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1.
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
2.
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
3.
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
4.
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
5.
Proc Natl Acad Sci U S A ; 121(25): e2322264121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38865265

RESUMO

Despite the tremendous clinical potential of nucleic acid-based vaccines, their efficacy to induce therapeutic immune response has been limited by the lack of efficient local gene delivery techniques in the human body. In this study, we develop a hydrogel-based organic electronic device (µEPO) for both transdermal delivery of nucleic acids and in vivo microarrayed cell electroporation, which is specifically oriented toward one-step transfection of DNAs in subcutaneous antigen-presenting cells (APCs) for cancer immunotherapy. The µEPO device contains an array of microneedle-shaped electrodes with pre-encapsulated dry DNAs. Upon a pressurized contact with skin tissue, the electrodes are rehydrated, electrically triggered to release DNAs, and then electroporate nearby cells, which can achieve in vivo transfection of more than 50% of the cells in the epidermal and upper dermal layer. As a proof-of-concept, the µEPO technique is employed to facilitate transdermal delivery of neoantigen genes to activate antigen-specific immune response for enhanced cancer immunotherapy based on a DNA vaccination strategy. In an ovalbumin (OVA) cancer vaccine model, we show that high-efficiency transdermal transfection of APCs with OVA-DNAs induces robust cellular and humoral immune responses, including antigen presentation and generation of IFN-γ+ cytotoxic T lymphocytes with a more than 10-fold dose sparing over existing intramuscular injection (IM) approach, and effectively inhibits tumor growth in rodent animals.


Assuntos
Eletroporação , Imunoterapia , Vacinas de DNA , Animais , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Eletroporação/métodos , Camundongos , Imunoterapia/métodos , Administração Cutânea , Neoplasias/terapia , Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Células Apresentadoras de Antígenos/imunologia , Feminino , Camundongos Endogâmicos C57BL , Humanos , Vacinação/métodos
6.
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
7.
J Pharm Biomed Anal ; 247: 116265, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38850849

RESUMO

Dingchuan Decoction (DCD) is a traditional Chinese medicine prescription commonly used in the treatment of asthma, but the mechanism of DCD in treating asthma has not yet been determined. In this study, we employed a combination of metabolomics and network pharmacology to investigate the mechanism of DCD in treating asthma. An allergic asthma rat model was induced by ovalbumin (OVA). Metabolomics based on 1H NMR and UHPLC-MS was used to identify differential metabolites and obtain the major metabolic pathways and potential targets. Network pharmacology was utilized to explore potential targets of DCD for asthma treatment. Finally, the results of metabolomics and network pharmacology were integrated to obtain the key targets and metabolic pathways of DCD for the therapy of asthma, and molecular docking was utilized to validate the key targets. A total of 76 important metabolites and 231 potential targets were identified through metabolomics. Using network pharmacology, 184 potential therapeutic targets were obtained. These 184 targets were overlaid with the 231 potential targets obtained through metabolomics and were analyzed in conjunction with metabolic pathways. Ultimately, the key targets were identified as aldehyde dehydrogenase 2 (ALDH2) and amine oxidase copper-containing 3 (AOC3), and the relevant metabolic pathways affected were glycolysis and gluconeogenesis as well as arginine and proline metabolism. Molecular docking showed that the key targets had high affinity with the relevant active ingredients in DCD, which further demonstrated that DCD may exert therapeutic effects by acting on the key targets. The present study demonstrated that DCD can alleviate OVA-induced allergic asthma and that DCD may have a therapeutic effect by regulating intestinal flora and polyamine metabolism through its effects on ALDH2 and AOC3.


