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1.
Int J Mol Sci ; 25(20)2024 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-39456794

RESUMO

Molecular hydrogen (H2) has antioxidant, anti-inflammatory, and anti-fibrotic effects. In a rat model simulating pulmonary fibrotic changes induced by monocrotaline-induced pulmonary hypertension (MPH), we had previously explored the impact of inhaled H2 on lung inflammation and blood pressure. In this study, we further focused the biological effects of H2 on mast cells (MCs) and the parameters of the fibrotic phenotype of the local tissue microenvironment. MPH resulted in a significantly increased number of MCs in both the pneumatic and respiratory parts of the lungs, an increased number of tryptase-positive MCs with increased expression of TGF-ß, activated interaction with immunocompetent cells (macrophages and plasma cells) and fibroblasts, and increased MC colocalization with a fibrous component of the extracellular matrix of connective tissue. The alteration in the properties of the MC population occurred together with intensified collagen fibrillogenesis and an increase in the integral volume of collagen and elastic fibers of the extracellular matrix of the pulmonary connective tissue. The exposure of H2 together with monocrotaline (MCT), despite individual differences between animals, tended to decrease the intrapulmonary MC population and the severity of the fibrotic phenotype of the local tissue microenvironment compared to changes in animals exposed to the MCT effect alone. In addition, the activity of collagen fibrillogenesis associated with MCs and the expression of TGF-ß and tryptase in MCs decreased, accompanied by a reduction in the absolute and relative content of reticular and elastic fibers in the lung stroma. Thus, with MCT exposure, inhaled H2 has antifibrotic effects involving MCs in the lungs of rats. This reveals the unknown development mechanisms of the biological effects of H2 on the remodeling features of the extracellular matrix under inflammatory background conditions of the tissue microenvironment.


Assuntos
Hidrogênio , Hipertensão Pulmonar , Pulmão , Mastócitos , Animais , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Ratos , Hidrogênio/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Microambiente Celular/efeitos dos fármacos , Masculino , Fator de Crescimento Transformador beta/metabolismo , Monocrotalina/toxicidade , Matriz Extracelular/metabolismo , Modelos Animais de Doenças , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Colágeno/metabolismo , Triptases/metabolismo
2.
Int J Mol Sci ; 25(20)2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39456844

RESUMO

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases. Topical treatments are recommended for all patients regardless of severity, making it essential to develop an effective topical AD treatment with minimal side effects; We investigated the efficacy of topical application of naringin in AD and explored the possible mechanisms using an AD mouse model induced by 1-chloro-2,4-dinitrobenzene (DNCB). Clinical, histological, and immunological changes related to AD and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling proteins in the skin tissues were measured as outcomes; Naringin treatment resulted in a significant improvement in dermatitis severity score and reduced epidermal thickness and mast cell count in the skin (p < 0.05). Naringin also demonstrated the ability to inhibit DNCB-induced changes in interleukin (IL) 4, chemokine (C-C motif) ligand (CCL) 17, CCL22, IL1ß, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) levels by quantitative real-time polymerase chain reaction (qRT-PCR) and IL13 by enzyme-linked immunosorbent assay (ELISA) (p < 0.05). Western blot results exhibited the decreased JAK1, JAK2, STAT1, STAT3, phospho-STAT3, and STAT6 expression in the naringin-treated groups (p < 0.05); The findings of this study suggest that topical naringin may effectively improve the symptoms of AD and could be used as a therapeutic agent for AD.


Assuntos
Dermatite Atópica , Flavanonas , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Animais , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Camundongos , Modelos Animais de Doenças , Dinitroclorobenzeno , Transdução de Sinais/efeitos dos fármacos , Citocinas/metabolismo , Camundongos Endogâmicos BALB C , Feminino , Pele/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Fatores de Transcrição STAT/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo
3.
Cell Biol Int ; 48(10): 1463-1472, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39418631

