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1.
Eur J Med Chem ; 187: 111978, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877536

RESUMO

Hydrogen sulfide (H2S) has been recognized as the third endogenous signaling gasotransmitter following nitric oxide (NO) and carbon monoxide (CO), and exhibits antiproliferative activity against several cancer cells. In order to stably and controllably release H2S, H2S donating compound (ADT-OH) was used in the present study and 18H2S releasing natural ent-kaurane diterpenoid oridonin derivatives were designed and synthesized. Most derivatives showed more potent antiproliferative activities than oridonin against HepG2 and K562 cell lines, while they were lack of sensitivity to HCT-116 and B16 cells. In particular, 12b showed the most potent antiproliferative activities against HepG2, HCT-116 and K562 cells with IC50 values of 2.57, 5.81 and 0.95 µM, respectively. Through cell cycle analysis, 12b caused cell cycle arrest at S phase in K562 cells and G1 phase in HepG2 cells. In Hoechst 33258 staining assay, cell shrinkage and fragmentation of cell nuclei indicated apoptotic morphological changes. Considering the decline of mitochondrial membrane potential and changes in the levels of apoptosis-related proteins, 12b was shown to induce apoptosis through extrinsic and intrinsic apoptosis pathways.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Sulfeto de Hidrogênio/farmacologia , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Sulfeto de Hidrogênio/química , Células K562 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1374-1379, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607286

RESUMO

OBJECTIVE: To investigate the influence of oridonin on the killing activity of NK-92 MI cells targeting THP1 and the related mechanism. METHODS: The killing activity of NK-92 MI to THP1 before and after oridonin treatment was detected by LDH release assay; the expression of natural killer cell ligands activating receptor D (NKG2D, including MICA, MICB, ULBP1, ULBP2 and ULBP3) was detected by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot respectively; the expression of cytokine TNF-α, TNF-ß and IFN-γ in the co-culture supernatant of NK-92 MI cells and THP1 cells were measured by ELISA. RESULTS: The killing efficiency after oridonin treatment at different effector-target ratio (1:1, 5:1, 10:1) was all significantly up-regulated in comparison with that before oridonin treatment (P<0.05). QRT-PCR and Western blot showed that the expressions of mRNA and protein levels of MICB, ULBP1, ULBP2 increased to varying degree (P<0.05), but the expression levels of MICA and ULBP3 were not statistically significant between experimental group and control group (P>0.05). ELISA results indicated that IFN-γ and TNF-ß release were significantly increased after oridonin treatment (P<0.05), however, the TNF-α release was not statistically different in comparison with control group (P>0.05). CONCLUSION: Oridonin can significantly improve killing efficiency of NK-92 MI on THP1, that might be related with up-regulation of MICB, ULBP1 and ULBP2 expression and promotion of IFN-γ and TNF-ß release.


Assuntos
Diterpenos de Caurano/farmacologia , Linhagem Celular Tumoral , Proteínas Ligadas por GPI , Antígenos de Histocompatibilidade Classe I , Humanos
3.
Eur J Med Chem ; 183: 111722, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563807

RESUMO

Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (Ki = 0.015 µM) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p < 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p < 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p < 0.01 and p < 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Trombose/tratamento farmacológico , Animais , Descoberta de Drogas , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Trombina/metabolismo
4.
Eur J Med Chem ; 182: 111645, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494472

RESUMO

As our research focus on anticancer drugs, two series of novel derivatives of Flexicaulin A (FA), an ent-kaurene diterpene, condensation with amino acid trifluoroacetate were synthesized, and their anti-proliferative activity against four human cancer cell lines (TE-1, MCF-7, A549 and MGC-803) were evaluated. Compared with FA, the anticancer activity and solubility of most derivatives were significantly improved. Among them, compound 6d had the best activity, and its IC50 value against Esophageal cancer cells (TE-1) was up to 0.75 µM. Subsequent cellular mechanism studies showed that compound 6d could inhibit the proliferation of cancer cells, the formation of cell colonies, and increase the level of ROS on TE-1 cells. In addition, 6d could up-regulate the expressions of SAPK/JNK pathway-associated proteins (p-ASK1, p-MKK4 and p-JNK) and pro-apoptotic proteins (Bak, Bad and Noxa), remarkably increase the ratio of Bax to Bcl-2 and activate Cleaved Caspase-3/9/PARP. These results indicate that compound 6d induces apoptosis through the ROS/JNK/Bcl-2 pathway and holds promising potential as an anti-proliferative agent.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Ácido Trifluoracético/farmacologia , Aminoácidos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ácido Trifluoracético/química , Células Tumorais Cultivadas
5.
Life Sci ; 233: 116709, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369760