Assuntos
Asma , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Metabolômica , Simulação de Acoplamento Molecular , Farmacologia em Rede , Ovalbumina , Ratos Sprague-Dawley , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Metabolômica/métodos , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Farmacologia em Rede/métodos , Masculino , Cromatografia Líquida de Alta Pressão/métodos , Redes e Vias Metabólicas/efeitos dos fármacos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Medicina Tradicional Chinesa/métodos
8.
Int J Biol Macromol ; 272(Pt 2): 132913, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38851606

RESUMO

Nasal vaccine is a non-invasive vaccine that activates systemic and mucosal immunity in the presence of an adjuvant, thereby enhancing immune function. In this work, chitosan/oligochitosan/tween 80 (CS-COS-T80) co-stabilized emulsion was designed and further used as the nasal adjuvant. CS-COS-T80 emulsion exhibited outstanding stability under pH 6-8 with uniformly dispersed droplets and nano-scale particle size (<0.25 µm), and maintained stable at 4 °C for 150-day storage. Addition of model antigen ovalbumin (OVA) had no effect on the stability of CS-COS-T80 emulsion. In vivo nasal immunity indicated that CS-COS-T80 emulsion prolonged the retention time of OVA in the nasal cavity (from 4 to 8 h to >12 h), as compared to T80-emulsion. CS-COS-T80 emulsion produced a stronger mucosal immune response to OVA, with secretory IgA levels 5-fold and 2-fold higher than those of bare OVA and commercial adjuvant MF59, respectively. Compared to MF59, CS-COS-T80 induced a stronger humoral immune response and a mixed Th1/Th2 immune response of OVA after immunization. Furthermore, in the presence of CS-COS-T80 emulsion, the secretion of IL-4 and IFN-γ and the activation of splenocyte memory T-cell differentiation increased from 173.98 to 210.21 pg/mL and from 75.46 to 104.01 pg/mL, respectively. Therefore, CS-COS-T80 emulsion may serve as a promising adjuvant platform.


Assuntos
Adjuvantes Imunológicos , Quitosana , Emulsões , Imunidade nas Mucosas , Mucosa Nasal , Ovalbumina , Quitosana/química , Animais , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos , Ovalbumina/imunologia , Ovalbumina/química , Mucosa Nasal/imunologia , Feminino , Administração Intranasal , Camundongos Endogâmicos BALB C , Citocinas/metabolismo , Tamanho da Partícula , Oligossacarídeos
9.
Food Funct ; 15(11): 5895-5907, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38727519

RESUMO

In order to explore the in vivo anti-food allergy activity of Lactobacillus sakei subsp. sakei-fermented Eucheuma spinosum polysaccharides F1-ESP-3, an ovalbumin (OVA)-induced food allergy mouse model was established by ascites immunization and gavage. The weight, temperature, incidence of diarrhea, levels of allergic mediators and inflammatory factors in the serum of mice were analyzed. We analyzed the differentiation of mouse spleen lymphocytes and the proportion of sensitized mast cells by flow cytometry. The intestinal barrier status of mice was analyzed by intestinal pathological tissue sections and microbiota sequencing. The results showed that F1-ESP-3 could alleviate the food allergy symptoms of mice, such as hypothermia and loose stool; levels of OVA-specific immunoglobulin E, mast cell protease and histamine in the serum of sensitized mice and the proportion of dendritic cells and mast cells in mouse spleen were significantly reduced; in addition, F1-ESP-3 may protect the intestinal barrier and further improve the intestinal microenvironment of food-allergic mice by regulating the abundance of Bacteroidetes and Firmicutes. F1-ESP-3 can further improve the intestinal microenvironment of food-allergic mice by upregulating the levels of Lachnospiraceae, and may affect the signal pathways such as NOD-like receptor, MAPK, I kappa B and antigen processing and presentation.


Assuntos
Hipersensibilidade Alimentar , Camundongos Endogâmicos BALB C , Polissacarídeos , Animais , Camundongos , Hipersensibilidade Alimentar/tratamento farmacológico , Polissacarídeos/farmacologia , Fermentação , Microbioma Gastrointestinal/efeitos dos fármacos , Feminino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Modelos Animais de Doenças , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Latilactobacillus sakei , Baço/efeitos dos fármacos , Ovalbumina , Lactobacillus , Algas Comestíveis , Rodófitas
10.
Int J Biol Macromol ; 270(Pt 1): 132310, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38740162

