Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor ...Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor X2(MRGPRX2),which has a low affinity for morphine.Neutrophils and macrophages can synthesize and release endogenous opioid peptides.Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species(ROS)in unstimulated leukocytes.Conversely,OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages.Morphine inhibits Toll-like receptor 4(TLR4)expression in macrophages,thereby attenuating inflammation,whereas methadone induces ROS production in mast cells through TLR4 activation.Stimulation of TLR4 triggersβ-endorphin synthesis in macrophages.The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury.Importantly,activation ofκ1-andμ-ORs suppresses proinflammatory cytokine production by leukocytes,thereby mitigating inflammatory injury to the heart and other organs.展开更多
MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis,atopic dermatitis,and chronic urticaria.Previously,we identified a class of diaryl urea(DPU)MRGPRX2 antagonists with sub-micromolar IC50...MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis,atopic dermatitis,and chronic urticaria.Previously,we identified a class of diaryl urea(DPU)MRGPRX2 antagonists with sub-micromolar IC50 values in vitro.However,the structureeactivity relationship remains unclear.Herein,we adopted a“relative symmetry with electronegativity of different key-groups”strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety.Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023,that possess relatively symmetric electron-withdrawing substituents,remarkable inhibited mast cell degranulation at a sub-micromolar IC50 in vitro and alleviated anaphylactic symptoms.Furthermore,B-1023,mitigated antigen-induced pulmonary inflammation(AIPI)in mice and competitively bonded to MRGPRX2.In summary,the“relative symmetry with electronegativity of different keygroups”strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.展开更多
肥大细胞在炎症和过敏反应中发挥重要作用,除了高亲和力的免疫球蛋白E(Immunoglobulin E,IgE)受体FcεRI外,肥大细胞还表达大量的G蛋白偶联受体(G-protein-coupled receptors,GPCRs),这是最大的膜受体蛋白群,也是药物治疗中最常见的靶...肥大细胞在炎症和过敏反应中发挥重要作用,除了高亲和力的免疫球蛋白E(Immunoglobulin E,IgE)受体FcεRI外,肥大细胞还表达大量的G蛋白偶联受体(G-protein-coupled receptors,GPCRs),这是最大的膜受体蛋白群,也是药物治疗中最常见的靶点。肥大细胞相关的G蛋白偶联受体X2(Mas-related G protein-coupled receptors X2,MrgprX2)是一种具有多种配体的内源性受体,在肥大细胞中选择性表达。抗菌宿主防御肽、神经肽、碱性蛋白、嗜酸性粒细胞过氧化物酶和许多美国食品和药物管理局(Food and Drug Administration,FDA)批准的肽类药物可通过该受体独立激活肥大细胞,引起肥大细胞脱颗粒和促炎介质的释放,并促进多细胞信号级联。MrgprX2在宿主防御、药物诱导的过敏性反应、神经源性炎症、疼痛、瘙痒和慢性炎症性疾病中发挥作用,是治疗多种疾病的潜在靶点。展开更多
基金supported by the Russian Science Foundation(Grant No.23-65-10017 to B.K.K.and M.K.)The Ministry of Science and Higher Education of the Russian Federation(Grant No.122020300042-4 to L.N.M.)supported the preparation of the minichapter titled"Opioids reduce inflammatory injury of the heart".
文摘Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor X2(MRGPRX2),which has a low affinity for morphine.Neutrophils and macrophages can synthesize and release endogenous opioid peptides.Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species(ROS)in unstimulated leukocytes.Conversely,OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages.Morphine inhibits Toll-like receptor 4(TLR4)expression in macrophages,thereby attenuating inflammation,whereas methadone induces ROS production in mast cells through TLR4 activation.Stimulation of TLR4 triggersβ-endorphin synthesis in macrophages.The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury.Importantly,activation ofκ1-andμ-ORs suppresses proinflammatory cytokine production by leukocytes,thereby mitigating inflammatory injury to the heart and other organs.
基金supported by the National Natural Science Foundation of China(grant Nos.81930096 and 82373830).
文摘MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis,atopic dermatitis,and chronic urticaria.Previously,we identified a class of diaryl urea(DPU)MRGPRX2 antagonists with sub-micromolar IC50 values in vitro.However,the structureeactivity relationship remains unclear.Herein,we adopted a“relative symmetry with electronegativity of different key-groups”strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety.Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023,that possess relatively symmetric electron-withdrawing substituents,remarkable inhibited mast cell degranulation at a sub-micromolar IC50 in vitro and alleviated anaphylactic symptoms.Furthermore,B-1023,mitigated antigen-induced pulmonary inflammation(AIPI)in mice and competitively bonded to MRGPRX2.In summary,the“relative symmetry with electronegativity of different keygroups”strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.
文摘肥大细胞在炎症和过敏反应中发挥重要作用,除了高亲和力的免疫球蛋白E(Immunoglobulin E,IgE)受体FcεRI外,肥大细胞还表达大量的G蛋白偶联受体(G-protein-coupled receptors,GPCRs),这是最大的膜受体蛋白群,也是药物治疗中最常见的靶点。肥大细胞相关的G蛋白偶联受体X2(Mas-related G protein-coupled receptors X2,MrgprX2)是一种具有多种配体的内源性受体,在肥大细胞中选择性表达。抗菌宿主防御肽、神经肽、碱性蛋白、嗜酸性粒细胞过氧化物酶和许多美国食品和药物管理局(Food and Drug Administration,FDA)批准的肽类药物可通过该受体独立激活肥大细胞,引起肥大细胞脱颗粒和促炎介质的释放,并促进多细胞信号级联。MrgprX2在宿主防御、药物诱导的过敏性反应、神经源性炎症、疼痛、瘙痒和慢性炎症性疾病中发挥作用,是治疗多种疾病的潜在靶点。