RESUMO

BACKGROUND: Cisplatin resistance has been found to contribute to the failure of ovarian carcinoma treatment. Oridonin is a natural en-kaurane tetracyclic diterpenoid compound discovered in Rabdosia rubescene (Henmsl.) Hara. Herein, we tested whether oridonin could exert chemo-sensitization activity on cisplatin-resistant ovarian carcinoma cells. METHODS: Firstly, A2780CP cells and SKOV3/DDP cells were exposed to cisplatin and/or oridonin treatment. Cell counting kit-8 (CCK-8) kit and Dead Cell Apoptosis Kit with Annexin V-FITC and PI were carried out to test cell viability and apoptosis, respectively. Then, pBeclin-1 was transfected to overexpress Beclin-1. 3-Methyladenine (3-MA) acted as autophagy inhibitor, while rapamycin acted as autophagy activator. Finally, the influence of cisplatin and/or oridonin treatment on human normal ovarian epithelial IOSE 364 cell viability and apoptosis were also detected. RESULTS: Oridonin incubation notably elevated the cisplatin-caused reduction of A2780CP and SKOV3/DDP cell viabilities and enhancement of cell apoptosis. Cisplatin-caused A2780CP and SKOV3/DDP cell autophagy was dramatically inhibited by oridonin. Overexpression of Beclin-1 mitigated the influence of oridonin on cisplatin-caused A2780CP and SKOV3/DDP cell autophagy. Inhibition of cell autophagy by 3-MA promoted the oridonin + cisplatin-caused A2780CP and SKOV3/DDP cell apoptosis, while activation of cell autophagy by rapamycin had opposite effects. Oridonin and cisplatin co-treatment had no significant effects on IOSE 364 cell viability and apoptosis. CONCLUSION: The chemo-sensitization activity of oridonin on cisplatin-resistant ovarian carcinoma cells was verified in this study. Oridonin elevated sensitivity of ovarian carcinoma cells to cisplatin via suppressing cisplatin-mediated autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cisplatino/farmacologia , Diterpenos de Caurano/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Neoplasias Ovarianas/patologia , Antineoplásicos/farmacologia , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
6.
Eur J Pharmacol ; 861: 172587, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377155

RESUMO

Oridonin is a diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara, a well-known herbal tea in China with many health benefits. To provide a better understanding of the potential cardioprotective effect of Oridonin, we investigated the metabolic alterations in heart tissue and serum of rat subjected to myocardial ischemia/reperfusion (MI/R) injury with or without pretreatment of Oridonin by UPLC-MS/MS metabolomics approach. Rats were randomly divided into groups as follows: Control, Sham, MI/R and pretreated with Oridonin (10 mg/kg)+MI/R. After 24 h of reperfusion, heart tissue and serum were collected for biochemical and metabolomic analysis. Pretreatment with Oridonin significantly decreased infarct size and reversed the abnormal elevated myocardial zymogram in serum. Moreover, Oridonin regulated several metabolic pathways, including glycolysis, branched chain amino acid, kynurenine, arginine, glutamine and bile acid metabolism. Our results suggest that Oridonin indeed displays outstanding cardioprotective effect mainly by regulating energy and amino acid metabolism.


