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1.
Cancer Sci ; 111(3): 817-825, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925976

RESUMO

Recent studies have reported that tumor-infiltrating mast cells (TIM) play an important role in tumor regression, but the effect of TIM in gallbladder cancer (GBC) remains unclear. The present study aims to investigate the prognostic value of TIM in GBC patients and its responsiveness to gemcitabine-based adjuvant chemotherapy (ACT). A total of 298 GBC patients from Zhongshan Hospital were recruited for this study. TIM infiltration was measured by immunohistochemical staining. Accumulation of TIM is significantly associated with prolonged overall survival in GBC patients. The benefit from gemcitabine-based ACT was superior among patients with high infiltration of TIM with GBC. Multivariate analysis identified TIM infiltration as an independent prognostic factor for overall survival. A heatmap showed that TIM-activated gene signatures were positively correlated with CD8+ T cells' gene signatures. Gene set enrichment analysis (GSEA) suggested that TIM was related to multiple T cell-related processes and signaling pathways, including the interferon gamma signaling pathway and the leukocyte migration signaling pathway. It was confirmed that CD8+ T cell infiltration was positively correlated with high TIM infiltration in tissue microarray (TMA), suggesting that TIM infiltration was linked to the immune surveillance in GBC. TIM can be used as an independent prognostic factor and a predictor of therapeutic response of gemcitabine-based ACT in GBC patients, which may mediate immune surveillance by recruiting and activating CD8+ T cells in GBC.


Assuntos
Neoplasias da Vesícula Biliar/patologia , Linfócitos do Interstício Tumoral/patologia , Mastócitos/patologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Quimioterapia Adjuvante/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/efeitos dos fármacos
2.
Food Chem Toxicol ; 135: 110924, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672514

RESUMO

BACKGROUND: Allergic conjunctivitis (AC) resulting from conjunctival reactive inflammation is a common ocular surface disease. Quercetin is known for its anti-allergic properties but its effects on conjunctivitis are less well understood. PURPOSE: In this study, we evaluated the anti-allergic effects of quercetin in animal models of conjunctivitis, and explored its molecular mechanism(s) of action in cultured human mast cells (MCs). KEY RESULTS: Quercetin inhibited the ovalbumin (OVA) induced expression of IgE, HA, IL-4, TNF-α and substance-P in the peripheral blood of AC mouse models. Quercetin also attenuated OVA induced MC degranulation, eosinophil number, substance P concentrations, and mRNA IL-4/TNF-α expression in the conjunctival tissue of AC models. In vitro analysis showed that quercetin reduced DNP-HSA/IgE induced calcium (Ca2+) influx, and suppressed degranulation and chemokine release in LAD2 cells (human primary mast cell). Quercetin also inhibited DNP-HSA/IgE induced Lyn/PLCγ/IP3R-Ca2+ activation, Lyn/ERK1/2 signaling, and Lyn/NF-κB activation in LAD2 cells, all of which promote inflammation. When added alone, quercetin had no effect on PLCγ1 phosphorylation or expression, but potently inhibited Lyn and phosphorylation-Lyn. Quercetin (200 µM) and Lyn inhibitors (Bafetinib, 10 µM) inhibit the activity of Lyn kinase, and quercetin can reduce the activation of Lyn kinase by Lyn agonist (Tolimidone, 10 µM). These data can be preliminarily determined that quercetin can inhibit allergic conjunctivitis as a Lyn kinase inhibitor. CONCLUSIONS AND IMPLICATIONS: This study illustrated the use of quercetin for the treatment of allergic conjunctivitis, which might act through its ability to inhibit Lyn/PLCγ/IP3R-Ca2+, Lyn/ERK1/2, and Lyn/NF-κB signaling. The inhibition of Lyn likely represents a major mechanism by which quercetin dampens the inflammatory response in AC disease models.


