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1.
Biomed Res Int ; 2019: 2595801, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240207

RESUMO

Triptolide has been proven to possess anticancer efficacy; however, its application in the clinical practice was limited by poor water solubility, hepatotoxicity, and nephrotoxicity. In this study, a triptolide-loaded exosomes delivery system (TP-Exos) was constructed and its effects on the proliferation and apoptosis of SKOV3 cells in vitro and in vivo were observed. SKOV3-exosomes (SK-Exos) were collected by ultracentrifugation and ultrafiltration centrifugation. TP-Exos was constructed by sonication and ultrafiltration centrifugation. SK-Exos and TP-Exos were characterized by transmission electron microscopy, western blotting, nanoparticle-tracking analysis, and high-performance liquid chromatography. Cellular uptake of exosomes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, bromodeoxyuridine (BrdU) cell proliferation assay, and cell apoptosis experiment were used to study the effect of TP-Exos on ovarian cancer in vitro. Tumor-targeting study of exosomes, monitoring the tumor volume of mice, and TdT-mediated dUTP Nick-End labeling (TUNEL) assay were used to evaluate the effect of TP-Exos on ovarian cancer in vivo. The toxicity of TP-Exos in vivo was evaluated by liver and kidney function and histopathology of major organs (heart, liver, spleen, lung, kidney, and ovary). The results revealed that TP-Exos not only have the general characteristics of exosomes but also have high drug encapsulation efficiency. Besides, PKH26 labeled exosomes (PKH26-Exos) could be uptaken by SKOV3 cells, and Dir labeled exosomes (Dir-Exos) could be enriched to the tumor site of tumor bearing mice. Furthermore, the cytotoxic and apoptotic effects on SKOV3 cells of TP-Exos were weaker than those of free TP, and tumor cell proliferation inhibition and tumor growth inhibition were stronger than that of free TP. Moreover, TP-Exos have toxic effect on liver and spleen. In conclusion, the TP-Exos could be a promising strategy for ovarian cancer, but they need to be further optimized to attenuate the damage to liver and spleen.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Exossomos/metabolismo , Neoplasias Ovarianas/metabolismo , Fenantrenos/farmacologia , Animais , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Diterpenos/uso terapêutico , Sistemas de Liberação de Medicamentos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Ovário , Fenantrenos/uso terapêutico , Coelhos , Testes de Toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Neurochem Res ; 44(8): 1977-1985, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31236795

RESUMO

Tripterygium Wilfordii Hook F has been exploited as a treatment for several diseases due to its neuroprotective, anti-tumor, and anti-inflammatory effects. Triptolide is one of its key bioactive compounds. Currently, the role of triptolide in cognitive dysfunction remains unclear. Here, the role of triptolide on cognitive dysfunction was investigated using chronic cerebral hypoperfusion-induced vascular dementia (VD) rat model. SD rats were administrated with Triptolide (5 µg/kg) for 6 weeks after undergoing permanent bilateral common carotid artery occlusion. The results show that triptolide treatment conferred neuroprotective effects in VD rats. Intraperitoneal injection of triptolide attenuated oxidative stress, learning and memory deficits, and neuronal apoptosis in the hippocampi. Moreover, triptolide enhanced the expression of SIRT1, PGC-1α, ZO-1, Claudin-5, and decreased the serum levels of NSE and S100B significantly. It also improved CCH-induced learning and memory deficits, and this is attributed to its capacity to promote SIRT1/PGC-1α signaling, confer antioxidant effects, and inhibit neuronal apoptosis. These findings indicate that triptolide may be an effective therapeutic agent for vascular cognitive dysfunction.


Assuntos
Demência Vascular/prevenção & controle , Diterpenos/uso terapêutico , Nootrópicos/uso terapêutico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fenantrenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Claudina-5/metabolismo , Compostos de Epóxi/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
3.
Spine (Phila Pa 1976) ; 44(12): E707-E714, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150368

