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1.
Allergol Immunopathol (Madr) ; 52(4): 91-96, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38970271

RESUMO

Asthma is a widely prevalent chronic disease that brings great suffering to patients and may result in death if it turns severe. Jolkinolide B (JB) is one diterpenoid component separated from the dried roots of Euphorbia fischeriana Steud (Euphorbiaceae), and has anti--inflammatory, antioxidative, and antitumor properties. However, the detailed regulatory role and associated regulatory mechanism in the progression of asthma remain elusive. In this work, it was demonstrated that the extensive infiltration of bronchial inflammatory cells and the thickening of airway wall were observed in ovalbumin (OVA)-induced mice, but these impacts were reversed by JB (10 mg/kg) treatment, indicating that JB relieved the provocative symptoms in OVA-induced asthma mice. In addition, JB can control OVA-triggered lung function and pulmonary resistance. Moreover, JB attenuated OVA-evoked inflammation by lowering the levels of interleukin (IL)-4, IL-5, and IL-13. Besides, the activated nuclear factor kappa B (NF-κB) and transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGFß/smad3) pathways in OVA-induced mice are rescued by JB treatment. In conclusion, it was disclosed that JB reduced allergic airway inflammation and airway remodeling in asthmatic mice by modulating the NF-κB and TGFß/smad3 pathways. This work could offer new opinions on JB for lessening progression of asthma.


Assuntos
Remodelação das Vias Aéreas , Asma , Modelos Animais de Doenças , Diterpenos , Camundongos Endogâmicos BALB C , NF-kappa B , Ovalbumina , Animais , Asma/tratamento farmacológico , Asma/imunologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Camundongos , Diterpenos/farmacologia , Diterpenos/administração & dosagem , Diterpenos/uso terapêutico , Ovalbumina/imunologia , NF-kappa B/metabolismo , Feminino , Fator de Crescimento Transformador beta/metabolismo , Citocinas/metabolismo , Proteína Smad3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Euphorbia/química
2.
Respir Res ; 25(1): 271, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987753

RESUMO

BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear. METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma. RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway. CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.


Assuntos
Asma , Camundongos Knockout , Necroptose , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Animais , Asma/metabolismo , Asma/patologia , Necroptose/fisiologia , Humanos , Camundongos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Masculino , Feminino , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Camundongos Endogâmicos C57BL , Proteínas Quinases/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Ovalbumina/toxicidade
3.
Int J Mol Sci ; 25(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39000141

RESUMO

Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.


Assuntos
Remodelação das Vias Aéreas , Asma , Modelos Animais de Doenças , Ovalbumina , Estresse Oxidativo , Ficocianina , Ratos Sprague-Dawley , Animais , Ficocianina/farmacologia , Ficocianina/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Asma/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Ovalbumina/efeitos adversos , Ratos , Remodelação das Vias Aéreas/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Masculino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Citocinas/metabolismo
4.
Clin Transl Med ; 14(7): e1765, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39031979

RESUMO

BACKGROUND: The meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll-like receptor (TLR) ligands as compared to CFA. METHODS: A comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein-3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme-linked immunosorbent assay quantified antigen-specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes. RESULTS: TLR ligands demonstrated efficacy in inducing PV-like symptoms in wild-type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self-antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study. CONCLUSIONS: The systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis. KEY POINTS/HIGHLIGHTS: Immunization with desmoglein 3 and Toll-like receptor (TLR) ligands effectively induces pemphigus symptoms in wild-type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10, leading to more effective immune responses.


Assuntos
Adjuvantes Imunológicos , Modelos Animais de Doenças , Pênfigo , Receptores Toll-Like , Animais , Pênfigo/imunologia , Camundongos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/agonistas , Adjuvantes Imunológicos/farmacologia , Adjuvante de Freund/imunologia , Camundongos Endogâmicos C57BL , Ligantes , Ovalbumina/imunologia , Feminino
5.
Int J Mol Sci ; 25(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-39000495

