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1.
J Ethnopharmacol ; 332: 118286, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-38723919

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Di-Long (Pheretima vulgaris) is a classic animal sourced traditional Chinese medicine. It has been used for the treatment of joint inflammation and arthralgia for over two thousand years due to its effects of Tong-Luo-Zhi-Tong (dredging collaterals and alleviating pain). Our previous study showed that Chinese medicine Di-Long has significant anti-rheumatoid arthritis (RA) effects. AIM OF THE STUDY: Considering Di-Long as a potential source of active compounds with specific anti-RA therapeutic effects, this research was to obtain the anti-RA target-specific active fraction from Di-Long extracts (DL), and to further explore the chemical basis and verify the anti-RA mechanism of this active fraction. MATERIALS AND METHODS: Transcriptomic was applied to obtain the main anti-RA targets of DL on human RA fibroblast-like synoviocytes (FLS) and validated by qPCR. The target-corresponding active fraction was isolated from DL by ethanol precipitation and gel chromatography, and analyzed by nanoliter chromatography-mass spectrometry. Anti-RA effects of this active fraction was investigated by collagen-induced arthritis (CIA) in mice, and anti-RA mechanisms were verified in cocultured model of rat FLS and peripheral blood lymphocytes. RESULTS: We confirmed that CXCL10/CXCR3 was the main anti-RA target of DL. The active fraction - A (2182 - 890 Da) was isolated from DL based on its CXCL10 inhibiting effects in RA-FLS. Fraction A contains 195 peptides (192 were newly discovered), 26 of which might be bioactive and were considered to be the chemical basis of its anti-RA effects. Fraction A significantly ameliorated the joint destruction and overall inflammation in CIA mice, and downregulated CXCR3 expression in mice joint. Fraction A inhibited the chemotaxis of Th-cells in rat peripheral blood lymphocytes towards the TNF-α-induced rat FLS through CXCL10/CXCR3 pathway. CONCLUSIONS: Our work indicated that active fraction from DL containing small peptides exhibits promising therapeutic effects for RA through inhibiting CXCL10/CXCR3 chemotaxis.


Assuntos
Antirreumáticos , Artrite Experimental , Artrite Reumatoide , Quimiocina CXCL10 , Quimiotaxia , Receptores CXCR3 , Membrana Sinovial , Animais , Receptores CXCR3/metabolismo , Quimiocina CXCL10/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Masculino , Antirreumáticos/farmacologia , Antirreumáticos/isolamento & purificação , Ratos , Humanos , Quimiotaxia/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo
4.
Respir Res ; 21(1): 161, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32586329

RESUMO

Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) commonly coexists in lung cancer and COPD. CS triggers many factors including matrix metalloproteinases (MMPs) production, contributing to EMT progression in the lungs. Here, how Shp2 signaling regulates the CS-induced MMP-9 production and EMT progression were investigated in mouse lungs and in pulmonary epithelial cell cultures (NCI-H292) found CS induced MMP-9 production, EMT progression (increased vimentin and α-SMA; decreased E-cadherin) and collagen deposition in lung tissues; cigarette smoke extract (CSE) induced MMP-9 production and EMT-related phenotypes in NCI-H292 cells, which were partially prevented by Shp2 KO/KD or Shp2 inhibition. The CSE exposure induced EMT phenotypes were suppressed by MMP-9 inhibition. Recombinant MMP-9 induced EMT, which was prevented by MMP-9 inhibition or Shp2 KD/inhibition. Mechanistically, CS and CSE exposure resulted in ERK1/2, JNK and Smad2/3 phosphorylation, which were suppressed by Shp2 KO/KD/inhibition. Consequentially, the CSE exposure-induced MMP-9 production and EMT progression were suppressed by ERK1/2, JNK and Smad2/3 inhibitors. Thus, CS induced MMP-9 production and EMT resulted from activation of Shp2/ERK1/2/JNK/Smad2/3 signaling pathways. Our study contributes to the underlying mechanisms of pulmonary epithelial structural changes in response to CS, which may provide novel therapeutic solutions for treating associated diseases, such as COPD and lung cancer.