RESUMO

STUDY DESIGN: The effect of triptolide on spinal cord injury (SCI) and inflammatory response was observed by establishing SCI rat model. And in vitro experiments were conducted to determine the underlying mechanism of triptolide-mediated in murine microglial cell line BV2. OBJECTIVE: To determine the underlying mechanism of triptolide in suppressing the microglia activation to improve SCI. SUMMARY OF BACKGROUND DATA: Triptolide, as a major active ingredient of Chinese herb Tripterygium wilfordii, can promote spinal cord repair through inhibiting microglia activation, but the underlying mechanism is not clear. METHODS: Locomotion recovery was accessed by Basso, Beattie, and Bresnahan score, the number of footfalls, stride length, and angle of rotation analysis. Expressions of microRNA 96 (miR-96), microglia activation marker Iba-1, and IκB kinase (IKKß)/nuclear factor (NF)-κB-related proteins were detected by qRT-PCR or western blot. Inflammatory cytokines tumor necrosis factor-α and interleukin -1ß were measured by enzyme-linked immuno sorbent assay. The regulation of miR-96 on IKKß was confirmed by dual luciferase reporter assay. RESULTS: Triptolide promoted locomotion recovery of SCI rats, upregulated the expression of miR-96, decreased microglia activation marker Iba-1 and IKKß/NF-κB-related proteins, and inhibited inflammatory cytokines tumor necrosis factor-α and interleukin-1ß levels in spinal cord tissues and lipopolysaccharide -induced microglia. Triptolide suppressed the microglia activation and inflammatory cytokines secretion in BV2 cells through up-regulating miR-96. We confirmed the interaction between miR-96 and IKKß, and IKKß expression was negatively regulated by miR-96. Finally, we determined that triptolide suppressed the microglia activation and inflammatory cytokines secretion through miR-96/IKKß pathway. CONCLUSION: Triptolide suppressed microglia activation after SCI through miR-96/IKKß/NF-κB pathway. LEVEL OF EVIDENCE: N/A.


Assuntos
Diterpenos/uso terapêutico , Quinase I-kappa B/biossíntese , MicroRNAs/biossíntese , Microglia/metabolismo , NF-kappa B/biossíntese , Fenantrenos/uso terapêutico , Traumatismos da Medula Espinal/metabolismo , Animais , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fenantrenos/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico
4.
Am J Chin Med ; 47(4): 769-785, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091976

RESUMO

Tripterygium wilfordii Hook F. (TWHF), a traditional Chinese medicine, has been widely used to treat autoimmune and inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis in China. Recently, studies have demonstrated that the bioactive components of TWHF have effective therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. In this paper, we summarize the research progress of triptolide and celastrol (the two major TWHF components) as well as their analogues in the treatment of neurodegenerative diseases. In addition, we review and discuss the molecular mechanisms and structure features of those two bioactive TWHF components, highlighting their therapeutic promise in neurodegenerative diseases.


Assuntos
Diterpenos/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Fenantrenos/uso terapêutico , Fitoterapia , Tripterygium/química , Triterpenos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Compostos de Epóxi/química , Compostos de Epóxi/isolamento & purificação , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Conformação Molecular , Fármacos Neuroprotetores , Doença de Parkinson/tratamento farmacológico , Fenantrenos/química , Fenantrenos/isolamento & purificação , Fenantrenos/farmacologia , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
5.
Trends Pharmacol Sci ; 40(5): 327-341, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30975442

RESUMO

Triptolide, a compound isolated from a Chinese medicinal herb, possesses potent antitumor, immunosuppressive, and anti-inflammatory properties, but is clinically limited due to its poor solubility, bioavailability, and toxicity. Recently, Minnelide, a water-soluble prodrug of triptolide, was shown to have potent antitumor activity in various preclinical cancer models. Minnelide is currently in Phase II clinical trials for treatment of advanced pancreatic cancer, which has fueled increased interest in this promising agent. Here, we review the recent advances in the biological activity of triptolide and its analogs, their mechanisms of actions, and their clinical developments. A special emphasis is given to proteins and pathways within the tumor and stromal compartments that are targeted by triptolide and its analogs as well as the ongoing clinical trials.