Assuntos
Antialérgicos/uso terapêutico , Conjuntivite Alérgica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quercetina/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Animais , Linhagem Celular , Quimiocinas/metabolismo , Conjuntivite Alérgica/induzido quimicamente , Conjuntivite Alérgica/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Imunoglobulina E/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Ovalbumina , Transdução de Sinais/efeitos dos fármacos , Pele/patologia
3.
Cardiovasc Pathol ; 44: 107154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31760242

RESUMO

Although the cause of eosinophilic coronary periarteritis (ECPA) remains unclear, an allergic background is present in fewer patients than expected. A 50-year-old man with no history of allergy or symptoms suggestive of cardiac or respiratory disorders suddenly died shortly after oral administration of loxoprofen sodium. Autopsy showed eosinophilic coronary periarteritis in three main branches of the coronary arteries, characterized by eosinophil-predominant inflammation without fibrinoid necrosis or granulomatous change in the adventitia and its surroundings of the three main branches of the coronary arteries, in addition to the localized sign of bronchial asthma in the lung. Immunohistochemical examination showed that many mast cells positive for human mast cell tryptase were evident in the perivascular tissue containing peripheral nerve trunks. Whereas the blood concentration of loxoprofen sodium was within the therapeutic range, significant elevation of the serum histamine and tryptase levels was found. The present case suggests that eosinophilic coronary periarteritis may be caused by a type I allergic reaction in some patients and that loxoprofen sodium can trigger a life-threatening type I allergic reaction, including eosinophilic coronary periarteritis, leading to sudden unexpected death.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doença da Artéria Coronariana/induzido quimicamente , Vasos Coronários/efeitos dos fármacos , Morte Súbita Cardíaca/etiologia , Hipersensibilidade a Drogas/etiologia , Eosinofilia/induzido quimicamente , Fenilpropionatos/efeitos adversos , Dor de Ombro/tratamento farmacológico , Autopsia , Causas de Morte , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/imunologia , Vasos Coronários/patologia , Morte Súbita Cardíaca/patologia , Hipersensibilidade a Drogas/imunologia , Hipersensibilidade a Drogas/patologia , Eosinofilia/imunologia , Eosinofilia/patologia , Evolução Fatal , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/patologia , Pessoa de Meia-Idade
4.
BMC Complement Altern Med ; 19(1): 361, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829185

RESUMO

BACKGROUND: Moringa oleifera Lam. is a commonly used plant in herbal medicine and has various reported bioactivities such as antioxidant, antimicrobial, anticancer and antidiabetes. It is rich in nutrients and polyphenols. The plant also has been traditionally used for alleviating allergic conditions. This study was aimed to examine the anti-allergic activity of M. oleifera extracts and its isolated compounds. METHOD: M. oleifera leaves, seeds and pods were extracted with 80% of ethanol. Individual compounds were isolated using a column chromatographic technique and elucidated based on the nuclear magnetic resonance (NMR) and electrospray ionisation mass spectrometry (ESIMS) spectral data. The anti-allergic activity of the extracts, isolated compounds and ketotifen fumarate as a positive control was evaluated using rat basophilic leukaemia (RBL-2H3) cells for early and late phases of allergic reactions. The early phase was determined based on the inhibition of beta-hexosaminidase and histamine release; while the late phase was based on the inhibition of interleukin (IL-4) and tumour necrosis factor (TNF-α) release. RESULTS: Two new compounds; ethyl-(E)-undec-6-enoate (1) and 3,5,6-trihydroxy-2-(2,3,4,5,6-pentahydroxyphenyl)-4H-chromen-4-one (2) together with six known compounds; quercetin (3), kaempferol (4), ß-sitosterol-3-O-glucoside (5), oleic acid (6), glucomoringin (7), 2,3,4-trihydroxybenzaldehyde (8) and stigmasterol (9) were isolated from M. oleifera extracts. All extracts and the isolated compounds inhibited mast cell degranulation by inhibiting beta-hexosaminidase and histamine release, as well as the release of IL-4 and TNF-α at varying levels compared with ketotifen fumarate. CONCLUSION: The study suggested that M. oleifera and its isolated compounds potentially have an anti-allergic activity by inhibiting both early and late phases of allergic reactions.