RESUMO

Cationic liposomes composed of cholesteryl-3ß-carboxyamidoethylene-N-hydroxyethylamine (OH-chol) and 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) inhibit mast cell degranulation mediated via crosslinking of high-affinity IgE receptors (FcεRI). Although the inhibitory efficiency of mast cell degranulation is altered by modifying the ratio of OH-chol and DOPE in cationic liposomes, the manner in which physicochemical properties, such as surface charge and size, influence suppression is not clear. We observed that positive surface charge, but not the size, of liposomes plays a role in suppressing rat basophilic leukemia (RBL-2H3) cell activation. Pretreatment with middle-ratio OH-chol liposomes (zeta potential, 62.2 ± 0.5 mV; diameter, 325.4 ± 7.3 nm) exhibited a larger suppression of RBL-2H3 cell degranulation evoked by FcεRI crosslinking compared with that by low-ratio OH-chol liposomes (zeta potential, 48.6 ± 1.9 mV; diameter, 344.4 ± 25.0 nm), although both liposomes were similarly attached to RBL-2H3 cells. Preparation of middle-ratio OH-chol liposomes, classified roughly by size using an extrusion method, revealed that the liposomal size did not affect the inhibitory efficiency of RBL-2H3 cell activation. Mechanistically, we found that middle-ratio OH-chol liposomes increased the inhibition of antigen-induced Akt phosphorylation compared to low-ratio OH-chol liposomes. We measured the phosphorylation of linker for activation of T cells (LAT) and paxillin, which are important proteins in FcεRI- and focal adhesions (FAs)-mediated signaling, respectively. Middle ratio OH-chol liposomes significantly suppressed antigen-induced paxillin phosphorylation, but did not affect LAT phosphorylation, suggesting that middle-ratio OH-chol liposomes attached to RBL-2H3 cells suppress the degranulation by impairing FA-mediated Akt phosphorylation evoked by FcεRI crosslinking.


Assuntos
Degranulação Celular , Lipossomos , Proteínas Proto-Oncogênicas c-akt , Animais , Ratos , Degranulação Celular/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Leucemia Basofílica Aguda/metabolismo , Leucemia Basofílica Aguda/patologia , Receptores de IgE/metabolismo , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/metabolismo , Fosfatidiletanolaminas/farmacologia
4.
PLoS One ; 19(10): e0311981, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39432538

RESUMO

BACKGROUND: Mast cells (MCs) are multifaceted immune cells that are capable of recognizing and responding to various stimuli by releasing an array of cytokines. We aimed to use human cord blood-derived mast cells (hCBMCs) as a model to evaluate different conditions under which chemokines and growth factors are expressed and secreted as mediators upon stimulation with the alarmin interleukin-33 (IL-33). METHODS: hCBMCs were stimulated with 10 ng/mL or 20 ng/mL of recombinant human IL-33 (rhIL-33) for 6 h (acute) or 24 h (chronic). The mRNA expression of chemokines and growth factors was analyzed using microarrays, and the mediators released in the supernatant were evaluated using a multiplex assay. RESULTS: The mRNA expression levels of C-C chemokine ligands (CCL) CCL1, CCL5, granulocyte macrophage colony-stimulating factor (GM-CSF), and macrophage inflammatory protein (MIP)-4/CCL18 were upregulated under all conditions. In contrast, C-X-C motif chemokine ligand (CXCL) CXCL8 and CCL24 levels increased only under acute (6 h) and prolonged (24 h) conditions, respectively. Moreover, high levels of CXCL8, MIP-1α, and MIP-1ß were secreted during acute inflammation, whereas the release of GM-CSF and CXCL9 proteins increased under all four conditions. CONCLUSIONS: This study highlights the sentinel role of MCs in mounting a specific immune response against a pathogenic-like stimulus in a timely and dose-dependent manner and is relevant for improving inflammatory treatment options.


Assuntos
Quimiocinas , Sangue Fetal , Interleucina-33 , Mastócitos , Humanos , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Sangue Fetal/citologia , Quimiocinas/metabolismo , Quimiocinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Células Cultivadas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia
5.
Int J Mol Sci ; 25(19)2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39409178

RESUMO

Virus-like particles (VLPs) have been studied and used as vaccines to control foot-and-mouth disease (FMD). Mast cells (MCs) express various pattern recognition receptors that recognize pathogens and secrete numerous cytokines to initiate and modulate immune responses. Our previous study showed that bone marrow-derived mast cells (BMMCs) can recognize foot-and-mouth disease virus-like particles (FMDV-VLPs) to differentially express various cytokines and that histone acetylation can regulate the cytokines secreted during BMMC recognition of FMDV-VLPs. To demonstrate the role of DNA methylation in this response process, BMMCs that recognize FMDV-VLPs were treated with azacytidine (5-AZA), an inhibitor of DNA methylation transferase. We prepared FMDV-VLPs as described previously and cultured the BMMCs. The transcription and expression of key cytokines and transcription factors were determined using real-time quantitative PCR (RT-qPCR) and Western blotting. Results showed that pre-treatment with AZA resulted in the increased transcription and expression of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-13, and IL-10, while the changes in IL-13 transcription and IL-6 expression were irrelevant to mannose receptors (MRs). Furthermore, analysis of the transcription factors indicated that both the transcription and expression of nuclear factor-kappa B (NF-κB) increased significantly in the AZA pre-treated group, indicating that DNA methylation may also regulate NF-κB expression to modulate TNF-α, IL-13, and IL-6. However, pre-treatment with AZA did not alter the expression of microphthalmia-associated transcription factor (MITF) or GATA-2. All the data demonstrate that DNA methylation negatively regulates the transcription and expression of TNF-α, IL-13, IL-10, and IL-6 secreted by recognizing FMDV-VLPs. These results provide new ideas for the mast cell-based design of more effective vaccine adjuvants and targeted therapies in the future.