Assuntos
Fumar Cigarros/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Metaloproteinase 9 da Matriz/biossíntese , Proteína Tirosina Fosfatase não Receptora Tipo 11/biossíntese , Animais , Linhagem Celular Tumoral , Fumar Cigarros/efeitos adversos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Exposição por Inalação/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia
5.
Respir Res ; 21(1): 22, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931796

RESUMO

Airway remodeling consists of the structural changes of airway walls, which is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the need for early and specific therapeutic interventions. The arachidonic acid cytochrome P-450 (CYP) pathway has thus far received relatively little attention in its relation to asthma. In this study, we studied the inhibition of soluble epoxide hydrolase (sEH) on airway remodeling and hyperresponsiveness (AHR) in a chronic asthmatic model which long-term exposure to antigen over a period of 12 weeks. The expression of sEH and CYP2J2, the level of 14, 15-epoxyeicosatrienoic acids (EETs), airway remodeling, hyperresponsiveness and inflammation were analyzed to determine the inhibition of sEH. The intragastric administration of 3 or 10 mg/kg ZDHXB-101, which is a structural derivative of natural product honokiol and a novel soluble epoxide hydrolase (sEH) inhibitor, daily for 9 weeks significantly increased the level of 14, 15-EETs by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. ZDHXB-101 reduced the expression of remodeling-related markers such as interleukin (IL)-13, IL-17, MMP-9 N-cadherin, α-smooth muscle actin, S100A4, Twist, goblet cell metaplasia, and collagen deposition in the lung tissue or in bronchoalveolar lavage fluid. Moreover, ZDHXB-101 alleviated AHR, which is an indicator that is used to evaluate the airway remodeling function. The inhibitory effects of ZDHXB-101 were demonstrated to be related to its direct inhibition of the extracellular signal-regulated kinase (Erk1/2) phosphorylation, as well as inhibition of c-Jun N-terminal kinases (JNK) and the signal transducer and activator of transcription-3 (STAT3) signal transduction. These findings first revealed the anti-remodeling potential of ZDHXB-101 lead in chronic airway disease.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Remodelação das Vias Aéreas/fisiologia , Animais , Antiasmáticos/química , Antiasmáticos/farmacologia , Citocromo P-450 CYP2J2 , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Epóxido Hidrolases/metabolismo , Feminino , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Fator de Transcrição STAT3/antagonistas & inibidores
6.
Eur J Pharmacol ; 868: 172874, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31866410

RESUMO

Airway remodeling in asthma is difficult to treat because of its complex pathophysiology that involves proinflammatory cytokines, as well as the arachidonic acid cytochrome P-450 (CYP) pathway; however, it has received little attention. In this study, we assessed the efficacy of a soluble epoxide hydrolase (sEH) on airway remodeling in a mouse model of chronic asthma. The expression of sEH and CYP2J2 and the level of 14,15-epoxyeicosatrienoic acid (14,15-EET), airway remodeling and hyperresponsiveness (AHR) were analyzed to determine the level of sEH inhibition. AUDA, a sEH inhibitor, was given daily for 9 weeks orally, which significantly increased the level of 14,15-EET by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. The inhibition of sEH reduced the expression of remodeling-related molecular markers, such as interleukin (IL)-13, IL-17, matrix metalloproteinase 9, N-cadherin, α-smooth muscle actin (α-SMA), S100A4, Twist, epithelial goblet cell metaplasia, and collagen deposition in bronchoalveolar lavage fluid (BAL fluid) and lung tissues. Moreover, remodeling-related eosinophil accumulation in the BAL fluid and infiltration into the lung tissue were improved by AUDA. Finally, AUDA alleviated AHR, which is a functional indicator of airway remodeling. The effect of AUDA on airway remodeling was related to the downregulation of extracellular-regulated protein kinases (Erk1/2), c-Jun N-terminal kinases (JNK) and signal transducer and activator of transcription 3 (STAT3). To our knowledge, this is the first report to demonstrate that inhibition of sEH exerts significant protective effects on airway remodeling in asthma.