Assuntos
Antialérgicos/farmacologia , Mastócitos/efeitos dos fármacos , Moringa oleifera , Extratos Vegetais/farmacologia , Animais , Antialérgicos/análise , Antialérgicos/química , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Frutas/química , Extratos Vegetais/análise , Extratos Vegetais/química , Folhas de Planta/química , Ratos
5.
Life Sci ; 239: 117079, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31756343

RESUMO

AIM: Cutaneous neurofibroma (cNF), a hallmark feature of neurofibromatosis type 1 (NF1), results in psychological and physical damage to patients. Considering the important role of mast cells in neurofibroma development, the aim of this study was to elucidate the underlying mechanism of the interaction between cNF cells and mast cells. MAIN METHODS: SW10 cells with Nf1 knocked down were used as a cNF cell model. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays, as well as a mouse xenograft tumor model, were used to assess the cNF tumor growth in vivo and in vitro. ELISAs and IHC were used to examine the inflammatory activity of mast cells. KEY FINDINGS: We demonstrated that cNF cells activated mast cells, which in turn promoted the cNF cell growth, while suppression of the inflammatory activity of cNF-associated mast cells reversed their stimulating effect on the growth of cNF cells. Mechanistic studies revealed that SW10 cells upregulated PLCγ/AKT/IκBα/p65 signaling in mast cells, thereby increasing inflammation. Moreover, PLCγ modulated the AKT/IκBα/p65 signaling activity and played a critical role in the interaction of mast cells and cNF cells. Knockdown of PLCγ in mast cells diminished their cNF cell-induced inflammatory activity and subsequently reduced the cNF cell growth in vivo and in vitro. SIGNIFICANCE: This study revealed a novel interaction between mast cells and cNF cells, suggesting a potential strategy for treating cNF by targeting the newly recognized signaling pathway.


Assuntos
Mastócitos/metabolismo , Neurofibromatose 1/metabolismo , Animais , Linhagem Celular , Proliferação de Células , China , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/metabolismo , Neurofibroma/metabolismo , Neurofibromatoses/metabolismo , Neurofibromatoses/fisiopatologia , Neurofibromatose 1/fisiopatologia , Fosfolipase C gama/metabolismo , Fosfolipase C gama/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Neoplasias Cutâneas/patologia , Fator de Transcrição RelA/metabolismo
6.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3792-3797, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602955

RESUMO

This paper was aimed to establish screening methods of anaphylactoid reaction caused by safflower yellow for injection based on RBL-2 H3 cell degranulation model and mice model for acute anaphylactoid reaction,and evaluate the hypersensitivity caused by safflower yellow for injection from different batches. An in vitro cell model was used to keep the cells stimulated for an hour with different batches of safflower yellow for injection as the drug group,serum-free MEM medium as negative control group and 30 mg·L-1 C48/80 as positive control group respectively. The supernatant was then absorbed,and neutral red staining technique was used to detect the effect of safflower yellow injection on the degranulation of RBL-2 H3 cells with the positive cell rate of degranulation as the indicator.An in vivo model was established to validate the experimental results,and mice model for acute anaphylactoid reaction and ELISA method were adopted to detect the plasma histamine content,and screen the hypersensitivity caused by safflower yellow for injection at the animal level by using plasma histamine content as a test index. The results of the neutral red staining experiments showed that the positive control C48/80 could cause cell degranulation,and most of the cells were deeply stained. There was significant difference in positive cell rate between different batches of safflower yellow and positive control group. In the mice model for acute anaphylactoid reaction,it was found that the positive control C48/80 significantly increased the histamine content in the plasma of mice,while the safflower yellow in each batch did not cause a significant increase in plasma histamine( P<0. 000 1). The mechanism of anaphylactoid reaction is relatively complicated. This study was mainly based on the release of histamine and other active substances by degranulation of mast cells. No significant degranulation reaction of RBL-2 H3 cells induced by safflower yellow for injection was detected,nor was the plasma histamine level significantly increased in mice from the in vitro and in vivo aspects.


Assuntos
Anafilaxia/induzido quimicamente , Degranulação Celular/efeitos dos fármacos , Chalcona/análogos & derivados , Mastócitos/efeitos dos fármacos , Animais , Células Cultivadas , Chalcona/efeitos adversos , Histamina/sangue , Camundongos
7.
J Dermatol Sci ; 95(3): 99-106, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31558225