Assuntos
Antineoplásicos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Fenantrenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Fenantrenos/química , Fenantrenos/uso terapêutico
6.
Int Immunopharmacol ; 71: 14-21, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30861393

RESUMO

Triptolide is a biologically active component of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus. However, its immunological mechanisms are poorly understood. Regulatory T cells (Treg) are pivotal for maintaining peripheral self-tolerance and controlling autoimmunity. This study was undertaken to examine the therapeutic effect of triptolide in lupus mice and the related molecular mechanisms. Our results showed that triptolide treatment ameliorated serum anti-dsDNA, proteinuria and renal histopathologic assessment in MRL/lpr mice, induced the miR-125a-5p expression and enhanced the proportion of Treg in vivo. In vitro, triptolide upregulated the proportion of Treg and the miR-125a-5p expression. Down-regulation of the miR-125a-5p expression reversed the effect of triptolide on Treg. In conclusion, triptolide could induce Treg and the miR-125a-5p expression in vivo and in vitro. Inhibiting the effect of miR-125a-5p could counteract the effect of triptolide on inducing Treg. The study has strong implications for the therapeutic applications of triptolide in systemic lupus erythematosus.


Assuntos
Antirreumáticos/uso terapêutico , Diterpenos/uso terapêutico , Rim/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fenantrenos/uso terapêutico , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Antinucleares/sangue , Proliferação de Células , Modelos Animais de Doenças , Compostos de Epóxi/uso terapêutico , Feminino , Humanos , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , MicroRNAs/genética , Proteinúria , Regulação para Cima
7.
Int J Nanomedicine ; 14: 851-863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774338

RESUMO

Purpose: This study was carried out to investigate the effects of a triptolide (TP) nanosuspension and methotrexate (MTX) nanosuspension on left ventricular remodeling and cardiac function for autoimmune myocarditis (EAM) in rats. The regulating effects on inflammatory cytokines in the peripheral serum and related mechanisms are also discussed. Methods: First, TP and MTX were prepared as a nanosuspension, and the EAM model was successfully established in rats with cardiac myosin. Then, the effect of TP and MTX suspensions was tested in an EAM model. Results: Results revealed that both TP and MTX suspensions could reduce the degree of myocardial fibrosis and delay the remodeling process of the left ventricle which could further improve cardiac function. Finally, it was found that inflammatory cytokines in the peripheral serum were regulated by the nonspecific immune system and the inhibition of nuclear factor-κB signaling might have partly occurred due to this mechanism. Conclusion: In summary, this study provided a complete foundation for EAM therapy of profound clinical relevance.


Assuntos
Diterpenos/uso terapêutico , Metotrexato/uso terapêutico , Miocardite/tratamento farmacológico , Miocardite/fisiopatologia , Nanopartículas/química , Fenantrenos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/sangue , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Testes de Função Cardíaca , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Masculino , Metotrexato/farmacologia , Miocardite/sangue , Miocardite/diagnóstico por imagem , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Tamanho da Partícula , Fenantrenos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos , Suspensões
8.
Int J Nanomedicine ; 13: 7229-7249, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510415

RESUMO

Aim: To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study. Materials and methods: The nanocarrier was constructed by conjugating 3,3'-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment. Results: Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group. Conclusion: These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.


Assuntos
Diterpenos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Micelas , Fenantrenos/administração & dosagem , Polímeros/química , Neoplasias da Próstata/tratamento farmacológico , Adsorção , Animais , Linhagem Celular Tumoral , Diterpenos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Sinergismo Farmacológico , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Masculino , Anidridos Maleicos/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Oxirredução , Tamanho da Partícula , Fenantrenos/uso terapêutico , Neoplasias da Próstata/patologia , Espectroscopia de Prótons por Ressonância Magnética , Eletricidade Estática
9.
BMC Cancer ; 18(1): 1103, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419860

RESUMO

BACKGROUND: Triptolide induces apoptosis and DNA damage followed by inhibition of DNA repair associated gene expression. However, there is the limited data for biomarker to predict the benefit to triptolide in various cancers including pancreatic cancer. METHODS: We investigated the anti tumor efficacy of triptolide in various pancreatic cancer cell lines (Capan-1, Capan-2, SNU-213, SNU-410, HPAFII, and Hs766T) and patient derived cells (PDCs) from metastatic pancreatic cancer patients. RESULTS: In vitro cell viability assay for triptolide in 6 PC cell lines, the IC50 was 0.01 uM, 0.02 uM, 0.0096 uM for triptolide in Capan-1, Capan-2 and SNU-213. However, the growth of tumor cells was not significantly reduced by triptolide in Hs766T, SNU-410 and HPAFII. The distinct difference of gene expression was also observed between Capan-1, Capan-2 and SNU-213 and Hs766T, SNU-410 and HPAFII. In analysis of pathway using gene expression profiles, the integrin mediated RAS signaling pathway was associated with the sensitivity of the triptolide in PC cell lines. Immunoblot assay showed that Chk2 phosphorylation after triptolide was distinctively observed in SNU-213 sensitive to triptolide but, not in SNU-410 insensitive to triptolide. This finding in immunoblot assay was also reproduced in PDCs originated from pancreatic cancer patients. CONCLUSIONS: Our findings might be helpful to completely capture the subset of patients who may benefit to tripolide (minnelide). More robust biomarkers such as KRAS mutation and Chk2 phosphorylation and careful clinical trial design using triptolide (minnelide) are warranted.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Diterpenos/farmacologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fenantrenos/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional/métodos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA , Diterpenos/uso terapêutico , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Expressão Gênica , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Fenantrenos/uso terapêutico , Transdução de Sinais , Transcriptoma , Proteínas ras/metabolismo
10.
JCI Insight ; 3(19)2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30282833

