Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treatin...Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.展开更多
Non-small cell lung cancer(NSCLC)is a malignant tumor with high incidence worldwide.Triptolide(TP),extracted from Tripterygium wilfordii Hook F,exhibits potent broad-spectrum antitumor activity.Although some mechanism...Non-small cell lung cancer(NSCLC)is a malignant tumor with high incidence worldwide.Triptolide(TP),extracted from Tripterygium wilfordii Hook F,exhibits potent broad-spectrum antitumor activity.Although some mechanisms through which TP inhibits NSCLC are well understood,those that involve ribosomal proteins remain yet to be understood.In this study,the transcriptome and proteome were integrated and analyzed.Our data indicated ribosomal protein L4(RPL4)to be a core hub protein in the protein-protein interaction network.RPL4 is overexpressed in NSCLC tissues and cells.Transfection with siRPL4 or TP treatment alone arrested the cell cycle in the G1 phase,induced cell apoptosis,and repressed cell invasion.Compared to treating cells with TP alone or siRPL4,treating them with siRPL4–TP enhanced the inhibition of NSCLC cells.Reduced RPL4 expression reinforced the inhibitory effects of TP on NSCLC cells by disrupting the MDM2-P53 pathway and by altering the expression of PARP1/Snail/cyclin D1.In vivo assays verified that TP induced cell apoptosis and reduced RPL4 expression in xenografts.These findings provide clues to facilitate the development of effective TP-based therapeutic strategies to kill NSCLC cells.展开更多
2015年12月29日,Oncotarget杂志（IF=6.359）在线发表西北农林科技大学生命科学学院雷鸣教授课题组的最新研究成果“Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate c...2015年12月29日,Oncotarget杂志（IF=6.359）在线发表西北农林科技大学生命科学学院雷鸣教授课题组的最新研究成果“Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells”（DOI：10.18632/oncotarget.6783）。展开更多
Dendritic cells (DCs) are the most potent antigen-presen ting cells that play crucial roles in the regulation of immune response. Triptol ide, an active component purified from the medicinal plant Tripterygium wilfor ...Dendritic cells (DCs) are the most potent antigen-presen ting cells that play crucial roles in the regulation of immune response. Triptol ide, an active component purified from the medicinal plant Tripterygium wilfor dii Hook F., has been demonstrated to act as a potent immunosuppressive drug c apab le of inhibiting T cell activation and proliferation. However, little is known a bout the effects of triptolide on DCs. The present study shows that triptolide d oes not affect phenotypic differentiation and LPS-induced maturation of murine DCs. But triptolide can dramatically reduce cell recovery by inducing apoptosis of DCs at concentration as low as 10 ng/ml, as demonstrated by phosphatidylserin e exposure, mitochondria potential decrease, and nuclear DNA condensation. Tript olide induces activation of p38 in DCs, which precedes the activation of caspase 3. SB203580, a specific kinase inhibitor for p38, can block the activation of caspase 3 and inhibit the resultant apoptosis of DCs. Our results suggest that t he anti-inflammatory and immunosuppressive activities of triptolide may be due, in part, to its apoptosis-inducing effects on DCs.展开更多
BACKGROUND:Triptolide(TPT)is a diterpenoid triepoxide extracted from the Chinese herb Tripterygium wilfordii Hook.F.It exhibits potent immunosuppressive and anti-inflammatory properties.This study was undertaken to in...BACKGROUND:Triptolide(TPT)is a diterpenoid triepoxide extracted from the Chinese herb Tripterygium wilfordii Hook.F.It exhibits potent immunosuppressive and anti-inflammatory properties.This study was undertaken to investigate its effects on prolongation of islet allograft survival in rodents.Additionally,we investigated whether TPT would be toxic to islet function in vivo.METHODS:We transplanted BALB/c islets to either chemically induced diabetic C57BL/6 mice or spontaneously diabetic nonobese diabetic(NOD)mice.TPT was injected within 2 weeks or continuously,until rejection,in the two combinations.Then, we evaluated the toxicity of TPT on islet function by daily injection to naive BALB/c or diabetic BALB/c that was cured by syngeneic islet transplantation under the kidney capsule.Mice injected with cyclosporine A(CsA)or vehicle served as controls.Intraperitoneal glucose tolerance tests(IPGTTs)performed at 4 and 8 weeks in the na?ve BALB/c group,and at 2,4,6,and 8 weeks in the syngeneic transplanted group.RESULTS:The medium survival time of islets allograft from TPT treated C57BL/6 and NOD recipients were 28.5 days(range 24-30 days,n=10)and 33.0 days(range 15-47 days,n=6), respectively,and they were significantly different from those of the vehicle treated controls,which were 14.0 days(range 13-16 days,n=6)and 5.0 days(range 4-10 days,n=6),respectively(all P<0.0001).The IPGTT demonstrated that there was no difference between the TPT treated and vehicle treated groups, either in the normal or syngeneic transplanted islet BALB/c mice.However,CsA injection impaired islet function in both normal and syngeneic transplanted mice as early as 4 weeks.CONCLUSION:TPT prolonged islets allograft survival in a chemically induced diabetic or an autoimmune diabetic murine model without impairment of islet function.展开更多
Triptolide,a component of the Chinese herb Tripterygium wilfordii Hook F,has been proved to be effective in the treatment of rheumatoid arthritis(RA).However,its underlying mechanisms on RA have not yet been well esta...Triptolide,a component of the Chinese herb Tripterygium wilfordii Hook F,has been proved to be effective in the treatment of rheumatoid arthritis(RA).However,its underlying mechanisms on RA have not yet been well established.We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes(FLS)induced by the complex of interleukin-6(IL-6)and the soluble form of the IL-6 receptor(sIL-6R).Furthermore,to clarify the underlying mechanisms,we treated FLS with the Janus-activated kinase 2(JAK2)inhibitor/signal transducer and activator of transcription 3(STAT3)activation blocker AZD1480.In this study,immunohistochemical staining was used to identify vimentin(+)and CD68(−)in FLS.The FLS proliferation was measured by cell proliferation assay,and the cell cycles were analyzed by flow cytometry.Furthermore,ELISA was used to detect the expression of the inflammatory factors in culture solution.The expression levels of p-JAK2,JAK2,p-STAT3 and STAT3 were investigated through Western blotting analysis.The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines,including IL-6,interleukin-1β(IL-1β)and vascular endothelial growth factor(VEGF).Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3.The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway.It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis.展开更多
