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1.
Chem Biol Interact ; 311: 108793, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421117

RESUMO

Polyphyllin I (PPI), a bioactive component extracted from Paris polyphylla, was reported to have potent anticancer activities in previous studies. However, there were few reports on the effects and underlying mechanism of PPI in human acute myeloid leukemia cells. The present study demonstrated that PPI had an inhibitory effect through inducing apoptosis and autophagy in THP-1 and NB4 cells. PPI induced apoptosis via activating JNK pathway, as evidenced by the decreased Bcl-2 levels and increased Bax, cleaved-caspase-3 and phosphorylated-JNK expressions. In addition, PPI promoted autophagy as evidenced with increased expressions of LC3-II and Beclin-1 in western blot and autophagic vacuoles in MDC staining, which was associated with the inhibition of AKT-mTOR pathway. Furthermore, JNK inhibitor SP600125 and autophagy inhibitor 3-MA were employed to evaluate the role of apoptosis and autophagy in PPI-induced cell death. We found that autophagy and apoptosis were both causes of cell death induced by PPI. These data suggested that PPI could be a potent therapeutic agent for the treatment of human acute myeloid leukemia.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diosgenina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(6): 746-749, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31315735

RESUMO

OBJECTIVE: To investigate the protective effect of Polyphyllin I (PPI) on myocardial ischemia/reperfusion (I/R) injury in rats and its mechanism. METHODS: The 6-month-old Sprague-Dawley (SD) rats were divided into sham operation group (Sham group), I/R model group, and low, medium, high dose PPI groups according to the random number table method, with 10 in each group. The rat myocardial I/R model was prepared by ligating the left anterior descending branch of the coronary artery by 30 minutes and reperfusion by 120 minutes. Sham group was exposure to open chest without ligation. Low, medium, high dose PPI groups were injected with PPI 75, 150, 300 mg×kg-1×d-1 in front of the film for 4 weeks; dimethyl sulfoxide (DMSO) was gastric infused in the I/R model group. After the end of reperfusion, the myocardial infarction area (IA) was determined by triphenyltetrazole (TTC) and Evans blue (EB) staining; the apoptosis of myocardial cells was detected by TdT-mediated dUTP nick end labeling stain (TUNEL); the expressions of apoptosis related protein (Bax, Bcl-2), and cytoplasmic and nucleus expressions of P65 in nuclear factor-ΚB (NF-ΚB) signal pathway were detected by Western Blot. RESULTS: Compared with the Sham group, the myocardial IA was significantly increased in the I/R model group, the apoptosis rate of myocardial cells was significantly increased, the expression of Bcl-2 was significantly decreased, and the expression of Bax was significantly increased, and the intranuclear transfer of P65 was significantly increased. Compared with the I/R model group, low, medium and high dose PPI pretreatment could significantly reduce the myocardial IA [(21.6±0.9)%, (14.3±1.6)%, (15.0±0.8)% vs. (29.6±1.4)%], the apoptosis rate of myocardial cells was significantly decreased [(38.6±1.9)%, (24.3±2.6)%, (26.3±2.8)% vs. (56.8±2.4)%], the protein expression of Bcl-2 was significantly increased, while the protein expression of Bax was significantly decreased (Bcl-2/GAPDH: 0.24±0.07, 0.36±0.02, 0.34±0.09 vs. 0.13±0.04; Bax/GAPDH: 0.39±0.10, 0.21±0.08, 0.23±0.06 vs. 0.53±0.12); and P65 nuclear transfer was significantly decreased after middle and high dose PPI pretreatment [nuclear P65/Histone 3: 0.49±0.09, 0.51±0.06 vs. 0.83±0.11; cytoplasmic P65/GAPDH: 0.31±0.03, 0.30±0.05 vs. 0.22±0.07], with statistically significant differences (all P < 0.05). However, there was no significant difference in each index between the medium and high dose PPI groups (all P > 0.05). CONCLUSIONS: PPI alleviates myocardial I/R injury in rats via NF-ΚB signal pathway, and the PPI effect of 150 mg×kg-1×d-1 is most especially significant.