RESUMO

BACKGROUND: Thimerosal has been used as a preservative in many products which may cause contact dermatitis. It is the second most common allergen in positive patch test reactions, though being a clinical irrelevant allergen. Thimerosal-induced contact dermatitis is generally considered to be a delayed-type hypersensitivity reaction, but it is difficult to explain the fact that most patients develop an allergic reaction upon first encounter with thimerosal. Recent studies have demonstrated the association between Mas-related G protein coupled receptor X2 (MRGPRX2) and pseudo-allergic reactions which occur at the first contact with stimulation. This suggests the possibility that thimerosal may cause contact dermatitis via MRGPRX2 mediated mechanism. OBJECTIVES: To investigate the role of Mas-related G-protein coupled receptor B2 (MrgprB2)/MRGPRX2 in contact dermatitis induced by thimerosal. METHODS: Thimerosal induced pseudo-allergic reactions via MrgprB2/ MRGPRX2 were investigated using a novel skin pseudo-allergic reaction mouse model, footpad swelling and extravasation assays in vivo and mast cell degranulation assay in vitro. RESULTS: Thimerosal induced contact dermatitis in dorsal skin and footpad swelling in wild-type mice, but had no significant effect in MrgprB2-knockout mice. Thimerosal-induced dermatitis is characterized by infiltration of inflammatory cells and elevation of serum histamine and inflammatory cytokines, rather than elevation of serum IgE level. Thimerosal increased the intracellular Ca2+ concentration in HEK293 cells overexpressing MrgprB2/MRGPRX2. Downregulation of MRGPRX2 resulted in the reduced degranulation of LAD2 human mast cells. CONCLUSIONS: MrgprB2 mediates thimerosal-induced mast cell degranulation and pseudo-allergic reaction in mice. MRGPRX2 may be a key contributor to human contact dermatitis.


Assuntos
Dermatite de Contato/etiologia , Hipersensibilidade Tardia/etiologia , Mastócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Conservantes Farmacêuticos/toxicidade , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Timerosal/efeitos adversos , Administração Cutânea , Animais , Degranulação Celular/efeitos dos fármacos , Dermatite de Contato/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Hipersensibilidade Tardia/patologia , Masculino , Mastócitos/patologia , Camundongos , Camundongos Knockout , Conservantes Farmacêuticos/administração & dosagem , Receptores Acoplados a Proteínas-G/genética , Timerosal/administração & dosagem
8.
Expert Opin Pharmacother ; 20(13): 1539-1550, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381378

RESUMO

Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.


Assuntos
Mastocitose Sistêmica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Humanos , Mesilato de Imatinib/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/metabolismo
9.
Biosci Biotechnol Biochem ; 83(12): 2280-2287, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31412751

RESUMO

The increasing number of patients suffering from allergic diseases is a global health problem. Grifola frondosa is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported that G. frondosa extract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells in vivo. Our findings suggest that G. frondosa, including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases.


Assuntos
Degranulação Celular/efeitos dos fármacos , Ergosterol/farmacologia , Grifola/química , Hipersensibilidade/prevenção & controle , Mastócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Alimento Funcional , Liberação de Histamina/efeitos dos fármacos , Hipersensibilidade/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
10.
Int J Mol Sci ; 20(15)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362339

RESUMO

Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents.


Assuntos
Imunomodulação , Interleucina-1/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Heparina/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Interleucina-1/farmacologia , Mastócitos/efeitos dos fármacos , Triptases/metabolismo
11.
Environ Toxicol Pharmacol ; 71: 103221, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31365892

RESUMO

Our aim was to compare the protective efficacy of two different formulations of methylprednisolone in T-2 toxin-induced cardiomyopathy. Methylprednisolone (soluble form, Lemod-solu® and/or depot form, Lemod-depo®, a total single dose of 40 mg/kg im) was given immediately after T-2 toxin (1 LD50 0.23 mg/kg sc). The myocardial tissue samples were examinated by using histopathology, semiquantitative and imaging analyses on day 1, 7, 14, 21, 28 and 60 of the study. Therapeutic application of Lemod-solu® significantly decreased the intensity of myocardial degeneration and haemorrhages, distribution of glycogen granules in the endo- and perimysium, a total number of mast cells and the degree of their degranulation was in correlation with the reversible heart structural lesions (p <  0.01 vs. T-2 toxin). These changes were completely abolished by the therapeutic use of Lemod-solu® plus Lemod-depo® (p <  0.001 vs. T-2 toxin). Our results show that a significant cardioprotective efficacy of methylprednisolone is mediated by its anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Metilprednisolona/uso terapêutico , Miocárdio/patologia , Toxina T-2/toxicidade , Animais , Anti-Inflamatórios/administração & dosagem , Cardiomiopatias/induzido quimicamente , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Glicogênio/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/patologia , Metilprednisolona/administração & dosagem , Miocárdio/metabolismo , Ratos Wistar
12.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426346

