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1.
Cancer Lett ; 420: 195-207, 2018 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-29425683

RESUMO

Uncontrolled excessive activation of Hedgehog (Hh) signaling pathway is linked to a number of human malignant tumorigenesis. To obtain valuable Hh pathway inhibitors from natural product, in present study, a pair of novel epimers, Cynanbungeigenin C (CBC) and D (CBD) from the plant Cynanchum bungei Decne were chemically characterized by multiple spectroscopic data and chemical derivatization, and evaluated for their inhibition on Hh pathway. Mechanistically, CBC and CBD block Hh pathway signaling not through targeting Smo and Sufu, but at the level of Gli. In addition, both eipmers significantly suppress Hh pathway-dependent Ptch+/-; p53-/- medulloblastoma in vitro and in vivo. Furthermore, both CBC and CBD inhibited two Smo mutants induced Hh pathway activation, which suggested that they are potential compounds for the treatment of medulloblastoma with primary or acquired resistance to current Smo inhibitors. These results highlight the potential of CBC and CBD as effective lead compounds in the treatment of medulloblastoma and other Hh-dependent malignancy.


Assuntos
Neoplasias Cerebelares/tratamento farmacológico , Cynanchum/química , Meduloblastoma/tratamento farmacológico , Fitosteróis/administração & dosagem , Fitosteróis/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias Cerebelares/metabolismo , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Camundongos , Células NIH 3T3 , Fitosteróis/química , Fitosteróis/farmacologia , Extratos Vegetais/análise , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco/metabolismo
2.
Eur J Pharmacol ; 789: 370-384, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27448502

RESUMO

Stephanthraniline A (STA), a C21 steroid isolated from Stephanotis mucronata (Blanco) Merr., was previously shown to inhibit T cells activation and proliferation in vitro and in vivo. The purpose of this study was to further evaluate the in vivo immunosuppressive activity of STA and to elucidate its potential mechanisms. The results showed that pretreatment with STA significantly attenuated concanavalin A (Con A)-induced hepatitis and reduced CD4(+) T cells activation and aggregation in hepatic tissue in mice. STA directly suppressed the activation and proliferation of Con A-induced CD4(+) T cells, and inhibited NFAT, NFκB and MAPK signaling cascades in activated CD4(+) T cells in vitro. Moreover, it was proved that STA inhibited T cells activation and proliferation through proximal T cell-receptor (TCR) signaling- and Ca(2+) signaling-independent way. The molecular docking studies predicted that STA could tight bind to PKCθ via five hydrogen. The further findings indicated STA directly inhibited PKCθ kinase activity, and its phosphorylation in activated CD4(+) T cells in vitro. Collectively, the present study indicated that STA could protect against CD4(+) T cell-mediated immunological hepatitis in mice through PKCθ and its downstream NFAT, NFκB and MAPK signaling cascades. These results highlight the potential of STA as an effective leading compound for use in the treatment of CD4(+) T cell-mediated inflammatory and autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diterpenos/farmacologia , Hepatite/tratamento farmacológico , Hepatite/imunologia , Isoenzimas/antagonistas & inibidores , Ativação Linfocitária/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Animais , Sinalização do Cálcio/efeitos dos fármacos , Domínio Catalítico , Agregação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/metabolismo , Diterpenos/uso terapêutico , Feminino , Hepatite/metabolismo , Hepatite/patologia , Isoenzimas/química , Isoenzimas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C/química , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Proteínas Quinases/metabolismo
3.
Chem Biodivers ; 13(11): 1484-1492, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27449706