Assuntos
Citocinas , Metilação de DNA , Vírus da Febre Aftosa , Mastócitos , Animais , Citocinas/metabolismo , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Vírus da Febre Aftosa/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Azacitidina/farmacologia , Febre Aftosa/imunologia , Células da Medula Óssea/metabolismo
6.
Life Sci ; 357: 123091, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39362587

RESUMO

AIMS: Accumulating evidence indicates the involvement of TRESK potassium channels in migraine, however, effects of TRESK activation on migraine-related mechanisms remain unclear. We explored effects of TRESK channel modulation on migraine-related behavioral and molecular markers in in-vivo and ex-vivo rat models of migraine. MAIN METHODS: The selective TRESK activator cloxyquin at different doses, the TRESK inhibitor A2764, and the migraine drug sumatriptan were tested alone or in different combinations in nitroglycerin (NTG)-induced in-vivo model, and in ex-vivo meningeal, trigeminal ganglion and brainstem preparations in which CGRP release was induced by capsaicin. Mechanical allodynia, CGRP and c-fos levels in trigeminovascular structures and meningeal mast cells were evaluated. KEY FINDINGS: Cloxyquin attenuated NTG-induced mechanical allodynia, brainstem c-fos and CGRP levels, trigeminal ganglion CGRP levels and meningeal mast cell degranulation and number, in-vivo. It also diminished capsaicin-induced CGRP release from ex-vivo meningeal, trigeminal ganglion and brainstem preparations. Specific TRESK inhibitor A2764 abolished all effects of cloxyquin in in-vivo and ex-vivo. Combining cloxyquin and sumatriptan exerted a synergistic effect ex-vivo, but not in-vivo. SIGNIFICANCE: Our findings provide the experimental evidence for the anti-migraine effect of TRESK activation in migraine-like conditions. The modulation of TRESK channels may therefore be an attractive alternative strategy to relieve migraine pain.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Modelos Animais de Doenças , Mastócitos , Meninges , Transtornos de Enxaqueca , Animais , Masculino , Ratos , Tronco Encefálico/metabolismo , Tronco Encefálico/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Meninges/metabolismo , Meninges/efeitos dos fármacos , Meninges/irrigação sanguínea , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/tratamento farmacológico , Nitroglicerina/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Canais de Potássio/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Sumatriptana/farmacologia , Gânglio Trigeminal/metabolismo , Gânglio Trigeminal/efeitos dos fármacos
7.
J Headache Pain ; 25(1): 178, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39407099

RESUMO

Migraine is a common and complex neurological disorder that has a high impact on quality of life. Recent advances with drugs that target the neuropeptide calcitonin gene-related peptide (CGRP) have helped, but treatment options remain insufficient. CGRP is released from trigeminal sensory fibers and contributes to peripheral sensitization, perhaps in part due to actions on immune cells in the trigeminovascular system. In this review, we will discuss the potential of cannabinoid targeting of immune cells as an innovative therapeutic target for migraine treatment. We will cover endogenous endocannabinoids, plant-derived phytocannabinoids and synthetically derived cannabinoids. The focus will be on six types of immune cells known to express multiple cannabinoid receptors: macrophages, monocytes, mast cells, dendritic cells, B cells, and T cells. These cells also contain receptors for CGRP and as such, cannabinoids might potentially modulate the efficacy of current CGRP-targeting drugs. Unfortunately, to date most studies on cannabinoids and immune cells have relied on cell cultures and only a single preclinical study has tested cannabinoid actions on immune cells in a migraine model. Encouragingly, in that study a synthetically created stable chiral analog of an endocannabinoid reduced meningeal mast cell degranulation. Likewise, clinical trials evaluating the safety and efficacy of cannabinoid-based therapies for migraine patients have been limited but are encouraging. Thus, the field is at its infancy and there are significant gaps in our understanding of the impact of cannabinoids on immune cells in migraine. Future research exploring the interactions between cannabinoids and immune cells could lead to more targeted and effective migraine treatments.