RESUMO

Patients with asthma experience elevated rates of mental illness. However, the molecular links underlying such lung-brain crosstalk remain ambiguous. Hypothalamic dysfunction is observed in many psychiatric disorders, particularly those with an inflammatory component due to many hypothalamic regions being unprotected by the blood-brain barrier. To gain a better insight into such neuropsychiatric sequelae, this study investigated gene expression differences in the hypothalamus following lung inflammation (asthma) induction in mice, using RNA transcriptome profiling. BALB/c mice were challenged with either bacterial lipopolysaccharide (LPS, E. coli) or ovalbumin (OVA) allergens or saline control (n = 7 per group), and lung inflammation was confirmed via histological examination of postmortem lung tissue. The majority of the hypothalamus was micro-dissected, and total RNA was extracted for sequencing. Differential expression analysis identified 31 statistically significant single genes (false discovery rate FDR5%) altered in expression following LPS exposure compared to controls; however, none were significantly changed following OVA treatment, suggesting a milder hypothalamic response. When gene sets were examined, 48 were upregulated and 8 were downregulated in both asthma groups relative to controls. REACTOME enrichment analysis suggests these gene sets are involved in signal transduction metabolism, immune response and neuroplasticity. Interestingly, we identified five altered gene sets directly associated with neurotransmitter signaling. Intriguingly, many of these altered gene sets can influence mental health and or/neuroinflammation in humans. These findings help characterize the links between asthma-induced lung inflammation and the brain and may assist in identifying relevant pathways and therapeutic targets for future intervention.


Assuntos
Asma , Modelos Animais de Doenças , Hipotálamo , Lipopolissacarídeos , Pulmão , Camundongos Endogâmicos BALB C , Transcriptoma , Animais , Asma/genética , Asma/metabolismo , Asma/patologia , Hipotálamo/metabolismo , Camundongos , Pulmão/metabolismo , Pulmão/patologia , Ovalbumina , Perfilação da Expressão Gênica , Feminino , Regulação da Expressão Gênica
6.
Respir Res ; 25(1): 273, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997751

RESUMO

BACKGROUND: Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4ß7 and fibronectin induces myofibroblast differentiation via this receptor. OBJECTIVES: To investigate the role of the ß7 integrin receptor subunit and α4ß7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. METHODS: C57BL/6 wild type (WT) and ß7 integrin null mice (ß7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4ß7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-ß (TGFß) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and ß7 -/- saline (SAL) and OVA treated mice was evaluated. RESULTS: Eosinophil numbers were similar in WT vs ß7-/- mice. Prolonged OVA exposure in ß7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFß and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4ß7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not ß7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in ß7-/- fibroblasts relative to WT. CONCLUSIONS: The ß7 integrin subunit and the α4ß7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation.


Assuntos
Remodelação das Vias Aéreas , Cadeias beta de Integrinas , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Animais , Remodelação das Vias Aéreas/fisiologia , Remodelação das Vias Aéreas/imunologia , Camundongos , Ovalbumina/toxicidade , Cadeias beta de Integrinas/metabolismo , Cadeias beta de Integrinas/genética , Alérgenos/imunologia , Alérgenos/toxicidade , Células Cultivadas , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/patologia , Pulmão/metabolismo , Pulmão/imunologia , Pulmão/patologia , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/imunologia , Fator de Crescimento Transformador beta/metabolismo
7.
Molecules ; 29(13)2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38998948

RESUMO

Herein, we report a transdermal patch prepared using an ionic liquid-based solid in oil (IL-S/O) nanodispersion and a pressure-sensitive adhesive (PSA) to deliver the macromolecular antigenic protein, ovalbumin (OVA). The IL-S/O nanodispersion and a PSA were first mixed at an equal weight ratio, then coated onto a release liner, and covered with a support film. To evaluate the effect of the PSA, three types of PSAs, DURO-TAK 87-4098, DURO-TAK 87-4287, and DURO-TAK 87-235A, were used to obtain the corresponding IL-S/O patches SP-4098, SP-4287, and SP-235A, respectively. The prepared IL-S/O patches were characterized for surface morphology, viscoelasticity, and moisture content. In vitro skin penetration and in vivo immunization studies of the IL-S/O patches were performed using Yucatan micropig skin and the C57BL/6NJc1 mice model, respectively. The SP-4098 and SP-4287 delivered 5.49-fold and 5.47-fold higher amounts of drug compared with the aqueous formulation. Although both patches delivered a similar amount of drug, SP-4287 was not detached fully from the release liner after 30 days, indicating low stability. Mice immunized with the OVA-containing SP-4098 produced a 10-fold increase in anti-OVA IgG compared with those treated with an aqueous formulation. These findings suggested that the IL-S/O patch may be a good platform for the transdermal delivery of antigen molecules.