Assuntos
Diterpenos de Caurano/farmacologia , Metabolômica , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Diterpenos de Caurano/uso terapêutico , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
7.
Food Chem Toxicol ; 133: 110765, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31430510

RESUMO

Oridonin (ORI) is a natural diterpenoid presented in some medicinal plants. The effects of pre-treatments from ORI against MPP+- or kainic acid (KA)-induced damage in nerve growth factor (NGF)-differentiated PC12 cells were investigated. Results showed that pre-treatments of ORI at 0.25-2 µM enhanced the viability and plasma membrane integrity of NGF-differentiated PC12 cells. MPP+ or KA exposure down-regulated Bcl-2 mRNA expression, up-regulated Bax mRNA expression, increased caspase-3 activity and decreased Na+-K+ ATPase activity. ORI pre-treatments at test concentrations reversed these changes. ORI pre-treatments decreased reactive oxygen species production, raised glutathione level, and increased glutathione peroxidase, glutathione reductase and catalase activities in MPP+ or KA treated cells. ORI pre-treatments lowered tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and prostaglandin E2 levels in MPP+ or KA treated cells. ORI also diminished MPP+ or KA induced increase in nuclear factor-κB binding activity. MPP+ exposure suppressed tyrosine hydroxylase (TH) mRNA expression and decreased dopamine content. KA exposure reduced glutamine synthetase (GS) mRNA expression, raised glutamate level and lowered glutamine level. ORI pre-treatments at 0.5-2 µM up-regulated mRNA expression of TH and GS, restored DA and glutamine content. These findings suggested that oridonin was a potent neuro-protective agent against Parkinson's disease and seizure.


Assuntos
1-Metil-4-fenilpiridínio/efeitos adversos , Diterpenos de Caurano/farmacologia , Ácido Caínico/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Diterpenos de Caurano/toxicidade , Regulação para Baixo/efeitos dos fármacos , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Fármacos Neuroprotetores/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Nutrients ; 11(9)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438580

RESUMO

The natural sweetener from Stevia rebaudiana Bertoni, steviol glycoside (SG), has been proposed to exhibit a range of antidiabetic properties. The objective of this systematic review was to critically evaluate evidence for the effectiveness of SGs on human health, particularly type 2 diabetic (T2D) biomarkers, collecting data from randomized controlled trials (RCTs). Electronic searches were performed in PubMed and EMBASE and the bibliography of retrieved full-texts was hand searched. Using the Cochrane criteria, the reporting quality of included studies was assessed. Seven studies, nine RCTs, including a total of 462 participants were included. A meta-analysis was performed to assess the effect of SGs on following outcomes: BMI, blood pressure (BP), fasting blood glucose (FBG), lipids, and glycated hemoglobin (HbA1c). The meta-analysis revealed an overall significant reduction in systolic BP in favour of SGs between SG and placebo, mean difference (MD): -6.32 mm Hg (-7.69 to 0.46). The overall effect of BMI, diastolic BP, FBG, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) was a non-significant reduction in favour of SGs, and a non-significant increase in low-density lipoprotein cholesterol and triglyceride, while no significant effect of HbA1c was found. Heterogeneity was significant for several analyses. More studies investigating the effect of SGs on human health, particularly T2D biomarkers, are warranted.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Biomarcadores/sangue , Glicemia , Ingestão de Energia/efeitos dos fármacos , Humanos , Insulina/sangue
9.
Phytother Res ; 33(11): 2904-2917, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31423662

RESUMO

Stevia rebaudiana Bertoni, a plant from South America and indigenous of Paraguay, has shown several biological effects and healthy properties, although it is especially used in South America and some Asiatic regions. In addition, it is a natural sweetener, almost 300 times sweeter than sucrose, being attributed to its phytoconstituents prominent antioxidant, antimicrobial, antidiabetic (antihyperglycemic, insulinotropic, and glucagonostatic), antiplatelet, anticariogenic, and antitumor effects. In this sense, this work aims to provide an extensive overview on the historical practices of stevia and its effects in human health based on its chemical composition and applications for both food and pharmaceutical industries.


