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1.
Org Lett ; 25(16): 2846-2851, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37058279

RESUMO

A photocatalyzed coupling-cyclization of sila-enynes with thiosulfonates has been developed. This reaction provides an efficient strategy to assemble thiosulfone-bifunctionalized benzosilacycles via sequential radical addition and radical coupling.

2.
PeerJ ; 10: e13908, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36032960

RESUMO

Background: Lung adenocarcinoma (LUAD) is a major type of lung cancer with poor prognosis and low 5-year survival rate, which urgently needs further investigation in order to elucidate its mechanisms completely and discover novel therapeutic targets. C1orf74 is a novel protein with unknown function either in normal cells or cancer cells. The aim of this study is to investigate the expression and function of C1orf74 in LUAD cells. Methods: The expression of C1orf74 in LUAD was analyzed using the LUAD datasets from public databases. The prognostic value of C1orf74 in LUAD was analyzed using Kaplan-Meier Plotter. C1orf74 expression in LUAD cell line A549, H1993 and HCC827 was silenced using small interfering RNA, and then the effects of C1orf74 knockdown on proliferation, migration and invasion of LUAD cells were detected by colony formation assay and Transwell assay, the role of C1orf74 in EGFR/AKT/mTORC1 signaling pathway was examined by Western blot, and the function of C1orf74 in cell cycle was detected by flow cytometry. Results: The results of LUAD clinical data showed that C1orf74 was upregulated in LUAD tissues, and its high expression was associated with poor prognosis. The results from cultured LUAD cells demonstrated that C1orf74 knockdown inhibited cell proliferation, migration and invasion, but induced cell cycle arrest and autophagy. Moreover, C1orf74 knockdown suppressed EGFR/AKT/mTORC1 signaling in LUAD cells. In conclusion, the present study revealed that C1orf74 is upregulated in LUAD tissues and plays an oncogenic role in LUAD, and that C1orf74 positively regulates cell proliferation and mobility through the EGFR/AKT/mTORC1 signaling pathway in LUAD cells.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Transdução de Sinais/genética , Receptores ErbB/genética
3.
Exp Ther Med ; 23(4): 252, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35261624

RESUMO

The ectopic expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been demonstrated to facilitate tumorigenesis and induce proliferation in a various types of cancer. However, the role of IGF2BP2 in esophageal squamous cell carcinoma (ESCC) has yet been fully elucidated. In this regard, the current study assessed the expression patterns and clinical significance of IGF2BP2 in 94 Chinese patients diagnosed with ESCC. Immunohistochemistry and reverse transcription-quantitative PCR assays were employed to assess IGF2BP2 expression in ESCC tissues compared with adjacent healthy tissues. The results revealed that the protein expression of IGF2BP2 was substantially upregulated in ESCC tissues compared with adjacent ESCC tissues. More specifically, higher IGF2BP2 expression strongly associated with tumor node metastasis stage, lymphatic infiltration and lymph node metastasis. Using two ESCC cell lines (TE-1 and TE-10), the inhibition of IGF2BP2 expression by small interfering RNA was proven to induce apoptosis and suppress proliferation, migration and cell cycle progression in vitro. Collectively, the present findings indicated that IGF2BP2 may serve a major role in the development of ESCC carcinogenesis. The present study may be helpful in the design of potential drug targets in the treatment of ESCC.