Assuntos
Canabinoides , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/imunologia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Animais , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Mastócitos/imunologia , Mastócitos/efeitos dos fármacos , Endocanabinoides/metabolismo
8.
Cell Physiol Biochem ; 58(4): 445-457, 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39230349

RESUMO

BACKGROUND/AIMS: Lemons (Citrus limon ) contain various nutrients and are among the most popular citrus fruit. Besides their antioxidant, anticancer, antibacterial, and anti-inflammatory properties, clinical studies have indicated their anti-allergic properties. METHODS: Using the differential-interference contrast (DIC) microscopy, we examined the effects of lemon juice and peel constituents, such as citric acid, ascorbic acid, hesperetin and eriodictyol, on the degranulation from rat peritoneal mast cells. Using fluorescence imaging with a water-soluble dye, Lucifer Yellow, we also examined their effects on the deformation of the plasma membrane. RESULTS: Lemon juice dose-dependently decreased the number of degranulated mast cells. At concentrations equal to or higher than 0.25 mM, citric acid, hesperetin, and eriodictyol significantly reduced the number of degranulating mast cells in a dose-dependent manner, while ascorbic acid required much higher doses to exert significant effects. At 1 mM, citric acid, hesperetin, and eriodictyol almost completely inhibited exocytosis and washed out the Lucifer Yellow trapped on the mast cell surface, while ascorbic acid did not. CONCLUSION: This study provides in vitro evidence for the first time that lemon constituents, such as citric acid, hesperetin, and eriodictyol, potently exert mast cell-stabilizing properties. These properties are attributable to their inhibitory effects on plasma membrane deformation in degranulating mast cells.


Assuntos
Ácido Ascórbico , Citrus , Flavanonas , Hesperidina , Mastócitos , Animais , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Citrus/química , Ratos , Ácido Ascórbico/farmacologia , Masculino , Hesperidina/farmacologia , Hesperidina/química , Flavanonas/farmacologia , Flavanonas/química , Ácido Cítrico/farmacologia , Ácido Cítrico/química , Degranulação Celular/efeitos dos fármacos , Sucos de Frutas e Vegetais/análise , Peritônio/citologia , Ratos Sprague-Dawley , Exocitose/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Frutas/química , Isoquinolinas
9.
Front Immunol ; 15: 1427563, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39221239

RESUMO

Rationale: Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation. Methods: In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin's effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using beta-hexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines. Results: Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased beta-hexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein-Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. Conclusion: These findings comprehensively present formononetin's mechanisms in regulating IgE production in plasma cells and degranulation in mast cells.


Assuntos
Hipersensibilidade Alimentar , Imunoglobulina E , Isoflavonas , Janus Quinases , Leucócitos Mononucleares , Mastócitos , Fatores de Transcrição STAT , Transdução de Sinais , Isoflavonas/farmacologia , Humanos , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Mastócitos/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Adulto , Degranulação Celular/efeitos dos fármacos , Animais , Pessoa de Meia-Idade
10.
Nutrients ; 16(17)2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39275335

RESUMO

As the relationship between the gut microbiome and allergies becomes better understood, targeted strategies to prevent and treat allergies through gut microbiome modulation are being increasingly developed. In the study presented herein, we screened various probiotics for their ability to inhibit mast cell degranulation and identified Lactiplatibacillus plantarum HD02 and MD159 as effective candidates. The two strains significantly attenuated vascular permeability induced by mast cell degranulation in a passive cutaneous anaphylaxis (PCA) model and, in the MC903-induced murine atopic dermatitis (AD) model, demonstrated comparable preventive effects against allergies, reducing blood levels of MCPT-1 (mast cell protease-1) and total IgE. In the house dust mite (HDM)-induced murine AD model, both L. plantarum HD02 and MD159 showed therapeutic effects, with L. plantarum HD02 demonstrating superior efficacy. Nevertheless, L. plantarum MD159 better suppressed transepidermal water loss (TEWL). Furthermore, L. plantarum HD02 and MD159 significantly increased the number of splenic Foxp3+ regulatory T cells, with L. plantarum MD159 having a more pronounced effect. However, only L. plantarum HD02 achieved a reduction in immune cells in the draining lymph nodes. Our findings highlight L. plantarum HD02 and MD159 as promising candidates for the prevention and treatment of allergies, demonstrating significant efficacy in suppressing mast cell degranulation, reducing the number of allergy biomarkers, and modulating immune responses in experimental models of AD. Their distinct mechanisms of action suggest potential complementary roles in addressing allergic diseases, underscoring their therapeutic promise in clinical applications.


Assuntos
Degranulação Celular , Dermatite Atópica , Modelos Animais de Doenças , Mastócitos , Probióticos , Animais , Dermatite Atópica/terapia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Mastócitos/efeitos dos fármacos , Probióticos/farmacologia , Camundongos , Degranulação Celular/efeitos dos fármacos , Imunoglobulina E/sangue , Camundongos Endogâmicos BALB C , Lactobacillus plantarum , Pyroglyphidae/imunologia , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Quimases
11.
J Ovarian Res ; 17(1): 192, 2024 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-39342316