Assuntos
Diosgenina/análogos & derivados , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Apoptose , Diosgenina/metabolismo , Modelos Animais de Doenças , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
3.
Food Chem ; 298: 125063, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31260979

RESUMO

Dioscorea opposita Thunb. cv. Tiegun (DTT), a type of homologous medicinal plant, is commonly used as food in daily life. However, there has always been confusion regarding removal of the peel, as the nutrient metabolite composition of the peel is unclear. Here, a nuclear magnetic resonance (NMR)-based metabolomics approach was used to determine the metabolite distribution in DTT exclude-peel and peel. Thirteen characteristic metabolites with statistical significance were identified and compared using multivariate, univariate and cluster analyses. The results demonstrated that the peel contained the higher levels of α-glucose, batatasin IV, batatasin I, asparagine, ß-glucose, protodioscin, threonine, protogracillin, dioscin, and ß-sitosteryl acetate, and the samples without the peel had the higher levels of leucine, glutamine and alanine. This study provided scientific data for understanding the distribution characteristics of metabolites in DTT samples, promoting reasonable consumption of DTT.


Assuntos
Dioscorea/metabolismo , Metabolômica/métodos , Análise por Conglomerados , Diosgenina/análogos & derivados , Diosgenina/química , Diosgenina/metabolismo , Leucina/metabolismo , Espectroscopia de Ressonância Magnética , Exsudatos de Plantas/metabolismo , Plantas Medicinais/metabolismo , Análise de Componente Principal , Saponinas/química , Saponinas/metabolismo
4.
Int J Nanomedicine ; 14: 4071-4090, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239668

RESUMO

Background: Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. Purpose: The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Methods and results: Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-ß1 (TGF-ß1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Conclusion: Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Daunorrubicina/uso terapêutico , Diosgenina/análogos & derivados , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Oligopeptídeos/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Movimento Celular/efeitos dos fármacos , Daunorrubicina/administração & dosagem , Daunorrubicina/farmacologia , Diosgenina/administração & dosagem , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Feminino , Humanos , Lipossomos , Neoplasias Pulmonares/irrigação sanguínea , Metaloproteinase 2 da Matriz , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Tamanho da Partícula , Eletricidade Estática , Cicatrização/efeitos dos fármacos
5.
Ann Clin Lab Sci ; 49(1): 97-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814084

RESUMO

PURPOSE: The objective of this research was to explore the effect of dioscin on myocardium in streptozotocin (STZ)-induced diabetic rats and the underlying mechanisms. METHODS: Diabetic rat model was established by a single intravenous injection of streptozocin (STZ). The rats were divided into 5 groups: control group, control+dioscin group, model group (diabetes), DDL group (diabetic rats treated with 100 µg/kg/day dioscin) and DDH group (diabetic rats treated with 200 µg/kg/day dioscin). Each group was continuously intervened for 6 weeks. Hemodynamic parameters were detected and pathological alterations of myocardium were observed by hematoxylin-eosin (HE) staining. Inflammatory response and related proteins in the NO-sGC-cGMP-PKG pathway were detected by western blot. RESULTS: Dioscin treatment can increase ejection fraction (EF) and decrease left ventricular end-diastolic pressure (LVEDP) as well as time constant of left ventricular pressure decay (Tau) parameters in diabetic rats, suggesting the improvement of left ventricular function. By histopathology observation, we found that dioscin treatment can also improve myocardial histological lesions caused by diabetes. In addition, the levels of inflammatory cytokines TGF-ß1, TNF-α and IL-1ß of the model group were remarkably higher than those in the control group (p<0.01), while after being treated with dioscin these cytokines were obviously decreased (p<0.05). The levels of PDE-5, PKG and p-VASP in the diabetic rats were significantly declined after being treated by dioscin in a dose-dependent manner (p<0.05). CONCLUSION: Dioscin may prevent the myocardial injury in diabetic rats by up-regulating NO-sGC-cGMP-PKG pathway.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Diosgenina/análogos & derivados , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Diosgenina/farmacologia , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/prevenção & controle , Ratos , Ratos Sprague-Dawley
6.
Am J Chin Med ; 47(2): 423-437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827153