Assuntos
Adamantano/análogos & derivados , Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Láuricos/farmacologia , Pulmão/efeitos dos fármacos , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/sangue , Adamantano/farmacologia , Adamantano/uso terapêutico , Remodelação das Vias Aéreas/imunologia , Animais , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocromo P-450 CYP2J2 , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Feminino , Humanos , Ácidos Láuricos/uso terapêutico , Pulmão/imunologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
7.
Eur J Pharmacol ; 848: 55-61, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30707957

RESUMO

Various studies have shown that flavones have several pharmacological activities including anti-allergy activities. However, the bioavailability of oral flavones is very low, and whether inhaled administration can improve efficacy in respiratory disease models is unclear. In the present study, the anti-allergic activities of inhaling 5,7-dimethoxy-3,4'-dihydroxyflavone (MHF), a synthetic flavonoid, was investigated by comparison with disodium cromoglycate (DSCG) and nedocromil sodium (NS) in rat allergic models. In an anti-DNP-IgE-induced asthmatic model, inhaled MHF dose-dependently inhibited the increase in airway resistance after antigen challenge. In an ovalbumin (OVA)-induced asthmatic model, inhaled MHF showed significant suppression of airway hyperresponsiveness; a decrease in eosinophil and neutrophil counts, IL-4, IL-5 and leukotriene D4 in bronchoalveolar lavage fluid; a reduction in total IgE and OVA-specific IgE levels in serum; and suppression of eosinophil infiltration in lung tissue after antigen challenge. The efficacy of inhaled MHF was comparable to that of NS and DSCG. In conclusion, based on these findings, the report for the first time that that inhaled MHF may be a potential drug for the treatment of allergic asthma.


Assuntos
Antialérgicos/administração & dosagem , Asma/tratamento farmacológico , Modelos Animais de Doenças , Flavonoides/administração & dosagem , Administração por Inalação , Animais , Antialérgicos/química , Asma/induzido quimicamente , Asma/metabolismo , Relação Dose-Resposta a Droga , Feminino , Flavonoides/química , Ovalbumina/toxicidade , Ratos , Ratos Sprague-Dawley
8.
Acta Haematol ; 140(3): 131-140, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30253384

RESUMO

BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer. METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal. RESULTS: A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D - early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks. CONCLUSION: The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.


Assuntos
Antígenos CD28/metabolismo , Biologia Computacional/métodos , Receptores de Antígenos Quiméricos/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Antineoplásicos/uso terapêutico , Bases de Dados Factuais , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Mapas de Interação de Proteínas/genética , Receptores de Antígenos Quiméricos/química , Resultado do Tratamento , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/química
9.
Lung Cancer ; 122: 44-53, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30032844

RESUMO

OBJECTIVES: Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is found in invasive or metastatic phenotypes in lung cancer and COPD. MK-2206, a pan Akt inhibitor, has failed in clinical trials for solid tumors when administered alone at tolerated doses, but it has been shown to have synergistic effects when applied with certain molecular targeted agents. In this study, we investigated the working mechanism of MK-2206 in CS-induced pulmonary EMT both in vivo and in vitro. MATERIALS AND METHODS: The expression of Akt, epithelial-mesenchymal transition (EMT) markers and signaling proteins were analyzed by immunohistochemistry, real-time PCR and Western blot in cigarette smoke extract (CSE)-treated pulmonary epithelia and CS-treated lung tissues in mice. RESULTS AND CONCLUSION: We demonstrated that exposure of the epithelium to CSE and exposure of the mice to CS can induce EMT by activating the Akt signaling pathway. Intragastric application of MK-2206 at a low dose (50 mg/kg) reversed the changes of the key indicators of EMT in the lungs of CS-exposed mice, including TGF-ß1, α-SMA, vimentin, MMP-9, MMP-2, S100A4, collagen deposition, and E-cadherin. MK-2206 at a non-cytotoxic concentration (0.5 µM) or Akt knockdown consistently reversed the changes of the key indicators of EMT in the pulmonary epithelia. Moreover, we found that the effects of Akt inhibition or knockdown on the CS/CSE-induced EMT acted via the TGF-ß1/Akt/Smad/mTOR and Akt/P38 MAPK pathways. Taken together, our data offer a novel perspective on the molecular mechanism of Akt for CS-induced EMT. This finding may enhance the understanding of the mechanism behind the synergistic use of a low dose of MK-2206 to achieve antitumor efficacy with reduced adverse reactions in patients with lung cancer and COPD.