RESUMO

Daidzein is a common isoflavone, having multiple biological effects such as anti-inflammation, anti-allergy, and anti-aging. α-Tocopherol is the tocopherol isoform with the highest vitamin E activity including anti-allergic activity and anti-cancer activity. Hesperetin is a flavone, which shows potent anti-inflammatory effects. These compounds have shortcomings, i.e., water-insolubility and poor absorption after oral administration. The glycosylation of bioactive compounds can enhance their water-solubility, physicochemical stability, intestinal absorption, and biological half-life, and improve their bio- and pharmacological properties. They were transformed by cultured Nicotiana tabacum cells to 7-ß-glucoside and 7-ß-gentiobioside of daidzein, and 3'- and 7-ß-glucosides, 3',7-ß-diglucoside, and 7-ß-gentiobioside of hesperetin. Daidzein and α-tocopherol were glycosylated by galactosylation with ß-glucosidase to give 4'- and 7-ß-galactosides of daidzein, which were new compounds, and α-tocopherol 6-ß-galactoside. These nine glycosides showed higher anti-allergic activity, i.e., inhibitory activity toward histamine release from rat peritoneal mast cells, than their respective aglycones. In addition, these glycosides showed higher tyrosinase inhibitory activity than the corresponding aglycones. Glycosylation of daidzein, α-tocopherol, and hesperetin greatly improved their biological activities.


Assuntos
Antialérgicos/síntese química , Cosméticos/síntese química , Glicosídeos/síntese química , Hesperidina/síntese química , Isoflavonas/síntese química , alfa-Tocoferol/síntese química , Animais , Antialérgicos/metabolismo , Biocatálise , Técnicas de Cultura de Células , Cosméticos/metabolismo , Alimento Funcional/análise , Glicosídeos/metabolismo , Glicosilação , Hesperidina/metabolismo , Humanos , Isoflavonas/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Células Vegetais/metabolismo , Cultura Primária de Células , Ratos , Ratos Wistar , Solubilidade , Tabaco/citologia , Tabaco/metabolismo , alfa-Tocoferol/metabolismo
13.
Cells ; 8(7)2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277247

RESUMO

Increased activity of secretory phospholipases A2 (sPLA2) type-II was previously observed in ileum of Crohn's disease (CD). Our aims were to explore the involvement of calcium-independent (i)PLA2ß in the release of sPLA2s from the human mast cell (MC) line (HMC-1) and investigate expressions of cytosolic (c)PLA2α, iPLA2ß, sPLA2-IIA and sPLA2-V in MCs of CD ileum. The release of sPLA2 was investigated in HMC-1 by immunocytochemistry and ELISA. The expression intensities of PLA2s in mucosal MCs, and the proportion of PLA2-positive MCs, were investigated in normal ileum and in ileum from patients with CD by immunohistochemistry. The calcium ionophore-stimulated release of sPLA2-IIA and sPLA2-V from HMC-1 was reduced by the iPLA2-inhibitor bromoenol lactone. All four PLA2s were detectable in mucosal MCs, both in normal ileum and in CD, but the proportion of iPLA2ß-containing mucosal MCs and the expression intensity of sPLA2-IIA was increased in CD. Results indicate that iPLA2ß is involved in the secretion of sPLA2s from HMC-1, and suggest that iPLA2ß-mediated release of sPLA2 from intestinal MCs may contribute to CD pathophysiology. Ex vivo studies on isolated mucosal mast cells are however needed to clarify the precise role of MC PLA2s in the inflammatory processes of CD.