RESUMO

Dioscin, a steroidal saponin isolated from Dioscorea nipponica Makino, has previously been shown to possess antiarthritic effects. However, the underlying mechanism is still elusive. Herein, we investigated the therapeutic effects of dioscin on collagen-induced arthritis (CIA) in DBA/1 mice and related mechanism. Cytokine production in CII-specific immune responses were measured by enzyme-linked immunosorbent assay (ELISA); Th17 cell-related gene expression, including IL-17A, ROR γτ and IL-23p19, were detected by qPCR analysis; Surface marker, T regulatory (Treg) cells and intracellular cytokines (IL-17A and IFN- γ ) were evaluated by flow cytometry. We performed Th17 cell differentiation assay in vitro. Results showed that, in vivo, dioscin treatment significantly reduced the severity of CIA, which was accompanied by decreased Th17 response, but not Th1 and Treg response; dioscin-treated mice also showed lower percentage of CD11b + Gr-1 + neutrophils; In vitro, dioscin treatment suppressed the differentiation of naive CD4 + T cells into Th17 cell and decreased IL-17A production. Collectively, our results indicate that dioscin exerts antiarthritic effects by inhibiting Th17 cell immune response.


Assuntos
Artrite/tratamento farmacológico , Artrite/imunologia , Colágeno/efeitos adversos , Dioscorea/química , Diosgenina/análogos & derivados , Fitoterapia , Células Th17/imunologia , Animais , Artrite/induzido quimicamente , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Diosgenina/administração & dosagem , Diosgenina/isolamento & purificação , Diosgenina/farmacologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA
7.
Eur J Pharmacol ; 849: 50-58, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30716316

RESUMO

Methyl protodioscin (MPD) is reported to relieve angina pectoris and myocardial ischemia, and mitochondrial E3 ubiquitin ligase 1 (Mul1) plays a key role in maintaining mitochondrial functions. Bioinformatic analysis shows potential interactions between MPD and Mul1. This study aims to explore whether MPD could protect rat brain against ischemia/reperfusion (I/R) injury through regulation of Mul1/ superoxide dismutase 2 (SOD2) pathway. The SD rat brains were subjected to 2 h of ischemia following by 24 h of reperfusion, which showed I/R injury (increase in neurological deficit score and infarct volume), up-regulation of Mul1 and down regulation of SOD2, these phenomena were attenuated by MPD treatment (3 or 10 mg/kg, i.g.). Consistently, in cultured HT22 cells, hypoxia-reoxygenation (H/R) treatment induced cellular injury (apoptosis and LDH release) concomitant with up-regulation of Mul1 and down regulation of SOD2, these phenomena were blocked in the presence of MPD (5 µM). Knockdown of Mul1 could also decrease SOD2 protein levels in HT22 cells accompanied by alleviation of H/R injury (reduction of apoptosis and LDH release). In agreement with the change of SOD2, reactive oxygen species generation was increased in H/R-treated HT22 cells while decreased in the presence of MPD. Based on these observations, we conclude that upregulation of Mul1 in rat brain contributes to cerebral I/R injury via suppression of SOD2 and that MPD protects rat brain from I/R injury through a mechanism involving regulation of Mul1/SOD2 pathway.


Assuntos
Produtos Biológicos/farmacologia , Encéfalo/efeitos dos fármacos , Diosgenina/análogos & derivados , Proteínas Mitocondriais/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Saponinas/farmacologia , Superóxido Dismutase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Caspase 3/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Citoproteção/efeitos dos fármacos , Diosgenina/farmacologia , Técnicas de Silenciamento de Genes , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/genética , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética
8.
Oxid Med Cell Longev ; 2018: 5758191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228856