RESUMO

BACKGROUND: High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in which patients have still yet to respond meaningfully to clinically available immunotherapies. Hence, novel immune targets are urgently needed. Our past work has identified that mast cells are significantly upregulated at the mRNA level in HGSOC patient tumors following neoadjuvant chemotherapy (NACT) exposure. Therefore, in this current investigation we sought to characterize intratumoral mast cell phenotypic changes as a result of NACT exposure and determine how these adaptations are associated with patient clinical outcomes. METHODS: Hematologic immunohistochemistry was employed to determine mast cell levels in 36 matched pre- and post-NACT HGSOC patient tumors. Fluorescent Immunohistochemistry was utilized to identify Tryptase+(carboxypeptidase A3 (CPA3) + mast cells as well as histamine levels in 29 and 20, respectively, matched pre- and post-NACT HGSOC patient tumors. Finally, human immortalized mast cells, LUVA were stimulated with carboplatin and paclitaxel and genomic changes were analyzed by quantitative PCR. RESULTS: Hematologic labeled intratumoral mast cells were significantly upregulated in the intraepithelial and stromal regions of the tumor, post-NACT. Lower levels of pre-NACT mast cells were significantly associated with an improved progression-free survival (PFS). Histamine, a marker of mast cell degranulation was similarly upregulated in post-NACT exposed tumors. Through the characterization of mast cell specific proteases Tryptase and CPA3, it was found that Tryptase+/ CPA3 + mast cells were significantly upregulated both in the intraepithelial and stromal compartments of the tumor, while Tryptase + cells were significantly upregulated in the stromal regions of the tumor. Lower post-NACT treated levels with Tryptase+/ CPA3 + cells were significantly associated with improved overall survival (OS) and PFS while higher Tryptase + mast cells were associated with improved OS. Finally, following chemotherapy exposure mast cell activating factors AREG and CCL2 were significantly upregulated while TGFB1, an inhibitor of mast cell activation was downregulated in LUVA cells. CONCLUSIONS: Enhanced mast cell numbers, as well as activation and degranulation are a consequence of NACT exposure. Post-NACT mast cells displayed differing associations with survival outcomes that was dependent upon granule classification. Ultimately, mast cells represent a clinically relevant putative HGSOC immune target.


Assuntos
Mastócitos , Terapia Neoadjuvante , Neoplasias Ovarianas , Humanos , Feminino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Terapia Neoadjuvante/métodos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Pessoa de Meia-Idade , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/genética , Idoso , Fenótipo , Gradação de Tumores , Histamina/metabolismo , Triptases/metabolismo , Triptases/genética
12.
Bull Exp Biol Med ; 177(4): 470-475, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39264566

RESUMO

The effect of polysaccharides isolated from the aboveground parts of Saussurea salicifolia (L.) DC on Th2 type immune response reactions was studied. Administration of water-soluble polysaccharides presented by arabino-galacturonans (weight average molecular weight 158.49 kDa) to mice against the background of experimental Th2 immunity reduced the severity of anaphylactic and local immediate type hypersensitivity reactions. It also suppressed the production of ovalbumin-specific IgE and IgG1 and increased the stability of mast cell membranes. The studied polysaccharide complex increased IFNγ secretion and inhibited IL-4 synthesis. These findings suggest that these polysaccharides may be considered as potential anti-allergic agents that suppress the development of allergy in its early stages.


Assuntos
Imunoglobulina E , Polissacarídeos , Saussurea , Células Th2 , Saussurea/química , Animais , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Camundongos , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Polissacarídeos/farmacologia , Polissacarídeos/isolamento & purificação , Polissacarídeos/química , Interleucina-4/imunologia , Interleucina-4/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Anafilaxia/imunologia , Anafilaxia/tratamento farmacológico , Anafilaxia/induzido quimicamente , Interferon gama/imunologia , Camundongos Endogâmicos BALB C , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Ovalbumina/imunologia , Feminino , Antialérgicos/farmacologia , Antialérgicos/isolamento & purificação
13.
Parasites Hosts Dis ; 62(3): 270-280, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39218626

RESUMO

Trichomoniasis is caused by a sexually transmitted flagellate protozoan parasite Trichomonas vaginalis. T. vaginalis-derived secretory products (TvSP) contain lipid mediators such as leukotriene B4 (LTB4) and various cysteinyl leukotrienes (CysLTs) which included LTC4, LTD4, and LTE4. However, the signaling mechanisms by which T. vaginalis-induced CysLTs stimulate interleukin (IL)-8 production in human mast cells remain unclear. In this study, we investigated these mechanisms in human mast cells (HMC-1). Stimulation with TvSP resulted in increased intracellular reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) activation compared to unstimulated cells. Pre-treatment with NOX2 inhibitors such as diphenyleneiodonium chloride (DPI) or apocynin significantly reduced ROS production in TvSP-stimulated HMC-1 cells. Additionally, TvSP stimulation increased NOX2 protein expression and the translocation of p47phox from the cytosol to the membrane. Pretreatment of HMC-1 cells with PI3K or PKC inhibitors reduced TvSP-induced p47phox translocation and ROS generation. Furthermore, NOX2 inhibitors or NOX2 siRNA prevented CREB phosphorylation and IL-8 gene expression or protein secretion induced by TvSP. Pretreatment with a CysLTR antagonist significantly inhibited TvSP-induced ROS production, CREB phosphorylation, and IL-8 production. These results indicate that CysLT-mediated activation of NOX2 plays a crucial role in ROS-dependent IL-8 production in human mast cells stimulated by T. vaginalis-secreted CysLTs. These findings enhance our understanding of the inflammatory response in trichomoniasis and may inform the development of targeted therapies to mitigate this response.