Assuntos
Doença de Crohn/imunologia , Fosfolipases A2 do Grupo VI/metabolismo , Mastócitos/imunologia , Fosfolipases A2 Secretórias/metabolismo , Adulto , Idoso , Ionóforos de Cálcio/farmacologia , Linhagem Celular Tumoral , Doença de Crohn/patologia , Feminino , Humanos , Íleo/citologia , Íleo/imunologia , Íleo/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pessoa de Meia-Idade
14.
Biomed Res Int ; 2019: 3505034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281834

RESUMO

Rhodomyrtus tomentosa, a flowering plant of Myrtaceae family from southern and southeastern Asia, was known to possess a rich source of structurally diverse and various biological activities. In this study, the inhibitory effect of R. tomentosa fruit extract (RFE) on allergic responses in calcium ionophore A23187-activated RBL-2H3 mast cells was investigated. The result showed that RFE was able to inhibit mast cell degranulation via decreasing ß-hexosaminidase release and intracellular Ca2+ elevation at the concentration of 400 µg/ml. Moreover, the suppressive effects of RFE on the production of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were evidenced. In addition, RFE effectively scavenged DPPH radical and suppressed the reactive oxygen species generation in a dose-dependent manner. Notably, the pretreatment of RFE caused the downregulation of tyrosine kinase Fyn phospholipid enzyme phospholipase Cγ (PLCγ), extracellular-signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) phosphorylation. These results indicated that RFE could be a promising inhibitor of allergic responses and may be developed as bioactive ingredient for prevention or treatment of allergic diseases.


Assuntos
Regulação para Baixo , Frutas/química , Hipersensibilidade/imunologia , Mastócitos/imunologia , Myrtaceae/química , Animais , Calcimicina/farmacologia , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/biossíntese , Regulação para Baixo/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Extratos Vegetais/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos
15.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356185

RESUMO

A suitable inflammatory signal influences extracellular matrix accumulation and determines the quality of the myocardial infarction scar. The aim of the present study was to determine the influence of mast cell sonicates or histamine on collagen accumulation in heart myofibroblast culture and on the deposition of collagen in the myocardial infarction scar. The histamine receptor involved in the process was investigated. Myocardial infarction was induced by ligation of the left coronary artery. Myofibroblasts were isolated from the scar of myocardial infarction. The effects of mast cell sonicates, histamine and its receptor antagonists, i.e. ketotifen (H1-receptor inhibitor), ranitidine (H2-receptor inhibitor), ciproxifan (H3-receptor inhibitor), JNJ7777120 (H4-receptor inhibitor), imetit (H3 receptor agonist), were investigated. The mast cell sonicates or histamine (10-10 - 10-5M) augmented collagen content in myofibroblast cultures; however, histamine-induced elevation was reduced by ciproxifan (10-5M, 10-6M). Imetit (10-9 - 10-5M) elevated collagen content in the culture. H3 receptor expression on myofibroblasts was confirmed. Our findings indicate that histamine increases the deposition of collagen in cultures of myofibroblasts isolated from the myocardial infarction scar. This effect is dependent on H3 receptor activation.


Assuntos
Cicatriz/metabolismo , Colágeno/metabolismo , Histamina/metabolismo , Miofibroblastos/metabolismo , Receptores Histamínicos/metabolismo , Animais , Células Cultivadas , Coração/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Ratos , Ratos Wistar , Tioureia/análogos & derivados , Tioureia/farmacologia
16.
APMIS ; 127(10): 688-695, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344274

RESUMO

Acetylshikonin has long been known as an anti-inflammatory and antioxidative reagent. However, the anti-allergic effect has not been studied. The aim of this study was to evaluate the effect of acetylshikonin on allergic rhinitis (AR) in mice. Mice were sensitized by intraperitoneal injection of OVA and aluminum hydroxide and challenged with intranasal instillation of OVA. Acetylshikonin was administered orally after nasal cavities challenge. Severity of allergic rhinitis was assessed according to nasal symptoms; serum OVA-specific immunoglobulin E (IgE), IgG1, and IgG2a level; and interleukin (IL)-4, IL-10, IL-5, IL-13, TNF-α, IL-12, and interferon (INF)-γ levels in nasal lavage fluid (NALF). Additionally, the histological change and the release of histamine in serum and nasal lavage fluid were evaluated by acid-Schiff stain and ELISA. Acetylshikonin attenuated manifestation of nasal symptoms in sensitized mice and inhibited production of Th2-related OVA-specific IgE, IgG1, and Th2 cell-produced IL-4, IL-5, IL-13, and mast cell produced histamine; however, it had no effect on Th1 cell-produced cytokines, like INF-γ. In addition, the degree of inflammatory cell infiltration and goblet cell hyperplasia was attenuated by acetylshikonin treatment. Our results suggest that acetylshikonin effectively reduces allergic inflammation in a mouse model of allergic rhinitis by its anti-allergic and anti-inflammatory properties.