RESUMO

With multiscale hierarchical structure, wood is suitable for a range of high-value applications, especially as a chromatographic matrix. Here, we have aimed to provide a weak anion-exchange polymeric monolithic column based on natural wood with high permeability and stability for effectively separating the targeted protein. The wood-polymeric monolithic column was synthesized by in situ polymerization of glycidyl methacrylate and ethylene glycol dimethacrylate in wood, and coupled with diethylaminoethyl hydrochloride. The wood-polymeric monolithic column can be integrated with fast-protein liquid chromatography for large-scale protein purification. According to the results, the wood-polymeric monolithic column showed high hydrophilicity, permeability and stability. Separation experiments verified that the wood-polymeric monolithic column could purify the targeted protein (spike protein of SARS-COV-2 and ovalbumin) from the mixed proteins by ion exchange, and the static adsorption capacity was 33.04 mg mL-1 and the dynamic adsorption capacity was 24.51 mg mL-1. In addition, the wood-polymerized monolithic column had good stability, and a negligible decrease in the dynamic adsorption capacity after 20 cycles. This wood-polymerized monolithic column can provide a novel, efficient, and green matrix for monolithic chromatographic columns.


Assuntos
Madeira , Madeira/química , Adsorção , Metacrilatos/química , Cromatografia por Troca Iônica/métodos , Polímeros/química , Ovalbumina/química , Ovalbumina/isolamento & purificação , Interações Hidrofóbicas e Hidrofílicas , SARS-CoV-2 , Polimerização , Compostos de Epóxi
11.
Int J Biol Macromol ; 270(Pt 2): 132389, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38754655

RESUMO

Currently, evidence from observational studies suggests dietary fiber intake may be associated with decreased risk of food allergy. As a type of dietary fiber, resistant starch was also widely reported to possess anti-allergic properties. However, there is a relative paucity of studies assessing the influence of resistant starch types on their anti-allergic activity and its possible underlying mechanisms. In the current study, the anti-allergic effects of RS3-type (retrograded starch), RS4-type (chemically modified starch, cross-bonded), and RS5-type (starch-palmitic acid complex) of lotus seed resistant starch were evaluated in the OVA (100 mg/kg)-induced food allergic mice model. The results showed that oral administration of RS3 or RS4 lotus seed resistant starch (0.3 g/100 g b.w.) for 25 days significantly improved adverse symptoms of food allergy such as weight loss, increases in allergy symptom score and diarrhea rate; with significant reduction of serum specific antibody IgE, TNF-α, IL-4 levels and improved Th1/Th2 balance being observed. The mechanism may involve the regulation of lotus seed resistant starch on intestinal flora and the metabolites short-chain fatty acids and bile acids. Taken together, the findings may enhance understanding towards ameliorative effects of resistant starch on food allergy, and offer valuable insights for the exploration of novel anti-allergic bioactive compounds.


Assuntos
Antialérgicos , Modelos Animais de Doenças , Lotus , Ovalbumina , Sementes , Animais , Lotus/química , Camundongos , Sementes/química , Antialérgicos/farmacologia , Amido Resistente/farmacologia , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/tratamento farmacológico , Imunoglobulina E/sangue , Amido/química , Amido/farmacologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos
12.
Vaccine ; 42(17): 3721-3732, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38719694

RESUMO

Nanotechnology has emerged as a promising avenue for enhancing the efficacy of vaccine delivery systems. This study investigates the utilization of nanogels as carriers for the model antigen ovalbumin, with a focus on in vivo assessments in equine and murine models. Nanogels, owing to their biocompatibility and tunable physicochemical properties, offer a versatile platform for efficient antigen encapsulation and controlled release. The encapsulation efficiency and physicochemical characteristics of ovalbumin-loaded nanogels were comprehensively characterized. In vitro biocompatibility was evaluated, finding excellent properties of these nanogels. In vivo evaluations were conducted on both equine and murine subjects, assessing immunogenicity through antibody and splenic cell response. Furthermore, the study propose the potential use of nanogels in tailoring immune responses through the modulation of antigen release kinetics. The results obtained in the in vitro assays showed an increase in the uptake of nanogels by APCs compared to free antigen (OVA). In mice, an absence of inflammatory response in the inoculation site was observed, without systemic damage in the evaluated organs. In addition, non-significant humoral response was found nor cellular proliferation and proinflammatory cytokine production, compared with a traditional adjuvant as aluminum hydroxide, in both animal models. These findings allow further insights into nanogel-based delivery systems and offer valuable insights into their application in various animal models. In conclusion, this research establishes the utility of nanogels as effective carriers for antigens-based vaccines, with interesting biocompatibility properties and highly taken affinity by antigen-presenting cells, without inducing inflammation at the injection site. The study underscores the potential of nanogel technology in revolutionizing vaccine design and highlights the importance of tailored approaches for diverse target species.


