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1.
Int Immunopharmacol ; 90: 107200, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33246825

RESUMO

Hypertrophic scar (HS) is a dermal fibroproliferative disease that often occurs following abnormal wound healing. To date, there is no satisfied treatment strategies for improvement of scar formation with few side effects. The effects of gambogenic acid (GNA) on scar hypertrophy has not been studied previously. The present study was undertaken to find out the scar-reducing effects of GNA (0.48, 0.96 or 1.92 mg/ml) on skin wounds in rabbit ears. Scar evaluation index (SEI), collagen I (Col1) and collagen III (Col3), microvascular density (MVD), CD4+T cells and macrophages, vascular endothelial growth factor receptor 2 (VEGFR2), fibroblast growth factor receptor 1 (FGFR1), phospho-VEGFR 2 (p-VEGFR2) and p-FGFR1, interleukin (IL)-1ß, IL-6, IL-10 and tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1 and connective tissue growth factor (CTGF) in scar tissue were detected using various methods, respectively. Our data showed that GNA significantly reduced SEI, and the expression of Col1 and Col3 in scar tissue in a concentration-dependent manner. Also, it decreased MVD, the infiltration of CD4+T cells and macrophages, and the levels of VEGFR2, p-VEGFR2, FGFR1, p-FGFR1, TGF-ß1, CTGF, IL-1ß, IL-6, TNF-α, in addition to upregulated IL-10 in scar tissue. As a result, this study revealed that GNA reduced HS formation, which was associated with the inhibition of neoangiogenesis, local inflammatory response and growth factor expression in scar tissue during wound healing. These findings suggested that GNA may be considered as a preventive and therapeutic candidate for HS.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Cicatriz Hipertrófica/prevenção & controle , Neovascularização Fisiológica/efeitos dos fármacos , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Xantenos/farmacologia , Proteínas Angiogênicas/metabolismo , Animais , Cicatriz Hipertrófica/imunologia , Cicatriz Hipertrófica/metabolismo , Cicatriz Hipertrófica/patologia , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Orelha , Feminino , Mediadores da Inflamação/metabolismo , Masculino , Coelhos , Transdução de Sinais , Pele/imunologia , Pele/metabolismo , Pele/patologia , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
2.
Int Immunopharmacol ; 83: 106418, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199349

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by synovial inflammation and hyperplasia resulting from an imbalance between the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs). Our previous study found that sorafenib had inhibitory effects in rats with adjuvant arthritis (AA). The present study investigated the role of sorafenib in the induction of AA FLS apoptosis in vitro. FLSs obtained from AA rats were cultured in vitro and identified. Cell apoptosis was detected using terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) labeling methods. Real-time PCR and Western blotting assays were used to quantify the expression levels of Fas, Caspase-3, Mcl-1, NF-κB and C-jun gene products in AA FLSs. Our data revealed that sorafenib (4 µmol/L) induced apoptosis in AA FLSs, and flow cytometry analysis showed that AA FLSs treated with sorafenib (4 µmol/L) in vitro accumulated in early and late apoptosis. There were significant increases in the expression levels of Fas, Caspase-3 and Mcl-1, and significant decreases in NF-κB and C-jun expression in AA FLSs treated with sorafenib. In summary, these results demonstrate that sorafenib promotes AA FLS apoptosis, which may be related to the upregulation of Fas and Caspase-3 and downregulation of NF-κB and C-jun. All of these findings suggest that sorafenib exerts an inhibitory effect on AA rats in vivo via AA FLS apoptotic induction, which has potential therapeutic implications for RA.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Experimental/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Sinoviócitos/efeitos dos fármacos , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Artrite Experimental/tratamento farmacológico , Caspase 3/metabolismo , Células Cultivadas , Adjuvante de Freund/toxicidade , Masculino , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos , Ratos Sprague-Dawley , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Receptor fas/metabolismo
3.
Anat Rec (Hoboken) ; 301(9): 1519-1526, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29752865

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane of joints. In this study, we aimed to investigate whether sorafenib exerts antiarthritic effects on RA in vivo. Adjuvant arthritis (AA) was induced (day 0) in male Sprague-Dawley rats by intradermal injection of 0.1 mL of complete Freund's complete adjuvant into the left hind paw. Sorafenib (10, 20, or 40 mg/kg/day) was administered intragastrically from day 10 to 24. Body weight, paw volume, synovial inflammation, and tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-10, and IL-17 serum levels were detected. In addition, microvascular density (MVD) and the expression of vascular endothelial growth factor receptor 2 (VEGFR-2) and fibroblast growth factor receptor 1 (FGFR-1) in synovial tissues were analyzed. Our data revealed that sorafenib administration led to significant body weight gain in AA rats but suppressed paw swelling, synovial hyperplasia, and inflammatory infiltration. Furthermore, it decreased TNF-α, IL-1ß, and IL-17 serum levels and upregulated IL-10. MVD and VEGFR-2 and FGFR-1 expression in synovial tissues were significantly reduced. Thus, this study shows that sorafenib exerts anti-arthritic effects in AA rats and therefore has potential in RA treatment. Anat Rec, 301:1519-1526, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Sorafenibe/uso terapêutico , Animais , Artrite Experimental/sangue , Citocinas/sangue , Adjuvante de Freund , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
4.
Biomed Pharmacother ; 91: 680-686, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28499239