Assuntos
Interleucina-8 , Mastócitos , NADPH Oxidase 2 , Espécies Reativas de Oxigênio , Receptores de Leucotrienos , Trichomonas vaginalis , Humanos , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Espécies Reativas de Oxigênio/metabolismo , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/parasitologia , Mastócitos/imunologia , Linhagem Celular , Receptores de Leucotrienos/metabolismo , Receptores de Leucotrienos/genética , NADPH Oxidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Leucotrienos/metabolismo
14.
Molecules ; 29(16)2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39202878

RESUMO

Allergies are one of the diseases whose incidence rates have increased in recent years due to the greenhouse effect and extreme climate change. Therefore, the development of new antiallergic drugs has attracted the interest of researchers in chemistry and pharmacy fields. Dicoumarin is a coumarin derivative with various biological activities, but its antiallergic activity has not been evaluated. In this study, 14 different dicoumarin derivatives were synthesized by diethylamine-catalyzed condensation reactions of 4-hydroxycoumarin with 14 different aldehydes, and they were identified on the basis of their spectral data. The dicoumarin derivatives were subjected to studies on the degranulation of rat basophilic leukemia cells (RBL-2H3 cells) and mouse bone-marrow-derived mast cells (mBMMCs), and some of them showed good inhibitory effects on the degranulation of the two types of mast cells, demonstrating their good antiallergic activity. This study presents a new method of developing new antiallergic drugs.


Assuntos
Antialérgicos , Degranulação Celular , Mastócitos , Animais , Antialérgicos/farmacologia , Antialérgicos/síntese química , Antialérgicos/química , Mastócitos/efeitos dos fármacos , Camundongos , Ratos , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Estrutura Molecular
15.
Biomed Pharmacother ; 179: 117321, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39191027

RESUMO

BACKGROUND: Atopic dermatitis is a common chronic inflammatory skin disease characterized by relapsing eczema and intense itch. DGT is a novel synthetic heterocyclic diterpenoid derived from plants. Its therapeutic potential and mechanism(s) of action are poorly understood. OBJECTIVES: We investigated the potent therapeutic effect of DGT on atopic dermatitis, exploring the underlying mechanisms and determining whether DGT is a safe and well-tolerated topical treatment. METHODS: We observed anti-inflammatory effects of DGT on tumor necrosis factor-α/interferon-γ-treated human keratinocytes, and anti-allergic effects on immunoglobulin E-sensitized bone marrow-derived mast cells. In vivo, DGT was topically applied to two experimental mouse models of atopic dermatitis: oxazolone-induced sensitization and topically applied calcipotriol. Then the therapeutic effects of DGT were evaluated physiologically and morphologically. Moreover, we performed nonclinical toxicology and safety pharmacology research, including general toxicity, pharmacokinetics, and safety pharmacology on the cardiovascular, respiratory, and central nervous systems. RESULTS: In keratinocytes, DGT reduced the expression of inflammatory factors, promoting the expression of barrier functional proteins and tight junctions and maintaining the steady state of barrier function. DGT also inhibited the activation and degranulation of mast cells induced by immunoglobulin E. Moreover, we found that interleukin-4 receptor-α was the possible target of DGT. Meanwhile, DGT had therapeutic effects on oxazolone/calcipotriol-treated mice. Notably, our pharmacology results demonstrated that DGT was safe and nontoxic in our studies. CONCLUSION: DGT's potent anti-inflammatory effects and good safety profile suggest that it is a potential candidate for the treatment of atopic dermatitis.