4.
Acta Cardiol ; 77(5): 375-384, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34582317

RESUMO

BACKGROUND: Congenital heart disease (CHD) is the most universal congenital defect disease. This study explores the interrelationship between miR-23b and GTAT6 in the development of CHD. METHODS: We collected clinical samples and constructed in vitro cell models to evaluate the expression of miR-23b, GATA6, and IGF-1. CHD cell models were constructed by hypoxia in H9C2 cells. The expression levels of GATA6 and IGF-1 in H9C2 cells were determined by western blot and qPCR. MiR-23b was knocked down by transfection miR-23b inhibitor. GATA6 knockdown or overexpression vectors were established by the lentiviral approach and cell transfection, respectively. According to the CCK-8 assay and flow cytometry analysis, the proliferation and apoptosis of H9C2 cells were detected. The binding relationship between GATA6 and miR-23b was detected by luciferase reporter assay. RESULTS: The expression level of miR-23b was escalated abnormally, while the expression levels of GATA6 and IGF-1 were decreased in the serum of CHD clinical patients and cell models. miR-23b knockdown in H9C2 cells could up-regulate the expression of GATA6, thus improved the proliferation and decreased apoptosis of H9C2 cells. Overexpression of GATA6 could up-regulate IGF-1 to promote proliferation and inhibit apoptosis in H9C2 cells. MiR-23b could target GATA6 and regulated IGF-1, thus affecting cell proliferation and apoptosis. CONCLUSION: The expression level of miR-23b was remarkably up-regulated in serum of CHD patients and H9C2 cells in vitro, while the expression of GATA6 and IGF-1 was significantly decreased. MiR-23b could influence the proliferation and apoptosis of cardiomyocytes by targeting the down-regulation of the GATA6/IGF-1 axis.


Assuntos
Fator de Transcrição GATA6/metabolismo , Cardiopatias Congênitas , Fator de Crescimento Insulin-Like I/metabolismo , MicroRNAs/metabolismo , Apoptose , Fator de Transcrição GATA6/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , MicroRNAs/genética , Miócitos Cardíacos/metabolismo
5.
Exp Ther Med ; 21(6): 625, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33936282

RESUMO

The NICE-3 protein serves an oncogenic role in hepatocellular carcinoma, but its role in lung adenocarcinoma (LUAD) remains unknown. The aim of the present study was to investigate the potential role and underlying mechanisms of NICE-3 in LUAD. In the present study, NICE-3 expression in LUAD tissues and its association with patient prognosis were analyzed using datasets from The Cancer Genome Atlas and Gene Express Omnibus. After NICE-3-knockdown with small interfering RNA in LUAD cells, cell proliferation was measured by cell counting, cell cycle was examined by flow cytometry, cell invasion and migration were detected by Transwell assays and autophagic markers LC3 and p62, as well as phosphorylation of S6K and AKT, were determined by western blotting. The results of public database analysis demonstrated that compared with normal lung tissues, NICE-3 expression was increased in LUAD tissues, where high expression levels were associated with a poor prognosis. The results of in vitro experimentation in LUAD cells indicated that NICE-3-knockdown inhibited proliferation, cell cycle, migration and invasion, but enhanced autophagy. Notably, NICE-3-knockdown inhibited AKT/mTORC1 signaling. The present results suggested that NICE-3 may serve an oncogenic role in LUAD via the AKT/mTORC1 signaling pathway and may therefore be a potential therapeutic target for LUAD.

6.
J Med Chem ; 64(9): 5485-5499, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33861929

RESUMO

Anticancer agents that present nonapoptotic cell death pathways are required for treating apoptosis-resistant pancreatic cancer. Here, we synthesized three fluorescent dithiocarbazate-copper complexes, {[CuII(L)(Cl)] 1, [CuII2(L)2(NO3)2] 2, and [CuII2CuI(L)2(Br)3] 3}, to assess their antipancreatic cancer activities. Complexes 1-3 showed significantly greater cytotoxicity toward several pancreatic cancer cell lines with better IC50 than those of the HL ligand and cisplatin. Confocal fluorescence imaging showed that complex 3 was primarily localized in the mitochondria. Primarily, compound 3 also can be applied to in vivo imaging. Further studies revealed that complex 3 kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex 3 is the first copper complex to evoke cellular events consistent with ferroptosis in cancer cells. Finally, it significantly retarded the ASPC-1 cells' growth in a mouse xenograft model.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Cobre/química , Hidrazinas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Ferroptose/efeitos dos fármacos , Meia-Vida , Humanos , Hidrazinas/uso terapêutico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Mitocôndrias/química , Mitocôndrias/metabolismo , Conformação Molecular , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Transplante Heterólogo
7.
Oncol Lett ; 21(4): 330, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33692862