Assuntos
Neoplasias Pulmonares/metabolismo , Pulmão/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/metabolismo , Animais , Células Cultivadas , Fumar Cigarros/efeitos adversos , Transição Epitelial-Mesenquimal , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia , Transdução de Sinais
10.
Hematology ; 23(5): 277-283, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29020881

RESUMO

OBJECTIVES: This study aimed to evaluate the effects of REGγ knockdown on the proliferation, apoptosis and migration of multiple myeloma (MM) cells, and reveal the potential regulatory mechanisms. METHODS: The expression of REGγ on myeloma cells of 28 MM patients was detected by Western blot. shRNA-REGγ-1 and shRNA-REGγ-2 were constructed to downregulate REGγ in RPMI-8226 cells. The proliferation, apoptosis and migration of transfected cells were analyzed by Cell Counting Kit 8 (CCK8), flow cytometry and transwell chamber, respectively. The expression of phosphorylated p65 (p-p65), p65, NF-kappa-B inhibitor ε (IkBε), matrix metalloproteinase 2 (MMP2), B-cell lymphoma xL (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) in transfected cells was detected by Western blot. Using cycloheximide (CHX), the half-life period of IkBε was detected by Western blot. RESULTS: The expression of REGγ was positive in myeloma cells. The proliferation and migration of RPMI-8226 cells were significantly inhibited by shRNA-REGγ-1/shRNA-REGγ-2, while the apoptosis rates were significantly increased (p < 0.05). The expression of p-p65 and IkBε was significantly reduced in RPMI-8226 cells transfected with shRNA-REGγ-1/shRNA-REGγ-2. The degradation of IkBε was significantly lower in RPMI-8226 cells transfected with shRNA-REGγ-1 than the control (longer half-life period). Besides, the expression of MMP2, Bcl-xL and XIAP in RPMI-8226 cells was significantly inhibited by shRNA-REGγ-1/shRNA-REGγ-2. DISCUSSION: Knockdown of REGγ may inhibit the proliferation and migration, and promote the apoptosis of RPMI-8226 cells possibly by downregulating NF-κB signal pathway.


Assuntos
Apoptose/genética , Autoantígenos/genética , Movimento Celular/genética , Proliferação de Células/genética , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Transdução de Sinais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoantígenos/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA , Adulto Jovem
11.
Biochim Biophys Acta Mol Basis Dis ; 1863(7): 1778-1788, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28428003

RESUMO

Cigarette smoke (CS) is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). Our previous studies have indicated that Rac1 is involved in lipopolysaccharide-induced pulmonary injury and CS-mediated epithelial-mesenchymal transition. However, the contribution of Rac1 activity to CS-induced lung inflammation remains not fully clear. In this study, we investigated the regulation of Rac1 in CS-induced pulmonary inflammation. Mice or 16HBE cells were exposed to CS or cigarette smoke extract (CSE) to induce acute inflammation. The lungs of mice exposed to CS showed an increase in the release of interleukin-6 (IL-6) and keratinocyte-derived chemokine (KC), as well as an accumulation of inflammatory cells, indicating high Rac1 activity. The exposure of 16HBE cells to CSE resulted in elevated Rac1 levels, as well as increased release of IL-6 and interleukin-8 (IL-8). Selective inhibition of Rac1 ameliorated the release of IL-6 and KC as well as inflammation in the lungs of CS-exposed mice. Histological assessment showed that treatment with a Rac1 inhibitor, NSC23766, led to a decrease in CD68 and CD11b positive cells and the infiltration of neutrophils and macrophages into the alveolar spaces. Selective inhibition or knockdown of Rac1 decreased IL-6 and IL-8 release in 16HBE cells induced by CSE, which correlated with CSE-induced Rac1-regulated Erk1/2 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3) signaling. Our data suggest an important role for Rac1 in the pathological alterations associated with CS-mediated inflammation. Rac1 may be a promising therapeutic target for the treatment of CS-induced pulmonary inflammation.