Assuntos
Antraquinonas/administração & dosagem , Citocinas/antagonistas & inibidores , Liberação de Histamina/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Mastócitos/efeitos dos fármacos , Rinite Alérgica/tratamento farmacológico , Células Th2/efeitos dos fármacos , Administração Oral , Alérgenos/administração & dosagem , Animais , Modelos Animais de Doenças , Injeções Intraperitoneais , Camundongos , Ovalbumina/administração & dosagem , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/patologia , Resultado do Tratamento
17.
Anesthesiology ; 131(1): 132-147, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31225809

RESUMO

BACKGROUND: As the meningeally derived, fibroblast-rich, mass-produced by intrathecal morphine infusion is not produced by all opiates, but reduced by mast cell stabilizers, the authors hypothesized a role for meningeal mast cell/fibroblast activation. Using the guinea pig, the authors asked: (1) Are intrathecal morphine masses blocked by opiate antagonism?; (2) Do opioid agonists not producing mast cell degranulation or fibroblast activation produce masses?; and (3) Do masses covary with Mas-related G protein-coupled receptor signaling thought to mediate mast cell degranulation? METHODS: In adult male guinea pigs (N = 66), lumbar intrathecal catheters connected to osmotic minipumps (14 days; 0.5 µl/h) were placed to deliver saline or equianalgesic concentrations of morphine sulfate (33 nmol/h), 2',6'-dimethyl tyrosine-(Tyr-D-Arg-Phe-Lys-NH2) (abbreviated as DMT-DALDA; 10 pmol/h; µ agonist) or PZM21 (27 nmol/h; biased µ agonist). A second pump delivered subcutaneous naltrexone (25 µg/h) in some animals. After 14 to 16 days, animals were anesthetized and perfusion-fixed. Drug effects on degranulation of human cultured mast cells, mouse embryonic fibroblast activation/migration/collagen formation, and Mas-related G protein-coupled receptor activation (PRESTO-Tango assays) were determined. RESULTS: Intrathecal infusion of morphine, DMT-DALDA or PZM21, but not saline, comparably increased thermal thresholds for 7 days. Spinal masses proximal to catheter tip, composed of fibroblast/collagen type I (median: interquartile range, 0 to 4 scale), were produced by morphine (2.3: 2.0 to 3.5) and morphine plus naltrexone (2.5: 1.4 to 3.1), but not vehicle (1.2: 1.1 to 1.5), DMT-DALDA (1.0: 0.6 to 1.3), or PZM21 (0.5: 0.4 to 0.8). Morphine in a naloxone-insensitive fashion, but not PZM21 or DMT-DALDA, resulted in mast cell degranulation and fibroblast proliferation/collagen formation. Morphine-induced fibroblast proliferation, as mast cell degranulation, is blocked by cromolyn. Mas-related G protein-coupled receptor activation was produced by morphine and TAN67 (∂-opioid agonist), but not by PZM21, TRV130 (mu biased ligand), or DMT-DALDA. CONCLUSIONS: Opiates that activate Mas-related G protein-coupled receptor will degranulate mast cells, activate fibroblasts, and result in intrathecal mass formation. Results suggest a mechanistically rational path forward to safer intrathecal opioid therapeutics.


Assuntos
Degranulação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Morfina/farmacologia , Receptores Acoplados a Proteínas-G/fisiologia , Coluna Vertebral/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Cobaias , Humanos , Infusão Espinal , Masculino , Modelos Animais , Morfina/administração & dosagem , Transdução de Sinais/fisiologia
18.
J Pharmacol Exp Ther ; 370(3): 437-446, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31248979