Assuntos
Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Stevia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Diterpenos de Caurano/isolamento & purificação , Diterpenos de Caurano/farmacologia , Diterpenos de Caurano/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/fisiologia , Stevia/química , Stevia/fisiologia , Edulcorantes/química , Edulcorantes/farmacologia , Edulcorantes/uso terapêutico
10.
Acta Biochim Biophys Sin (Shanghai) ; 51(8): 814-825, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31314060

RESUMO

Recent studies have demonstrated that the expression of the long non-coding RNA (lncRNA) AFAP1-AS1 in pancreatic cancer is negatively correlated with survival and prognosis. However, the effects of oridonin and lncRNA AFAP1-AS1 on the epithelial-to-mesenchymal transition (EMT) and migration of pancreatic cancer cells have not been fully elucidated. Surgery is the only potentially curative method for pancreatic cancer, but postoperative recurrence and metastasis are common. The aim of the present study was to assess the effect of oridonin and lncRNA AFAP1-AS1 silencing on pancreatic cancer cells. The pancreatic cancer cell lines BxPC-3 and PANC-1 cells were transfected with siAFAP1-AS1 and its negative control (siNC). After that, oridonin was used to treat the siAFAP1-AS1-transfected cells. The expression of lncRNA AFAP1-AS1 was downregulated in the pancreatic cancer cell lines BxPC-3 and PANC-1. The apoptosis and cell cycle progression of pancreatic cancer cells were evaluated by flow cytometry and Hoechst 33258 staining. Metastasis and invasion of BxPC-3 and PANC-1 cells were detected by transwell migration assay, real-time cell analysis, and western blot analysis. Cells were transfected with the lentiviral siAFAP1-AS1 and siNC, and tumorigenesis was evaluated in BALB/C nude mice. Immunohistochemical examination was used to verify the effects of oridonin and siAFAP1-AS1 on pancreatic cancer. The results demonstrated that the combination of oridonin and siAFAP1-AS1 inhibited pancreatic cancer cell proliferation, induced apoptosis, arrested cell cycle progression, prevented the migration, regulated EMT-related protein expression in BxPC-3 and PANC-1 cells, and inhibited pancreatic cancer cell tumorigenicity and EMT in nude mice.


Assuntos
Diterpenos de Caurano/farmacologia , Transição Epitelial-Mesenquimal , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno/metabolismo
11.
Molecules ; 24(15)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31357638

RESUMO

To obtain diterpene glycosides from an aqueous extract of the aerial parts of Isodon henryi and further investigate their cytotoxicities, in this study, a total of seven compounds were isolated, including six ent-kaurane diterpene glycosides (1-6) and one diterpene aglycon (7). Among the seven ent-kaurane diterpenes obtained, four were novel compounds, including ent-7,20-epoxy- kaur-16-en-1α,6ß,7ß,15ß-tetrahydroxyl-11-O-ß-d-glucopyranoside (1), ent-7,20-epoxy-kaur-16-en- 6ß,7ß,14ß,15ß-tetrahydroxyl-1-O-ß-d-glucopyranoside (2), ent-7,20-epoxy-kaur-16-en-6ß,7ß,15ß- trihydroxyl-1-O-ß-d-glucopyranoside (3), and ent-7,20-epoxy-kaur-16-en-7ß,11ß,14α,15ß-tetrahydr- oxyl-6-O-ß-d-glucopyranoside (4), and three were isolated from this plant for the first time (5-7). Their structures were elucidated by utilizing spectroscopic methods and electronic circular dichroism analyses. Furthermore, the cytotoxicities of all seven compounds were investigated in four human cancer cell lines, including A2780, BGC-823, HCT-116, and HepG2. The IC50 values of these diterpenes ranged from 0.18 to 2.44 mM in the tested cell lines. In addition, the structure-cytotoxicity relationship of diterpene glycosides was also evaluated to study the effect of glycosylation on the cytotoxicity of diterpene compounds.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Isodon/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Modelos Moleculares , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
12.
Biochimie ; 165: 108-114, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336136

RESUMO

Oridonin is a diterpenoid isolated from the Rabdosia rubescens and has multiple biological effects, such as anti-inflammation and anti-tumor activities. In present study, we revealed that the sensitizing effect of oridonin on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in several cancer cells, but not in normal cells. Oridonin enhanced death-signaling inducing complexes (DISC) formation and DR5 glycosylation without affecting expression of downstream intracellular apoptosis-related proteins. Oridonin upregulated peptidyl O-glycosyltransferase GALNT14 in a dose- and time-dependent manner. Knockdown of GALNT14 by siRNA and Endo H treatment reduced oridonin-induced DR5 glycosylation. Furthermore, treatment with inhibitor of glycosylation (benzyl-α-GalNAc) blocked oridonin plus TRAIL-induced apoptosis. Collectively, our results suggest that oridonin-induced DR5 glycosylation contributes to TRAIL-induced apoptotic cell death in cancer cells.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , N-Acetilgalactosaminiltransferases/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Linhagem Celular , Glicosilação , Humanos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
13.
Artif Cells Nanomed Biotechnol ; 47(1): 2585-2592, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31220945