RESUMO

Methyltransferase-like 1 (METTL1) is a transfer RNA and microRNA modifying enzyme. However, its role in lung adenocarcinoma (LUAD) remains unknown. The present study aimed to investigate the effect of METTL1 in LUAD and determine the association between METTL1 expression and prognosis of patients with LUAD. The expression profile of METTL1 in LUAD tissues was downloaded from public cancer databases and analyzed using the Gene Expression Profiling Interactive Analysis database and UALCAN online software. In addition, the association between METTL1 expression and prognosis of patients with LUAD was assessed using the Kaplan-Meier Plotter software. The effect of METTL1 in the A549 cell line was determined in vitro via overexpression and knockdown experiments. The results demonstrated that METTL1 was upregulated in LUAD tissues, and its increased expression was associated with unfavorable prognosis. Furthermore, METTL1 promoted proliferation and colony formation of A549 cells, and inhibited autophagy via the AKT/mechanistic target of rapamycin complex 1 signaling pathway. Taken together, the results of the present study suggest that METTL1 acts as an oncogene in LUAD, thus may be a potential prognostic predictor and therapeutic target for LUAD.

8.
Oncol Lett ; 21(4): 334, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33692866

RESUMO

Melanocyte proliferating gene 1 (MYG1) is an exonuclease that participates in RNA processing and is required for normal mitochondrial function. However, its role in tumorigenesis remains unknown. The present study aimed to investigate the role of MYG1 and its underlying mechanisms in human lung adenocarcinoma (LUAD). The expression levels of MYG1 in tumor tissues of patients with LUAD were obtained from public cancer databases and analyzed using the UALCAN online software. The association between MYG1 expression levels and the prognosis of patients with LUAD was analyzed using the Kaplan-Meier plotter. In addition, the role of MYG1 in the LUAD A549 and H1993 cell lines was determined by knocking down MYG1 expression with a specific small interfering RNA or by overexpressing it with a MYG1-containing plasmid. The results demonstrated that MYG1 expression levels were upregulated in LUAD tissues compared with those in normal lung tissues from healthy subjects, and high MYG1 expression levels were associated with an unfavorable prognosis. MYG1 promoted the proliferation, migration and invasion of A549 and H1993 cells. In addition, MYG1 inhibited autophagy via the AMP-activated protein kinase/mTOR complex 1 signaling pathway. Collectively, the present results suggested that MYG1 may serve an oncogenic role in LUAD and may be a potential therapeutic target for LUAD.

9.
J Cell Mol Med ; 24(22): 13303-13313, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33021072

RESUMO

DEP domain containing 1(DEPDC1) is involved in the tumorigenesis of a variety of cancers. But its role in tumorigenesis of lung adenocarcinoma (LUAD) is not fully understood. Here, we investigated the role and the underlying mechanisms of DEPDC1 in the development of LUAD. The expression and prognostic values of DEPDC1 in LUAD were analysed by using the data from public databases. Gene enrichment in TCGA LUAD was analysed using GSEA software with the pre-defined gene sets. Cell proliferation, migration and invasion of A549 cells were examined with colony formation, Transwell and wound healing assays. The function of DEPDC1 in autophagy and RAS-ERK1/2 signalling was determined with Western blot assay upon DEPDC1 knockdown and/or overexpression in A549, HCC827 and H1993 cells. The results demonstrated that DEPDC1 expression was up-regulated in LUAD tissues, and its high expression was correlated with unfavourable prognosis. The data also showed that DEPDC1 knockdown impaired proliferation, migration and invasion of A549 cells. Most notably, the results showed that DEPDC1 up-regulated RAS expression and thus enhanced ERK1/2 activity, through which DEPDC1 could inhibit autophagy. In conclusion, our study revealed that DEPDC1 is up-regulated in LUAD tissues and plays an oncogenic role in LUAD, and that DEPDC1 inhibits autophagy through the RAS-ERK1/2 signalling in A549, HCC827 and H1993 cells.