RESUMO

Multiple sclerosis is a neurodegenerative disease affecting predominantly female patients between 20 and 45 years of age. We previously reported the significant contribution of mouse mast cell protease 4 (mMCP-4) in the synthesis of endothelin-1 (ET-1) in healthy mice and in a murine model of experimental autoimmune encephalomyelitis (EAE). In the current study, the cardiovascular effects of ET-1 and big endothelin-1 (big-ET-1) administered systemically or intrathecally were assessed in the early preclinical phase of EAE in telemetry instrumented/conscious mice. Chymase-specific enzymatic activity was also measured in the lung, brain, and mast cell extracts in vitro. Finally, the impact of EAE immunization was studied on the pulmonary and brain mRNA expression of different genes of the endothelin pathway, interleukin-33 (IL-33), and monitoring of immunoreactive tumor necrosis factor-α (TNF-α). Systemically or intrathecally administered big-ET-1 triggered increases in blood pressure in conscious mice. One week post-EAE, the pressor responses to big-ET-1 were potentiated in wild-type (WT) mice but not in mMCP-4 knockout (KO) mice. EAE triggered mMCP-4-specific activity in cerebral homogenates and peritoneal mast cells. Enhanced pulmonary, but not cerebral preproendothelin-1 and IL-33 mRNA were found in KO mice and further increased 1 week post-EAE immunization, but not in WT animals. Finally, TNF-α levels were also increased in serum from mMCP-4 KO mice, but not WT, 1 week post-EAE. Our study suggests that mMCP-4 activity is enhanced both centrally and systemically in a mouse model of EAE.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Endotelina-1/administração & dosagem , Endotelina-1/farmacologia , Serina Endopeptidases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Técnicas de Inativação de Genes , Hemodinâmica/efeitos dos fármacos , Injeções Espinhais , Interleucina-33/deficiência , Interleucina-33/genética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina Endopeptidases/deficiência , Serina Endopeptidases/genética , Regulação para Cima/efeitos dos fármacos
19.
Molecules ; 24(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195760

RESUMO

Hispidulin (4',5,7-trihydroxy-6-methoxyflavone) is a natural compound derived from traditional Chinese medicinal herbs, and it is known to have an anti-inflammatory effect. Here, we investigated the effect of hispidulin on the immunoglobulin E (IgE)-mediated allergic responses in rat basophilic leukemia (RBL)-2H3 mast cells. When RBL-2H3 cells were sensitized with anti-dinitrophenyl (anti-DNP) IgE and subsequently stimulated with DNP-human serum albumin (HSA), histamine and ß-hexosaminidase were released from the cells by degranulation of activated mast cells. However, pretreatment with hispidulin before the stimulation of DNP-HSA markedly attenuated release of both in anti-DNP IgE-sensitized cells. Furthermore, we investigated whether hispidulin inhibits anti-DNP IgE and DNP-HSA-induced passive cutaneous anaphylaxis (PCA), as an animal model for Type I allergies. Hispidulin markedly decreased the PCA reaction and allergic edema of ears in mice. In addition, activated RBL-2H3 cells induced the expression of inflammatory cytokines (tumor necrosis factor-α and interleukin-4), which are critical for the pathogenesis of allergic disease, through the activation of c-Jun N-terminal kinase (JNK). Inhibition of JNK activation by hispidulin treatment reduced the induction of cytokine expression in the activated mast cells. Our results indicate that hispidulin might be a possible therapeutic candidate for allergic inflammatory diseases through the suppression of degranulation and inflammatory cytokines expression.


Assuntos
Citocinas/metabolismo , Regulação para Baixo , Flavonas/uso terapêutico , Liberação de Histamina , Hipersensibilidade/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Mastócitos/patologia , Animais , Degranulação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Liberação de Histamina/efeitos dos fármacos , Hipersensibilidade/complicações , Imunoglobulina E/metabolismo , Inflamação/complicações , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Fosforilação/efeitos dos fármacos
20.
J Mol Neurosci ; 69(2): 235-245, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201657

RESUMO

Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell-deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell-deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell-deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.


Assuntos
Dor do Câncer/tratamento farmacológico , Carcinoma/complicações , Degranulação Celular , Mastócitos/metabolismo , Neoplasias Pancreáticas/complicações , Dor Visceral/tratamento farmacológico , Adulto , Animais , Dor do Câncer/etiologia , Feminino , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Cetotifeno/farmacologia , Cetotifeno/uso terapêutico , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fator de Crescimento Neural/metabolismo , Secretagogos/farmacologia , Secretagogos/uso terapêutico , Triptases/metabolismo , Dor Visceral/etiologia
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