RESUMO

Oridonin (Orid) has been diffusely applied to remedy dissimilar cancers. Howbeit, the influence of Orid in ischemic heart disease (IHD) remains imprecise. The current study uncovered the functions of Orid in hypoxia-caused apoptosis and autophagy in H9c2 cells. H9c2 cells received hypoxia and Orid manipulation, cell viability, apoptosis, apoptosis-interrelated factors and autophagy-correlative factors were appraised. After the extraordinary vectors transfections, the impacts of miR-214 inhibition on hypoxia-triggered apoptosis and autophagy were investigated. Further, dual luciferase reporter assay was enforced for ascertaining the pertinence between miR-214 and PTEN. PI3K/AKT/mTOR pathway was finally determined using western blot. We found that, Orid significantly alleviated hypoxia-induced apoptosis and autophagy through regulation their associated proteins in H9c2 cells. Up-regulation of miR-214 was found in hypoxia and Orid co-managed cells, meanwhile, repression of miR-214 obviously annulled the modulatory functions of Orid in hypoxia-evoked apoptosis and autophagy. Additionally, PTEN was forecasted to be a firsthand target of miR-214. Besides, we observed that Orid evoked PI3K/AKT/mTOR activation through elevation of miR-214 in hypoxia-managed H9c2 cells. In conclusion, the amusing results corroborated that Orid relieved hypoxia-caused apoptosis and autophagy via adjusting PI3K/AKT/mTOR pathway through enhancement of miR-214 in H9c2 cells.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , MicroRNAs/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
Eur J Med Chem ; 178: 446-457, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202992

RESUMO

Motivated by our interest in hydrogen sulfide bio-chemistry and ent-kaurane diterpenoid chemistry, 14 hydrogen sulfide donating derivatives (9, 11a-c, 12a-c, 13, 14, 16a-c and 17a-b) of ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane were designed and synthesized. Four human cancer cell lines (K562, Bel-7402, SGC-7901 and A549) and two normal cell lines (L-02 and PBMC) were selected for antiproliferative assay. Most derivatives showed more potent activities than the lead ent-kaurane oridonin. Among them, compound 12b exhibited the most potent antiproliferative activities, with IC50 values of 1.01, 0.88, 4.36 and 5.21 µM against above human cancer cell lines, respectively. Further apoptosis-related mechanism study indicated that 12b could arrest Bel-7402 cell cycle at G1 phase and induce apoptosis through mitochondria related pathway. Through Western blot assay, 12b was shown to influence the intrinsic pathway by increasing the expression of Bax, cleaved caspase-3, cytochrome c and cleaved PARP, meanwhile suppressing procaspase-3, Bcl-2, Bcl-xL and PARP.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Desenho de Drogas , Sulfeto de Hidrogênio/farmacologia , Espironolactona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Sulfeto de Hidrogênio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Espironolactona/química , Relação Estrutura-Atividade
15.
Bull Exp Biol Med ; 167(2): 201-206, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236885

RESUMO

The role of NF-κB, cAMP/PKA, JAKs/STAT3, ERK1/2, p38, JNK, and p53 signaling pathways in the realization of growth potential of mesenchymal, neural, erythroid, and granulomonocytic progenitor cells were examined in vitro. Using selective blockers of signaling molecules, we revealed some principal distinctions of their involvement in determination of proliferation-differentiation status of the progenitor cells of different functional classes. The most salient peculiarities were observed in the roles of cAMP/PKA, JNK, and JAKs/STAT3 signaling pathways in the control of functions of various types of the regeneration-competent elements. The specific features of intracellular signaling revealed in histogenetically and functionally different progenitor cells attest to visibility of differentiated pharmacological stimulation of regeneration in individual tissues and prospectiveness in the development of targeted remedies for regenerative medicine based on modifiers of activity of the intracellular signaling molecules.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neurais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antracenos/farmacologia , Antraquinonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Didesoxiadenosina/farmacologia , Diterpenos de Caurano/farmacologia , Flavonoides/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Janus Quinases/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno , NF-kappa B/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Medicina Regenerativa , Fator de Transcrição STAT3/metabolismo , Sulfonamidas/farmacologia
16.
ACS Appl Mater Interfaces ; 11(26): 22915-22924, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252460

