injection of 50 µL of 5% hypertonic saline into the vitreous and a stable OHT model (100 µL 0.1% carbomer in the anterior chamber) to address the potential IOP-lowering ability of H3 receptor (H3R) antagonists (ciproxifan, DL76 and GSK189254). IOPs were performed with a Tono-Pen at baseline and 60, 120 and 240 min post treatment after transient OHT induction and, every day for 12 days in the stable OHT model. All histamine receptor subtypes were localized in the rabbit retina and ciliary body/trabecular meshwork. All the treatments lowered IOP in a dose-dependent fashion between 0.3% and 1%. More specifically, the effects were maximal with ciproxifan at 60 min post-dose (IOP60 change = −18.84 ± 4.85 mmHg, at 1%), remained stable until 120 min (IOP120 change = −16.38 ± 3.8 mmHg, at 1%) and decayed thereafter to reach baseline values at 240 min. These effects were highly specific and dependent on histamine release as pre-treatment with imetit (H3R agonist, 1%) or pyrilamine (H1R antagonist, 1%) largely blocked ciproxifan-mediated effects. Color Doppler ultrasound examination was performed to evaluate changes in ophtalmic artery resistivity index (RI) before and after repeated dosing with DL 76, GSK189254, ciproxifan and timolol. Chronic treatments with H3R antagonists and timolol improved the vascular performance of ophthalmic arteries and reduced retinal ganglion cell death. Oxidative stress was also reduced and measured 8-Hydroxy-2′-deoxyguanosine (8OHdG) expression, and by dihidroethydium (DHE) staining. These results demonstrated that the histamine system participates in IOP regulation and that H3R antagonists could represent a future promising therapy for glaucoma. Further studies should be focused on the long-term IOP circadian fluctuations. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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7 pages, 1506 KiB  
Article
Activation of Human Peripheral Basophils in Response to High IgE Antibody Concentrations without Antigens
by Yuhki Yanase, Yoshimi Matsuo, Tomoko Kawaguchi, Kaori Ishii, Akio Tanaka, Kazumasa Iwamoto, Shunsuke Takahagi and Michihiro Hide
Int. J. Mol. Sci. 2019, 20(1), 45; https://doi.org/10.3390/ijms20010045 - 22 Dec 2018
Cited by 14 | Viewed by 6035
Abstract
Basophils and mast cells have high affinity IgE receptors (FcεRI) on their plasma membrane and play important roles in FcεRI-associated allergic diseases, such as pollen allergy, food allergy, chronic spontaneous urticarial (CSU), and atopic dermatitis (AD). To date, several reports have revealed that [...] Read more.
Basophils and mast cells have high affinity IgE receptors (FcεRI) on their plasma membrane and play important roles in FcεRI-associated allergic diseases, such as pollen allergy, food allergy, chronic spontaneous urticarial (CSU), and atopic dermatitis (AD). To date, several reports have revealed that high IgE antibody concentrations activate mast cells—which reside in tissue—in the absence of any antigens (allergens). However, IgE antibody-induced activation of basophils—which circulate in blood—has not been reported. Here, we investigated whether IgE antibodies may regulate functions of human peripheral basophils without antigens in vitro. We successfully removed IgE antibodies bound to FcεRI on the surface of human peripheral basophils by treating with 0.1% lactic acid. We also demonstrated that high IgE antibody concentrations (>1 μM) induced histamine release, polarization, and CD203c upregulation of IgE antibody-stripped basophils. Thus, high IgE antibody concentrations directly activate basophils, which express IgE-free FcεRI on the cell surface. This mechanism may contribute to the pathogenesis of patients with AD and CSU who have higher serum IgE concentrations compared to healthy donors. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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14 pages, 1443 KiB  
Article
Suppression of IFN-γ Production in Murine Splenocytes by Histamine Receptor Antagonists
by Miho Kamei, Yukie Otani, Hidenori Hayashi, Tadaho Nakamura, Kazuhiko Yanai, Kazuyuki Furuta and Satoshi Tanaka
Int. J. Mol. Sci. 2018, 19(12), 4083; https://doi.org/10.3390/ijms19124083 - 17 Dec 2018
Cited by 3 | Viewed by 3134
Abstract
Accumulating evidence suggests that histamine synthesis induced in several types of tumor tissues modulates tumor immunity. We found that a transient histamine synthesis was induced in CD11b+Gr-1+ splenocytes derived from BALB/c mice transplanted with a syngeneic colon carcinoma, CT-26, when [...] Read more.