RESUMO

Hypertrophic scar (HS) is a dermal fibroproliferative disorder characterized by the excessive proliferation of fibroblasts and is thought to result from a cellular imbalance caused by the increased growth and reduced apoptosis of hypertrophic scar fibroblasts (HSFs). Our recent study demonstrated that recombinant human endostatin (rhEndostatin) plays a key role in the inhibition of HSF proliferation in vitro, with a resulting decrease in dermal thickness and scar hypertrophy. However, the effect of this protein on HSF apoptosis is unknown. The present study was undertaken to directly examine the effect of rhEndostatin on HSF apoptosis in the rabbit ear model. Transmission electron microscopy and flow cytometry were used to investigate HSF apoptosis in scar tissues and cultured HSFs in vitro, respectively. The expression levels of the c-jun, c-fos, NF-κB, fas, caspase-3, and bcl-2 gene products in HSFs were quantified using real-time PCR and Western blotting assays. Our data reveal that rhEndostatin (2.5 or 5mg/ml) induces HSF apoptotic cell death in scar tissue. Additionally, HSFs treated with rhEndostatin (100mg/L) in vitro accumulated in early and late apoptosis and displayed significantly decreased expression of c-jun, c-fos, NF-κB, fas, caspase-3 and bcl-2. In sum, these results demonstrate that rhEndostatin induces HSF apoptosis, and this phenotypeis partially due to downregulation of NF-κB and bcl-2. These findings suggest that rhEndostatin may have an inhibitory effect on scar hypertrophy in vivo via HSF apoptotic induction and therefore has potential therapeutic use for the treatment of HS.


Assuntos
Cicatriz Hipertrófica/tratamento farmacológico , Orelha/patologia , Endostatinas/uso terapêutico , Fibroblastos/patologia , Proteínas Recombinantes/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Modelos Animais de Doenças , Endostatinas/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/ultraestrutura , Humanos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Proteínas Recombinantes/farmacologia , Receptor fas/metabolismo
5.
Eur J Pharmacol ; 791: 647-654, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27693124

RESUMO

Hypertrophic scar (HS) is a pathological scar that particularly occurs after traumatic injuries, surgical procedures and burning. Abnormal activation of hypertrophic scar fibroblasts (HSFs) intensifies fibrosis during wound healing. Our previous studies demonstrated that recombinant human endostatin (rhEndostatin) prevented synovial thickening in adjuvant arthritis (AA) rats via inhibition of proliferation and enhancement of apoptosis in synovial fibroblasts. However, the effect of this protein on HSF proliferation is not known. This study investigated the inhibitory effect of rhEndostatin on the proliferation of cultured HSFs in a rabbit ear model. MTT assay and flow cytometric detection were performed to investigate HSF proliferation and cell cycle progression, respectively. The expression levels of p53, p21, cyclinD1, cyclin-dependent kinase 4 (CDK4) and proliferating cell nuclear antigen (PCNA) in HSFs were detected using real-time PCR and Western blotting. Our data revealed that HSFs treated with rhEndostatin were significantly inhibited in a concentration-dependent manner with an IC50 value of 100mg/L. Also, rhEndostatin (100mg/L) primarily induced G0/G1 and partially G2/M cell cycle arrest of HSFs. There were significant decreases in the expression levels of p53, p27, CDK4, cyclinD1 and PCNA in HSFs treated with rhEndostatin. In conclusion, rhEndostatin inhibited HSF proliferation via G0/G1 and/or G2/M phase arrest of the cell cycle, which was partially due to the down-regulation of cyclinD1, CDK4 and PCNA. These findings suggest that rhEndostatin may reduce scar hypertrophy in vivo via inhibition of HSF proliferation and may be a novel agent for HS treatment.


Assuntos
Cicatriz Hipertrófica/patologia , Orelha/patologia , Endostatinas/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Proteínas Recombinantes/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cicatriz Hipertrófica/tratamento farmacológico , Modelos Animais de Doenças , Endostatinas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Coelhos , Proteínas Recombinantes/uso terapêutico
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