The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a ...The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a natural extract from the vine-like herb Tripterygium wilfordii Hook F,has potent anti-inflammatory and immunosuppressive efficacy.Therefore,we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease.We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice(aged 4–4.5 months) for 45 days.Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells,and transformed microglial cells into the resting state.Further,triptolide(5 μg/kg/d) also reduced the total number of hippocampal astrocytes.Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.展开更多
As a well-known anticancer drug,paclitaxel(PTX),a first-line chemotherapeutic agent,remains unsatisfactory for gastric cancer therapy.It is reported that triptolide(TPL)could enhance the anti-gastric cancer effect of ...As a well-known anticancer drug,paclitaxel(PTX),a first-line chemotherapeutic agent,remains unsatisfactory for gastric cancer therapy.It is reported that triptolide(TPL)could enhance the anti-gastric cancer effect of PTX.Considering the poor solubility of both drugs,we developed a red blood cell membrane-biomimetic nanosystem,an emerging tool in drug delivery,to co-load paclitaxel and triptolide(red blood cell membrane coated PTX and TPL co-loaded poly(lactic-co-glycolic acid)[PLGA]nanoparticles,RP(P/T)).The successful preparation was confirmed in terms of particle size,morphology,and surface markers assays.This biomimetic system could prolong circulation and escape immune surveillance.And these properties were verified by stability,in vitro drug release,and cellular uptake assays.Moreover,the MTT and colony formation assays demonstrated the superior anti-proliferation effect of the RP(P/T)to free drugs.The enhanced antitumor effects of RP(P/T)on migration and invasion were also evaluated by wound-healing and transwell assays.Overall,the bionic co-delivery nanoplatform with improved efficacy in vitro is a promising therapy for gastric cancer.展开更多
The combination of Ce6,an acknowledged photosensitizer,and TPL,a natural anticancer agent,has been demonstrated as a useful strategy to reinforce the tumor growth suppression,as well as decrease the systemic side effe...The combination of Ce6,an acknowledged photosensitizer,and TPL,a natural anticancer agent,has been demonstrated as a useful strategy to reinforce the tumor growth suppression,as well as decrease the systemic side effects compared with their monotherapy.However,in view of the optimal chemo-photodynamic combination efficiency,there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL,and stimuli-responsively burst release drugs in tumor site.Herein,we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem,mediated by the host–guest complexing betweenβ-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG,showing the shell–core structural micelles with the tightβ-CD layer coating.Both Ce6 and TPLwere facilely co-loaded into the spherical supramolecular NPs(TPL+Ce6/NPs)by one-step nanoprecipitation method,with an ideal particle size(156.0 nm),acid pH-responsive drug release profile,and enhanced cellular internalization capacity.In view of the combination benefit of photodynamic therapy and chemotherapy,as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs,TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation,boost ROS level,lower MMP,and promote cellular apoptosis in vitro.Particularly,fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area,with higher intensity than that of free Ce6.As expected,upon 650-nm laser irradiation,TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearingmice and B16 tumor-bearingmice.More importantly,lower systemic toxicitywas found in the tumor-bearingmice treated with TPL+Ce6/NPs.Overall,the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.展开更多
Objective:To explore the molecular mechanisms of antitumor properties of triptolide,a bioactive component isolated from the Chinese herb Tripterygium wolfordii Hook F.Methods:Human fibrosarcoma HT-1080 cells were trea...Objective:To explore the molecular mechanisms of antitumor properties of triptolide,a bioactive component isolated from the Chinese herb Tripterygium wolfordii Hook F.Methods:Human fibrosarcoma HT-1080 cells were treated with different doses of triptolide for 72 h.Then the expression and activity of matrix metalloproteinase(MMP)-2 and -9 were measured and the invasiveness of triptolide-treated HT-1080 cells was compared with that of anti-MMP-9- treated HT-1080 cells.Results:18 nmol/L triptolide inhibited the gene expression and activity of MMP-9,but not those of MMP-2,in HT-1080 cells.In addition,both 18 nmol/L triptolide and 3μg/mL anti-MMP-9 significantly reduced the invasive potential of HT-1080 cells,by about 50%and 35%, respectively,compared with the control.Whereas there was no significant difference between the effect of 18 nmol/L triptolide and that of anti-MMP-9 on invasive potential of HT-1080 cells. Conclusions:These data suggest that triptolide inhibits tumor cell invasion partly by reducing MMP-9 gene expression and activity.展开更多