Accumulating evidence suggests that histamine synthesis induced in several types of tumor tissues modulates tumor immunity. We found that a transient histamine synthesis was induced in CD11b+Gr-1+ splenocytes derived from BALB/c mice transplanted with a syngeneic colon carcinoma, CT-26, when they were co-cultured with CT-26 cells. Significant levels of IFN-γ were produced under this co-culture condition. We explored the modulatory roles of histamine on IFN-γ production and found that several histamine receptor antagonists, such as pyrilamine, diphenhydramine, JNJ7777120, and thioperamide, could significantly suppress IFN-γ production. However, suppression of IFN-γ production by these antagonists was also found when splenocytes were derived from the Hdc−/− BALB/c mice. Suppressive effects of these antagonists were found on IFN-γ production induced by concanavalin A or the combination of an anti-CD3 antibody and an anti-CD28 antibody in a histamine-independent manner. Murine splenocytes were found to express H1 and H2 receptors, but not H3 and H4 receptors. IFN-γ production in the Hh1r−/− splenocytes induced by the combination of an anti-CD3 antibody and an anti-CD28 antibody was significantly suppressed by these antagonists. These findings suggest that pyrilamine, diphenhydramine, JNJ7777120, and thioperamide can suppress IFN-γ production in activated splenocytes in a histamine-independent manner. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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9 pages, 1512 KiB  
Communication
Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H1 Receptors
by Shigeru Hishinuma, Yuri Tamura, Chihiro Kobayashi, Chizuru Akatsu and Masaru Shoji
Int. J. Mol. Sci. 2018, 19(12), 4067; https://doi.org/10.3390/ijms19124067 - 15 Dec 2018
Cited by 5 | Viewed by 6332
Abstract
Cetirizine is a zwitterionic second-generation antihistamine containing R- and S-enantiomers, levocetirizine, and (S)-cetirizine. Levocetirizine is known to have a higher affinity for the histamine H1 receptors than (S)-cetirizine; ligand-receptor docking simulations have suggested the importance of [...] Read more.
Cetirizine is a zwitterionic second-generation antihistamine containing R- and S-enantiomers, levocetirizine, and (S)-cetirizine. Levocetirizine is known to have a higher affinity for the histamine H1 receptors than (S)-cetirizine; ligand-receptor docking simulations have suggested the importance of the formation of a salt bridge (electrostatic interaction) between the carboxylic group of levocetirizine and the Lys191 residue at the fifth transmembrane domain of human histamine H1 receptors. In this study, we evaluated the roles of Lys191 in the regulation of the thermodynamic binding forces of levocetirizine in comparison with (S)-cetirizine. The binding enthalpy and entropy of these compounds were estimated from the van ‘t Hoff equation, by using the dissociation constants obtained from their displacement curves against the binding of [3H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing wild-type human H1 receptors and their Lys191 mutants to alanine at various temperatures. We found that the higher binding affinity of wild-type H1 receptors for levocetirizine than (S)-cetirizine was achieved by stronger forces of entropy-dependent hydrophobic binding of levocetirizine. The mutation of Lys191 to alanine reduced the affinities for levocetirizine and (S)-cetirizine, through a reduction in the entropy-dependent hydrophobic binding forces of levocetirizine and the enthalpy-dependent electrostatic binding forces of (S)-cetirizine. These results suggested that Lys191 differentially regulates the binding enthalpy and entropy of these enantiomers, and that Lys191 negatively regulates the enthalpy-dependent electrostatic binding forces of levocetirizine, contrary to the predictions derived from the ligand-receptor docking simulations. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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23 pages, 11904 KiB  
Article
Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats
by Alaa Alachkar, Dorota Łażewska, Gniewomir Latacz, Annika Frank, Agata Siwek, Annamaria Lubelska, Ewelina Honkisz-Orzechowska, Jadwiga Handzlik, Holger Stark, Katarzyna Kieć-Kononowicz and Bassem Sadek
Int. J. Mol. Sci. 2018, 19(11), 3386; https://doi.org/10.3390/ijms19113386 - 29 Oct 2018
Cited by 20 | Viewed by 3751
Abstract
A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (116) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration [...] Read more.