RESUMO

Tribulus terrestris (TT) has been considered as a potential stimulator of testosterone production, which has been related with steroidal saponins prevailing in this plant. Cyclophosphamide (CP) is the most commonly used anticancer and immunosuppressant drug, which causes several toxic effects, especially on the reproductive system. Patients who need to use CP therapy exhibit reduced fertility or infertility, which impacts both physically and emotionally on the decision to use this drug, especially among young men. We hypothesized that the treatment with TT dry extract would protect the male reproductive system against CP toxicity. Mice received dry extract of TT (11 mg/kg) or vehicle by gavage for 14 days. Saline or CP was injected intraperitoneally at a single dose (100 mg/kg) on the 14th day. Animals were euthanized 24 h after CP administration, and testes and epididymis were removed for biochemical and histopathological analysis and sperm evaluation. The dry extract of TT was evaluated by HPLC analysis and demonstrated the presence of protodioscin (1.48%, w/w). CP exposure increased lipid peroxidation, reactive species, and protein carbonylation and altered antioxidant enzymes (SOD, CAT, GPx, GST, and GR). Moreover, acute exposure to CP caused a reduction on 17 ß-HSD activity, which may be related to the reduction in serum testosterone levels, histopathological changes observed in the testes, and the quality of the semen. The present study highlighted the role of TT dry extract to ameliorate the alterations induced by CP administration in mice testes, probably due to the presence of protodioscin.


Assuntos
Ciclofosfamida/efeitos adversos , Substâncias Protetoras/farmacologia , Reprodução/efeitos dos fármacos , Tribulus/química , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Sulfato de Desidroepiandrosterona/metabolismo , Diosgenina/análogos & derivados , Diosgenina/análise , Masculino , Camundongos , Extratos Vegetais/farmacologia , Padrões de Referência , Saponinas/análise , Sêmen/metabolismo , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testosterona/sangue
9.
Int J Mol Sci ; 19(8)2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072674

RESUMO

Spinal cord injury (SCI) is a severe traumatic lesion of central nervous system (CNS) with only a limited number of restorative therapeutic options. Diosgenin glucoside (DG), a major bioactive ingredient of Trillium tschonoskii Max., possesses neuroprotective effects through its antioxidant and anti-apoptotic functions. In this study, we investigated the therapeutic benefit and underlying mechanisms of DG treatment in SCI. We found that in Sprague-Dawley rats with traumatic SCI, the expressions of autophagy marker Light Chain 3 (LC3) and Beclin1 were decreased with concomitant accumulation of autophagy substrate protein p62 and ubiquitinated proteins, indicating an impaired autophagic activity. DG treatment, however, significantly attenuated p62 expression and upregulated the Rheb/mTOR signaling pathway (evidenced as Ras homolog enriched in brain) due to the downregulation of miR-155-3p. We also observed significantly less tissue injury and edema in the DG-treated group, leading to appreciable functional recovery compared to that of the control group. Overall, the observed neuroprotection afforded by DG treatment warrants further investigation on its therapeutic potential in SCI.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diosgenina/análogos & derivados , Glucosídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/prevenção & controle , Animais , Diosgenina/química , Diosgenina/uso terapêutico , Glucosídeos/química , MicroRNAs/genética , Fármacos Neuroprotetores/química , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Trillium/química
10.
Life Sci ; 209: 420-429, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30125581

RESUMO

Cardiac hypertrophy occurs in response to multiple stimuli and develops into congestive heart failure with morbidity and mortality. Dioscin exerts protective effects against tumor growth and ischemia/reperfusion injury. However, whether and how dioscin attenuates angiotensin II (AngII)-induced cardiac hypertrophy is still unknown. In the current study, we found that dioscin attenuated cardiac hypertrophy and restored the impaired cardiac function induced by AngII infusion in vivo. In addition, dioscin blocked the activation of the MAPK and Akt/GSK3ß/mTOR pathways and nuclear accumulation of p-Akt1 in AngII-infused mice. In vitro, dioscin inhibited the activation of the MAPK and Akt/GSK3ß/mTOR pathways and nuclear translocation of p-Akt1 and thus alleviated the hypertrophic growth. Our study demonstrated dioscin protects against AngII-induced cardiac hypertrophy via inhibition of the MAPK and Akt/GSK3ß/mTOR pathways and is a potential therapeutic candidate.