Assuntos
Adenocarcinoma/metabolismo , Autofagia , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas ras/metabolismo , Células A549 , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Fosforilação , Prognóstico , Transdução de Sinais , Regulação para Cima
10.
Exp Ther Med ; 18(5): 4157-4164, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602251

RESUMO

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a newly identified cytosolic DNA sensor, but its function in lung epithelial cells is relatively unknown. In the present study, the effects of lipopolysaccharide (LPS) on the expression and function of cGAS in the A549 lung epithelial cell line was investigated. The cells were treated with LPS at different concentrations (e.g., 100, 200, 400 and 800 ng/ml), and the cGAS expression levels were examined via western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The cells were pretreated with LPS, followed by E. coli DNA transfection using Lipofectamine® 3000. After 24 h, interferon (IFN)-ß production was measured using ELISA and the expression of the autophagic markers, microtubule-associated proteins 1A/1B light chain 3 and sequestosome-1, were determined using western blot analysis. The cells were also pretreated with either a toll-like receptor (TLR) 4 inhibitor, a serine/threonine-protein kinase TBK1 (TBK1) inhibitor or an nuclear factor (NF)-κB inhibitor, followed by LPS treatment, and the cGAS expression levels were examined via western blot analysis and RT-qPCR. The result showed that LPS treatment upregulated cGAS expression in a dose-dependent manner. E. coli DNA treatment could induce IFN-ß production and autophagy via cGAS, which was enhanced by LPS pretreatment. The effect of LPS on cGAS expression was suppressed by treatment with a TLR4 inhibitor, a TBK1 inhibitor and an NF-κB inhibitor. In conclusion, LPS enhances DNA-induced IFN-ß production and autophagy by upregulating cGAS expression through the myeloid differentiation primary response protein MyD88-independent TLR4 signaling pathway in A549 cells.

11.
Exp Cell Res ; 384(1): 111545, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31470016

RESUMO

Cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD) and dampens antiviral response, which increases viral infections and leads to COPD acute exacerbation (AECOPD). Adenovirus, a nonenveloped DNA virus, is linked with AECOPD, whose DNAs trigger innate immune response via interacting with pattern recognition receptors (PRRs). Stimulator of interferon genes (STING), as a cytosolic DNA sensor, participates in adenovirus-induced interferon ß (IFNß)-dependent antiviral response. STING is involved in various pulmonary diseases, but role of STING in pathogenesis of AECOPD is not well documented. In the present study, we explored relationship between STING and AECOPD induced by recombinant adenovirus vectors (rAdVs) and CS in wild type (WT) and STING-/- mice; and also characterized the inhibition of STING- IFNß pathway in pulmonary epithelium exposed to cigarette smoke extract (CSE). We found that CS or CSE exposure alone dramatically inhibited STING expression, but not significantly effected IFNß production. Moreover, CS or CSE-exposed significantly suppressed activation of STING-IFNß pathway induced by rAdVs and suppressed clearance of rAdVs DNA. Inflammation, fibrosis and emphysema of lung tissues were exaggerated when treated with CS plus rAdVs, which further deteriorate in absences of STING. In A549 cells with knockdown of STING, we also observed enhancing apoptosis related to emphysema, especially CSE and adenovirus vectors in combination. Therefore, STING may play a protective role in preventing the progress of COPD.


Assuntos
Infecções por Adenoviridae/genética , Vetores Genéticos/genética , Interferon beta/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Células A549 , Adenoviridae/efeitos dos fármacos , Infecções por Adenoviridae/tratamento farmacológico , Animais , Linhagem Celular , Linhagem Celular Tumoral , Vetores Genéticos/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Pulmão/efeitos dos fármacos , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/virologia , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/genética , Enfisema Pulmonar/virologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fumar/efeitos adversos
12.
Oncol Lett ; 16(1): 949-955, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29963168