AIM:To investigate the effects of triptolide on proinflammatory cytokine and chemokine expression induced by the fungal component zymosan in cultured human corneal fibroblasts(HCFs).·METHODS:HCFs were cultured in...AIM:To investigate the effects of triptolide on proinflammatory cytokine and chemokine expression induced by the fungal component zymosan in cultured human corneal fibroblasts(HCFs).·METHODS:HCFs were cultured in the absence or presence of zymosan or triptolide.The release of interleukin(IL)-6,IL-8,and monocyte chemoattractant protein-1(MCP-1)into culture supernatants was measured with enzyme-linked immunosorbent assays.The cellular abundance of the m RNAs for these proteins was determined by reverse transcription and real-time polymerase chain reaction analysis.The phosphorylation of mitogen-activated protein kinases(MAPKs)and the endogenous nuclear factor-κB(NF-κB)inhibitor IκB-αwas examined by immunoblot analysis.The release of lactate dehydrogenase(LDH)activity from HCFs was measured with a colorimetric assay.·RESULTS:Triptolide inhibited the zymosan-induced release of IL-6,IL-8,and MCP-1 from HCFs in a concentration-and time-dependent manner.It also inhibited the zymosan-induced up-regulation of IL-6,IL-8,and MCP-1 m RNA abundance in these cells.Furthermore,triptolide attenuated zymosan-induced phosphorylation of the MAPKs extracellular signalregulated kinase(ERK),c-Jun NH2-terminal kinase(JNK),and p38 as well as the phosphorylation and degradation of IκB-α.Triptolide did not exhibit cytotoxicity for HCFs.·CONCLUSION:Triptolide inhibited proinflammatory cytokine and chemokine production by HCFs exposed tozymosan,with this action likely being mediated by suppression of MAPK and NF-κB signaling pathways.This compound might thus be expected to limit the infiltration of inflammatory cells into the cornea associated with fungal infection.展开更多
[Objectives]To investigate the potential mechanisms of action of triptolide,an active component in the traditional Chinese medicine Tripterygium wilfordii Hook F,in colorectal cancer(CRC).[Methods]Public databases wer...[Objectives]To investigate the potential mechanisms of action of triptolide,an active component in the traditional Chinese medicine Tripterygium wilfordii Hook F,in colorectal cancer(CRC).[Methods]Public databases were first searched for genes and proteins known to be associated with CRC,as well as those predicted to be targets of triptolide,and then Ingenuity Pathway Analysis(IPA)was applied to identify enriched gene pathways and networks.Networks and pathways that overlapped between CRC-associated proteins and triptolide target proteins were then used to predict candidate protein targets of triptolide in CRC.[Results]The following proteins were found to be expressed in both CRC-associated networks and triptolide target networks:JUN,FOS,CASP3,BCL2,IFNG,and VEGFA.Docking studies suggested that triptolide can fit in the binding pocket of the four top candidate triptolide target proteins(CASP3,BCL2,VEGFA and IFNG).The overlapping pathways were activation of neuroinflammation signaling,glucocorticoid receptor signaling,T helper(Th)cell differentiation,Th1/Th2 activation,and colorectal cancer metastasis signaling.[Conclusions]These results show that network pharmacology can be used to generate hypotheses about how triptolide exerts therapeutic effects in CRC.Network pharmacology may be a useful method for characterizing multi-target drugs in complex diseases.展开更多
Aim To explore the role of transcription factor Foxp3 and the regulating effect of triptolide （TP） in the progression of myocardial hypertrophy in mice. Methods Fifty male mice were randomly divided into 5 groups, i...Aim To explore the role of transcription factor Foxp3 and the regulating effect of triptolide （TP） in the progression of myocardial hypertrophy in mice. Methods Fifty male mice were randomly divided into 5 groups, i. e., normal control group, myocardial hypertrophy model group and TP （10, 30, 90μg · kg^-1） treated groups. Myocardial hypertrophy was induced by isoprenaline （ISO） 5 mg kg^-1 once daily for 14 days. Triptolide was giv- en intraperitoneally once daily. Left ventricle tissue was subjected to HE staining and chemiluminescence technique to assess effects on hypertrophy, fibrosis and inflammation, quantitative assessment of hypertrophy regulatory genes were performed by qPCR and WB. Results After 14 days of treatment, myocardial expressions of Foxp3 and CD4 were significantly reduced in the model group compared with controls. The expression level of TGFβ1 in control group was lower, while that in model group increased obviously. TP could significantly lessen myocardial tissue damage, and reduce the heart index and left ventricular index. Compared with model group, TP （30, 90 μg · kg^-1 ） significantly increased myocardial expression ratio of α-MHC to β-MHC, reduced serumal levels of BNP and troponin I, elevated mRNA and protein expressions of Foxp3 and CD4 in myocardial tissue and reduced the protein expression of TGFβ1 by comparison of those in model group. Conclusion TP can effectively ameliorate myocardial damage and inhibit left ventricular remodeling through elevating the expression of CD4 and Foxp3 and decreasing that of TGF-β.展开更多
● AIM: To determine if triptolide influences the contractility and fibronectin production in human Tenon fibroblasts(HTFs).● METHODS: HTFs were cultured in type I collagen gels with or without transforming growth fa...● AIM: To determine if triptolide influences the contractility and fibronectin production in human Tenon fibroblasts(HTFs).● METHODS: HTFs were cultured in type I collagen gels with or without transforming growth factor beta(TGF-β) and/or triptolide. The diameter of the collagen gel was used to measure contraction. Immunoblot analysis was used to quantify myosin light chain(MLC) phosphorylation and integrin expression. Laser confocal fluorescence microscopy was used to monitor the formation of actin stress fibers. Fibronectin production was measured with an enzyme immunoassay.● RESULTS: Triptolide inhibition of contraction in TGF-β-induced collagen gel mediated by HTFs was dosedependent and statistically significant at 3 nmol/L(P<0.05) and maximal at 30 nmol/L and significantly time dependent at 2 d(P<0.05). Triptolide reduced TGF-β-induced expression of integrins α5 and β1, phosphorylation of MLC, and formation of stress fibers in HTFs. Furthermore, the inhibition of triptolide on the attenuated TGF-β-induced production of fibronectin by HTFs was concentration-dependent and significant at 1 nmol/L(P<0.05) and maximal at 30 nmol/L.● CONCLUSION: Triptolide suppress the contractility of HTFs induced by TGF-β and the production of fibronectin by these cells. It is promising that triptolide treatment may possibly inhibit scar formation after glaucoma filtration surgery.展开更多
