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1.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3330-3334, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602891

RESUMO

Triptolide( TP) is isolated from the traditional Chinese medicine Tripterygium wilfordii,which exhibits notable immuneregulative effect. Th17 cells involve in inflammatory response and Treg cells contribute to immune tolerance. They both play an important role in immune response. Previous studies have investigated that TP induced hepatic Th17/Treg imbalance. However,the effect of TP on spleen Th17/Treg cells remains unclear. Therefore,the aim of present study was to investigate the effect of TP on Th17/Treg cells in spleen. In this study,the effect of TP on the proliferation of splenic lymphocyte was detected by cytotoxicity test in vitro. After different concentrations of TP( 2. 5,5,20,40 nmol·L~(-1)) were given to splenic lymphocyte,cytokines secreted from the supernatant of splenic lymphocyte were detected by cytometric bead array,and the expression of suppressor of cytokine signaling( SOCS) mRNA was detected by qRT-PCR. Female C57 BL/6 mice were continuously observed for 24 h after treatment of 500 µg·kg-1 TP. The effects of TP on the splenic tissue structure and the percentage of Th17/Treg cells were examined. The results showed that the IC50 of TP was19. 6 nmol·L~(-1) in spleen lymphocytes. TP inhibited the secretion of IL-2 and IL-10 and induced the expression of SOCS-1/3 mRNA in spleen lymphocytes at the dosage of 2. 5 and 5 nmol·L~(-1) after 24 h in vitro. Administration of TP at dosage of 500 µg·kg-1 had no significant spleen toxicity in vivo. TP treatment increased the percentage of Th17 cells after 12 h and inhibited the proportion of Treg cells after 12 and 24 h. In conclusion,TP reduced the secretion of IL-2 and IL-10 through SOCS-1/3 signaling pathway,thereby induced the percentage of Th17 cells and inhibited the percentage of Treg cells.


Assuntos
Diterpenos/farmacologia , Fenantrenos/farmacologia , Baço/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Células Th17/citologia , Animais , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Baço/citologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
2.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3391-3398, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602900

RESUMO

Tumors are major chronic diseases and seriously threaten human health all over the world. How to effectively control and cure tumors is one of the most pivotal problems in the medical field. At present,surgery,radiotherapy and chemotherapy are still the main treatment methods. However,the side effects of radiotherapy and chemotherapy cannot be underestimated. Therefore,it is of great practical significance to find new anti-cancer drugs with low toxicity,high efficiency and targeting to cancer cells. With the increasing incidence of tumor,the anti-tumor effect of traditional Chinese medicine has increasingly become a research hotspot. Triptolide,which is a natural diterpenoid active ingredient derived from of Tripterygium wilfordii,as one of the highly active components,has anti-inflammatory,immunosuppressive,anti-tumor and other multiple effects. A large number of studies have confirmed that it has good anti-tumor activity against various tumors in vivo and in vitro. It can play an anti-tumor role by inhibiting the proliferation of cancer cells,inducing apoptosis of cancer cells,inducing autophagy of cancer cells,blocking the cell cycle,inhibiting the migration,invasion and metastasis of cancer cells,reversing multidrug resistance,mediating tumor immunity and inhibiting angiogenesis. On the basis of literatures,this paper reviews the anti-tumor effect and mechanism of triptolide,and analyzes the current situation of triptolide combined with other chemotherapy drugs,in order to promote deep research and better clinical application about triptolide.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Neoplasias/tratamento farmacológico , Fenantrenos/farmacologia , Tripterygium/química , Apoptose , Autofagia , Pontos de Checagem do Ciclo Celular , Compostos de Epóxi/farmacologia , Humanos
3.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3423-3428, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602904

RESUMO

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Diterpenos/farmacologia , NF-kappa B/metabolismo , Fenantrenos/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo , Animais , Compostos de Epóxi/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
4.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3429-3434, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602905