Assuntos
Administração Cutânea , Antígenos , Imunização , Líquidos Iônicos , Ovalbumina , Adesivo Transdérmico , Líquidos Iônicos/química , Animais , Camundongos , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Antígenos/imunologia , Antígenos/administração & dosagem , Antígenos/química , Suínos , Pele/metabolismo , Pele/imunologia , Sistemas de Liberação de Medicamentos , Camundongos Endogâmicos C57BL , Feminino , Absorção Cutânea
8.
Molecules ; 29(13)2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-38999173

RESUMO

Ovalbumin (OVA), a protein vital for chick embryo nutrition, hydration, and antimicrobial protection, together with other egg-white proteins, migrates to the amniotic fluid and is orally absorbed by the embryo during embryogenesis. Recently, it has been shown that for optimal eggshell quality, the hen diet can be supplemented with manganese. Although essential for embryonic development, manganese in excess causes neurotoxicity. This study investigates whether OVA may be involved in the regulation of manganese levels. The binding of Mn(II) to OVA was investigated using electron paramagnetic resonance (EPR) spectroscopy. The results show that OVA binds a maximum of two Mn(II) ions, one with slightly weaker affinity, even in a 10-fold excess, suggesting it may have a protective role from Mn(II) overload. It seems that the binding of Mn(II), or the presence of excess Mn(II), does not affect OVA's tertiary structure, as evidenced from fluorescence and UV/vis measurements. Comparative analysis with bovine and human serum albumins revealed that they exhibit higher affinities for Mn(II) than OVA, most likely due to their essentially different physiological roles. These findings suggest that OVA does not play a role in the transport and storage of manganese; however, it may be involved in embryo protection from manganese-induced toxicity.


Assuntos
Desenvolvimento Embrionário , Homeostase , Manganês , Ovalbumina , Manganês/metabolismo , Animais , Embrião de Galinha , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Humanos , Ligação Proteica , Bovinos , Galinhas
9.
J Gene Med ; 26(7): e3718, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38979822

RESUMO

BACKGROUND: Icariin (ICA) inhibits inflammatory response in various diseases, but the mechanism underlying ICA treating airway inflammation in asthma needs further understood. We aimed to predict and validate the potential targets of ICA against asthma-associated airway inflammation using network pharmacology and experiments. METHODS: The ovalbumin-induced asthma-associated airway inflammation mice model was established. The effects of ICA were evaluated by behavioral, airway hyperresponsiveness, lung pathological changes, inflammatory cell and cytokines counts. Next, the corresponding targets of ICA were mined via the SEA, CTD, HERB, PharmMapper, Symmap database and the literature. Pubmed-Gene and GeneCards databases were used to screen asthma and airway inflammation-related targets. The overlapping targets were used to build an interaction network, analyze gene ontology and enrich pathways. Subsequently, flow cytometry, quantitative real-time PCR and western blotting were employed for validation. RESULTS: ICA alleviated the airway inflammation of asthma; 402 targets of ICA, 5136 targets of asthma and 4531 targets of airway inflammation were screened; 216 overlapping targets were matched and predicted ICA possesses the potential to modulate asthmatic airway inflammation by macrophage activation/polarization. Additionally, ICA decreased M1 but elevated M2. Potential targets that were disrupted by asthma inflammation were restored by ICA treatment. CONCLUSIONS: ICA alleviates airway inflammation in asthma by inhibiting the M1 polarization of alveolar macrophages, which is related to metabolic reprogramming. Jun, Jak2, Syk, Tnf, Aldh2, Aldh9a1, Nos1, Nos2 and Nos3 represent potential targets of therapeutic intervention. The present study enhances understanding of the anti-airway inflammation effects of ICA, especially in asthma.