RESUMO

A previous study revealed that DEP domain containing 1 (DEPDC1) is involved in the carcinogenesis of bladder cancer via forming a complex with zinc finger protein 224 (ZNF224) to suppress A20 expression, resulting in the activation of the nuclear factor (NF)-κB signaling pathway; however, the role of DEPDC1 in liver cancer remains unclear. Hep G2 cells were treated with 11R-DEP: 611-628, a peptide capable of disrupting the DEPDC1-ZNF224 complex. Cell proliferation was examined using an MTT assay and apoptosis was analyzed via detection of the apoptotic marker caspase-3 using western blot analysis. A20 expression was examined via reverse transcription-quantitative polymerase chain reaction and NF-κB subcellular localization was determined via immunofluorescence staining. microRNA (miR)-130a was overexpressed in HepG2 cells and its effects on proliferation and apoptosis were examined. The results demonstrated that 11R-DEP: 611-628 (3 µM) and miR-130a inhibited cell proliferation and promoted apoptosis in HepG2 cells by activating A20 expression, which blocks the nuclear transportation of NF-κB. In addition, the results demonstrated that the 11R-DEP: 611-628 (3 µM) treatment resulted in downregulation of DEPDC1 expression, indicating that DEPDC1 expression is regulated by the DEPDC1-ZNF224 complex. In conclusion, the data indicated that DEPDC1 suppresses apoptosis to promote cell proliferation through the NF-κB signaling pathway in HepG2 cells and that DEPDC1 is a potential target for the treatment of liver cancer.

13.
Exp Cell Res ; 363(2): 291-298, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29355493

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal and progressive fibro-proliferative lung disease, and fibroblast-to-myofibroblast differentiation is a crucial process in the development of IPF. Elongation factor-2 kinase (eEF2K) has been reported to play an important role in various disease types, but the role of eEF2K in IPF is unknown. In this study, we investigated the role of eEF2K in normal lung fibroblast (NHLF) proliferation, differentiation, apoptosis, and autophagy as well as the interaction between eEF2K and p38 MAPK signaling through in vitro experiments. We found that the inhibition of eEF2K markedly augmented cell proliferation and differentiation, suppressed apoptosis and autophagy, and reversed the anti-fibrotic effects of a p38 MAPK inhibitor. Together, our results indicate that eEF2K might inhibit TGF-ß1-induced NHLF proliferation and differentiation and activate NHLF cell apoptosis and autophagy through p38 MAPK signaling, which might ameliorate lung fibroblast-to-myofibroblast differentiation.


Assuntos
Quinase do Fator 2 de Elongação/metabolismo , Fibroblastos/metabolismo , Miofibroblastos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Autofagia/efeitos dos fármacos , Diferenciação Celular/fisiologia , Sobrevivência Celular , Células Cultivadas , Humanos , Pulmão/metabolismo
14.
Onco Targets Ther ; 10: 4443-4454, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979136

RESUMO

Ectopic expression of DEP domain containing 1 (DEPDC1) in lung adenocarcinomas is associated with poor prognosis, but its role and the underlying mechanism remain unknown. In this study, DEPDC1 expression in lung cancer cell lines was examined with Western blot assay, and DEPDC1-positive cell A549 was selected for further experiments. DEPDC1 inhibitor miR-130a was overexpressed in A549 cells, and the proliferation and apoptosis of these cells were analyzed with cell counting and flow cytometry assay. Interfering peptide 11R-DEP:611-628 and JNK inhibitor SP600125 were used alone or in combination to treat A549 cells, and the cell proliferation and apoptosis were assessed by flow cytometry assay; caspase 3 and cleaved caspase 3, phosphor-JNK, and total JNK were detected by Western blotting; and nuclear factor kappa B (NF-κB) localization was determined by immunofluorescence staining. We found that miR-130a and 11R-DEP:611-628 peptides (5 µM) both inhibited A549 proliferation and induced apoptosis. We observed that 11R-DEP:611-628 peptide treatment resulted in elevated A20 expression, dramatically reduced nuclear NF-κB, and increased phosphor-JNK. These findings indicate that DEPDC1 inhibits apoptosis of A549 cell by suppressing A20 expression to regulate NF-κB activity, and that JNK plays a protective role upon 11R-DEP:611-628 peptide treatment. In conclusion, DEPDC1 might be a novel therapeutic target for lung cancer, and the 11R-DEP:611-628 peptide is a potent apoptosis inducer in A549 cells.