RESUMO

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eµ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos de Epóxi/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Macrolídeos/farmacologia , Sulfonamidas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/uso terapêutico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Macrolídeos/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosfoproteínas/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Processamento de RNA/genética , Spliceossomos/efeitos dos fármacos , Spliceossomos/metabolismo , Sulfonamidas/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico
11.
Int J Biol Sci ; 14(11): 1545-1557, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30263007

RESUMO

Triptolide possesses the trait of renal protection. Epithelial-mesenchymal transition (EMT) is closely linked to the pathogenesis of diabetic kidney disease (DKD). MicroRNAs have recently emerged as critical regulators of DKD. However, it is poorly understood whether triptolide alleviates renal EMT by regulating microRNAs in DKD. In this study, we found that triptolide decreased albuminuria, improved the renal structure and reduced renal EMT in rats with DKD. Furthermore, activation of the PI3K/AKT signaling pathway was increased in diabetic rats, which was partly reversed by triptolide. Triptolide also alleviated glucose-induced EMT in HK-2 cells in vitro. PI3K/AKT signaling pathway activation was reduced after triptolide treatment. Moreover, triptolide decreased the increase in miR-188-5p expression stimulated by high glucose levels in HK-2 cells. miR-188-5p inhibited PTEN expression by directly interacting with the PTEN 3'-untranslated region. Additionally, downregulation of miR-188-5p, which imitates the effects of triptolide, attenuated the activation of the PI3K/AKT pathway and HG-induced EMT, whereas miR-188-5p overexpression reversed the effects of triptolide on the PI3K/AKT pathway and EMT. In conclusion, we demonstrated that triptolide ameliorates renal EMT via the PI3K/AKT signaling pathway through the interaction between miR-188-5p and PTEN, indicating that miR-188-5p may be a therapeutic target of triptolide in DKD.


Assuntos
Nefropatias Diabéticas/metabolismo , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/metabolismo , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Masculino , PTEN Fosfo-Hidrolase/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
12.
J Cell Biochem ; 119(12): 9866-9877, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30156009

RESUMO

Medulloblastoma is a primitive neuroectodermal-derived brain tumor and the most common malignant brain tumor in children. Triptolide (TPL) is the major active component extracted from Tripterygium wilfordii Hook F. This study aimed to explore the effects of TPL on medulloblastoma cell proliferation, migration, and apoptosis, as well as the underlying possible molecular mechanism. Viability, proliferation, and apoptosis of Daoy cells were measured using cell counting kit-8 assay, 5-bromo-2'-deoxyuridine incorporation assay, and Guava Nexin assay, respectively. Cell migration was detected using two-chamber transwell assay and wound healing assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to determine the relative expression of microRNA-138 (miR-138) in Daoy cells. Cell transfection was used to change the expression of miR-138 in cells. Western blot analysis was used to analyze the expression of key factors involved in cell apoptosis, cell migration, the phosphatidylinositol 3-kinase (PI3K)/protein kinase 3 (AKT) pathway, and the Notch pathway in Daoy cells. We found that TPL significantly inhibited the viability, proliferation, and migration of Daoy cells but promoted Daoy cell apoptosis. The expression levels of matrix metalloproteinases (MMP)-2 and MMP-9 after TPL treatment were decreased. The expression of miR-138 in Daoy cells after TPL treatment was increased. Suppression of miR-138 obviously reversed the TPL-induced Daoy cell proliferation, migration inhibition, and cell apoptosis enhancement, as well as the inactivation of the PI3K/AKT and Notch pathways. Cyclin-dependent kinase 6 (CDK6) was a direct target gene of miR-138, which might be involved in the antitumor effects of TPL on Daoy cells. In conclusion, our study verified that TPL exerted anticancer effects on medulloblastoma cells possibly via upregulating miR-138 and inactivating the PI3K/AKT and Notch pathways.