RESUMO

Graphene oxide (GO) possessing plenty of hydroxyls and carboxyls is often used in the field of biomedicine. To improve its water solubility and biocompatibility, 6-armed poly(ethylene glycol) (PEG) was bonded on the surface of GO sheets via a facile amidation process to form the universal drug delivery platform (GO-PEG10K-6arm) with a 200 nm size in favor of the enhanced permeability and retention effect. Herein, we prepared the stable and biocompatible platform of GO-PEG10K-6arm under mild conditions and characterized the chemical structure and micromorphology via thermogravimetric analysis and atomic force microscopy. This nanosized GO-PEG10K-6arm was found to be of very low toxicity to human normal cells of 293T and tumor cells of CAL27, MG63, and HepG2. Moreover, oridonin and methotrexate (MTX), widely used hydrophobic cancer chemotherapy drugs, were compounded with GO-PEG10K-6arm via π-π stacking and hydrophobic interactions so as to afford nanocomplexes of oridonin@GO-PEG10K-6arm and MTX@GO-PEG10K-6arm, respectively. Both nanocomplexes could quickly enter into tumor cells, which was evidenced by inverted fluorescence microscopy using fluorescein isothiocyanate as a probe, and they both showed remarkably high cytotoxicity to the tumor cells of CAL27, MG63, and HepG2 within a broad range of concentration in comparison with free drugs. This kind of nanoscale drug delivery system based on GO-PEG10K-6arm may have potential applications in biomedicine, and GO-PEG10K-6arm would be a universal and available carrier for extensive hydrophobic anticarcinogens.


Assuntos
Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Materiais Biocompatíveis/química , Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Grafite/química , Grafite/farmacologia , Células Hep G2 , Humanos , Metotrexato/química , Metotrexato/farmacologia , Polietilenoglicóis/química
17.
Eur J Med Chem ; 178: 365-379, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200238

RESUMO

The biological function of the natural ent-kaurene diterpenoid isolated from genus Isodon, oridonin, has been intensively studied. However, its mechanism studies and clinical applications were hampered by its moderate biological activities. In order to enlarge the applied range of oridonin and explore its mechanism of action, a series of derivatives were designed and synthesized based on the structure of oridonin. Some of the derivatives were significantly more potent than oridonin against four cancer cell lines. Especially, the most potent compound 20 markedly inhibited the proliferation of well differentiated HepG2 and poorly differentiated PLC/PRF/5 cells, with IC50 values as low as 1.36 µM and 0.78 µM respectively, while the IC50 values of oridonin are 8.12 µM and 7.41 µM. We found that compound 20 inhibited liver cancer cell proliferation via arresting cell cycle at G1 phase. Moreover, it induced liver cancer cell apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular reactive oxygen species level and inducing the expression of apoptosis-related proteins. Furthermore, compound 20 significantly inhibited growth of PLC/PRF/5 xenograft tumors in nude mice and had no observable toxic effect. Altogether, these results indicated that compound 20 is a promising lead for liver cancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Humanos , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Neurosci Lett ; 705: 195-201, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31039426