Catalytic asymmetric formal synthesis of(-)-Triptophenolide and(+)-Triptolide have been achieved.Key reaction involves Palladium catalyzed asymmetric conjugate addition of aryl boronic acid to 3-methyl cyclohexe-1-non...Catalytic asymmetric formal synthesis of(-)-Triptophenolide and(+)-Triptolide have been achieved.Key reaction involves Palladium catalyzed asymmetric conjugate addition of aryl boronic acid to 3-methyl cyclohexe-1-none to form quaternary carbon.Claisen rearrangement and subsequent aldol reaction furnished trans-decaline key intermediate,which assured a formal total synthesis of(-)-Triptophenolide and(+)-Triptolide.展开更多
We established a monolayer polarized cell model using human kidney 2 (HK-2) cells cultured in a transwell chamber to examine the changes in the morphology and physiological functions of human-derived renal proximal tu...We established a monolayer polarized cell model using human kidney 2 (HK-2) cells cultured in a transwell chamber to examine the changes in the morphology and physiological functions of human-derived renal proximal tubular epithelial cells caused by tripterygium tablet extract (TTE) and triptolide. HK-2 cells were cultured on PCF membranes to form a complete monolayer of cells. A MTT assay was used to select 10, 40, 160, 640 μg·ml-1 TTE or 4, 16, 64, 256 ng·ml-1 triptolide to treat HK-2 monolayer cells. After 24 hours, a FITC permeability assay was performed;GGT, LDH and NAG secretion on the apical (AP) and basolateral (BL) sides of the cells by HK-2 cells were examined. The morphology and the monolayer structure of HK-2 cells was observed via optical microscope and scanning electron microscope, respectively. The effect on the cytoskeleton of HK-2 cells was observed under a fluorescence microscope. The IC50 of TTE was 277.122 μg·ml-1, and the IC50 of triptolide was 148.035 ng·ml-1. Compared with the DMSO group, the FITC leakage rate with TTE 160, 640 μg·ml-1 treated group and 4 - 256 ng·ml-1 triptolide dose group exhibited statistically significant increase. TTE significantly increased secretion of GGT and LDH at 160, 640 μg·ml-1, meanwhile, dramatically increased the AP/BL ratio of LDH at 160 μg·ml-1;triptolide significantly increased secretion and AP/BL ratio of GGT and LDH at 256 ng·ml-1. The morphological observations via optical and electron microscope indicated various degrees of damage to HK-2 cells by TTE and triptolide, and the degree of damage correlated positively with the dosage of the tested articles. Compared with DMSO group, the cellular damage degrees at TTE dosages of 40 - 640 μg·ml-1 and triptolide dose group at 16, 256 ng·ml-1 exhibited statistically significant differences via observation under optical microscope. Both TTE and triptolide caused various degrees of shortening and thickening of intracellular F-actin bundles of HK-2 cells;aggravation of these changes was observed with increasing drug dosage. Thus, we conclude both TTE and triptolide caused damage to human renal proximal tubular epithelial cells at certain dosages;TTE dosages of 40 μg·ml-1 and above and triptolide dose group at 16 ng·ml-1 and above exhibited the changes in the morphology, meanwhile, TTE dosages of 160 μg·ml-1 and above and triptolide dose group at 256 ng·ml-1 exhibited the changes in the physiological functions such as secretion of HK-2 cell.展开更多
Triptolide(TP),a major active component of Tripterygium wilfordii Hook.F.(TWHF),is used to treat rheumatoid arthritis(RA).However,it has a narrow therapeutic window due to its serious toxicities.To increase the therap...Triptolide(TP),a major active component of Tripterygium wilfordii Hook.F.(TWHF),is used to treat rheumatoid arthritis(RA).However,it has a narrow therapeutic window due to its serious toxicities.To increase the therapeutic index,a new triptolide-loaded transdermal delivery system,named triptolide-loaded liposome hydrogel patch(TP-LHP),has been developed.In this paper,we used a micro-needle array to deliver TP-LHP to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of TP-LHP in a rat model of collagen-induced arthritis(CIA).The pharmacokinetic results showed that transdermal delivery of microneedle TP-LHP yielded plasma drug levels which fit a onecompartment open model.The relationship equation between plasma concentration and time was C=303.59(e 0.064 t e 0.287t).The results of pharmacodynamic study demonstrated that TP-LHP treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1,fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1α in synovium.Other indicators were also reduced by TP-LHP,including hyperfunction of immune,interleukin-1β and interleukin-6 levels in serum.The therapeutic mechanism of TP-LHP might be regulation of the balance between Th1 and Th2,as well as inhibition of the expression and biological effects of vascular endothelial growth factor.展开更多
基金supported by grants from the National Key Research and Development Program of China(Grant Nos.:2020YFA0908000,2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-C-202002)+7 种基金the National Natural Science Foundation of China(Grant Nos.:82201786,82141001,82274182,82074098,82173914)the CACMS Innovation Fund(Grant Nos.:CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Grant No.:CI2021B014)the Science and Technology Foundation of Shenzhen(Grant Nos.:JCYJ20220818102613029,JCYJ20210324114014039,JCYJ20210324115800001)Guangdong Basic and Applied Basic Research Foundation(Grant Nos.:2020A1515110549,2021A1515110646)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the National Key R&D Program of China Key projects for international cooperation on science,technology and innovation(Grant No.:2020YFE0205100)and the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grant Nos.:ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010,ZZ15-ND-10).
