الملخص
Objective To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine(MDMA)and its metabolite 4,5-methylene dioxy amphetamine(MDA)in rats af-ter single and continuous administration of MDMA,providing reference data for the forensic identifica-tion of MDMA.Methods A total of 24 rats in the single administration group were randomly divided into 5,10 and 20 mg/kg experimental groups and the control group,with 6 rats in each group.The ex-perimental group was given intraperitoneal injection of MDMA,and the control group was given intraperi-toneal injection of the same volume of normal saline as the experimental group.The amount of 0.5 mL blood was collected from the medial canthus 5 min,30 min,1 h,1.5 h,2 h,4 h,6 h,8 h,10 h,12 h after administration.In the continuous administration group,24 rats were randomly divided into the experi-mental group(18 rats)and the control group(6 rats).The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5,7,9,11,13,15,17 mg/kg per day,respectively,while the control group was given the same volume of normal saline as the experimental group by in-traperitoneal injection.On the eighth day,the experimental rats were randomly divided into 5,10 and 20 mg/kg dose groups,with 6 rats in each group.MDMA was injected intraperitoneally,and the con-trol group was injected intraperitoneally with the same volume of normal saline as the experimental group.On the eighth day,0.5 mL of blood was taken from the medial canthus 5 min,30 min,1 h,1.5 h,2 h,4 h,6 h,8 h,10 h,12 h after administration.Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels,and statistical software was employed for data analysis.Results In the single-administration group,peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration,respectively,with the largest detection time limit of 12 h.In the continuous administration group,peak concentrations were reached at 30 min and 1.5 h af-ter administration,respectively,with the largest detection time limit of 10 h.Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows:T=10.362C-1.183,R2=0.974 6;T=7.397 3C-0.694,R2=0.961 5(T:injection time;C:concentration ratio of MDMA to MDA in plasma).Conclusions The toxicokinetic data of MDMA and its metabolite MDA in rats,obtained through single and continuous administration,including peak concentration,peak time,detection time limit,and the relationship between concentration ratio and administration time,provide a theoretical and data foundation for relevant forensic identification.
الملخص
Fibroblast-like synoviocytes (FLS) play a pivotal role in Rheumatoid arthritis (RA) pathogenesis through aggressive migration and invasion. Madecassoside (Madec), a triterpenoid saponin present in Centella asiatica herbs, has a potent anti-inflammatory effect. In the present study, Madec exerted an obvious therapeutic effect in reversing the histological lesions in adjuvant-induced arthritis (AIA) rats. To recognize the anti-rheumatoid potentials of Madec, we further investigated whether Madec interfered with FLS invasion and metalloproteinase (MMP) expression. In cultures of primary FLS isolated from the AIA rats, Madec (10 and 30 μmol·L) was proven to considerably inhibit migration and invasion of FLS induced by interleukin 1β (IL-1β), but exhibiting no obvious effect on cell proliferation. Madec repressed IL-1β-triggered FLS invasion by prohibiting the expression of MMP-13. Additionally, Madec suppressed MMP-13 transcription via inhibiting the MMP-13 promoter-binding activity of NF-κB. Our results further showed that Madec down-regulated the translocation and phosphorylation of NF-κB as demonstrated by Western blotting and immunofluorescence assays. In conclusion, our results suggest that Madec exerts anti-RA activity via inhibiting the NF-κB/MMP-13 pathway.
الموضوعات
Animals , Rats , Antirheumatic Agents , Chemistry , Pharmacology , Therapeutic Uses , Arthritis, Experimental , Drug Therapy , Pathology , Cell Movement , Cell Nucleus , Metabolism , Cells, Cultured , Gene Expression Regulation, Enzymologic , Interleukin-1beta , Pharmacology , Matrix Metalloproteinase 13 , Genetics , NF-kappa B , Genetics , Metabolism , Phosphorylation , Protein Transport , Signal Transduction , Synoviocytes , Metabolism , Transcriptional Activation , Triterpenes , Chemistry , Pharmacology , Therapeutic Usesالملخص
Objective To investigate the effect of TRIM11(tripartite motif-containing protein 11) target regulating miR-24-3p on the proliferation and invasion of breast cancer cells,and potentiol relation between TRIM11 high ex-pression and the prognosis of breast cancer. Methods Immunohistochemical method was used to detect the expres-sion of TRIM11 in 31 cases of breast cancer and 31 cases of adjacent breast cancer normal tissues. The siRNA TRIM11 lentivirus and miR-24-3p lentivirus were transfected into human breast cancer MCF7 cell lines,observing the correlation expression of TRIM11 and miR- 24- 3p mRNA and protein by using real-time fluorescence quantitative PCR (RT-qPCR) and Western bolt,luciferase reporter experiments were used to verify that the miR-24-3p as a direct target of TRIM11,MTT and Transwell were used to investigate the cells proliferation,activity and invasion. Results The expression of TRIM11 in breast cancer tissues or MCF7 cells was significantly higher (P<0.05),and TRIM11 high expression predicts poor prognosis of breast cancer(P<0.05). siRNA TRIM11 significantly inhibited the expression of TRIM11 in MCF7 cells,moreover,which inhibited the MCF7 cells proliferation,viability and invasion (P<0.05). miR-24-3p significantly reduced 3′-UTR TRIM11 luciferase activity in wild-type (P<0.05),but no effect was found in mutant type.The expression of miR-24-3p was decreased,miR-24-3p and TRIM11 mRNA expression was negatively correlated in MCF7 cells(P<0.05),miR-24-3p inhibition protein and mRNA ex-pression of TRIM11 in MCF7 cells,and inhibit MCF7 cells proliferation,viability and invasion (P<0.05). Conclu-sions The expression of TRIM11 is up-regulated in breast cancer and cells,promote the proliferation and invasion of breast cancer cells though regulating miR-24-3p expression,TRIM11 high expression predicts poor prognosis of breast cancer,TRIM11/miR-24-3p axis is expected to become a new target for treatment of breast cancer.
الملخص
Fibroblast-like synoviocytes (FLS) play a pivotal role in Rheumatoid arthritis (RA) pathogenesis through aggressive migration and invasion. Madecassoside (Madec), a triterpenoid saponin present in Centella asiatica herbs, has a potent anti-inflammatory effect. In the present study, Madec exerted an obvious therapeutic effect in reversing the histological lesions in adjuvant-induced arthritis (AIA) rats. To recognize the anti-rheumatoid potentials of Madec, we further investigated whether Madec interfered with FLS invasion and metalloproteinase (MMP) expression. In cultures of primary FLS isolated from the AIA rats, Madec (10 and 30 μmol·L) was proven to considerably inhibit migration and invasion of FLS induced by interleukin 1β (IL-1β), but exhibiting no obvious effect on cell proliferation. Madec repressed IL-1β-triggered FLS invasion by prohibiting the expression of MMP-13. Additionally, Madec suppressed MMP-13 transcription via inhibiting the MMP-13 promoter-binding activity of NF-κB. Our results further showed that Madec down-regulated the translocation and phosphorylation of NF-κB as demonstrated by Western blotting and immunofluorescence assays. In conclusion, our results suggest that Madec exerts anti-RA activity via inhibiting the NF-κB/MMP-13 pathway.