Assuntos
Cardiomegalia/tratamento farmacológico , Diosgenina/análogos & derivados , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Angiotensina II/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Diosgenina/farmacologia , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Vasoconstritores/toxicidade
11.
J Pharmacol Sci ; 137(3): 305-312, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30119963

RESUMO

The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A) indicates poor prognosis and promotes EMT and metastasis. EMT, a crucial cellular process that occurs during cancer progression and metastasis, has been reported to promote drug resistance in several previous studies. Consequently, ongoing research has been focused on exploring therapeutic options for preventing EMT to delay or reverse drug resistance. Polyphyllin I (PPI) is a natural component extracted from Paris polyphylla that displays anti-cancer properties. In the present study, we investigated whether PPI can be used in the cisplatin (DDP)-resistant human gastric cancer cell line SGC7901/DDP. The results demonstrated that PPI treatment significantly inhibited cell proliferation, invasion and EMT. TGF-ß1 is known to promote EMT-induced metastasis in numerous tumor types. PPI inhibited the invasion of TGFß1-induced SGC7901/DDP cells in vitro. PPI also increased the mRNA and protein expression levels of E-cadherin but decreased the expression levels of vimentin. Further examination of the mechanism revealed that the CIP2A/PP2A/Akt pathway is partially involved in this regulation of EMT-related biomarkers and invasion. Furthermore, xenograft tests also confirmed the antitumor effects of PPI in vivo. We propose that PPI could be developed as a candidate drug for treating cancer invasion and migration.


Assuntos
Antineoplásicos Fitogênicos , Autoantígenos/genética , Autoantígenos/metabolismo , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Diosgenina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metástase Neoplásica/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Depressão Química , Diosgenina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Invasividade Neoplásica/prevenção & controle , Fator de Crescimento Transformador beta1/fisiologia , Vimentina/genética , Vimentina/metabolismo
12.
Food Chem Toxicol ; 120: 143-154, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29990575

RESUMO

Dioscin has been known for its anti-cancer activity; however, its detailed molecular mechanisms have not been studied so far. Herein, we evaluated the anti-cancer activity of dioscin for proliferation inhibition and apoptosis in HepG2 cancer cells. Initially, dioscin was purified and identified from Polygonatum sibiricum by HPLC, MS, and NMR analysis, respectively. Dioscin inhibited the cell multiplication at IC50 of 8.34 µM, altered the cell morphology, arrested the cell cycle in G2/M phase and led to considerable programmed cell death. Furthermore, it has efficiently promoted the mitochondrial pathway and death receptor pathway. The inhibition of Caspase-8 and Caspase-9 proteins in these pathways abolished the dioscin induced apoptosis significantly; while dioscin inhibited the PI3K/Akt/mTOR pathway. Moreover, dioscin exposure led to enhanced intracellular ROS generation and the mRNA expression of JNK gene which emphasized their involvement in the apoptosis process in HepG2 cells.


Assuntos
Anticarcinógenos/farmacologia , Proteínas de Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Diosgenina/análogos & derivados , Fase G2/efeitos dos fármacos , Genes cdc/efeitos dos fármacos , Anticarcinógenos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/isolamento & purificação , Diosgenina/farmacologia , Células Hep G2 , Humanos , Concentração Inibidora 50 , Mitocôndrias/efeitos dos fármacos , Polygonatum/química , Espécies Reativas de Oxigênio/metabolismo , Receptores de Morte Celular/efeitos dos fármacos , Receptores de Morte Celular/metabolismo
13.
Int Immunopharmacol ; 61: 204-214, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29890414