15.
Mol Med Rep ; 16(3): 3111-3116, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28714001

RESUMO

The aim of the present study was to investigate the role of the Toll­like receptor (TLR)4 signaling pathway in cellular response to lipopolysaccharide (LPS) in rat pulmonary artery smooth muscle cells (PASMCs). Chronic obstructive pulmonary disease (COPD) rats were established with passive inhaling cigarette smoke plus injection of LPS. The TLR4 protein in lung tissues was determined with immunohistochemical staining and protein levels of the components of the TLR4 pathway in PASMCs were analyzed with western blotting. The production of interferon (IFN)­Î³ upon LPS stimulation in PASMCs was measured with ELISA. TLR4 expression in lung tissue from COPD rats was increased obviously compared with that in normal group. LPS enhances TLR4 expression in rat PASMCs and induced production of IFN­Î³ dramatically. LPS treatment resulted in increased phosphor­interleukin­1 receptor­associated kinase (IRAK), IκB and IκB kinase, as well as the total protein of nuclear factor (NF)­κB p65. TLR4 inhibitor TAK­242, IRAK1/4 inhibitor and NF­κB inhibitor Bay 117082 were capable of suppressing the effects of LPS. TLR4 signaling pathway is functional in PASMCs, and may be involved in the inflammatory response during the pathogenesis of COPD.


Assuntos
Interferon gama/biossíntese , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Artéria Pulmonar/patologia , Receptor 4 Toll-Like/metabolismo , Animais , Feminino , Pulmão/patologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Nitrilas/farmacologia , Doença Pulmonar Obstrutiva Crônica/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonas/farmacologia
16.
Exp Ther Med ; 14(1): 561-566, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28672967

RESUMO

The present study aimed to determine the underlying molecular mechanism of the antifibrotic effect of artesunate in pulmonary fibrosis (PF). Primary lung fibroblasts were isolated from the lung tissues of rats, and treated with artesunate (8 µg/ml) and transforming growth factor (TGF)-ß1 (5 ng/ml). For in vivo experiments, the rats were administered bleomycin intratracheally, followed by daily intraperitoneal artesunate injections for 27 days. Western blotting, and immunohistochemical and immunofluorescent staining were used to assess the expression of key components of the Notch signaling pathway, including α-smooth muscle actin (α-SMA) and type IV collagen. Artesunate (8 µg/ml) was identified to inhibit TGF-ß1-induced α-SMA and collagen protein expression, and repress the Notch signaling pathway, in primary lung fibroblasts. Downregulation of α-SMA and collagen by artesunate was associated with inhibition of the Notch signaling pathway. The daily intraperitoneal injection of artesunate (1 mg/kg) in rats was determined to inhibit bleomycin-induced overexpression of α-SMA and type IV collagen proteins, and inhibit the Notch signaling pathway, in lung tissues. In conclusion, the results of the current study indicate that artesunate inhibits the TGF-ß1-induced differentiation of rat primary lung fibroblasts into myofibroblasts and ameliorates bleomycin-induced PF. In addition, the results of the present study suggest that the underlying molecular mechanism for these effects of artesunate is repression of the Notch signaling pathway.