RESUMO

Stemucronatoside K (SMK) and its aglycone stephanthraniline A (STA) are the most representative of a series of novel C21 steriodal compounds that we have previously isolated from Asclepiadaceae plants. The objectives of this study were to investigate the antitumor activity of SMK and STA, and clarify the effect of the sugar chain at the C(3) position. Our results showed that both SMK and STA decreased the growth of HT-29 cells in a dose- and time-dependent manner. Meanwhile, STA showed much stronger inhibitory effect than SMK. Treatment of HT-29 cells with STA increased the apoptotic cell numbers and the protein expression of cleaved caspase 3 and cleaved-PARP. G1 phase cell cycle arrest and decreased expression of cyclin D1 and cyclin-dependent kinases 4 were also observed after STA treatment. Furthermore, STA reduced the mRNA levels of four Hedgehog pathway components (GLI1, GLI2, GLI3, and PTCH1) and suppressed Shh-induced Hedgehog pathway activation in a concentration-dependent manner. These results indicated that SMK and STA could inhibit the growth of HT-29 cells by inducing apoptosis, cell cycle arrest, and hedgehog pathway inhibition. The loss of sugar chain at C(3) position could enhance SMK's activity. This study is beneficial to understand the use of natural C21 steroids as antitumor lead compounds.


Assuntos
Apoptose/efeitos dos fármacos , Carboidratos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HT29 , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Conformação Molecular , Saponinas/química , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 22(1): 642-4, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22079028

RESUMO

Novel analogs of SGLT2 inhibitors containing the 1,2,3-triazole motif were designed and synthesized for urinary glucose excretion evaluation. The C-glucosides with triazole aglycone can be easily constructed by click chemistry. Most of the synthesized compounds increased urinary glucose excretion and demonstrated inhibition of glucose transport.


Assuntos
Química Farmacêutica/métodos , Inibidores do Transportador 2 de Sódio-Glicose , Triazóis/síntese química , Motivos de Aminoácidos , Animais , Transporte Biológico , Química Click/métodos , Diabetes Mellitus/tratamento farmacológico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Humanos , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio , Fatores de Tempo , Triazóis/farmacologia
5.
Zhonghua Fu Chan Ke Za Zhi ; 46(2): 101-4, 2011 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-21426766

RESUMO

OBJECTIVE: To evaluate clinical outcome and complications of mesh-augmented vaginal reconstructive surgery in treatment of pelvic organ prolapse. METHODS: From Feb 2007 to Jan 2009, mesh-augmented vaginal reconstructive surgery were performed on 66 women with pelvic organ prolapse stage III-IV. Pre and postoperative symptoms, pelvic organ prolapse quantitation (POP-Q) stage and pelvic floor distress inventory-short form 20 (PFDI-20) measurements were studied to assess anatomic and quality-of-life outcome. Operative complications were also analyzed. RESULTS: Totally 65 patients underwent successful surgeries. The rate of follow-up was 97% (63/65) with a median follow-up of 17.2 months. Subjective cure rate and objective cure rate were both 97% (61/63) at 6 and 12 months after surgeries, 51 women completed PFDI-20 measurements and scores were 102 ± 50 before surgery, 16 ± 21 at 6 months and 15 ± 20 at 12 months. It reached statistical difference when scores were compared before and after surgeries (P < 0.05). Among 66 patients, 2 patients underwent organ injuries, 2 had recurrent prolapse, 4 had mesh-related complications and 1 had severe de novo stress urinary incontinence. Six patients underwent second surgery. CONCLUSIONS: Mesh-augmented vaginal reconstructive surgery in treatment of pelvic organ prolapsed brought satisfied clinical outcome. The incidence of mesh-related complications was low and secondary operative interventions were effective.


Assuntos
Procedimentos Cirúrgicos em Ginecologia/métodos , Prolapso de Órgão Pélvico/cirurgia , Qualidade de Vida , Telas Cirúrgicas , Vagina/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Procedimentos Cirúrgicos em Ginecologia/instrumentação , Humanos , Histerectomia Vaginal , Complicações Intraoperatórias/epidemiologia , Complicações Intraoperatórias/cirurgia , Pessoa de Meia-Idade , Polipropilenos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/cirurgia , Recidiva , Índice de Gravidade de Doença , Telas Cirúrgicas/efeitos adversos , Inquéritos e Questionários , Resultado do Tratamento , Prolapso Uterino/cirurgia , Útero/cirurgia
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