Assuntos
Proliferação de Células , Neoplasias Cerebelares/tratamento farmacológico , Diterpenos/farmacologia , Meduloblastoma/tratamento farmacológico , MicroRNAs/genética , Fenantrenos/farmacologia , Transdução de Sinais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/fisiopatologia , Diterpenos/uso terapêutico , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/fisiopatologia , Fenantrenos/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo
13.
Mol Immunol ; 101: 210-220, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30007231

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cellular infiltration into the joints and cartilage destruction. Neutrophils play a crucial role in the pathogenesis of RA. Triptolide (TP) is a bioactive compound derived from Tripterygium wilfordii Hook F, which has been used in folk medicine as a treatment for a variety of inflammatory disorders, including RA, for many centuries. Previous studies have shown that TP possesses anti-arthritic activity. However, the anti-arthritic mechanism of TP remains to be fully defined. In the present study, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TP on RA and neutrophil function. TP alleviated AA by reducing neutrophil recruitment and suppressing the expression of interleukin-6 and tumour necrosis factor-α in vivo. TP also suppressed the expression of pro-inflammatory cytokines in neutrophils, promoted neutrophil apoptosis and inhibited the migration, NETosis and autophagy of neutrophils in vitro. Based on our findings, TP effectively ameliorates RA by down-regulating neutrophil inflammatory functions, indicating that TP represents a potential therapeutic agent for RA.


Assuntos
Artrite Reumatoide/patologia , Diterpenos/farmacologia , Inflamação/patologia , Neutrófilos/patologia , Fenantrenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Artrite Experimental/patologia , Autofagia/efeitos dos fármacos , Doença Crônica , Citocinas/biossíntese , Diterpenos/uso terapêutico , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Armadilhas Extracelulares/efeitos dos fármacos , Inflamação/tratamento farmacológico , Elastase de Leucócito/metabolismo , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo , Fenantrenos/uso terapêutico
14.
J Cancer Res Ther ; 14(Supplement): S271-S275, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29970675

RESUMO

In recent years, cancer has become the most common human disease worldwide, and great attentions have been paid to clarifying the carcinogenesis and identifying new effective antitumor therapy. Although great progress has been made in this research field, human malignant diseases could still not be radically cured. Thunder god vine is a herbal medicine, which has proved to exert efficient antitumor activity in various human cancers such as lung cancer, pancreatic cancer, and colon cancer. In vivo and in vitro experiments showed that thunder god vine extract triptolide could inhibit tumor cell proliferation, cell migration, and cell invasion. Here, we overviewed the functional role of triptolide in human malignancies and its promising therapeutic potential in treating such deadly diseases.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Diterpenos/uso terapêutico , Neoplasias/tratamento farmacológico , Fenantrenos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Humanos , Prognóstico
15.
Diabetologia ; 61(9): 1918-1922, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29992370

RESUMO

AIMS/HYPOTHESIS: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.


Assuntos
Aminopeptidases/antagonistas & inibidores , Cinamatos/uso terapêutico , Cicloexanos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Compostos de Epóxi/uso terapêutico , Metaloendopeptidases/antagonistas & inibidores , Sesquiterpenos/uso terapêutico , Adolescente , Adulto , Idoso , Aminopeptidases/metabolismo , Fármacos Antiobesidade/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Glicoproteínas , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metaloendopeptidases/metabolismo , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Perda de Peso/efeitos dos fármacos , Adulto Jovem
16.
Genome Med ; 10(1): 49, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29950180