Assuntos
Asma , Modelos Animais de Doenças , Flavonoides , Ativação de Macrófagos , Macrófagos Alveolares , Farmacologia em Rede , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Camundongos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Citocinas/metabolismo , Ovalbumina , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Feminino
10.
Nanoscale ; 16(25): 12149-12162, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38833269

RESUMO

Together, tumor and virus-specific tissue-resident CD8+ memory T cells (TRMs) of hepatocellular carcinoma (HCC) patients with Hepatitis B virus (HBV) infection can provide rapid frontline immune surveillance. The quantity and activity of CD8+ TRMs were correlated with the relapse-free survival of patients with improved health. However, HBV-specific CD8+ TRMs have a more exhausted phenotype and respond more actively under anti-PDL1 or PD1 treatment of HBV+HCC patients. Vaccination strategies that induce a strong and sustained CD8+ TRMs response are quite promising. Herein, a biodegradable poly(D,L-lactide-co-glycolide) microsphere and nanosphere particle (PLGA N.M.P) delivery system co-assembled by anti-PD1 antibodies (aPD1) and loaded with ovalbumin (OVA-aPD1 N.M.P) was fabricated and characterized for size (200 nm and 1 µm diameter), charge (-15 mV), and loading efficiencies of OVA (238 µg mg-1 particles) and aPD1 (40 µg mg-1 particles). OVA-aPD1 N.M.P could stimulate the maturation of BMDCs and enhance the antigen uptake and presentation by 2-fold compared to free OVA. The nanoparticles also induced the activation of macrophages (RAW 264.7) to produce a high level of cytokines, including TNF-α, IL-6 and IL-10. In vivo stimulation of mice using OVA-aPD1 N.M.P robustly enhanced IFN-γ-producing-CD8+ T cell infiltration in tumor tissues and the secretion of IgG and IgG2a/IgG1 antibodies. OVA-aPD1 N.M.P delivered OVA to increase the activation and proliferation of OVA-specific CD8+ TRMs, and its combination with anti-PD1 antibodies promoted complete tumor rejection by the reversal of tumor-infiltrating CD8+ T cell exhaustion. Thus, PLGA N.M.P could induce a strong CD8+ TRMs response, further highlighting its therapeutic potential in enhancing an antitumor immune response.


Assuntos
Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Camundongos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Ovalbumina/química , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Nanopartículas/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Células T de Memória/imunologia , Vacinação , Humanos , Células RAW 264.7 , Memória Imunológica
11.
Int Immunopharmacol ; 136: 112395, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38833845

RESUMO

Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.


Assuntos
Proteínas Quinases Ativadas por AMP , Asma , Modelos Animais de Doenças , Ovalbumina , Receptores de Adiponectina , Transdução de Sinais , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/induzido quimicamente , Asma/metabolismo , Camundongos , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Ovalbumina/imunologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Citocinas/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adiponectina , Antiasmáticos/uso terapêutico , Antiasmáticos/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Imunoglobulina E/sangue , Humanos , Dexametasona/uso terapêutico , Dexametasona/farmacologia , Piperidinas
12.
Cell Death Dis ; 15(6): 400, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849380

RESUMO

Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1ß, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1ß were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd-/-) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1ß was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1ß production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd-/- mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.


Assuntos
Asma , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Knockout , Ovalbumina , Proteínas de Ligação a Fosfato , Animais , Asma/genética , Asma/patologia , Asma/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Humanos , Remodelação das Vias Aéreas , Feminino , Inflamação/patologia , Inflamação/metabolismo , Inflamação/genética , Camundongos Endogâmicos C57BL , Masculino , Citocinas/metabolismo , Piroptose , Pulmão/patologia , Pulmão/metabolismo , Gasderminas
13.
Respir Res ; 25(1): 230, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824593

RESUMO

BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.


Assuntos
Remodelação das Vias Aéreas , Aminoácido Oxirredutases , Asma , Ovalbumina , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Aminoácido Oxirredutases/metabolismo , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/biossíntese , Ovalbumina/toxicidade , Remodelação das Vias Aéreas/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Humanos , Asma/patologia , Asma/metabolismo , Asma/enzimologia , Asma/genética , Transdução de Sinais/fisiologia , Feminino , Camundongos Endogâmicos BALB C , Masculino , Transição Epitelial-Mesenquimal/fisiologia
14.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892470