Assuntos
Fumar Cigarros/efeitos adversos , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuropeptídeos/metabolismo , Pneumonia/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Fumar Cigarros/genética , Fumar Cigarros/metabolismo , Citocinas/genética , Citocinas/metabolismo , Inflamação/etiologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/genética , Neuropeptídeos/genética , Infiltração de Neutrófilos/genética , Neutrófilos/metabolismo , Neutrófilos/patologia , Pneumonia/etiologia , Pneumonia/genética , Pneumonia/patologia , Fator de Transcrição STAT3/genética , Proteínas rac1 de Ligação ao GTP/genética
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(7): 594-8, 2016 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-27412540

RESUMO

OBJECTIVE: To investigate the cognitive characteristics in early school-age children with attention deficit hyperactivity disorder (ADHD) using event-related potential (ERP) and Achenbach Child Behavior Checklist (CBCL), as well as the correlation between ERP and behavioral problems. METHODS: A total of 22 children aged 6-7 years with ADHD and 19 healthy children matched by age were enrolled. Continue Performance Test-AX (CPT-AX) was performed for ERP test. The amplitude and latency of N2 and P3 of Go and Nogo were compared. The CBCL was completed by the parents, and the correlation between behavioral factors and ERP was analyzed. RESULTS: The ADHD group had a significantly higher number of ERP omissions than the normal control group (10±8 vs 5±4; P<0.05), while the reaction time and number of commission errors showed no significant differences between the two groups (P>0.05). The ADHD group showed a significantly lower Go-N2 amplitude than the normal control group (-8±5 µV vs -10±4 µV; P<0.05). In the ADHD group, the detection rates of hyperactivity, attack, and discipline violation were 27%, 27% and 9% respectively. The scores on attack and discipline violation subscales were negatively correlated with the Go-N2 amplitude of ERP (r=-0.43 and -0.48 respectively; P<0.05), while the score on hyperactivity subscale was positively correlated with the latency of Go-P3 (r=0.50, P<0.05). CONCLUSIONS: The early school-age children with ADHD show the tendency to the impairment of attention/executive function, but the inhibition function defect has not been noted. In early school-age children with ADHD, the behavioral problems such as hyperactivity, attack, and discipline violation are associated with ERP.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos do Comportamento Infantil/etiologia , Potenciais Evocados/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Humanos
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(6): 496-500, 2016 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-27324536

RESUMO

OBJECTIVE: To evaluate the effects of school entrance age on cognition and behaviors in children with attention deficit hyperactivity disorder (ADHD) using mathematical event-related potential (ERP), behavioral test, and Conners Parent Symptom Questionnaire (PSQ). METHODS: Fifty-eight ADHD children aged 7-12 years were enrolled and classified into older age and younger age groups according to the school entrance age (n=29 each). The children in the older age group were admitted at an age of 6 years and 6 months to 6 years and 11 months, and those in the younger age group were admitted at an age of 6 years to 6 years and 5 months. The ERP with a mathematical task was used to detect the difference in brain electrical activity between the two groups, and the behavioral test results were compared. The children's parents were asked to complete the PSQ, and the scores on each subscale were compared. RESULTS: The ERP detection showed that the older age group had a significantly higher P2 amplitude for wrong answers than the younger age group (10.9±5.0 µv vs 8.5±3.6 µv; P<0.05). The younger age group had a significantly shorter time of response to wrong answers than the older age group (619±340 ms vs 870±418 ms; P<0.05). The scores on the subscales of learning problems and impulse-hyperactivity of PSQ were significantly higher in the younger age group than in the older age group (P<0.05). CONCLUSIONS: School entrance age can affect cognition and behaviors in children with ADHD, and the ADHD children with a younger school entrance age have an obvious defect in executive function, especially the function of error detection, which leads to the prominent problems in impulse-hyperactivity and learning.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Potenciais Evocados/fisiologia , Fatores Etários , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Comportamento Infantil , Feminino , Humanos , Masculino
14.
Int Immunopharmacol ; 33: 90-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26881857