RESUMO

BACKGROUND: Abnormal pre-mRNA splicing regulation is common in cancer, but the effects of chemotherapy on this process remain unclear. METHODS: To evaluate the effect of chemotherapy on slicing regulation, we performed meta-analyses of previously published transcriptomic, proteomic, phosphoproteomic, and secretome datasets. Our findings were verified by LC-MS/MS, western blotting, immunofluorescence, and FACS analyses of multiple cancer cell lines treated with cisplatin and pladienolide B. RESULTS: Our results revealed that different types of chemotherapy lead to similar changes in alternative splicing by inducing intron retention in multiple genes. To determine the mechanism underlying this effect, we analyzed gene expression in 101 cell lines affected by ɣ-irradiation, hypoxia, and 10 various chemotherapeutic drugs. Strikingly, оnly genes involved in the cell cycle and pre-mRNA splicing regulation were changed in a similar manner in all 335 tested samples regardless of stress stimuli. We revealed significant downregulation of gene expression levels in these two pathways, which could be explained by the observed decrease in splicing efficiency and global intron retention. We showed that the levels of active spliceosomal proteins might be further post-translationally decreased by phosphorylation and export into the extracellular space. To further explore these bioinformatics findings, we performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally, we demonstrated that the splicing inhibitor pladienolide B impairs the cellular response to DNA damage and significantly increases the sensitivity of cancer cells to chemotherapy. CONCLUSIONS: Decreased splicing efficiency and global intron retention is a novel stress response mechanism that may promote survival of malignant cells following therapy. We found that this mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin which makes it a good candidate drug for improving the efficiency of cancer therapy.


Assuntos
Regulação para Baixo/genética , Neoplasias/genética , Neoplasias/terapia , Precursores de RNA/genética , Processamento de RNA/genética , Estresse Fisiológico/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Dano ao DNA/genética , Regulação para Baixo/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Íntrons/genética , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Fosforilação , Proteômica , Precursores de RNA/metabolismo , Processamento de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Oncol ; 53(3): 987-1000, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29956738

RESUMO

Parthenolide (PTL) is a sesquiterpene lactone compound obtained from Tanacetum parthenium (feverfew) and inhibits the activation of nuclear factor (NF)-κB. Epoxymicheliolide (EMCL) is a compound which is structurally related to PTL; however, EMCL is more stable under acidic and alkaline conditions. As a biologically active molecule, the detailed mechanism by which EMCL inhibits tumor activity remains to be elucidated. The present study evaluated the effect of EMCL on renal cell carcinoma (RCC) cells and identified the underlying mechanisms. It was found that treatment with EMCL significantly inhibited the proliferation of RCC cells in vitro and increased the induction of apoptosis by activating the mitochondria- and caspase-dependent pathway. Simultaneously, EMCL suppressed cell invasion and metastasis by inhibiting epithelial-mesenchymal transition, as observed in a microfluidic chip assay. Furthermore, using immunofluorescence analysis, an electrophoretic mobility shift assay and a dual-luciferase reporter assay, it was shown that treatment with EMCL significantly suppressed the expression of cyclooxygenase­2 by inhibiting the translocation of NF­κB p50/p65 and the activity of NF­κB. Collectively, the results indicated that EMCL suppressed tumor growth by inhibiting the activation of NF­κB and suggested that EMCL may be a novel anticancer agent in the treatment of RCC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Compostos de Epóxi/farmacologia , Quinase I-kappa B/metabolismo , Neoplasias Renais/tratamento farmacológico , Sesquiterpenos de Guaiano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/química , Compostos de Epóxi/uso terapêutico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Renais/patologia , Leucina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/uso terapêutico
18.
Biomed Pharmacother ; 104: 771-780, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29807227

RESUMO

Cancer cell resistance to current anticancer therapeutics as well as the side effects are still obstacles to successful cancer therapy. Hence, the development of novel anticancer agents or therapeutics is of vital significance, and especially rational adjuvant therapies containing low-cost natural products with multiple targets have attracted great interests. Triptolide, the main biocomponent of Tripterygium wilfordii Hook F, is restricted in clinical applications mainly due to its severe systemic toxicities, although it has shown strong antitumor activities in preclinical studies. Mounting evidence suggests that triptolide at low doses as an adjuvant therapeutic agent circumvents resistance to current anticancer therapies, enhances the anticancer effectiveness, and relieves toxicities of both triptolide and anticancer therapies. Furthermore, several unique antitumor targets of triptolide make it superior to other therapeutics. The molecular mechanisms of triptolide-induced anti-resistance and sensitization effects include changes in ATP-binding cassette transporters, induction of apoptosis pathways, increase in tumor suppressors and decrease in oncogenic factors, and interactions with the RNA polymerase II complex; targeting cancer stem cells and tumor-microenvironment-mediated resistance are also involved. Besides, some synthetic derivatives and novel delivery systems of triptolide are also developed to enhance the water-solubility and reduce the toxicity, which will also be discussed.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos
19.
BMC Musculoskelet Disord ; 19(1): 129, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703208