A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (116) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist 13, without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist 4 in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (R)-α-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist 4 in PTZ-induced seizure and H3R antagonist 13 in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound 4. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist 4 was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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Review

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16 pages, 2829 KiB  
Review
The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy
by Kohei Yamauchi and Masahito Ogasawara
Int. J. Mol. Sci. 2019, 20(7), 1733; https://doi.org/10.3390/ijms20071733 - 08 Apr 2019
Cited by 74 | Viewed by 19437
Abstract
Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous [...] Read more.
Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous clinical trials of H1 receptor antagonists (H1RAs) as a treatment for asthma were not successful. In recent years, type 2 innate immunity has been demonstrated to be involved in allergic airway inflammation. Allergic asthma is defined by IgE antibody-mediated mast cell degranulation, while group 2 innate lymphoid cells (ILC2) induce eosinophilic inflammation in nonallergic asthma without allergen-specific IgE. Anti-IgE therapy has demonstrated prominent efficacy in the treatment of severe allergic asthmatics sensitized with specific perennial allergens. Furthermore, recent trials of specific cytokine antagonists indicated that these antagonists were effective in only some subtypes of asthma. Accordingly, H1RAs may show significant clinical efficacy for some subtypes of allergic asthma in which histamine is deeply associated with the pathophysiology. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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14 pages, 1141 KiB  
Review
Histamine N-Methyltransferase in the Brain
by Takeo Yoshikawa, Tadaho Nakamura and Kazuhiko Yanai
Int. J. Mol. Sci. 2019, 20(3), 737; https://doi.org/10.3390/ijms20030737 - 10 Feb 2019
Cited by 32 | Viewed by 11065
Abstract
Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed [...] Read more.
Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood–brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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13 pages, 543 KiB  
Review
Expression of Histidine Decarboxylase and Its Roles in Inflammation
by Noriyasu Hirasawa
Int. J. Mol. Sci. 2019, 20(2), 376; https://doi.org/10.3390/ijms20020376 - 16 Jan 2019
Cited by 56 | Viewed by 5970
Abstract
Histamine is a well-known mediator of inflammation that is released from mast cells and basophils. To date, many studies using histamine receptor antagonists have shown that histamine acts through four types of receptors: H1, H2, H3, and H4. Thus, histamine plays more roles [...] Read more.
Histamine is a well-known mediator of inflammation that is released from mast cells and basophils. To date, many studies using histamine receptor antagonists have shown that histamine acts through four types of receptors: H1, H2, H3, and H4. Thus, histamine plays more roles in various diseases than had been predicted. However, our knowledge about histamine-producing cells and the molecular mechanisms underlying histamine production at inflammatory sites is still incomplete. The histamine producing enzyme, histidine decarboxylase (HDC), is commonly induced at inflammatory sites during the late and chronic phases of both allergic and non-allergic inflammation. Thus, histamine levels in tissues are maintained at effective concentrations for hours, enabling the regulation of various functions through the production of cytokines/chemokines/growth factors. Understanding the regulation of histamine production will allow the development of a new strategy of using histamine antagonists to treat inflammatory diseases. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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17 pages, 7504 KiB  
Review
Antihistamines for Allergic Rhinitis Treatment from the Viewpoint of Nonsedative Properties
by Hideyuki Kawauchi, Kazuhiko Yanai, De-Yun Wang, Koju Itahashi and Kimihiro Okubo
Int. J. Mol. Sci. 2019, 20(1), 213; https://doi.org/10.3390/ijms20010213 - 08 Jan 2019
Cited by 74 | Viewed by 26742
Abstract
Antihistamines targeting the histamine H1 receptor play an important role in improving and maintaining the quality of life of patients with allergic rhinitis. For more effective and safer use of second-generation drugs, which are recommended by various guidelines, a classification based on [...] Read more.