RESUMO

The nanosized vesicles secreted from various cell types into the surrounding extracellular space are called extracellular vesicles (EVs). Although mesenchymal stem cell-derived EVs are known to have immunomodulatory effects in asthmatic mice, the role of identified pulmonary genes in the suppression of allergic airway inflammation remains to be elucidated. Moreover, the major genes responsible for immune regulation in allergic airway diseases have not been well documented. This study aims to evaluate the immunomodulatory effects of secretoglobin family 1C member 1 (SCGB1C1) on asthmatic mouse models. C57BL/6 mice were sensitized to ovalbumin (OVA) using intraperitoneal injection and were intranasally challenged with OVA. To evaluate the effect of SCGB1C1 on allergic airway inflammation, 5 µg/50 µL of SCGB1C1 was administrated intranasally before an OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), the cytokine profiles of BALF and lung-draining lymph nodes (LLN), and the T cell populations in LLNs. The intranasal administration of SCGB1C1 significantly inhibited AHR, the presence of eosinophils in BALF, eosinophilic inflammation, goblet cell hyperplasia in the lung, and serum total and allergen-specific IgE. SCGB1C1 treatment significantly decreased the expression of interleukin (IL)-5 in the BALF and IL-4 in the LLN, but significantly increased the expression of IL-10 and transforming growth factor (TGF)-ß in the BALF. Furthermore, SCGB1C1 treatment notably increased the populations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in asthmatic mice. The intranasal administration of SCGB1C1 provides a significant reduction in allergic airway inflammation and improvement of lung function through the induction of Treg expansion. Therefore, SCGB1C1 may be the major regulator responsible for suppressing allergic airway inflammation.


Assuntos
Asma , Camundongos Endogâmicos C57BL , Ovalbumina , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Asma/imunologia , Asma/metabolismo , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Eosinófilos/imunologia , Eosinófilos/metabolismo
15.
Int J Biol Macromol ; 273(Pt 1): 133010, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38852735

RESUMO

Lipids are increasingly being incorporated into delivery systems due to their ability to facilitate intestinal absorption of lipid-soluble nutrients through molecular solubilization and micellization. In this work, self-assembled complexes of ovalbumin (OVA) and nine dietary fatty acids (FAs) were constructed to improve the processability and absorbability of lutein (LUT). Results showed that all FAs could form stable hydrophilic particles with OVA under the optimized ultrasound-coupled pH conditions. Fourier infrared spectroscopy and transmission electron microscopy analysis showed that these binary complexes effectively encapsulated LUT with an encapsulation rate > 90.0 %. Stability experiments showed that these complexes protected LUT well, which could improve thermal stability and in vitro digestive stability by 1.66-3.58-fold and 1.27-2.74-fold, respectively. Besides, the bioaccessibility of LUT was also enhanced by 7.16-24.99-fold. The chain length and saturation of FAs affected the stability and absorption of LUT. Therefore, these results provided some reference for the selection of FAs for efficient delivery of lipid-soluble nutrients.


Assuntos
Ácidos Graxos , Luteína , Ovalbumina , Água , Luteína/química , Ácidos Graxos/química , Ovalbumina/química , Água/química , Digestão , Disponibilidade Biológica , Solubilidade , Concentração de Íons de Hidrogênio , Temperatura , Estabilidade de Medicamentos , Interações Hidrofóbicas e Hidrofílicas
16.
Int J Biol Macromol ; 273(Pt 1): 133067, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38866287

RESUMO

Adjuvants, as the essential component of vaccines, are crucial in enhancing the magnitude, breadth and durability of immune responses. Unfortunately, commonly used Alum adjuvants predominantly provoke humoral immune response, but fail to evoke cellular immune response, which is crucial for the prevention of various chronic infectious diseases and cancers. Thus, it is necessary to develop effective adjuvants to simultaneously induce humoral and cellular immune response. In this work, we obtained a water soluble polysaccharide isolated and purified from Poria cocos, named as PCP, and explored the possibility of PCP as a vaccine adjuvant. The PCP, with Mw of 20.112 kDa, primarily consisted of →6)-α-D-Galp-(1→, with a small amount of →3)-ß-D-Glcp-(1 â†’ and →4)-ß-D-Glcp-(1→. Our results demonstrated that the PCP promoted the activation of dendritic cells (DCs) and macrophages in vitro. As the adjuvant to ovalbumin, the PCP facilitated the activation of DCs in lymph nodes, and evoked strong antibody response with a combination of Th1 and Th2 immune responses. Moreover, compared to Alum adjuvant, the PCP markedly induced a potent cellular response, especially the cytotoxic T lymphocytes response. Therefore, we confirmed that the PCP has great potential to be an available adjuvant for simultaneously inducing humoral and cellular immune responses.