文摘Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.
基金supported by the National Natural Science Foundation of China(Grant Nos.82004007 and 81774026).
文摘Non-small cell lung cancer(NSCLC)is a malignant tumor with high incidence worldwide.Triptolide(TP),extracted from Tripterygium wilfordii Hook F,exhibits potent broad-spectrum antitumor activity.Although some mechanisms through which TP inhibits NSCLC are well understood,those that involve ribosomal proteins remain yet to be understood.In this study,the transcriptome and proteome were integrated and analyzed.Our data indicated ribosomal protein L4(RPL4)to be a core hub protein in the protein-protein interaction network.RPL4 is overexpressed in NSCLC tissues and cells.Transfection with siRPL4 or TP treatment alone arrested the cell cycle in the G1 phase,induced cell apoptosis,and repressed cell invasion.Compared to treating cells with TP alone or siRPL4,treating them with siRPL4–TP enhanced the inhibition of NSCLC cells.Reduced RPL4 expression reinforced the inhibitory effects of TP on NSCLC cells by disrupting the MDM2-P53 pathway and by altering the expression of PARP1/Snail/cyclin D1.In vivo assays verified that TP induced cell apoptosis and reduced RPL4 expression in xenografts.These findings provide clues to facilitate the development of effective TP-based therapeutic strategies to kill NSCLC cells.
文摘2015年12月29日,Oncotarget杂志（IF=6.359）在线发表西北农林科技大学生命科学学院雷鸣教授课题组的最新研究成果“Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells”（DOI：10.18632/oncotarget.6783）。
文摘Dendritic cells (DCs) are the most potent antigen-presen ting cells that play crucial roles in the regulation of immune response. Triptol ide, an active component purified from the medicinal plant Tripterygium wilfor dii Hook F., has been demonstrated to act as a potent immunosuppressive drug c apab le of inhibiting T cell activation and proliferation. However, little is known a bout the effects of triptolide on DCs. The present study shows that triptolide d oes not affect phenotypic differentiation and LPS-induced maturation of murine DCs. But triptolide can dramatically reduce cell recovery by inducing apoptosis of DCs at concentration as low as 10 ng/ml, as demonstrated by phosphatidylserin e exposure, mitochondria potential decrease, and nuclear DNA condensation. Tript olide induces activation of p38 in DCs, which precedes the activation of caspase 3. SB203580, a specific kinase inhibitor for p38, can block the activation of caspase 3 and inhibit the resultant apoptosis of DCs. Our results suggest that t he anti-inflammatory and immunosuppressive activities of triptolide may be due, in part, to its apoptosis-inducing effects on DCs.
文摘BACKGROUND:Triptolide(TPT)is a diterpenoid triepoxide extracted from the Chinese herb Tripterygium wilfordii Hook.F.It exhibits potent immunosuppressive and anti-inflammatory properties.This study was undertaken to investigate its effects on prolongation of islet allograft survival in rodents.Additionally,we investigated whether TPT would be toxic to islet function in vivo.METHODS:We transplanted BALB/c islets to either chemically induced diabetic C57BL/6 mice or spontaneously diabetic nonobese diabetic(NOD)mice.TPT was injected within 2 weeks or continuously,until rejection,in the two combinations.Then, we evaluated the toxicity of TPT on islet function by daily injection to naive BALB/c or diabetic BALB/c that was cured by syngeneic islet transplantation under the kidney capsule.Mice injected with cyclosporine A(CsA)or vehicle served as controls.Intraperitoneal glucose tolerance tests(IPGTTs)performed at 4 and 8 weeks in the na?ve BALB/c group,and at 2,4,6,and 8 weeks in the syngeneic transplanted group.RESULTS:The medium survival time of islets allograft from TPT treated C57BL/6 and NOD recipients were 28.5 days(range 24-30 days,n=10)and 33.0 days(range 15-47 days,n=6), respectively,and they were significantly different from those of the vehicle treated controls,which were 14.0 days(range 13-16 days,n=6)and 5.0 days(range 4-10 days,n=6),respectively(all P<0.0001).The IPGTT demonstrated that there was no difference between the TPT treated and vehicle treated groups, either in the normal or syngeneic transplanted islet BALB/c mice.However,CsA injection impaired islet function in both normal and syngeneic transplanted mice as early as 4 weeks.CONCLUSION:TPT prolonged islets allograft survival in a chemically induced diabetic or an autoimmune diabetic murine model without impairment of islet function.
基金the Shenzhen City Science and Technology Bureau of China(No.JCYJ20170307111755218)“San-Ming”Project of Medicine in Shenzhen(No.SZSM201612092).