Assuntos
Dermatite Atópica , Diterpenos , Queratinócitos , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Diterpenos/farmacologia , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Anti-Inflamatórios/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Modelos Animais de Doenças , Oxazolona/toxicidade , Imunoglobulina E , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Calcitriol/análogos & derivados , Calcitriol/farmacologia , Masculino , Feminino , Células HaCaT
16.
Cells ; 13(16)2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39195277

RESUMO

Various extracts are tested for anti-allergic or anti-inflammatory properties on in vitro models. RBL-2H3 cells are widely used in allergic or immunological studies. FCεRI and its downstream signaling cascades, such as MAPK, NF-κB, and JAK/STAT signaling pathways, are important allergic or inflammatory signaling mechanisms in mast and basophil cells. This systematic review aims to study common signaling pathways of the anti-allergic or anti-inflammatory compounds on RBL-2H3 cells. We selected the relevant research articles published after 2015 from the PubMed, Scopus, Science Direct and Web of Science databases. The risk of bias of the studies was assessed based on the modified CONSORT checklist for in vitro studies. The cell lines, treatments, assay, primary findings, and signaling pathways on RBL-2H3 cells were extracted to synthesize the results. Thirty-eight articles were included, and FCεRI and its downstream pathways, such as Lyn, Sky, PLCγ, and MAPK, were commonly studied. Moreover, the JAK/STAT pathway was a potential signaling mechanism in RBL-2H3 cells. However, the findings based on RBL-2H3 cells needed to be tested along with human mast cells to confirm its relevance to human health. In conclusion, a single plant extract may act as an anti-inflammatory reagent in RBL-2H3 cells via multiple signaling pathways besides the MAPK signaling pathway.


Assuntos
Antialérgicos , Anti-Inflamatórios , Transdução de Sinais , Animais , Ratos , Antialérgicos/farmacologia , Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Linhagem Celular , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/imunologia , Receptores de IgE/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
17.
Cells ; 13(15)2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39120272

RESUMO

Sulphated glycosaminoglycans (GAGs) such as heparin are a major component of mast cell granules and form the matrix within which biogenic mediators are stored. Since GAGs released from mast cells also play an important role in helminth expulsion, understanding GAG storage can offer new insights into mast cell function. Sodium butyrate (NaBu), a short-chain fatty acid, causes ultrastructural changes within the granules of human mast cells (HMC-1) and increases their histamine content. Therefore, we hypothesized that NaBu treatment would also modify the storage of polysaccharides such as GAGs. NaBu (1 mM) significantly increased GAG content and granularity in a time- and concentration-dependent manner without affecting cell viability and metabolic activity. NaBu increased the expression of enzymes associated with heparin biosynthesis (GLCE, NDST1, NDST2, HS6ST1, and GALT1) in a time-dependent manner. A cholesteryl butyrate emulsion (CholButE) increased heparin content after 24 and 48 h and modestly altered the expression of genes involved in heparin biosynthesis. Similar to NaBu, CholButE reduced cell proliferation without significantly altering viability or metabolic activity. These data show that butyrate increases the synthesis and storage of heparin in human mast cells, perhaps by altering their metabolic pathways.


Assuntos
Heparina , Mastócitos , Humanos , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Heparina/farmacologia , Heparina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Butiratos/farmacologia , Butiratos/metabolismo , Proliferação de Células/efeitos dos fármacos , Ácido Butírico/farmacologia , Linhagem Celular , Ésteres do Colesterol/metabolismo
18.
Sci Rep ; 14(1): 17837, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090190

RESUMO

Immunotherapy is a promising alternative treatment for canine mast cell tumour (MCT). However, evasion of immune recognition by downregulating major histocompatibility complex (MHC) molecules might decline treatment efficiency. Enhancing MHC expression through interferon-gamma (IFN-γ) is crucial for effective immunotherapy. In-house and reference canine MCT cell lines derived from different tissue origins were used. The impacts of IFN-γ treatment on cell viability, expression levels of MHC molecules, as well as cell apoptosis were evaluated through the MTT assay, RT-qPCR and flow cytometry. The results revealed that IFN-γ treatment significantly influenced the viability of canine MCT cell lines, with varying responses observed among different cell lines. Notably, IFN-γ treatment increased the expression of MHC I and MHC II, potentially enhancing immune recognition and MCT cell clearance. Flow cytometry analysis in PBMCs-mediated cytotoxicity assays showed no significant differences in overall apoptosis between IFN-γ treated and untreated canine MCT cell lines across various target-to-effector ratios. However, a trend towards higher percentages of late and total apoptotic cells was observed in the IFN-γ treated C18 and CMMC cell lines, but not in the VIMC and CoMS cell lines. These results indicate a variable response to IFN-γ treatment among different canine MCT cell lines. In summary, our study suggests IFN-γ's potential therapeutic role in enhancing immune recognition and clearance of MCT cells by upregulating MHC expression and possibly promoting apoptosis, despite variable responses across different cell lines. Further investigations are necessary to elucidate the underlying mechanisms and evaluate IFN-γ's efficacy in in vivo models.