RESUMO

Oral and injection administration of ambroxol has been clinically used to treat airway disease. However, little is known about its potentials in inhalation therapy. In present studies, we tested the effects of ambroxol by inhalation with intravenous administration, and explored the underlying working mechanism. The mice received 10 cigarettes exposure every day for 4 days. Inhaled solution of ambroxol was aerosolized 20 min before the exposure of cigarette smoke (CS). The effect of ambroxol on the expression of mucoprotein 5 AC (MUC5AC) and proinflammatory cytokines in NCI-H292 cells stimulated with cigarette smoke extract (CSE). Four days of daily inhalation of ambroxol at 3.75 or 7.5mg/ml for 20 min suppressed the accumulation of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) and lung tissues, and inhibited increases in the mRNA and protein levels of tumor necrosis factor (TNF)-α, CCL-2 and KC, but not interleukin (IL)-1ß in the CS-exposed mice. Moreover, ambroxol at 3.75 or 7.5mg/ml facilitated airway mucosa cilia clearance, reduced glycosaminoglycans level in BALF and MUC5AC mRNA levels in lung tissues. The effects of ambroxol by inhalation at 7.5mg/ml was comparable to that of ambroxol at 20mg/kg i.v. and dexamethasone at 0.5mg/kg i.p. Using cultured lung epithelial cells, we demonstrated that pretreatment with ambroxol at 2 or 20 µM inhibited the CSE-induced up-regulation of MUC5AC, TNF-α, IL-1ß mRNA levels, which was through inhibiting Erk signaling pathway. Our results demonstrate the beneficial effects of ambroxol as an inhalation replace systemic administration for COPD therapy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ambroxol/uso terapêutico , Expectorantes/uso terapêutico , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Mucosa Respiratória/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Administração por Inalação , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos ICR , Mucina-5AC/genética , Mucina-5AC/metabolismo , Depuração Mucociliar/efeitos dos fármacos , Neutrófilos/imunologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Fumar/efeitos adversos
15.
Eur J Pharmacol ; 775: 138-48, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26872986

RESUMO

Ambroxol, a metabolite of bromhexine, is shown to exert several pharmacological activities, including secretolytic, anti-inflammatory and antioxidant actions. Oral and intravenous administration of ambroxol is useful for the airway inflammatory diseases. However, little is known about its potential in inhalation therapy for lipopolysaccharide (LPS)-induced mucous hypersecretion and inflammatory response. In the present study, we compared the pharmacological effects of ambroxol by inhalation with intravenous administration and preliminarily explored its mechanism of action. Our results demonstrated that ambroxol administered by inhalation inhibited MUC5AC expression, reduced glycosaminoglycan levels, enhanced the function of mucociliary clearance and promoted sputum excretion, suggesting that ambroxol increases expectoration of sputum by reducing its viscosity. Moreover, ambroxol significantly alleviated LPS-induced the influx of inflammatory cells and the extracellular signal-regulated kinase 1/2 (Erk 1/2) expression in lung tissues, and inhibited increases in the mRNA expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, CCL-2 (monocyte chemotactic protein-1), KC (keratinocyte cell protein) and interleukin (IL)-1ß in lung tissues. The secretolytic and anti-inflammatory effects of inhaled ambroxol at a dose of 7.5 mg/ml was comparable to that of ambroxol at 20 mg/ml i.v. and dexamethasone at 0.5 mg/kg i.p. In addition, we found that ambroxol dose-dependently inhibited LPS-induced increases in the mRNA expression of MUC5AC, TNF-α, and IL-1ß in human bronchial epithelial cell (NCI-H292) by inhibiting the Erk signaling pathway. These results demonstrate the beneficial effects of ambroxol in inhalation therapy for the airway inflammatory diseases.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ambroxol , Anti-Inflamatórios , Expectorantes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Administração por Inalação , Ambroxol/administração & dosagem , Ambroxol/farmacologia , Ambroxol/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Citocinas/genética , Expectorantes/administração & dosagem , Expectorantes/farmacologia , Expectorantes/uso terapêutico , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos Endogâmicos ICR , Mucina-5AC/genética , Depuração Mucociliar/efeitos dos fármacos , Muco/metabolismo , RNA Mensageiro/metabolismo
16.
PLoS One ; 10(6): e0128278, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26035589