RESUMO

Diosgenin, a precursor of steroid hormones in plants, is known to exhibit diverse pharmacological activities including anti-inflammatory properties. In this study, (3ß, 25R)­spirost­5­en­3­oxyl (2­((2((2­aminoethyl)amino)ethyl)amino)ethyl) carbamate (DGP), a new synthetic diosgenin derivative incorporating primary amine was used to investigate its anti-inflammatory effects and underlying mechanisms of action in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. Pretreatment with DGP resulted in significant inhibition of nitric oxide (NO) synthesis, and down-regulation of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated microglial BV2 cells. In addition, DGP decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines such as interleukin (IL)-6, IL-1ß, and tumor necrosis factor alpha (TNF-α). The inhibitory effects of DGP on these inflammatory mediators in LPS-stimulated microglial BV2 cells were regulated by NF-κB signaling through blocking p65 nuclear translocation and NF-κB p65/DNA binding activity. DGP also blocked the phosphorylation of c-Jun amino-terminal kinase (JNK), but not p38 kinase or extracellular signal-regulated kinases (ERK). The NF-κB inhibitor JSH-23 and JNK-specific inhibitor SP600125 significantly decreased NO production and IL-6 release in LPS-stimulated BV2 cells, respectively. The overall results demonstrate that DGP has anti-inflammatory effects on LPS-stimulated BV2 cells via inhibition of NF-κB and JNK activation, suggesting that DGP is a potential prophylactic agent in various neurodegenerative disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Diosgenina/farmacologia , Microglia/fisiologia , Animais , Anti-Inflamatórios/síntese química , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Diosgenina/análogos & derivados , Diosgenina/síntese química , Regulação para Baixo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , MAP Quinase Quinase 4/metabolismo , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Neuroimunomodulação , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
14.
Int J Oncol ; 53(3): 1279-1288, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29956727

RESUMO

Polyphyllin I (PPI) is a natural compound extracted from the rhizomes of Paris polyphylla and has been used to treat fevers and headaches in China. In the present study, the antitumor activity of PPI in prostate cancer (PC) cells was evaluated. At low doses, PPI decreased proliferation, invasion and epithelial-mesenchymal transition (EMT) in PC cells. PPI decreased the expression of matrix metalloproteinase 7 (MMP7), an enzyme that is critical for tumor metastasis. PPI also decreased the expression of Snail and vimentin, which are EMT-associated factors. Additionally, PPI suppressed AP-1 transcriptional activity and AP-1 binding to the MMP7 and vimentin promoters. The results demonstrated that PPI downregulated the phosphorylation of extracellular signaling­related kinase (ERK), which is upstream modulator of AP-1. The results of the present study demonstrated that PPI may inhibit the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/ERK axis, downregulate the expression of MMP7, vimentin, and Snail, and suppress tumor invasion and EMT. A PC xenograft mouse model was employed and the results revealed that PPI may decrease tumor growth and weight. Additionally, PPI may inhibit proliferating cell nuclear antigen expression and CIP2A/PP2A/ERK signaling pathway in PPI-treated tumors. Therefore, the results of the present study suggest that PPI may suppress the growth, invasion and EMT of PC cells via inhibition of CIP2A/PP2A/ERK signaling axis. As a result, PPI may be a novel target for the treatment of PC.


Assuntos
Antineoplásicos/farmacologia , Diosgenina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Autoantígenos/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Regulação para Baixo , Avaliação Pré-Clínica de Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Melanthiaceae/química , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/prevenção & controle , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/patologia , Proteína Fosfatase 2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Eur J Pharmacol ; 833: 237-246, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29886239

