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1.
《Saudi Pharmaceutical Journal》2022,30(11):1572-1588
Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components. 相似文献
2.
叶晓鸥 《浙江中西医结合杂志》2020,30(4)
摘要 目的 验证丹参二萜醌类活性成分对胰腺癌和多发性骨髓瘤的抑制效应,阐明其诱导胰腺癌和多发性骨髓瘤凋亡的作用机制。方法 胰腺癌细胞AsPC-1、BxPC-3用含10% gibco胎牛血清的RPMI1640培养液培养,按隐丹参酮组(30μM)、丹参新酮组(15μM)、去氢丹参新酮组(15μM)分别加药处理。cell-counting-kit-8(CCK8)法检测细胞存活率;AnnexinⅤ-FITC/PI流式细胞术检测细胞凋亡;Western Blot检测相关PKC同工酶磷酸化水平;对AsPC-1和BxPC-3细胞进行siRNA转染,Western Blot检测相关PKC同工酶磷酸化水平。结果 隐丹参酮组AsPC-1、BxPC-3细胞存活率分别为40.1%±5.0%、36.2%±5.4%;丹参新酮组AsPC-1、BxPC-3细胞存活率分别为52.1%±5.1%、47.2%±5.7%;去氢丹参新组AsPC-1、BxPC-3细胞存活率分别为46.1%±5.0%、42.2%±5.4%(P<0.01)。流式细胞术结果显示:AsPC-1组内空白对照组、隐丹参酮组、丹参新酮组、去氢丹参新酮组细胞的凋亡率分别为4.71%、30.10%、52.26%、42.30%;BxPC-3组内空白对照组、隐丹参酮组、丹参新酮组、去氢丹参新酮组细胞的凋亡率分别为5.10%、30.66%、33.76%、51.76%(P<0.01)。Western Blot检测显示隐丹参酮组、丹参新酮组、去氢丹参新酮组较空白对照组,胰腺癌AsPC-1、BxPC-3细胞p-PKD/PKCμ ser916、p-PKCδ thr505、p-PKD/PKCμ ser744/748的水平降低。Western Blot检测显示,siRNA沉默胰腺癌AsPC-1、BxPC-3细胞PKCδ,胰腺癌AsPC-1、BxPC-3细胞PKD/PKCμ ser744/748的磷酸化水平下调。结论 隐丹参酮、丹参新酮、去氢丹参新酮通过抑制PKCδthr505的磷酸化水平,继而PKD1μser744/748磷酸化水平下调,从而显著促进胰腺癌AsPC-1和BxPC-3细胞凋亡发生。 相似文献
3.
4.
《Vaccine》2016,34(30):3500-3507
We describe the preclinical development of a dengue virus vaccine targeting the dengue virus serotype 2 (DENV2) envelope domain III (EDIII). This study provides proof-of-principle that a dengue EDIII protein scaffold/DNA vaccine can protect against dengue challenge. The dengue vaccine (EDIII-E2) is composed of both a protein particle and a DNA expression plasmid delivered simultaneously via intramuscular injection (protein) and gene gun (DNA) into rhesus macaques. The protein component can contain a maximum of 60 copies of EDIII presented on a multimeric scaffold of Geobacillus stearothermophilus E2 proteins. The DNA component is composed of the EDIII portion of the envelope gene cloned into an expression plasmid. The EDIII-E2 vaccine elicited robust antibody responses to DENV2, with neutralizing antibody responses detectable following the first boost and reaching titers of greater than 1:100,000 following the second and final boost. Vaccinated and naïve groups of macaques were challenged with DENV2. All vaccinated macaques were protected from detectable viremia by infectious assay, while naïve animals had detectable viremia for 2–7 days post-challenge. All naïve macaques had detectable viral RNA from day 2–10 post-challenge. In the EDIII-E2 group, three macaques were negative for viral RNA and three were found to have detectable viral RNA post challenge. Viremia onset was delayed and the duration was shortened relative to naïve controls. The presence of viral RNA post-challenge corresponded to a 10–30-fold boost in neutralization titers 28 days post challenge, whereas no boost was observed in the fully protected animals. Based on these results, we determine that pre-challenge 50% neutralization titers of >1:6000 correlated with sterilizing protection against DENV2 challenge in EDIII-E2 vaccinated macaques. Identification of the critical correlate of protection for the EDIII-E2 platform in the robust non-human primate model lays the groundwork for further development of a tetravalent EDIII-E2 dengue vaccine. 相似文献
5.
PTEN基因蛋白在胆囊癌组织中表达的研究 总被引:4,自引:0,他引:4
目的 :探讨抑癌基因PTEN蛋白在胆囊癌组织中的表达情况及其临床病理意义。方法 :应用免疫组化对 2 8例胆囊腺癌 ,4例胆囊鳞癌及其相应癌旁组织中PTEN蛋白进行检测 ,并结合患者的临床病理资料进行分析。结果 :PTEN蛋白在 32例癌旁组织中全都呈阳性表达 ,而癌组织中PTEN阳性表达率仅 34.4 %。胆囊癌组织中PTEN蛋白阳性表达与患者性别、年龄及组织类型无明显相关性 ,但与组织分化程度明显相关。结论 :PTEN蛋白在胆囊癌组织中阳性表达率较低 ,说明该基因失活可能在胆囊癌发生发展中起重要作用。PTEN阳性表达对胆囊癌患者的预后有一定意义 相似文献
6.