RESUMO

The aim of this paper was to observe the concentration,time and mechanism of autophagy induced by triptolide( TP) in ovarian granulosa cells( OGCs). CCK-8 method was used to compare the inhibitory effects of TP at different concentrations on primary cultured rat OGCs and IC50 was calculated. The effects of TP at different concentrations and time points on the expression of OGCs autophagy factor protein and the cascade of PI3 K/AKT/m TOR pathway were detected by Western blot. The effects of TP,autophagy inducer( brefeldin A) and PI3 K/m TOR inhibitor( NVP-BEZ235) on the expression of PI3 K/AKT/m TOR cascade and autophagy related factor protein were detected by Western blot. The results show that the IC50 of different concentrations of TP on OGCs of rat ovary was14. 65 µmol·L-1,and the minimum inhibitory concentration of TP was 0. 1 µmol·L-1( 100 nmol·L-1). Compared with the control group,the expression levels of beclin1 and LC3Ⅱ in each group were significantly higher than those in the control group( P<0. 05 or P<0. 01). After 12 hours of treatment with TP,brefeldin A and NVP-BEZ235,respectively,compared with the control group,TP could significantly promote the expression level of downstream autophagy effect or molecule beclin1,LC3Ⅱ and inhibit the expression level of LC3Ⅰ,p62 protein( P<0. 05 or P< 0. 01). Moreover,the expression of beclin1 and LC3Ⅱ/LC3Ⅰ in TP group was higher than that in brefeldin A group( P<0. 05 or P<0. 01),and the expression of p62 in TP group was lower than that in brefeldin A group( P<0. 05 or P<0. 01). At the same time,TP could significantly inhibit the expression of p-PI3 K,p-AKT,p-mTOR protein,and the inhibitory effect of TP was better than that of NVP-BEZ235 group. This study suggests that 100 nmol·L-1 TP could induce OGCs autophagy successfully in cultured rat ovary for 12 h; TP may induce OGCs autophagy by inhibiting PI3 k/Akt/m TOR signaling pathway.


Assuntos
Autofagia , Diterpenos/farmacologia , Células da Granulosa/efeitos dos fármacos , Fenantrenos/farmacologia , Transdução de Sinais , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Compostos de Epóxi/farmacologia , Feminino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3448-3453, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602908

RESUMO

The aim of this paper was to study the influence of triptolide in the immune response pathways of acquired immune deficiency syndrome( AIDS). Target proteins of triptolide and related genes of AIDS were searched in PubChem and Gene databases on line. Molecular networks and canonical pathways comparison analyses were performed by bioinformatics software( IPA). There were 15 targets proteins of triptolide and 258 related genes of AIDS. Close biological relationships of molecules of triptolide and AIDS were established by networks analysis. There were 21 common immune response pathways of triptolide and AIDS,including neuroinflammation signaling pathway,Th1 and Th2 activation pathway and role of pattern recognition receptors in recognition of bacteria and viruses. Triptolide stimulated immune response pathways by the main molecules of IFNγ,JAK2,NOD1,PTGS2,RORC. IFNγ is the focus nodes of triptolide and AIDS,and regulates genes of AIDS directly or indirectly. Triptolide may against AIDS by regulating molecules IFNγ in immune response pathways.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Diterpenos/farmacologia , Interferon gama/genética , Fenantrenos/farmacologia , Síndrome de Imunodeficiência Adquirida/imunologia , Biologia Computacional , Compostos de Epóxi/farmacologia , Redes Reguladoras de Genes , Humanos , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais , Linfócitos T/imunologia
6.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3520-3525, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602917

RESUMO

The effect of triptolide( TP) on VEGFA,SDF-1,CXCR4 pathway were investigated in vitro to explore the mechanism in improving platelet activation in patients with ankylosing spondylitis( AS). Peripheral blood mononuclear cells( PBMC) were used for the experiment and divided into 4 groups: normal group( NC),model group( MC),triptolide group( TP),and AMD3100 group. The optimal concentration of TP was measured by the MTT method. The expressions of TNF-α,IL-1ß,IL-4,IL-10,VEGFA and VEGFR were detected by ELISA. The expressions of SDF-1,CXCR4 and VEGFA were detected by real-time quantitative PCR( RT-qPCR).The expressions of SDF-1,CXCR4,VEGFA and VEGFR were detected by Western blot. The expression levels of CD62 p,CD40 L and PDGFA were detected by immunofluorescence. MTT results showed that medium-dose TP had the strongest inhibitory effect on cells at24 h. The results of ELISA and PCR showed that TP inhibited mRNA expressions of IL-1ß,TNF-α,VEGFA,VEGFR and SDF-1,CXCR4 and VEGFA. The results of Western blot indicated that TP inhibited SDF-1,CXCR4 and VEGFA,VEGFR protein expressions; immunofluorescence results indicate that TP can inhibit the expressions of CD62 p,CD40 L,PDGFA. TP may regulate platelet activation by down-regulating SDF-1,CXCR4,VEGFA and VEGFR mRNA expressions,thereby down-regulating IL-1ß and TNF-αexpressions,and up-regulating the expressions of IL-4 and IL-10 cytokines.