Assuntos
Adjuvantes Imunológicos , Células Dendríticas , Polissacarídeos , Solubilidade , Água , Animais , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Polissacarídeos/farmacologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Camundongos , Água/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Wolfiporia/química , Ovalbumina/imunologia , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Poria/química
17.
Int J Biol Macromol ; 273(Pt 2): 133139, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38878929

RESUMO

The microencapsulation of polysaturated fatty acids by spray drying remains a challenge due to their susceptibility to oxidation. In this work, antioxidant Pickering emulsions were attempted as feeds to produce oxidation stable tuna oil microcapsules. The results indicated that the association between chitosan (CS) and ovalbumin (OVA) was a feasible way to fabricate antioxidant and wettable complexes and a high CS percentage favored these properties. The particles could yield tuna oil Pickering emulsions with enhanced oxidation stability through high-pressure homogenization, which were successfully spray dried to produce microcapsules with surface oil content of 8.84 % and microencapsulation efficiency of 76.65 %. The microcapsules exhibited significantly improved oxidation stability and their optimum peroxide values after storage at 50 °C, 85 % relative humidity, or natural light for 15 d were 48.67 %, 60.07 %, and 39.69 % respectively lower than the powder derived from the OVA-stabilized emulsion. Hence, Pickering emulsions stabilized by the CS/OVA polyelectrolyte complexes are potential in the production of oxidation stable polyunsaturated fatty acid microcapsules by spray drying.


Assuntos
Cápsulas , Quitosana , Emulsões , Ovalbumina , Oxirredução , Secagem por Atomização , Atum , Quitosana/química , Emulsões/química , Ovalbumina/química , Animais , Óleos de Peixe/química , Polieletrólitos/química , Antioxidantes/química , Tamanho da Partícula
18.
Neuroreport ; 35(11): 729-733, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-38829951

RESUMO

OBJECTIVE: Solute transport in the brain is essential for maintaining cerebral homeostasis. Recent studies have shown that neuronal activity enhances the transport of cerebrospinal fluid solutes, but its impact on interstitial solute transport has not been established. In this study, we investigated whether neuronal activity affects the transport of interstitial solutes. METHODS: Fluorescent Texas Red ovalbumin was injected intracortically into the unilateral sensorimotor area of the Sprague-Dawley rats. Regional neuronal activity around the injection site was elicited by transdermal electrical stimulation of a corresponding forelimb for 90 min ( n  = 6). The control group of rats ( n  = 6) did not receive any electrical stimulation. Subsequently, the spatial distributions of the tracer over the cortical surface and from the brain sections were imaged and compared between two groups. The ovalbumin fluorescence from the cervical lymph nodes was also compared between the groups to evaluate the effect of neuronal activity on solute clearance from the brain. RESULTS: Tracer distribution over the brain surface/sections revealed a significantly higher uptake of ovalbumin in the hemisphere ipsilateral to the injection among the stimulated animals compared to the unstimulated group. This difference, however, was not seen in the hemisphere contralateral to injection. A trace amount of ovalbumin in the lymph nodes was equivalent between the groups, which indicated a considerable time needed for interstitial solutes to be drained from the brain. CONCLUSION: The results suggest that neuronal activity enhances interstitial solute transport, calling for further examination of ultimate routes and mechanisms for brain solute clearance.


Assuntos
Ratos Sprague-Dawley , Animais , Masculino , Ratos , Ovalbumina , Estimulação Elétrica/métodos , Córtex Sensório-Motor/metabolismo , Córtex Sensório-Motor/fisiologia , Transporte Biológico/fisiologia , Linfonodos/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Xantenos
19.
Biomed Res ; 45(3): 115-123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38839354