文摘Triptolide,a component of the Chinese herb Tripterygium wilfordii Hook F,has been proved to be effective in the treatment of rheumatoid arthritis(RA).However,its underlying mechanisms on RA have not yet been well established.We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes(FLS)induced by the complex of interleukin-6(IL-6)and the soluble form of the IL-6 receptor(sIL-6R).Furthermore,to clarify the underlying mechanisms,we treated FLS with the Janus-activated kinase 2(JAK2)inhibitor/signal transducer and activator of transcription 3(STAT3)activation blocker AZD1480.In this study,immunohistochemical staining was used to identify vimentin(+)and CD68(−)in FLS.The FLS proliferation was measured by cell proliferation assay,and the cell cycles were analyzed by flow cytometry.Furthermore,ELISA was used to detect the expression of the inflammatory factors in culture solution.The expression levels of p-JAK2,JAK2,p-STAT3 and STAT3 were investigated through Western blotting analysis.The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines,including IL-6,interleukin-1β(IL-1β)and vascular endothelial growth factor(VEGF).Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3.The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway.It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis.
基金supported by China Postdoctoral Science Foundation,No.2016M590757the Postdoctoral Science Foundation of Xiangya Hospital of Central South University of China,No.20+4 种基金the Hunan Provincial Natural Science Foundation of China,No.2015JJ6010a grant from the Basic Research Program of Science and Technology Commission Foundation of Hunan Province of China,No.2015JC3059the Project Fund of the Department of Education in Hunan Province of China,No.15A023,13C1107the Scientific Research Project Fund of Health Department of Hunan Province of China,No.B2011-071,B2016096a grant from the Construction Program of the Key Discipline in Hunan Province of China
文摘The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a natural extract from the vine-like herb Tripterygium wilfordii Hook F,has potent anti-inflammatory and immunosuppressive efficacy.Therefore,we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease.We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice(aged 4–4.5 months) for 45 days.Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells,and transformed microglial cells into the resting state.Further,triptolide(5 μg/kg/d) also reduced the total number of hippocampal astrocytes.Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.
基金the National Natural Science Foundation of China(No.82073308 and No.81773211)the High-level startup fund of Nanjing Medical University(No.KY109RC2019010).
文摘As a well-known anticancer drug,paclitaxel(PTX),a first-line chemotherapeutic agent,remains unsatisfactory for gastric cancer therapy.It is reported that triptolide(TPL)could enhance the anti-gastric cancer effect of PTX.Considering the poor solubility of both drugs,we developed a red blood cell membrane-biomimetic nanosystem,an emerging tool in drug delivery,to co-load paclitaxel and triptolide(red blood cell membrane coated PTX and TPL co-loaded poly(lactic-co-glycolic acid)[PLGA]nanoparticles,RP(P/T)).The successful preparation was confirmed in terms of particle size,morphology,and surface markers assays.This biomimetic system could prolong circulation and escape immune surveillance.And these properties were verified by stability,in vitro drug release,and cellular uptake assays.Moreover,the MTT and colony formation assays demonstrated the superior anti-proliferation effect of the RP(P/T)to free drugs.The enhanced antitumor effects of RP(P/T)on migration and invasion were also evaluated by wound-healing and transwell assays.Overall,the bionic co-delivery nanoplatform with improved efficacy in vitro is a promising therapy for gastric cancer.
基金supported by National Natural Science Foundation of China (No.81973662)Distinguished Young Scholar of Sichuan Provincial Science and Technology Department (No.2019JDJQ0049)111 Project (No.B18035)
文摘The combination of Ce6,an acknowledged photosensitizer,and TPL,a natural anticancer agent,has been demonstrated as a useful strategy to reinforce the tumor growth suppression,as well as decrease the systemic side effects compared with their monotherapy.However,in view of the optimal chemo-photodynamic combination efficiency,there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL,and stimuli-responsively burst release drugs in tumor site.Herein,we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem,mediated by the host–guest complexing betweenβ-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG,showing the shell–core structural micelles with the tightβ-CD layer coating.Both Ce6 and TPLwere facilely co-loaded into the spherical supramolecular NPs(TPL+Ce6/NPs)by one-step nanoprecipitation method,with an ideal particle size(156.0 nm),acid pH-responsive drug release profile,and enhanced cellular internalization capacity.In view of the combination benefit of photodynamic therapy and chemotherapy,as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs,TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation,boost ROS level,lower MMP,and promote cellular apoptosis in vitro.Particularly,fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area,with higher intensity than that of free Ce6.As expected,upon 650-nm laser irradiation,TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearingmice and B16 tumor-bearingmice.More importantly,lower systemic toxicitywas found in the tumor-bearingmice treated with TPL+Ce6/NPs.Overall,the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.
基金supported by the National Natural Science Foundation of China(No.30700882)supported by a grant from the Department of Immunology,Tongji Medical College, Huazhong University of Science and Technology,Wuhan, China.
文摘Objective:To explore the molecular mechanisms of antitumor properties of triptolide,a bioactive component isolated from the Chinese herb Tripterygium wolfordii Hook F.Methods:Human fibrosarcoma HT-1080 cells were treated with different doses of triptolide for 72 h.Then the expression and activity of matrix metalloproteinase(MMP)-2 and -9 were measured and the invasiveness of triptolide-treated HT-1080 cells was compared with that of anti-MMP-9- treated HT-1080 cells.Results:18 nmol/L triptolide inhibited the gene expression and activity of MMP-9,but not those of MMP-2,in HT-1080 cells.In addition,both 18 nmol/L triptolide and 3μg/mL anti-MMP-9 significantly reduced the invasive potential of HT-1080 cells,by about 50%and 35%, respectively,compared with the control.Whereas there was no significant difference between the effect of 18 nmol/L triptolide and that of anti-MMP-9 on invasive potential of HT-1080 cells. Conclusions:These data suggest that triptolide inhibits tumor cell invasion partly by reducing MMP-9 gene expression and activity.