Assuntos
Ovalbumina , Animais , Camundongos , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Cavalos/imunologia , Nanogéis/química , Vacinas/imunologia , Vacinas/administração & dosagem , Feminino , Portadores de Fármacos/química , Antígenos/imunologia , Antígenos/administração & dosagem , Camundongos Endogâmicos BALB C , Materiais Biocompatíveis/química , Adjuvantes Imunológicos/administração & dosagem , Citocinas/metabolismo , Polietilenoglicóis/química , Sistemas de Liberação de Medicamentos , Polietilenoimina/química
13.
Mol Biol Rep ; 51(1): 698, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811424

RESUMO

BACKGROUND: Existing investigations suggest that the blockade of phosphoinositide 3-kinase (PI3K) activity contributes to inflammatory solution in allergic asthma, but whether this inhibition directly attenuates neutrophilic airway inflammation in vivo is still unclear. We explored the pharmacological effects of LY294002, a specific inhibitor of PI3K on the progression of neutrophilic airway inflammation and investigated the underlying mechanism. METHODS AND RESULTS: Female C57BL/6 mice were intranasally sensitized with ovalbumin (OVA) together with lipopolysaccharide (LPS) on days 0 and 6, and challenged with OVA on days 14-17 to establish a neutrophilic airway disease model. In the challenge phase, a subset of mice was treated intratracheally with LY294002. We found that treatment of LY294002 attenuates clinic symptoms of inflammatory mice. Histological studies showed that LY294002 significantly inhibited inflammatory cell infiltration and mucus production. The treatment also significantly inhibited OVA-LPS induced increases in inflammatory cell counts, especially neutrophil counts, and IL-17 levels in bronchoalveolar lavage fluid (BALF). LY294002 treated mice exhibited significantly increased IL-10 levels in BALF compared to the untreated mice. In addition, LY294002 reduced the plasma concentrations of IL-6 and IL-17. The anti-inflammatory effects of LY29402 were correlated with the downregulation of NLRP3 inflammasome. CONCLUSIONS: Our findings suggested that LY294002 as a potential pharmacological target for neutrophilic airway inflammation.


Assuntos
Asma , Líquido da Lavagem Broncoalveolar , Cromonas , Modelos Animais de Doenças , Inflamassomos , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Morfolinas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neutrófilos , Ovalbumina , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Asma/tratamento farmacológico , Asma/induzido quimicamente , Asma/metabolismo , Asma/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cromonas/farmacologia , Morfolinas/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Interleucina-17/metabolismo
14.
Int Immunopharmacol ; 134: 112199, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38713938

RESUMO

Asthma is a prevalent chronic respiratory disease, yet understanding its ecology and pathogenesis remains a challenge. Trim27, a ubiquitination ligase belonging to the TRIM (tripartite motif-containing) family, has been implicated in regulating multiple pathophysiological processes such as inflammation, oxidative stress, apoptosis, and cell proliferation. However, the role of Trim27 in asthma has not been investigated. Our study found that Trim27 expression significantly increases in the airway epithelium of asthmatic mice. Knockdown of Trim27 expression effectively relieved ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and lung tissue histopathological changes. Moreover, Trim27 knockdown exhibited a significant reduction in airway inflammation and oxidative stress in asthmatic mice, and in vitro analysis confirmed the favorable effect of Trim27 deletion on inflammation and oxidative stress in mouse airway epithelial cells. Furthermore, our study revealed that deletion of Trim27 in MLE12 cells significantly decreased NLRP3 inflammasome activation, as evidenced by reduced expression of NLRP3, ASC, and pro-IL-1ß mRNA. This downregulation was reversed when Trim27, but not its mutant lacking ubiquitination ligase activity, was replenished in these cells. Consistent with these findings, protein levels of NLRP3, pro-caspase-1, pro-IL-1ß, cleaved-caspase-1, and cleaved-IL-1ß were higher in Trim27-replenished cells compared to cells expressing Trim27C/A. Functionally, the downregulation of IL-1ß and IL-18 levels induced by Trim27 deletion was rescued by replenishing Trim27. Overall, our findings provide evidence that Trim27 contributes to airway inflammation and oxidative stress in asthmatic mice via NLRP3 inflammasome activation, providing crucial insights into potential therapeutic interventions targeting Trim27 as a way to treat asthma.