RESUMO

Mixed lymphocyte culture under the blockade of CD80/CD86-CD28 co-stimulation induces anergic (completely hyporesponsive) T cells with immune suppressive function (inducible suppressing T cells: iTS cells). Previously, iTS cell therapy has demonstrated outstanding benefits in clinical trials for organ transplantation. Here, we examined whether peptide antigen-specific iTS cells are inducible. DO 11.10 iTS cells were obtained from splenocytes of BALB/c DO 11.10 mice by stimulation with OVA peptide and antagonistic anti-CD80/CD86 mAbs. When DO 11.10 iTS or Foxp3- DO 11.10 iTS cells were stimulated with OVA, these cells produced IL-13, but not IL-4. DO 11.10 iTS cells decreased IL-4 and increased IL-13 production from OVA-stimulated naïve DO 11.10 splenocytes. When Foxp3+ DO 11.10 iTS cells were prepared, these cells significantly inhibited the production of IL-4 and IL-13 compared with freshly isolated Foxp3+ DO 11.10 T cells. Moreover, an increase in the population expressing OX40, ICOS, and 4-1BB suggested activation of Foxp3+ DO 11.10 iTS cells. Thus, blockade of CD80/CD86-CD28 co-stimulation during peptide antigen stimulation augments the inhibitory function of Foxp3+ regulatory T cells, and does not induce anergic Foxp3- conventional T cells. Peptide-specific Foxp3+ regulatory iTS cells could be useful for the treatment of allergic and autoimmune diseases without adverse effects.


Assuntos
Antígeno B7-1 , Antígeno B7-2 , Antígenos CD28 , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Camundongos , Antígeno B7-1/metabolismo , Antígeno B7-1/imunologia , Antígeno B7-2/metabolismo , Antígeno B7-2/imunologia , Camundongos Endogâmicos BALB C , Fatores de Transcrição Forkhead/metabolismo , Peptídeos/farmacologia , Peptídeos/imunologia , Ativação Linfocitária/imunologia , Interleucina-4/metabolismo , Interleucina-4/imunologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Ovalbumina/imunologia , Baço/imunologia , Baço/citologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologia
20.
Immun Inflamm Dis ; 12(6): e1307, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860753

RESUMO

BACKGROUND: The hygiene hypothesis suggests that early life exposure to helminth infections can reduce hypersensitivity in the immune system. OBJECTIVE: The present study aims to evaluate the effects of Toxocara cati (T. cati) somatic products on allergic airway inflammation. METHODS: Between 2018 and 2020, T. cati adult worms were collected from stray cats in Mashhad, Iran (31 out of 186 cats), and their somatic extract was collected. Thirty BALB/c mice were equally divided into three groups, including the OVA group (sensitized and challenged with ovalbumin), the somatic administered group (received somatic extract along with ovalbumin sensitization), and the PBS group (sensitized and challenged with phosphate buffer saline). Bronchoalveolar lavage (BAL) fluid was collected to assess the number of cells, and lung homogenates were prepared for cytokine analysis. Histopathological analysis of the lungs was performed, and inflammatory cells and mucus were detected. Cytokine levels (IL-4, IL-5, IL-10) were measured using enzyme-linked immunosorbent assay (ELISA), and ovalbumin-specific immunoglobulin E (IgE) levels were determined using a capture ELISA. RESULTS: The somatic group significantly decreased regarding the lung pathological changes, including peribronchiolitis, perivasculitis, and eosinophil influx, compared to the group treated with ovalbumin alone. These changes were accompanied by a decrease in proinflammatory cytokines IL-4 and IL-5 and an increase in the anti-inflammatory cytokine IL-10, indicating a shift toward a more balanced immune response. The number of inflammatory cells in the BAL fluid was also significantly reduced in the somatic group, indicating a decrease in inflammation. CONCLUSION: These preclinical findings suggest that in experimental models, T. cati somatic extract exhibits promising potential as a therapeutic agent for mitigating allergic airway inflammation. Its observed effects on immune response modulation and reduction of inflammatory cell infiltration warrant further investigation in clinical studies to assess its efficacy and safety in human patients.


Assuntos
Citocinas , Camundongos Endogâmicos BALB C , Toxocara , Animais , Camundongos , Toxocara/imunologia , Toxocara/efeitos dos fármacos , Citocinas/metabolismo , Citocinas/imunologia , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Ovalbumina/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/parasitologia , Pulmão/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/imunologia , Asma/imunologia , Asma/tratamento farmacológico , Modelos Animais de Doenças , Gatos , Feminino , Toxocaríase/tratamento farmacológico , Toxocaríase/imunologia , Toxocaríase/parasitologia
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