基金Supported by the National Natural Science Foundation of China(No.81100635)the Norman Bethune Program of Jilin University(No.2012213)
文摘AIM:To investigate the effects of triptolide on proinflammatory cytokine and chemokine expression induced by the fungal component zymosan in cultured human corneal fibroblasts(HCFs).·METHODS:HCFs were cultured in the absence or presence of zymosan or triptolide.The release of interleukin(IL)-6,IL-8,and monocyte chemoattractant protein-1(MCP-1)into culture supernatants was measured with enzyme-linked immunosorbent assays.The cellular abundance of the m RNAs for these proteins was determined by reverse transcription and real-time polymerase chain reaction analysis.The phosphorylation of mitogen-activated protein kinases(MAPKs)and the endogenous nuclear factor-κB(NF-κB)inhibitor IκB-αwas examined by immunoblot analysis.The release of lactate dehydrogenase(LDH)activity from HCFs was measured with a colorimetric assay.·RESULTS:Triptolide inhibited the zymosan-induced release of IL-6,IL-8,and MCP-1 from HCFs in a concentration-and time-dependent manner.It also inhibited the zymosan-induced up-regulation of IL-6,IL-8,and MCP-1 m RNA abundance in these cells.Furthermore,triptolide attenuated zymosan-induced phosphorylation of the MAPKs extracellular signalregulated kinase(ERK),c-Jun NH2-terminal kinase(JNK),and p38 as well as the phosphorylation and degradation of IκB-α.Triptolide did not exhibit cytotoxicity for HCFs.·CONCLUSION:Triptolide inhibited proinflammatory cytokine and chemokine production by HCFs exposed tozymosan,with this action likely being mediated by suppression of MAPK and NF-κB signaling pathways.This compound might thus be expected to limit the infiltration of inflammatory cells into the cornea associated with fungal infection.
基金National Natural Science Foundation of China(U1804179)Key Scientific and Technological Project in Henan Province(202102310190)+1 种基金Henan Science and Technology Innovation Team,Investigation on Plant Resources in Dabie Mountains and the Study and Utilization of Active Components of Special Plants(2017083)Nanhu Scholars Program for Young Scholars of Xinyang Normal University(2018001).
文摘[Objectives]To investigate the potential mechanisms of action of triptolide,an active component in the traditional Chinese medicine Tripterygium wilfordii Hook F,in colorectal cancer(CRC).[Methods]Public databases were first searched for genes and proteins known to be associated with CRC,as well as those predicted to be targets of triptolide,and then Ingenuity Pathway Analysis(IPA)was applied to identify enriched gene pathways and networks.Networks and pathways that overlapped between CRC-associated proteins and triptolide target proteins were then used to predict candidate protein targets of triptolide in CRC.[Results]The following proteins were found to be expressed in both CRC-associated networks and triptolide target networks:JUN,FOS,CASP3,BCL2,IFNG,and VEGFA.Docking studies suggested that triptolide can fit in the binding pocket of the four top candidate triptolide target proteins(CASP3,BCL2,VEGFA and IFNG).The overlapping pathways were activation of neuroinflammation signaling,glucocorticoid receptor signaling,T helper(Th)cell differentiation,Th1/Th2 activation,and colorectal cancer metastasis signaling.[Conclusions]These results show that network pharmacology can be used to generate hypotheses about how triptolide exerts therapeutic effects in CRC.Network pharmacology may be a useful method for characterizing multi-target drugs in complex diseases.
文摘Aim To explore the role of transcription factor Foxp3 and the regulating effect of triptolide （TP） in the progression of myocardial hypertrophy in mice. Methods Fifty male mice were randomly divided into 5 groups, i. e., normal control group, myocardial hypertrophy model group and TP （10, 30, 90μg · kg^-1） treated groups. Myocardial hypertrophy was induced by isoprenaline （ISO） 5 mg kg^-1 once daily for 14 days. Triptolide was giv- en intraperitoneally once daily. Left ventricle tissue was subjected to HE staining and chemiluminescence technique to assess effects on hypertrophy, fibrosis and inflammation, quantitative assessment of hypertrophy regulatory genes were performed by qPCR and WB. Results After 14 days of treatment, myocardial expressions of Foxp3 and CD4 were significantly reduced in the model group compared with controls. The expression level of TGFβ1 in control group was lower, while that in model group increased obviously. TP could significantly lessen myocardial tissue damage, and reduce the heart index and left ventricular index. Compared with model group, TP （30, 90 μg · kg^-1 ） significantly increased myocardial expression ratio of α-MHC to β-MHC, reduced serumal levels of BNP and troponin I, elevated mRNA and protein expressions of Foxp3 and CD4 in myocardial tissue and reduced the protein expression of TGFβ1 by comparison of those in model group. Conclusion TP can effectively ameliorate myocardial damage and inhibit left ventricular remodeling through elevating the expression of CD4 and Foxp3 and decreasing that of TGF-β.