Assuntos
Diterpenos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Fenantrenos/farmacologia , Ativação Plaquetária , Espondilite Anquilosante , Células Cultivadas , Quimiocina CXCL12/metabolismo , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
J Agric Food Chem ; 67(33): 9220-9231, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31347838

RESUMO

Slow-release fungicide formulations (azoxystrobin, epoxiconazole, and tebuconazole) shaped as pellets and granules in a matrix of biodegradable poly(3-hydroxybutyrate) and natural fillers (clay, wood flour, and peat) were constructed. Infrared spectroscopy showed no formation of chemical bonds between components in the experimental formulations. The formulations of pesticides had antifungal activity against Fusarium verticillioides in vitro. A study of biodegradation of the experimental fungicide formulations in the soil showed that the degradation process was mainly influenced by the type of formulation without significant influence of the type of filler. More active destruction of the granules led to a more rapid accumulation of fungicides in the soil. The content of fungicides present in the soil as a result of degradation of the formulations and fungicide release was determined by their solubility. Thus, all formulations are able to function in the soil for a long time, ensuring gradual and sustained delivery of fungicides.


Assuntos
Argila/química , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Fungicidas Industriais/química , Hidroxibutiratos/química , Poliésteres/química , Solo/química , Madeira/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Composição de Medicamentos/instrumentação , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fungicidas Industriais/farmacologia , Fusarium/efeitos dos fármacos , Cinética , Pirimidinas/química , Pirimidinas/farmacologia , Estrobilurinas/química , Estrobilurinas/farmacologia , Triazóis/química , Triazóis/farmacologia
8.
Anticancer Res ; 39(7): 3651-3660, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262891

RESUMO

BACKGROUND/AIM: Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. MATERIALS AND METHODS: PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. RESULTS: Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor. CONCLUSION: ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.


Assuntos
Adenocarcinoma/terapia , Proteínas de Caenorhabditis elegans/genética , Suplementos Nutricionais , Compostos de Epóxi/farmacologia , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Ômega-3/farmacologia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia
9.
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
10.
Eur J Med Chem ; 176: 378-392, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31121546

RESUMO

In the past decades, triptolide has attracted considerable interests in the organic and medicinal chemistry society owing to its intriguing structure features and promising multiple pharmacological activities. However, its limited water solubility and oral bioavailability, imprecise mechanism of action and sever toxicity, scares from nature and difficulty in the synthesis have greatly hindered its clinical potential. Hence, to circumvent such problems, a lot of elegant total synthesis have been developed. With the advancement of the total synthesis, various triptolide derivatives have been synthesized and tested in the search for more drug-like derivatives for potential anticancer agents, anti-inflammatory agents, immunosuppressive agents and anti-Alzheimer's agents, etc. Meanwhile, through designing and synthesizing of various of bioactive probes, some molecular targets that are responsible for the multiple pharmacology activities as well as toxicity of triptolide have been identified. It is no doubt will help the future development of new drug-like triptolide derivatives. In order to gain a comprehensive and deep understanding of the area and provides suggestions for triptolide's further studies, i) the medicinal chemistry advancement, ii) bioactive probes-based cellular target identification and iii) clinical progress of triptolide derivatives are reviewed in this article.


Assuntos
Diterpenos/química , Diterpenos/farmacologia , Fenantrenos/química , Fenantrenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Ensaios Clínicos como Assunto , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
11.
Int J Mol Med ; 44(1): 291-300, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115521

RESUMO

Lung cancer is the leading cause of cancer­associated mortality and current treatments are not sufficiently effective. Numerous studies have revealed that triptolide (TP), a classical traditional Chinese medicine compound widely used as an anti­inflammatory and antirheumatic drug, also has an antitumor effect. This effect is hypothesized to be mediated by multiple pathways, with signal transducer and activator of transcription 3 (STAT3) possibly one of them. Evidence indicates that STAT3 participates in the initiation and progression of lung cancer during cell proliferation, apoptosis and migration; however, whether and how TP affects STAT3 and its targets remain unclear. In this study, the potential role of TP in the proliferation, apoptosis, and migration of non­small cell lung cancer cell lines was investigated and evaluated the impact of TP on the interleukin­6 (IL­6)/STAT3 axis. The results showed that TP inhibited cell proliferation and migration and induced apoptosis. TP decreased the phosphorylation of STAT3, inhibited STAT3 translocation into the nucleus, and reduced the expression of STAT3 target genes involved in cell survival, apoptosis and migration, e.g. C­myc, BCL­2, myeloid cell leukemia­1 (MCL­1), and matrix metallopeptidase 9 (MMP­9). Additionally, IL­6­induced activation of STAT3 target genes (e.g. MCL­1 and BCL­2) was attenuated by TP and homoharringtonine. In conclusion, the effect of TP on STAT3 signaling points to a promising strategy for drug development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diterpenos/farmacologia , Interleucina-6/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Fenantrenos/farmacologia , Fator de Transcrição STAT3/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos
12.
J Exp Clin Cancer Res ; 38(1): 217, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122284