RESUMO

Epilepsy is associated with increased morbidity and mortality together and places a large financial burden on individuals and society. To evaluate the anticonvulsant action of protodioscin (PDSN) in experiments with animals with pilocarpine-induced convulsions. We assessed the activity of PDSN in pilocarpine induced seizures in combination with different agents which are acting via diverse receptors, such as atropine, memantine, nimodipine, diazepam, and flumazenil, to determine the exact receptors responsible for the action of PDSN. Furthermore, the level of antioxidant markers was investigated in the cerebellum and cerebral cortex in mice to define the antioxidant action of PDSN. The effects of PDSN on proapoptotic markers (i.e., Bcl-2, Bax, and caspase-3) was investigated via western blot analysis. PDSN significantly enhanced latency to the first convulsion and survival compared to the group treated with pilocarpine alone. Moreover, PDSN improved animal survival, and subjects experiencing no convulsions. Striatal glutamate and aspartate levels were not modified, and gamma amino butyric acid (GABA) levels increased, as a result of treatment with PDSN. The results suggest that the anticonvulsive action of PDSN is dependent on inhibitory amino acids. PDSN treatment also significantly decreased nitrite levels in the blood and brain cortex compared to the normal control. In the western blot analysis, PDSN exerted its neuroprotective effect via the upregulation of Bcl-2 and downregulation of Bax and caspase-3. The results of this study suggest that PDSN exerts neuroprotective effects via multiple mechanisms.


Assuntos
Anticonvulsivantes/farmacologia , Apoptose/efeitos dos fármacos , Diosgenina/análogos & derivados , Epilepsia/tratamento farmacológico , Saponinas/farmacologia , Animais , Anticonvulsivantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Caspase 3/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia/induzido quimicamente , Epilepsia/mortalidade , Humanos , Masculino , Camundongos , Pilocarpina/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Saponinas/uso terapêutico , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo , Ácido gama-Aminobutírico/metabolismo
16.
Org Lett ; 20(11): 3403-3407, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29790756

RESUMO

A synthetic strategy for accessing protoaculeine B (1), the N-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of 1 with a 12-mer poly(propanediamine). The synthesis of mono(propanediamine) analog 2, as well as core amino acid 3, was demonstrated by this strategy. New amino acid 3 induced convulsions in mice; however, compound 2 showed no such activity.


Assuntos
Indóis/química , Poliaminas/química , Sequência de Aminoácidos , Aminoácidos , Animais , Diosgenina/análogos & derivados , Camundongos , Estrutura Molecular , Saponinas
17.
Cell Physiol Biochem ; 47(2): 759-773, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29807357

RESUMO

BACKGROUND/AIMS: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. METHODS: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. RESULTS: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. CONCLUSIONS: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.


Assuntos
Apoptose/efeitos dos fármacos , Diosgenina/análogos & derivados , Mucina-1/metabolismo , Feniltioidantoína/análogos & derivados , RNA Longo não Codificante/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Mucina-1/genética , Subunidade p50 de NF-kappa B/metabolismo , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Fator de Transcrição RelA/genética
18.
Mol Med Rep ; 18(1): 973-980, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29845299

RESUMO

Cardiovascular diseases are common diseases in Sweden as in most countries. In 2016, 25,700 persons suffered from coronary heart disease (CHD) and 25% of these died within 28 days. The present study investigated whether dioscin may exert protective effects against CHD­induced heart apoptosis, oxidative stress and inflammation in a pig model and the potential underlying mechanisms. Adult pigs were used to establish a CHD model group and 80 mg/kg dioscin was administered for 4 weeks. Histological analysis and measurement of serum levels of heart injury markers demonstrated that 80 mg/kg dioscin markedly alleviated CHD, while left ventricular ejection fraction and left ventricular systolic internal diameter measurements indicated that 80 mg/kg dioscin also increased heart function in the CHD pig model. Furthermore, western blotting demonstrated that 80 mg/kg dioscin significantly reduced protein levels of apoptosis markers in the heart of CHD model pigs, including Bcl­2­associated X and caspase­3, potentially via the suppression of poly (ADP­ribose) polymerase 1 (PARP)/p53 expression. Additionally, the results of ELISA and western blotting demonstrated that 80 mg/kg dioscin may reduce oxidative stress and inflammation in CHD model pigs through the promotion of sirtuin 1 (Sirt1)/nuclear factor erythroid 2­related factor 2 (Nrf2) protein expression and the suppression of PARP/p53 and p38 mitogen­activated protein kinase (MAPK) expression. The results of the current study indicate that dioscin may protect against CHD by regulating oxidative stress and inflammation via Sirt1/Nrf2 and p38 MAPK pathways.