17.
Acta Biochim Biophys Sin (Shanghai) ; 47(12): 981-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26525950

RESUMO

In the present study, paclitaxel (PTX) were encapsulated with polyethylene glycol (PEG)-polylactide (PLA)/D-α tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-PLA/TPGS) and the enhanced anti-tumor activity of this PTX mixed micelles (PTX-MM) was evaluated in lung cancer cells. The PTX-MM prepared by a solvent evaporation method was demonstrated to have high drug-loading efficiency (23.2%), high encapsulation efficiency (76.4%), and small size (59 nm). In vitro release assay showed the slow release behavior of PTX-MM, suggesting the good stability of the PTX-MM essential for long circulation time. In vitro kinetics assay demonstrated that PTX-MM could promote absorption and increase relative bioavailability. The anti-cancer efficiency of PTX-MM was also examined by both in vitro and in vivo studies. PTX-MM exhibits obvious cytotoxicity against lung cancer cells with much lower IC50 value when compared with commercial formulated PTX or PTX + TPGS. The xenograft tumor model studies on nude mice indicated that PTX-MM inhibits tumor growth more effectively than other formulations. It was also found that most of mixed micelles were integral in tumor site to exhibit anti-cancer activity. Our results suggested that the use of PTX-MM as an anti-cancer drug may be an effective approach to treat lung cancer.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Paclitaxel/administração & dosagem , Células A549 , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Solventes/química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Med Rep ; 12(1): 1291-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25816117

RESUMO

The present study aimed to determine whether artesunate has beneficial effects on bleomycin-induced pulmonary fibrosis in rats and to examine the possible mechanisms underlying these effects. All experiments were performed with male Sprague Dawley rats weighing 180-250 g. Animals were randomly divided into four experimental groups that were administered either saline alone, artesunate alone, bleomycin alone or bleomycin + artesunate. Lung histopathology was investigated by hematoxylin and eosin staining and Masson staining. Lung profibrotic molecules were analyzed by reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry. In rats treated with artesunate, pulmonary fibrosis induced by bleomycin was significantly reduced. Administration of artesunate significantly improved bleomycin-induced morphological alterations. Profibrotic molecules, including transforming growth factor-ß1, Smad3, heat shock protein 47, α-smooth muscle actin and collagen type I were also reduced by artesunate. These findings suggest that artesunate improves bleomycin-induced pulmonary fibrosis pathology in rats possibly by inhibiting profibrotic molecules associated with pulmonary fibrosis.


Assuntos
Artemisininas/farmacologia , Pulmão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Actinas/antagonistas & inibidores , Actinas/genética , Actinas/metabolismo , Animais , Artesunato , Bleomicina , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP47/antagonistas & inibidores , Proteínas de Choque Térmico HSP47/genética , Proteínas de Choque Térmico HSP47/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
19.
Biomed Rep ; 3(2): 225-229, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25798247

RESUMO

Our previous study revealed that serum deprivation upregulated human alkaline ceramidase 2 (haCER2) activity and mRNA in HeLa cells, but the mechanism remains unknown. In the present study, serum deprivation also upregulated haCER2 activity in HepG2 human hepatoma cell line cells due to an increase in haCER2 mRNA, in which mRNA transcription, not mRNA stability, is involved. Furthermore, p38 mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathway is involved in haCER2 mRNA upregulation by serum deprivation, and this mechanism may explain why haCER2 is upregulated in human liver cancer. In conclusion, p38 MAPK, AP-1 or haCER2 may be used as targets in liver cancer therapy.

20.
Oncol Lett ; 10(6): 3629-3634, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26788181

RESUMO

Lung cancer is the most frequent cancer worldwide, in terms of incidence and mortality. Due to challenges in the diagnosis of the disease, the 5-year overall survival rate is only ~16%. Previous studies have suggested that malignant transformations originate from adult stem cells, and malignant lesions may therefore express stem-cell-associated markers. The purpose of the present study is to investigate the expression and clinical significance of the stem cell-associated markers Sal-like protein 4 (SALL4) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in lung cancer, and to provide novel diagnostic markers and targets for the treatment of lung cancer. The expression of the stem cell-associated markers SALL4 and LGR5 was analyzed by immunohistochemistry performed on 135 human lung cancer tissue specimens and 10 non-cancer lung tissue specimens. The clinical significance of the expression of these markers and correlation between their expression and clinical parameters was also assessed. SALL4 expression was highly upregulated in lung cancer tissues, but was not present in non-cancerous lung tissues, and the sensitivity and specificity of SALL4 reached 88% and 100%, respectively. By contrast, LGR5 demonstrated 97% sensitivity, but the specificity was poor. Therefore, SALL4 may be an extremely useful diagnostic marker for lung cancer, but LGR5 is not as useful.

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