RESUMO

Amyloid-ß (Aß) plays a critical role in the pathogenesis of Alzheimer's disease (AD), an age-related neurodegenerative ailment. Emerging evidence suggests that Tenuifolin (TEN) significantly decreases Aß secretion and relieves cellular inflammatory responses. However, the mechanism of this activity has not been fully elucidated. In the present study, we investigate the effect of TEN on autophagy, a process that plays an important role in the generation and metabolism of Aß, in the presence or absence of the autophagy inhibitor 3-MA. The obtained results show that TEN prevents Aß25-35-induced inflammation and decreases Aß1-40 and Aß1-42 levels by decreasing BACE1 in SH-SY5Y cells. Moreover, TEN decreases the mRNA levels of BACE1 but has no impact on the gene expressions of amyloid precursor proteins (APP). 3-MA, the most widely used autophagy inhibitor, reverses the effects of TEN in Aß25-35-induced SH-SY5Y cells. The association between TEN and autophagy was further investigated by examining the levels of autophagy markers LC3 II and Beclin 1, as well as the protein levels of mTOR, AMPK, and ULK1. The results showed that TEN increases LC3 II, Beclin 1, and mTOR, inhibits the degradation of AMPK, and increases the expression of ULK1. This suggests that TEN protects against Aß25-35-induced cellular inflammation in an AD cell model through the regulation of autophagy, which, in part, is mediated by the activation of the AMPK/mTOR/ULK1 pathway.


Assuntos
Doença de Alzheimer/metabolismo , Autofagia/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/metabolismo , Apoptose/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Serina-Treonina Quinases TOR/metabolismo
19.
Mol Omics ; 15(3): 222-232, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31069354

RESUMO

Diabetes is one of the most severe chronic diseases worldwide. It is widely accepted that apoptosis of the pancreatic beta cell is an important cause for the induction of hyperglycemia and high levels of free fatty acids (FFAs), also called lipotoxicity associated with pancreatic beta cell dysfunction. Lipotoxicity has been proven to be an important pathogenic factor of diabetes. However, until now, the mechanism of FFA-induced lipotoxicity in INS-1 cells has not been fully understood. Current anti-diabetic drugs that protect islet cells are often toxic to healthy cells, resulting in negative side effects. Thus, there is an urgent need to identify more effective and safer anti-diabetic agents to protect pancreatic islet cells. Rubusoside (RUB) is a major ingredient in the leaves of Rubus suavissimus S. Lee, which decreases blood glucose levels by protecting pancreatic islet cells. However, the exact mechanism of this effect is unknown. In this study, metabolomics experiments based on UPLC-Q/TOF MS characterized a total of 15 metabolites as potential biomarkers associated with lipotoxicity induced by palmitic acid in INS-1 cells. According to the metabolic pathway analysis, pentose and glucuronate interconversions, and glycerophospholipid metabolism were recognized as the most influenced metabolic pathways associated with lipotoxicity. Unexpectedly, deviations of 14 metabolites in lipotoxic INS-1 cells were regulated by RUB, suggesting synergistic mediation of the abnormal metabolic pathways. The metabolomics strategy based on UPLC/Q-TOF MS analysis provides a new insight into the mechanisms of lipotoxicity induced by palmitic acid and the anti-lipotoxic activity of RUB in INS-1 cells.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Glucosídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica , Ácido Palmítico/farmacologia , Animais , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Inibidores Enzimáticos/farmacologia , Espectrometria de Massas/métodos , Camundongos , Edulcorantes/farmacologia
20.
Anal Chim Acta ; 1068: 80-86, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31072480

RESUMO

Effective detection of the intracellular expression level of transcription factors is important for biological research and medical diagnosis. This study proposes a rapid and simple fluorescence sensing strategy for highly sensitive detection of a transcription factor, nuclear factor-kappa B (NF-κB). NF-κB binds to double-stranded DNA duplex, one of which is then protected from Exonuclease III (Exo III) digestion. An Exo III-mediated hydrolysis cycle on TaqMan probes is then triggered to achieve highly sensitive detection of NF-κB. This method can detect NF-κB with concentration as low as 45.6 pM. Furthermore, sequence-specific binding of NF-κB to DNA provides good selectivity. This method can be used for the direct quantification of nuclear proteins extracted from cells. More importantly, by simply replacing the sequence of the probe binding site, this method can also be used for reliable quantification of other DNA-binding proteins and is thus a universal sensing protocol. This strategy can be a powerful technology in the areas of disease diagnosis and pharmaceutical research.


Assuntos
Técnicas Biossensoriais , Exodesoxirribonucleases/metabolismo , NF-kappa B/análise , Diterpenos de Caurano/farmacologia , Humanos , NF-kappa B/antagonistas & inibidores , Espectrometria de Fluorescência
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