RESUMO

BACKGROUND: Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis. METHODS: The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET). RESULTS: Triptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (ApcMin/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA. CONCLUSIONS: Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Diterpenos/administração & dosagem , Fenantrenos/administração & dosagem , Fator de Transcrição TFIIIB/metabolismo , Transcrição Genética/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Diterpenos/farmacologia , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Camundongos , Fenantrenos/farmacologia , Regiões Promotoras Genéticas , RNA Ribossômico 5S , RNA de Transferência/genética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
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
14.
Chem Pharm Bull (Tokyo) ; 67(8): 864-871, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142691

RESUMO

Lung cancer is one of the most common malignant cancers in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a second- or third-line therapy for mutated non-small cell lung cancer (NSCLC). It usually becomes drug resistance after a period of treatment. Triptolide (TPL) is an epoxy diterpenoid lactone compound extracted from Tripterygium wilfordii HOOK. F. and many studies demonstrated that TPL has a synergistic effect when combined with chemotherapy drugs. In this research, we plan to evaluate the combined effect of TPL and EGFR-TKIs (Gefitinib, Erlotinib, and Icotinib) and investigate the possible mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to detect the cell viabilities, combined effect was evaluated by Combination Index. Molecular docking study was used to predict the binding ability of TPL. The expression of proteins was detected by Western blot. MTT results showed TPL had synergistic effect with three EGFR-TKIs at different concentrations on H1975 cells but not on H1299 cells. Molecular docking study demonstrated that TPL with T790M/L858R EGFR can form a more stable compound than that with wild type EGFR. Western blot results showed TPL inhibited the EGFR/Akt pathway and increased the expression of Bax and the ratio of Bax and Bcl-2 in H1975 cells. In conclusion, TPL had synergistic effect with three EGFR-TKIs on H1975 cells but not on H1299 cells, which may be due to the binding ability of TPL and different-type EGFR. The synergistic effect of TPL on H1975 cells may be partly related to the inhibition of the EGFR/Akt pathway.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diterpenos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Fenantrenos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenantrenos/síntese química , Fenantrenos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade
15.
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
16.
Artif Cells Nanomed Biotechnol ; 47(1): 1273-1280, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30963795

RESUMO

Pladienolide B is a potent cancer cell growth inhibitor that targets the SF3b1 subunit of the spliceosome. There is considerable interest in the compound as a tool to study SF3b1 function in cancer. However, so far little information is available on the molecular mechanism of SF3b1 eliciting apoptosis in cancer cells. Here, we investigated the molecular mechanism of SF3b1 eliciting apoptosis in human cervical carcinoma cells. We demonstrated that inhibition of SF3b1 by pladienolide B inhibited proliferation of HeLa cells at low nanomolar concentrations in a dose- and time-dependent manner. It also induced G2/M phase arrest and significant rise of apoptotic cells. Moreover, it is indicated that inhibition of SF3b1 by pladienolide B induced Tap73/ΔNp73 expression and consequently down-regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression. Thus, our results showed that SF3b1 plays a pivotal role in cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells, suggesting that SF3b1 could be used as a potential candidate for cervical cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Macrolídeos/farmacologia , Fosfoproteínas/antagonistas & inibidores , Fatores de Processamento de RNA/antagonistas & inibidores , Processamento de RNA/efeitos dos fármacos , Proteína Tumoral p73/genética , Neoplasias do Colo do Útero/patologia , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-30857727