Antihistamines targeting the histamine H1 receptor play an important role in improving and maintaining the quality of life of patients with allergic rhinitis. For more effective and safer use of second-generation drugs, which are recommended by various guidelines, a classification based on their detailed characteristics is necessary. Antihistamines for first-line therapy should not have central depressant/sedative activities. Sedative properties (drowsiness and impaired performance) are associated with the inhibition of central histamine neurons. Brain H1 receptor occupancy (H1RO) is a useful index shown to be correlated with indices based on clinical findings. Antihistamines are classified into non-sedating (<20%), less-sedating (20–50%), and sedating (≥50%) groups based on H1RO. Among the non-sedating group, fexofenadine and bilastine are classified into “non-brain-penetrating antihistamines” based on the H1RO. These two drugs have many common chemical properties. However, bilastine has more potent binding affinity to the H1 receptor, and its action tends to last longer. In well-controlled studies using objective indices, bilastine does not affect psychomotor or driving performance even at twice the usual dose (20 mg). Upon selecting antihistamines for allergic rhinitis, various situations should be taken into our consideration. This review summarizes that the non-brain-penetrating antihistamines should be chosen for the first-line therapy of mild allergic rhinitis. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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15 pages, 3432 KiB  
Review
Research Advances and Prospects on Mechanism of Sinomenin on Histamine Release and the Binding to Histamine Receptors
by Yu-Shi Zhang, Jia-Yin Han, Omer Iqbal and Ai-Hua Liang
Int. J. Mol. Sci. 2019, 20(1), 70; https://doi.org/10.3390/ijms20010070 - 24 Dec 2018
Cited by 28 | Viewed by 3428
Abstract
Sinomenine (SIN) is widely used in China to treat a variety of rheumatic diseases (RA), and has various pharmacological effects such as anti-inflammatory, analgesic, and anti-tumor effects. However, due to the histamine release characteristics of SIN, its adverse reactions such as allergic reactions, [...] Read more.
Sinomenine (SIN) is widely used in China to treat a variety of rheumatic diseases (RA), and has various pharmacological effects such as anti-inflammatory, analgesic, and anti-tumor effects. However, due to the histamine release characteristics of SIN, its adverse reactions such as allergic reactions, gastrointestinal reactions, and circulatory systemic reactions have been drawing increasing attention. We present here a systematic review of the chemical structure, pharmacological effects, clinical application, and adverse reactions of SIN, a detailed discussion on the relationship between histamine/histamine receptor and mechanism of action of SIN. In addition, we simulated the binding of SIN to four histamine receptors by using a virtual molecular docking method and found that the bonding intensity between SIN and receptors varied in the order shown as follows: H1R > H2R ~ H3R > H4R. The docking results suggested that SIN might exhibit dual regulatory effects in many processes such as cyclooxygenase-2 (COX-2) expression, NF-κB pathway activation, and degranulation of mast cells to release histamine, thereby exhibiting pro-inflammatory (adverse reactions)/anti-inflammatory effects. This study provides a theoretical basis for the clinical treatment of inflammations seen such as in RA using SIN, and also suggests that SIN has great potential in the field of cancer treatment and will have very important social and economic significance. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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