Assuntos
Asma , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Animais , Asma/metabolismo , Asma/imunologia , Asma/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Linhagem Celular , Feminino , Modelos Animais de Doenças , Inflamação/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Proteínas com Motivo Tripartido , Proteínas de Ligação a DNA
15.
J Agric Food Chem ; 72(23): 13320-13327, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38819406

RESUMO

Conventional radical grafting of proteins with catechins consumed the most antioxidant-active hydroxyls during grafting, thus failing to effectively retain antioxidant activity in conjugates. In this study, a novel strategy of selective protection of the most reactive hydroxyls before grafting was developed to preserve the most reactive hydroxyls and effectively retain antioxidant activity in conjugates. Selective protection of the most reactive hydroxyls of (-)-epigallocatechin-3-gallate (EGCG) was successfully realized in a yield of 87% applying trimethyl orthopropionate and catalytic calcium triflate at 40 °C. The novel ovalbumin (OVA)-EGCG conjugate with 93% grafting ratio was prepared by radical grafting with the selectively protected EGCG and subsequent deprotection. Substantially enhanced antioxidant performance of the novel OVA-EGCG conjugate in liposomes was unveiled with notably reduced curcumin degradation and leakage. The strategy and approaches developed in this study will be valuable to effectively improve the antioxidant activities of protein-catechin grafting conjugates.


Assuntos
Antioxidantes , Catequina , Ovalbumina , Ovalbumina/química , Catequina/química , Catequina/análogos & derivados , Antioxidantes/química , Lipossomos/química
16.
J Control Release ; 370: 379-391, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697317

RESUMO

Although various types of mRNA-based vaccines have been explored, the optimal conditions for induction of both humoral and cellular immunity remain rather unknown. In this study, mRNA vaccines of nucleoside-modified mRNA in lipoplexes (LPXs) or lipid nanoparticles (LNPs) were evaluated after administration in mice through different routes, assessing mRNA delivery, tolerability and immunogenicity. In addition, we investigated whether mRNA vaccines could benefit from the inclusion of the adjuvant alpha-galactosylceramide (αGC), an invariant Natural Killer T (iNKT) cell ligand. Intramuscular (IM) vaccination with ovalbumin (OVA)-encoding mRNA encapsulated in LNPs adjuvanted with αGC showed the highest antibody- and CD8+ T cell responses. Furthermore, we observed that addition of signal peptides and endocytic sorting signals of either LAMP1 or HLA-B7 in the OVA-encoding mRNA sequence further enhanced CD8+ T cell activation although reducing the induction of IgG antibody responses. Moreover, mRNA LNPs with the ionizable lipidoid C12-200 exhibited higher pro-inflammatory- and reactogenic activity compared to mRNA LNPs with SM-102, correlating with increased T cell activation and antitumor potential. We also observed that αGC could further enhance the cellular immunity of clinically relevant mRNA LNP vaccines, thereby promoting therapeutic antitumor potential. Finally, a Listeria monocytogenes mRNA LNP vaccine supplemented with αGC showed synergistic protective effects against listeriosis, highlighting a key advantage of co-activating iNKT cells in antibacterial mRNA vaccines. Taken together, our study offers multiple insights for optimizing the design of mRNA vaccines for disease applications, such as cancer and intracellular bacterial infections.