RESUMO

Cytochrome P-450 epoxygenase (EPOX)-derived epoxyeicosatrienoic acids (EETs), 5-lipoxygenase (5-LO), and leukotriene B4 (LTB4), the product of 5-LO, all play a pivotal role in the vascular inflammatory process. We have previously shown that EETs can alleviate oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation in primary rat pulmonary artery endothelial cells (RPAECs). Here, we investigated whether ox-LDL can promote LTB4 production through the 5-LO pathway. We further explored how exogenous EETs influence ox-LDL-induced LTB4 production and activity. We found that treatment with ox-LDL increased the production of LTB4 and further led to the expression and release of both monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 (ICAM-1). All of the above ox-LDL-induced changes were attenuated by the presence of 11,12-EET and 14,15-EET, as these molecules inhibited the 5-LO pathway. Furthermore, the LTB4 receptor 1 (BLT1 receptor) antagonist U75302 attenuated ox-LDL-induced ICAM-1 and MCP-1/CCL2 expression and production, whereas LY255283, a LTB4 receptor 2 (BLT2 receptor) antagonist, produced no such effects. Moreover, in RPAECs, we demonstrated that the increased expression of 5-LO and BLT1 following ox-LDL treatment resulted from the activation of nuclear factor-κB (NF-κB) via the p38 mitogen-activated protein kinase (MAPK) pathway. Our results indicated that EETs suppress ox-LDL-induced LTB4 production and subsequent inflammatory responses by downregulating the 5-LO/BLT1 receptor pathway, in which p38 MAPK phosphorylation activates NF-κB. These results suggest that the metabolism of arachidonic acid via the 5-LO and EPOX pathways may present a mutual constraint on the physiological regulation of vascular endothelial cells.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Araquidonato 5-Lipoxigenase/química , Leucotrieno B4/metabolismo , Lipoproteínas LDL/farmacologia , Artéria Pulmonar/metabolismo , Receptores do Leucotrieno B4/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Western Blotting , Células Cultivadas , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Fosforilação/efeitos dos fármacos , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Leucotrieno B4/genética , Receptores do Leucotrieno B4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vasodilatadores/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Eur J Pharmacol ; 761: 161-7, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26003274

RESUMO

Inhaled corticosteroid (ICS) therapy in combination with long-acting ß-adrenergic agonists (LABA) is the most important treatment for allergic asthma, although the mechanism still remains unclear. However, mast cells play a central role in the pathogenesis of asthma. In this study, we explored the sole or synergetic effects of des-ciclesonide (ICS) and formoterol (LABA) on the cytokines IL-4 and IL-13 and on histamine release from mast cells (RBL-2H3 cells). We found that des-ciclesonide (0.1, 1 and 10nM) and formoterol (0.1, 1 and 10µM) alone attenuated DNP-BSA-induced IL-4 and IL-13 production, respectively, in a concentration-dependent manner in DNP-IgE-sensitized mast cells. Des-ciclesonide (0.2nM) and formoterol (1µM) alone also reduced histamine production. However, the combination of des-ciclesonide (0.2nM) and formoterol (1µM) had a synergistic inhibition effect on IL-4 mRNA expression and protein production but not IL-13 and histamine release. The JNK inhibitor SP600125 (10µM) inhibited antigen-induced mRNA expression and protein production of IL-4. Des-ciclesonide and formoterol alone inhibited the activation of JNK in a concentration-dependent manner, and the combination of des-ciclesonide (0.2nM) and formoterol (1µM) exhibited greater inhibition effect compared with des-ciclesonide (0.2nM) or formoterol (1µM) alone. Taken together, these synergistic effects on mast cells might provide the rationale for the development of the most recent ICS/LABA combination approved for asthma therapy.