RESUMO

DNA damage is ubiquitous and can arise from endogenous or exogenous sources. DNA-damaging alkylating agents are present in environmental toxicants as well as in cancer chemotherapy drugs and are a constant threat, which can lead to mutations or cell death. All organisms have multiple DNA repair and DNA damage tolerance pathways to resist the potentially negative effects of exposure to alkylating agents. In bacteria, many of the genes in these pathways are regulated as part of the SOS reponse or the adaptive response. In this work, we probed the cellular responses to the alkylating agents chloroacetaldehyde (CAA), which is a metabolite of 1,2-dichloroethane used to produce polyvinyl chloride, and styrene oxide (SO), a major metabolite of styrene used in the production of polystyrene and other polymers. Vinyl chloride and styrene are produced on an industrial scale of billions of kilograms annually and thus have a high potential for environmental exposure. To identify stress response genes in E. coli that are responsible for tolerance to the reactive metabolites CAA and SO, we used libraries of transcriptional reporters and gene deletion strains. In response to both alkylating agents, genes associated with several different stress pathways were upregulated, including protein, membrane, and oxidative stress, as well as DNA damage. E. coli strains lacking genes involved in base excision repair and nucleotide excision repair were sensitive to SO, whereas strains lacking recA and the SOS gene ybfE were sensitive to both alkylating agents tested. This work indicates the varied systems involved in cellular responses to alkylating agents, and highlights the specific DNA repair genes involved in the responses.


Assuntos
Acetaldeído/análogos & derivados , Alquilantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Resposta SOS (Genética)/genética , Acetaldeído/farmacologia , DNA Bacteriano/genética , Esterases/genética , Recombinases Rec A/genética
18.
Appl Microbiol Biotechnol ; 103(8): 3249-3264, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852659

RESUMO

Diepoxy-containing compounds are widely distributed in nature. These metabolites are found in plants and marine organisms and are also produced by many microorganisms, fungi, or fungal endophytes. Many of these metabolites are antibiotics and exhibit a wide variety of biological activities. More than 80 α,ß-diepoxy-containing compounds are presented in this article, which belong to different classes of chemical compounds including lipids, terpenoids, alkaloids, quinones, hydroquinones, and pyrones. The main activities that characterize α,ß-diepoxy-containing compounds are antineoplastic with confidence up to 99%, antifungal with confidence up to 94%, antiinflammatory with confidence up to 92%, or antibacterial with confidence up to 78%. In addition, these metabolites can be used as a lipid metabolism regulator with a certainty of up to 81%, antiviral (Arbovirus) activity with a certainty of up to 71%, or antiallergic activity with confidence up to 69%. These data on the biological activity of diepoxy-containing compounds are of considerable interest to pharmacologists, chemists, and medical professionals who are involved in phytomedicine and related areas of science and industry.


Assuntos
Produtos Biológicos/farmacologia , Compostos de Epóxi/farmacologia , Animais , Antialérgicos/química , Antialérgicos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Compostos de Epóxi/química , Fungos/química , Insetos/química , Plantas/química , Plantas/microbiologia
19.
Biomed Pharmacother ; 111: 1467-1477, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841462

RESUMO

Tripterygium wilfordii Hook. F. is a plant used in traditional Chinese medicine to treat rheumatoid arthritis, lupus erythematosus, and psoriasis in China. However, its main active substance, triptolide, has toxic effects on the heart, liver, and kidneys, which limit its clinical application. Therefore, determining the mechanism of cardiotoxicity in triptolide and identifying effective early-warning biomarkers is beneficial for preventing irreversible myocardial injury. We observed changes in microRNAs and aryl hydrocarbon receptor (AhR) as potential biomarkers in triptolide-induced acute cardiotoxicity by using techniques such as polymerase chain reaction (PCR) assay. The results revealed that triptolide increased the heart/body ratio and caused myocardial fiber breakage, cardiomyocyte hypertrophy, increased cell gaps, and nuclear dissolution in treated male rats. Real-time PCR array detection revealed a more than 2-fold increase in the expression of 108 microRNA genes in the hearts of the male rats; this not only regulated the signaling pathways of ErbB, FOXO, AMPK, Hippo, HIF-1α, mTOR, and PI3K-Akt but also participated in biological processes such as cell adhesion, cell cycling, action potential, locomotory behavior, apoptosis, and DNA binding. Moreover, triptolide reduced the circulatory and cardiac levels of AhR protein as a target of these microRNAs and the messenger RNA expression of its downstream gene CYP1 A1. However, decreases in myocardial lactate dehydrogenase, creatine kinase MB, catalase, and glutathione peroxidase activity and an increase in circulating cardiac troponin I were observed only in male rats. Moreover, plasma microRNAs exhibited dynamic change. These results revealed that circulating microRNAs and AhR protein are potentially early-warning biomarkers for triptolide-induced cardiotoxicity.


Assuntos
Biomarcadores/metabolismo , Cardiotoxicidade/genética , Diterpenos/farmacologia , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Fenantrenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Cardiotoxicidade/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Compostos de Epóxi/farmacologia , Feminino , Masculino , Medicina Tradicional Chinesa/métodos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tripterygium/química
20.
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
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