基金Supported by the National Natural Science Foundation of China(No.81770889)the Natural Science Foundation of Guangdong Province(No.2017A030313774)the International Cooperation Item from Research Fund of Jilin Provincial Science and Technology Department(No.20160414055GH)
文摘● AIM: To determine if triptolide influences the contractility and fibronectin production in human Tenon fibroblasts(HTFs).● METHODS: HTFs were cultured in type I collagen gels with or without transforming growth factor beta(TGF-β) and/or triptolide. The diameter of the collagen gel was used to measure contraction. Immunoblot analysis was used to quantify myosin light chain(MLC) phosphorylation and integrin expression. Laser confocal fluorescence microscopy was used to monitor the formation of actin stress fibers. Fibronectin production was measured with an enzyme immunoassay.● RESULTS: Triptolide inhibition of contraction in TGF-β-induced collagen gel mediated by HTFs was dosedependent and statistically significant at 3 nmol/L(P<0.05) and maximal at 30 nmol/L and significantly time dependent at 2 d(P<0.05). Triptolide reduced TGF-β-induced expression of integrins α5 and β1, phosphorylation of MLC, and formation of stress fibers in HTFs. Furthermore, the inhibition of triptolide on the attenuated TGF-β-induced production of fibronectin by HTFs was concentration-dependent and significant at 1 nmol/L(P<0.05) and maximal at 30 nmol/L.● CONCLUSION: Triptolide suppress the contractility of HTFs induced by TGF-β and the production of fibronectin by these cells. It is promising that triptolide treatment may possibly inhibit scar formation after glaucoma filtration surgery.
基金This work was financially supported by the foundations from NSFC(21372229)High End Talent Program of Yunnan Province(2015HA028)the Applied Basic Research Plan of Yunnan Province Science and Technology Department(No.2013FB064).
文摘Catalytic asymmetric formal synthesis of(-)-Triptophenolide and(+)-Triptolide have been achieved.Key reaction involves Palladium catalyzed asymmetric conjugate addition of aryl boronic acid to 3-methyl cyclohexe-1-none to form quaternary carbon.Claisen rearrangement and subsequent aldol reaction furnished trans-decaline key intermediate,which assured a formal total synthesis of(-)-Triptophenolide and(+)-Triptolide.
文摘We established a monolayer polarized cell model using human kidney 2 (HK-2) cells cultured in a transwell chamber to examine the changes in the morphology and physiological functions of human-derived renal proximal tubular epithelial cells caused by tripterygium tablet extract (TTE) and triptolide. HK-2 cells were cultured on PCF membranes to form a complete monolayer of cells. A MTT assay was used to select 10, 40, 160, 640 μg·ml-1 TTE or 4, 16, 64, 256 ng·ml-1 triptolide to treat HK-2 monolayer cells. After 24 hours, a FITC permeability assay was performed;GGT, LDH and NAG secretion on the apical (AP) and basolateral (BL) sides of the cells by HK-2 cells were examined. The morphology and the monolayer structure of HK-2 cells was observed via optical microscope and scanning electron microscope, respectively. The effect on the cytoskeleton of HK-2 cells was observed under a fluorescence microscope. The IC50 of TTE was 277.122 μg·ml-1, and the IC50 of triptolide was 148.035 ng·ml-1. Compared with the DMSO group, the FITC leakage rate with TTE 160, 640 μg·ml-1 treated group and 4 - 256 ng·ml-1 triptolide dose group exhibited statistically significant increase. TTE significantly increased secretion of GGT and LDH at 160, 640 μg·ml-1, meanwhile, dramatically increased the AP/BL ratio of LDH at 160 μg·ml-1;triptolide significantly increased secretion and AP/BL ratio of GGT and LDH at 256 ng·ml-1. The morphological observations via optical and electron microscope indicated various degrees of damage to HK-2 cells by TTE and triptolide, and the degree of damage correlated positively with the dosage of the tested articles. Compared with DMSO group, the cellular damage degrees at TTE dosages of 40 - 640 μg·ml-1 and triptolide dose group at 16, 256 ng·ml-1 exhibited statistically significant differences via observation under optical microscope. Both TTE and triptolide caused various degrees of shortening and thickening of intracellular F-actin bundles of HK-2 cells;aggravation of these changes was observed with increasing drug dosage. Thus, we conclude both TTE and triptolide caused damage to human renal proximal tubular epithelial cells at certain dosages;TTE dosages of 40 μg·ml-1 and above and triptolide dose group at 16 ng·ml-1 and above exhibited the changes in the morphology, meanwhile, TTE dosages of 160 μg·ml-1 and above and triptolide dose group at 256 ng·ml-1 exhibited the changes in the physiological functions such as secretion of HK-2 cell.
基金supported by National Science and Technology Major Project on Significant Creation of New Drugs of China(2009ZX09502-019)
文摘Triptolide(TP),a major active component of Tripterygium wilfordii Hook.F.(TWHF),is used to treat rheumatoid arthritis(RA).However,it has a narrow therapeutic window due to its serious toxicities.To increase the therapeutic index,a new triptolide-loaded transdermal delivery system,named triptolide-loaded liposome hydrogel patch(TP-LHP),has been developed.In this paper,we used a micro-needle array to deliver TP-LHP to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of TP-LHP in a rat model of collagen-induced arthritis(CIA).The pharmacokinetic results showed that transdermal delivery of microneedle TP-LHP yielded plasma drug levels which fit a onecompartment open model.The relationship equation between plasma concentration and time was C=303.59(e 0.064 t e 0.287t).The results of pharmacodynamic study demonstrated that TP-LHP treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1,fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1α in synovium.Other indicators were also reduced by TP-LHP,including hyperfunction of immune,interleukin-1β and interleukin-6 levels in serum.The therapeutic mechanism of TP-LHP might be regulation of the balance between Th1 and Th2,as well as inhibition of the expression and biological effects of vascular endothelial growth factor.