Assuntos
Vacinas Anticâncer , Galactosilceramidas , Camundongos Endogâmicos C57BL , Nanopartículas , Ovalbumina , Animais , Galactosilceramidas/administração & dosagem , Galactosilceramidas/química , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Feminino , Nanopartículas/química , Nanopartículas/administração & dosagem , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Vacinas de mRNA , Adjuvantes Imunológicos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , RNA Mensageiro/administração & dosagem , Camundongos , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Lipídeos/química , Lipossomos
17.
Biomater Sci ; 12(12): 3175-3192, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38742916

RESUMO

The tumor immunosuppressive microenvironment (TIME) and uncontrollable release of antigens can lower the efficacy of nanovaccine-based immunotherapy (NBI). Therefore, it is necessary to develop a new strategy for TIME reshaping and controllable release of antigens to improve the NBI efficacy. Herein, an acidity-responsive Schiff base-conjugated polyphenol-coordinated nanovaccine was constructed for the first time to realize bidirectional TIME reshaping and controllable release of antigens for activating T cells. In particular, an acidity-responsive tannic acid-ovalbumin (TA-OVA) nanoconjugate was prepared via a Schiff base reaction. FeIII was coordinated with TA-OVA to produce a FeIII-TA-OVA nanosystem, and 1-methyltryptophan (1-MT) as an indoleamine 2,3-dioxygenase inhibitor was loaded to form a polyphenol-coordinated nanovaccine. The coordination between FeIII and TA could cause photothermal ablation of primary tumors, and the acidity-triggered Schiff base dissociation of TA-OVA could controllably release OVA to realize lysosome escape, initiating the body's immune response. More importantly, oxidative stress generated by a tumor-specific Fenton reaction of Fe ions could promote the polarization of tumor-associated macrophages from the M2 to M1 phenotype, resulting in the upregulation of cytotoxic T cells and helper T cells. Meanwhile, 1-MT could downregulate immunosuppressive regulatory T cells. Overall, such skillful combination of bidirectional TIME reshaping and controllable antigen release into one coordination nanosystem could effectively enhance the NBI efficacy of tumors.


Assuntos
Imunoterapia , Ovalbumina , Polifenóis , Bases de Schiff , Taninos , Microambiente Tumoral , Animais , Microambiente Tumoral/efeitos dos fármacos , Ovalbumina/imunologia , Ovalbumina/química , Ovalbumina/administração & dosagem , Polifenóis/química , Polifenóis/farmacologia , Camundongos , Taninos/química , Taninos/farmacologia , Bases de Schiff/química , Concentração de Íons de Hidrogênio , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Triptofano/química , Triptofano/análogos & derivados , Nanoconjugados/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Linhagem Celular Tumoral , Compostos Férricos/química , Nanovacinas
18.
Environ Pollut ; 355: 124195, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38776998

RESUMO

The respiratory effects of particulate matter (PM) in subway station platforms or tunnels have attracted considerable research attention. However, no studies have characterized the effects of subway PM on allergic immune responses. In this study, iron oxide (α-Fe2O3 and Fe3O4) particles-the main components of subway PM-were intratracheally administered to BALB/c mice where ovalbumin (OVA) induced allergic pulmonary inflammation. Iron oxide particles enhanced OVA-induced eosinophil recruitment around the bronchi and mucus production from airway epithelium. The concentrations of type 2 cytokines, namely, interleukin (IL)-5 and IL-13, in bronchial alveolar lavage fluids were increased by iron oxide particles. Iron oxide particles also increased the number of type 2 innate lymphoid cells and CD86+ cells in the lung. Moreover, phagocytosis of particles in lung cells was confirmed by Raman spectroscopy. In a subsequent in vitro study, bone marrow-derived antigen-presenting cells (APCs) isolated from NC/Nga mice were exposed to iron oxide particles and OVA. They were also exposed to outdoor ambient PM: Vehicle Exhaust Particulates (VEP) and Urban Aerosols (UA) as references. Iron oxide particles promoted the release of lactate dehydrogenase, C-X-C motif chemokine ligand 1 and IL-1α from APCs, which tended to be stronger than those of VEP. These results suggest that iron oxide particles enhance antigen presentation in the lungs, promoting allergic immune response in mice; iron oxide particles-induced death and inflammatory response of APCs can contribute to allergy exacerbation. Although iron oxide particles do not contain various compounds like VEP, iron oxide alone may have sufficient influence.