Assuntos
Apoptose , Interferon gama , Leucócitos Mononucleares , Animais , Cães , Interferon gama/metabolismo , Interferon gama/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Mastócitos/efeitos dos fármacos , Complexo Principal de Histocompatibilidade , Mastocitoma/veterinária , Mastocitoma/imunologia , Doenças do Cão/imunologia , Citotoxicidade Imunológica , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética
19.
Int J Biol Macromol ; 277(Pt 4): 134344, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39089545

RESUMO

Canine atopic dermatitis (AD) arises from hypersensitive immune reactions. AD symptoms entail severe pruritus and skin inflammation, with frequent relapses. Consequently, AD patients require continuous management, imposing financial burdens and mental fatigue on pet owners. In this study, we aimed to investigate the therapeutic relevance of secretome from canine adipose tissue-derived mesenchymal stem cells (MSCs), especially after encapsulation in nano-villi chitosan microspheres (CS-MS) to expect improved efficacy. Conditioned media (CM) from MSCs significantly inhibited the proliferation of splenocytes, induced the generation of regulatory T cells, and decreased mast cell degranulation. We found that beneficial soluble factors known to reduce AD symptoms, including transforming growth factor-beta 1, were detectable after sequential concentration and lyophilization of CM. The CS-MS, developed by a phase inversion regeneration method, showed high loading and sustained release of the secretome. Local injection of secretome-loaded CS-MS (ST/SC-MS) effectively reduced clinical severity compared to groups treated with secretome. Histological analysis revealed that ST/SC-MS potently suppressed epidermal hyperplasia, immunocyte infiltration and mast cell activation in the lesion. Taken together, this study presents a novel therapeutic approach exhibiting more potent and prolonged immunoregulatory efficacy of MSC secretome for canine AD treatment.


Assuntos
Quitosana , Dermatite Atópica , Células-Tronco Mesenquimais , Microesferas , Secretoma , Dermatite Atópica/terapia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Animais , Cães , Quitosana/química , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Proliferação de Células/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/imunologia , Meios de Cultivo Condicionados/farmacologia , Preparações de Ação Retardada
20.
J Ethnopharmacol ; 335: 118677, 2024 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-39121927

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium officinale Kimura et Migo as a valuable Chinese medicine has been used in China for more than 2000 years. Its main active components, polysaccharide (DOP), has been reported to have various pharmacological effects, including anti-inflammatory, antioxidant and alleviating AD effects. However, the precise mechanism underlying its therapeutic effect in AD remains largely unclear. AIM OF THE STUDY: The present study sought to assess the efficacy of DOP and elucidate its intricate mechanisms in ameliorating DNFB-induced AD. MATERIALS AND METHODS: Mice were sensitized with DNFB and treated with DOP application for 14 days. Treatment effects were assessed using dermatitis scores, ear thickness and scratching frequency. Epidermal thickness, mast cells and CD4+ T cells infiltration were detected by using H&E, toluidine blue staining and immunofluorescence staining respectively. Serum histamine (HIS), immunoglobulin E (IgE), thymic stromal lymphopoietin (TSLP), skin SOD, MDA, GHS, CAT, inflammatory cytokines (TNF-α, IFN-γ, IL-1ß, IL-4, IL-5, IL-13) and chemokine (MIP-α, MDC, MCP-1) levels were quantify by ELISA and immunohistochemistry. Additionally, qPCR and Western blot analyses were performed to assess genes and proteins expression associated with MAPK/NF-κB/STAT3 signaling pathway. RESULTS: The results indicated that DOP effectively mitigated AD-like skin lesions in mice through multiple pathways. It reduced epidermal thickness, ear thickness and scratching frequency in AD mice. Additionally, DOP mitigated inflammatory responses by decreasing the levels of inflammatory factors, as well as reducing serum levels of IgE, HIS, and TSLP. Moreover, DOP inhibited infiltration of mast cells and CD4+ T cells, suppressed the expression of skin chemokines such as MDC, MCP-1, and MIP-α, and enhanced filaggrin content in AD mice. Furthermore, DOP significantly boosted antioxidant capacity, as well as significantly reduced the expression of JAK1, STAT3, NF-κB p65, IκBα, ERK1/2, and p38 proteins and phosphorylated proteins such as p-JAK1, p-STAT3, p-NF-κB p65, p-IκBα, p-ERK1/2, and p-p38. CONCLUSIONS: These findings suggested that DOP has significant anti-AD activity, primarily through reducing inflammatory responses, improving antioxidant capacity, repairing the skin barrier, and down-regulating key genes and proteins in MAPK/NF-κB/STAT3 signaling pathway, and that this study may provide valuable insights into the development of innovative therapies for the treatment of AD.


Assuntos
Citocinas , Dendrobium , Dermatite Atópica , NF-kappa B , Polissacarídeos , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Dermatite Atópica/tratamento farmacológico , Dendrobium/química , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Camundongos , Transdução de Sinais/efeitos dos fármacos , Citocinas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Mastócitos/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Modelos Animais de Doenças
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