RESUMO

BACKGROUND: It was indicated that inhibition of PPARγ probably represents a novel therapy for steroid-related osteonecrosis. In this study, we investigated the preventive effects of PPARγ inhibition on steroid-related osteonecrosis in a rabbit model. METHODS: Rabbits were randomly divided into three groups (normal group, model group and BADGE group). Osteonecrosis was induced in rabbits in the model group and the BADGE group. The BADGE group also received bisphenol a diglycidyl ether(BADGE), a PPARγ antagonist, for 6 weeks. RESULTS: Histopathological results indicated that rabbits treated with BADGE exhibited significantly reduced osteonecrotic changes, incidence of osteonecrosis and bone marrow adiposity. Furthermore, BADGE-treated rabbits exhibited reduced intraosseous pressure and increased femoral blood perfusion. Micro-computed tomography and bone histomorphometry indicated that the BADGE group exhibited significantly improved bone quality and mineral appositional rate compared with the model group. Furthermore, the BADGE group showed a significant increase in circulating levels of the bone formation marker osteocalcin and reduced levels of the bone resorption marker TRACP. Overall, BADGE-treated rabbits exhibited reduced marrow adiposity concomitant with improved bone formation. CONCLUSIONS: In conclusion, these observations demonstrated that pharmacological inhibition of PPARγ might represent an effective therapy for steroid-related osteonecrosis in the near future.


Assuntos
Compostos Benzidrílicos/farmacologia , Modelos Animais de Doenças , Compostos de Epóxi/farmacologia , Osteonecrose/induzido quimicamente , Osteonecrose/prevenção & controle , PPAR gama/antagonistas & inibidores , Esteroides/efeitos adversos , Animais , Compostos Benzidrílicos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Masculino , Metilprednisolona/efeitos adversos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteonecrose/diagnóstico por imagem , PPAR gama/fisiologia , Coelhos , Distribuição Aleatória
20.
Int J Mol Med ; 41(6): 3127-3136, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512681

RESUMO

Myocardial ischemia/reperfusion (I/R) induces cardiac cell injury; however, the mechanism underlying cardiac damage remains unclear. A previous study demonstrated that triptolide (TP) exerts protective effects against I/R in cerebral cells. The present study aimed to evaluate the protective effects of TP on cardiac cells, and investigated the potential mechanisms involved in I/R­induced damage. Rats and cardiac H9C2 cells undergoing I/R were pretreated with TP, and cell damage was assessed in vivo and in vitro. Hematoxylin and eosin and terminal deoxynucleotidyl­transferase­mediated dUTP nick end labeling staining were employed to evaluate I/R injury in rat cardiac tissue. Inflammatory factors, including tumor necrosis factor­α, interleukin (IL)­1ß and IL­6, were detected by ELISA. Biochemical analyses were performed to evaluate the bioactivity of superoxide dismutase, malondialdehyde and catalase. In addition, viability of H9C2 cells was measured using the Cell Counting kit 8 assay. Flow cytometry was used to evaluate cell apoptosis and reactive oxygen species (ROS) generation. Furthermore, the expression levels of proteins associated with apoptosis, peroxide and inflammation were measured using western blot analysis. H9C2 cells were also treated with N­acetylcysteine and pyrrolidine dithiocarbamate, and cell injury was assessed after peroxidation or I/R. The results demonstrated that TP exerted a significant protective effect on cardiac cells in vivo and in vitro. TP reduced the inflammatory response, as determined by nuclear factor­κB inhibition. In addition, TP decreased ROS­mediated lipid peroxidation, and reduced ROS generation. TP also inhibited cell apoptosis by activating the extracellular signal­regulated kinase 1/2 pathway. In conclusion, TP may protect cardiac cells from I/R injury; the potential protective mechanisms of TP against I/R include anti­inflammatory action, antioxidation and apoptotic resistance.


Assuntos
Diterpenos/uso terapêutico , NF-kappa B/metabolismo , Fenantrenos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Compostos de Epóxi/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
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