Assuntos
Corticosteroides/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Dinitrofenóis/imunologia , Fumarato de Formoterol/farmacologia , Imunoglobulina E/imunologia , Interleucina-4/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mastócitos/efeitos dos fármacos , Pregnenodionas/farmacologia , Soroalbumina Bovina/imunologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Ativação Enzimática , Regulação da Expressão Gênica , Liberação de Histamina/efeitos dos fármacos , Interleucina-13/metabolismo , Interleucina-4/genética , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Mastócitos/enzimologia , Mastócitos/imunologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
18.
Eur J Pharmacol ; 727: 43-51, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24486707

RESUMO

Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor-κB (NF-κB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1µM). Furthermore, the endothelial receptor of lectin-like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100µg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-κB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IκBα, and activation of NF-κB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-κB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Inflamação/prevenção & controle , Lipoproteínas LDL/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Receptores Depuradores Classe E/efeitos dos fármacos , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Células Cultivadas , Sistema Enzimático do Citocromo P-450/metabolismo , Família 2 do Citocromo P450 , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Ativação Enzimática , Inflamação/genética , Inflamação/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação , Artéria Pulmonar/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores Depuradores Classe E/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Biochim Biophys Acta ; 1840(6): 1838-49, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24508121

RESUMO

BACKGROUND: Epithelial-mesenchymal transition (EMT) is the major pathophysiological process in lung fibrosis observed in chronic obstructive pulmonary disease (COPD) and lung cancer. Smoking is a risk factor for developing EMT, yet the mechanism remains largely unknown. In this study, we investigated the role of Rac1 in cigarette smoke (CS) induced EMT. METHODS: EMT was induced in mice and pulmonary epithelial cells by exposure of CS and cigarette smoke extract (CSE) respectively. RESULTS: Treatment of pulmonary epithelial cells with CSE elevated Rac1 expression associated with increased TGF-ß1 release. Blocking TGF-ß pathway restrained CSE-induced changes in EMT-related markers. Pharmacological inhibition or knockdown of Rac1 decreased the CSE exposure induced TGF-ß1 release and ameliorated CSE-induced EMT. In CS-exposed mice, pharmacological inhibition of Rac1 reduced TGF-ß1 release and prevented aberrations in expression of EMT markers, suggesting that Rac1 is a critical signaling molecule for induction of CS-stimulated EMT. Furthermore, Rac1 inhibition or knockdown abrogated CSE-induced Smad2 and Akt (PKB, protein kinase B) activation in pulmonary epithelial cells. Inhibition of Smad2, PI3K (phosphatidylinositol 3-kinase) or Akt suppressed CSE-induced changes in epithelial and mesenchymal marker expression. CONCLUSIONS AND GENERAL SIGNIFICANCE: Altogether, these data suggest that CS initiates EMT through Rac1/Smad2 and Rac1/PI3K/Akt signaling pathway. Our data provide new insights into the fundamental basis of EMT and suggest a possible new course of therapy for COPD and lung cancer.


Assuntos
Transição Epitelial-Mesenquimal , Neuropeptídeos/fisiologia , Nicotiana/efeitos adversos , Alvéolos Pulmonares/patologia , Fumaça/efeitos adversos , Proteínas rac1 de Ligação ao GTP/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteína Smad2/fisiologia , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/biossíntese
20.
Int Immunopharmacol ; 18(2): 358-64, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24389380

RESUMO

Glycopyrronium bromide (GB) is a muscarinic receptor antagonist that has been used as a long-acting bronchodilator in chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to investigate the anti-inflammatory activity of inhaled GB in a cigarette smoke-induced acute lung inflammation mouse model. We found that aerosol pre-treatment with GB suppresses the accumulation of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) in cigarette smoke (CS)-exposed mice. GB at doses of 300 and 600 µg/ml significantly inhibited the CS-induced increases in the mRNA and protein expression levels of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1 and transforming growth factor (TGF)-ß1 in lung tissues and the BALF. Moreover, GB at a dose of 600 µg/ml significantly inhibited the CS-induced changes in glutathione (GSH) and myeloperoxidase (MPO) activities in the BALF, decreased the CS-induced expression of matrix metalloproteinases (MMP)-9, and increased the CS-induced expression of tissue inhibitor of metalloproteinases (TIMP)-1, as determined through the immunohistochemical staining of lung tissue. Our results demonstrate the beneficial effects of inhaled GB on the inflammatory reaction in COPD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Glicopirrolato/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Glicopirrolato/farmacologia , Linfócitos/imunologia , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/imunologia , Camundongos , Camundongos Endogâmicos ICR , Antagonistas Muscarínicos/farmacologia , Neutrófilos/imunologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumaça , Inibidor Tecidual de Metaloproteinase-1/imunologia , Nicotiana
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