Assuntos
Doença das Coronárias/prevenção & controle , Diosgenina/análogos & derivados , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Doença das Coronárias/metabolismo , Doença das Coronárias/patologia , Diosgenina/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Suínos , Porco Miniatura
19.
Cell Prolif ; 51(4): e12458, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29608021

RESUMO

OBJECTIVES: To investigate the synergistic mechanisms of Paris Saponin II (PSII) and Curcumin (CUR) in lung cancer. MATERIALS AND METHODS: The combination changed the cellular uptake of CUR and PSII, apoptosis, cell cycle arrest and cytokine levels were analysed on different lung cancer cells. RESULTS: The combination displayed a synergistic anti-cancer effect through promoting the cellular uptake of CUR on different lung cancer cells. Hoechst H33258 staining and FACS assay indicated that the combination of PSII and CUR induced cell cycle arrest and apoptosis. Western blot and cytokine antibody microarray suggested that the combination activated death receptors such as DR6, CD40/CD40L, FasL and TNF-α to induce cancer cells apoptosis, and up-regulated IGFBP-1 leading to inhibition of PI3K/Akt pathway and increase of p21 and p27, which therefore induced a G2 phase arrest in NCI-H446 cells. Meanwhile, the combination suppressed PCNA and NF-κB pathway in 4 kinds of lung cancer cells. They activated the phosphorylation of p38 and JNK, and inhibited PI3K in NCI-H460 and NCI-H446 cells, enhanced the phosphorylation of JNK in NCI-H1299 cells, and increased the phosphorylation of p38 and ERK, and suppressed PI3K in NCI-H520 cells. CONCLUSIONS: PSII combined with CUR had a synergistic anti-cancer effect on lung cancer cells. These findings provided a rationale for using the combination of curcumin and PSII in the treatment of lung cancer in future.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Curcumina/farmacologia , Diosgenina/análogos & derivados , Saponinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/química , Diosgenina/química , Diosgenina/farmacologia , Sinergismo Farmacológico , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Saponinas/química , Transdução de Sinais/efeitos dos fármacos
20.
Biochem Biophys Res Commun ; 497(4): 1129-1134, 2018 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-29499193

RESUMO

The aim of this study was to identify the anti-cancer mechanism of Polyphyllin I (PPI) on gastric cancer cells via its activity on cancer-associated fibroblasts (CAFs). We cultured purified gastric CAFs obtained from fresh human gastric cancer tissue and examined the effect of Polyphyllin I on CAF proliferation using a colorimetric viability assay. In addition, we established a nude mouse xenograft model to examine the effect of Polyphyllin I administration on tumorigenesis. Using Western analysis, we quantified protein expression of the CAF-derived cytokines fibroblast activation protein alpha (FAP), secreted protein acidic and cysteine rich (SPARC), stromal cell-derived factor 1 (SDF-1), hepatocyte growth factor tenascin-C (TNC), and hepatocyte growth factor (HGF) in both in vitro and in vivo models. We found that Polyphyllin I inhibits the proliferation of CAFs in a concentration-dependent manner. Following treatment with 2 µg/ml PPI for 24 h in vitro, the expression of FAP, SDF-1 and HGF protein in CAFs was significantly lower than that in the control group, but there was no significant difference in SPARC and TNC protein expression between the two groups. In the nude mouse xenograft model, the tumor inhibition rate was 45.5% when PPI was administered early and 29.4% with administration in the third week. The expression of FAP and HGF in the xenografts was significantly decreased, while the expression of SPARC, SDF-1, and TNC was largely unaltered. Altogether, these data suggest that Polyphyllin I can inhibit the proliferation of gastric cancer cells by downregulating the expression of FAP and HGF in CAFs in vivo.


Assuntos
Fibroblastos Associados a Câncer/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/análogos & derivados , Gelatinases/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Neoplasias Gástricas/patologia , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Diosgenina/administração & dosagem , Diosgenina/farmacologia , Regulação para Baixo , Xenoenxertos , Humanos , Camundongos , Neoplasias Gástricas/tratamento farmacológico , Células Tumorais Cultivadas
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