Assuntos
Poluentes Atmosféricos , Compostos Férricos , Hipersensibilidade , Camundongos Endogâmicos BALB C , Material Particulado , Animais , Material Particulado/toxicidade , Camundongos , Poluentes Atmosféricos/toxicidade , Hipersensibilidade/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Citocinas/metabolismo , Ovalbumina , Líquido da Lavagem Broncoalveolar/química , Emissões de Veículos/toxicidade , Feminino
19.
Food Chem ; 453: 139630, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-38781895

RESUMO

Rutin is a polyphenol with beneficial pharmacological properties. However, its bioavailability is often compromised due to low solubility and poor stability. Encapsulation technologies, such as emulsion systems, have been proven to be promising delivery vehicles for enhancing the bioavailability of bioactive compounds. Thus, this study was proposed and designed to investigate the colonic targeting and colonic fermentation characteristics of rutin-loaded ovalbumin-ferulic acid-polysaccharide (OVA-FA-PS) complex emulsions. The results indicate that OVA-FA-PS emulsion effectively inhibits the degradation of rutin active substances and facilitates its transport of rutin to the colon. The analysis revealed that the OVA-FA-κ-carrageenan emulsion loaded with rutin exhibited superior elasticity and colon targeting properties compared to the OVA-FA-hyaluronic acid or OVA-FA-sodium alginate emulsions loaded with rutin in the composite emulsion. Additionally, it was observed that the rutin loaded within the OVA-FA-κ-carrageenan emulsion underwent degradation and was converted to 4-hydroxybenzoic acid during colonic fermentation.


Assuntos
Colo , Ácidos Cumáricos , Emulsões , Fermentação , Ovalbumina , Polissacarídeos , Colo/metabolismo , Colo/microbiologia , Emulsões/química , Emulsões/metabolismo , Ovalbumina/química , Ovalbumina/metabolismo , Ácidos Cumáricos/química , Ácidos Cumáricos/metabolismo , Polissacarídeos/química , Polissacarídeos/metabolismo , Animais , Rutina/química , Rutina/metabolismo , Masculino
20.
Biomed Pharmacother ; 175: 116788, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38772153

RESUMO

AIMS: Penicilazaphilone C (PAC) is hypothesized to potentially serve as a therapeutic treatment for allergic airway inflammation by inhibiting the NLRP3 inflammasome and reducing oxidative stress. METHODS: An allergic asthma model was induced in female BALB/c mice of the OVA, OVA+PAC, OVA+PAC+LPS, and OVA+Dex groups by sensitizing and subsequently challenging them with OVA. The OVA+PAC and Normal+PAC groups were treated with PAC, while the OVA+PAC+LPS group also received LPS. The OVA+Dex group was given dexamethasone (Dex). Samples of serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for histological and cytological analysis. RESULTS: Allergic mice treated with PAC or Dex showed inhibited inflammation and mucus production in the lungs. There was a decrease in the number of inflammatory cells in the BALF, lower levels of inflammatory cytokines in the serum and BALF, and a reduction in the protein expression of NLRP3, ASC, cleaved caspase-1, IL-1ß, activated gasdermin D, MPO, Ly6G, and ICAM-1. Additionally, oxidative stress was reduced, as shown by a decrease in MDA and DCF, but an increase in SOD and GSH. Treatment with PAC also resulted in a decrease in pulmonary memory CD4+ T cells and an increase in regulatory T cells. However, the positive effects seen in the PAC-treated mice were reversed when the NLRP3 inflammasome was activated by LPS, almost returning to the levels of the Sham-treated mice. SIGNIFICANCE: PAC acts in a similar way to anti-allergic inflammation as Dex, suggesting it may be a viable therapeutic option for managing allergic asthma inflammation.


Assuntos
Asma , Líquido da Lavagem Broncoalveolar , Inflamassomos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Feminino , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Asma/tratamento farmacológico , Asma/imunologia , Asma/induzido quimicamente , Camundongos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/imunologia , Estresse Oxidativo/efeitos dos fármacos , Ovalbumina , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Modelos Animais de Doenças , Dexametasona/farmacologia , Anti-Inflamatórios/farmacologia
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