T B Vree Y A Hekster M W Tijhuis E F Termond J F Nouws 《Biopharmaceutics & drug disposition》1986,7(3):239-252
Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes. 相似文献
7.
稳定性核素测定大鼠小肠蛋白质合成 总被引:2,自引:1,他引:1
目的:建立稳定性核素([L-^15N]亮氨酸)测定大鼠小肠蛋白质合成率的方法。方法:分别测定静脉注射相同剂量[L-^15N]亮氨酸不同时相的大鼠小肠^15N丰度及不同剂量[L-^15N]亮氨酸同一时相的大鼠小肠^15N丰度。结果:大鼠小肠游离氨基酸池中^15N核素丰度在注射后0.5h内呈线性上升并达高峰,维持4h后缓慢下降,小肠蛋白质中的^15N丰度0.5h至12h基本维持不变;随着注射剂量的增加,大鼠小肠蛋白质分数合成率(FSR)亦增加,当[L-^15N]亮氨酸剂量在1.0mmol/kg以上,FSR并不随施加[L15N]亮氨酸剂量的加大而增加。结论:在进行大鼠小肠蛋白质合成率测定时,一次性静脉注射的测量最佳时限为0.5h,剂量为1.0mmol/kg。 相似文献
8.
The role of intracellular Zn2+ in the translocation of protein kinase C from cytosol to membrane fractions was examined by the [3H]phorbol 12,13-dibutyrate (PDBu) binding method in guinea pig cerebral synaptoneurosomes. N-methyl-d-aspartate (NMDA, 100 μM) and calcium ionophore A23187 (0.3–30 μM) decreased the binding activity in the cytosol with a concomitant increase in the membrane fractions. Pretreatment of synaptoneurosomes with a heavy metal chelator, N,N,N′,N′-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN), inhibited the NMDA- and A23187-induced changes of the distribution of [3H]PDBu binding sites in cytosol and membrane fractions. The inhibitory effect of TPEN was negated by a preincubation of TPEN with equimolar Zn2+ but not by that with Ca2+. The addition of 500 μM Zn2+ to the lysate of synaptoneurosomes induced an increase of [3H]PDBu binding activity in the membrane fraction with a concomitant decrease in the cytosol fraction, as did 100 μM Ca2+. Low concentrations of Zn2+ (10 μM), which alone had no effect on the distribution of the binding, significantly enhanced the effect of 10 μM Ca2+ in the lysate. Under those conditions TPEN inhibited the Zn2+-potentiated Ca2+-dependent changes in the binding. These results suggest that intracellular Zn2+ is essential for the agonist-induced translocation of protein kinase C in guinea pig synaptoneurosomes. 相似文献
9.
目的:探讨survivin反义寡核苷酸(ASODN)对人肝癌细胞HepG2的抑制作用。方法:采用免疫组织化学法检测肝细胞癌(HCC)组织中survivin的表达。采用脂质体介导survivin ASODN体外转染人肝癌细胞株HepG2,Western blot检测细胞survivin蛋白的表达,FCM检测细胞的凋亡率,观察细胞在软琼脂中的集落形成能力。建立人肝癌裸鼠皮下移植瘤模型,观察survivin ASODN的体内抑癌作用。 结果:(1)肝癌组织中survivin表达阳性率为75.8%(25/33),明显高于癌旁组织和正常肝组织(P<0.01);(2)survivin ASODN体外转染可明显下调HepG2细胞survivin蛋白表达,ASODN组HepG2细胞凋亡率明显高于空白对照组和SODN组(P<0.01),ASODN组HepG2细胞在软琼脂中形成的集落数目明显少于空白对照组和SODN组(P<0.01);(3)ASODN组瘤体生长速度较空白对照组和SODN组明显减慢(P<0.01),ASODN组瘤体重量较空白对照组和SODN组明显减轻(P<0.05)。结论:Survivin在HCC组织中高表达;survivin ASODN可以诱导HepG2细胞凋亡,在体外实验和动物实验中对HepG2细胞生长都有抑制作用。 相似文献
10.
目的:探讨胰腺癌与癌旁组织中p16基因启动子区异常甲基化的改变及其蛋白表达的特点,以及其与胰腺癌发生发展的关系。方法:分别采用免疫组化SP法及甲基化特异PCR(MSP)检测46例人胰腺癌和癌旁组织中p16基因表达及其甲基化的水平,并结合临床资料进行分析。结果:胰腺癌中p16蛋白表达率为41.3%(19/46),而癌旁组织表达率为95.7%(44/46),两者有差异显著性(P<0.01)。p16蛋白阳性的19例胰腺癌标本中均未检出基因甲基化;p16蛋白缺失的27例标本中有18例检出基因甲基化,甲基化率为39.1%。p16基因甲基化与蛋白缺失有明显关系(P<0.05)。p16基因表达及其启动子区甲基化的发生率与胰腺癌的大小,患者性别﹑年龄的差异无显著意义(P>0.05),但与组织分化程度﹑淋巴结转移﹑PTNM分期有显著意义(P<0.05)。结论:p16基因启动子的异常甲基化可影响p16蛋白的表达,它们与胰腺癌的发生发展有关;p16甲基化和蛋白表达可能成为胰腺癌诊断及预后的候选标志物之一。 相似文献