“Pincer movement”: Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles

The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers. Intracellular glutathione (GSH) detoxification of cisplatin under the catalysis of glutathione S-transferases (GST) plays important roles in the development of cisplatin resistance. Herein, a strategy of “pincer movement” based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy. Specifically, a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid (EA), a GST inhibitor. Responding to high level of intracellular GSH, the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds, which further promotes drug release. Meanwhile, the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance. Moreover, the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma. The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion, GST inhibition, and consequent tumor growth suppression. Overall, this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance, which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.KEY WORDS: Cancer therapy, Cisplatin, Drug resistance, Glutathione depletion, Glutathione S-transferases, Disulfide bonds, Organosilica hybrid nanoparticles, Ethacrynic acid     

Network pharmacology-based pharmacological mechanism prediction on Eucommia ulmoides against rheumatoid arthritis

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Eucommia ulmoides (EU) is a kidney-tonifying Chinese medicine that has been applied to treat RA for decides. The present study aims to explore pharmacological mechanisms of EU against RA using network pharmacology approach. Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of EU, and their relative targets were fished from UniProt database. RA-related targets were screened from GeneCards database and DisGeNET database. The overlapping genes between EU and RA were identified by Venn diagram, and further analyzed for protein-protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Fifty active ingredients were identified in EU, and corresponded to 207 targets. Meanwhile, 499 targets were closely associated with RA development. A total of 50 overlapping genes between EU and RA were identified, which were regarded as therapeutically relevant. GO enrichment analysis indicated that EU exerted antiRA effects depending on regulating multiple biological processes including inflammatory response, oxidative stress, cell apoptosis and matrix catabolism. Several key pathways such as TNF pathway, IL-17 pathway, T cell receptor pathway, NOD-like receptor pathway and Toll-like receptor pathway, were involved in the above biological processes. Network pharmacology revealed that EU exerts therapeutic effects on RA through multi-ingredients, multi-targets and multi-pathways, which provides basis for its clinical application and promising directions for subsequent research.     

氨茶碱联合黄芪治疗病毒性心肌炎致难治性缓慢心律失常的临床观察

目的 探讨快速静滴氨茶碱联合口服黄芪治疗病毒性心肌炎合并缓慢性心律失常的临床意义。方法 对1990年3月～2000年3月的心动过缓患者36例,在提高心室率、心肌缺血性改变和临床症状改善,进行心电图、超声心动图和阿托品运动试验前后比较。结果 发现氨茶碱组总有效率达91.7％,与对照组比较有显著性差异(P<0.01)。结论 氨茶碱和黄芪具有起效快、易接受的优点,特别对老年人及Adamo-Stores综合征可免戴心脏起搏器,是临床简易有效的治疗方法。     

Chemical constituents from Amentotaxus yunnanensis and Torreyayunnanensis

In a chemical study of taxonomically related Taxaceae plants of Yunnan Province, China, seven compounds, including a new amentoflavone biflavonoid, 2,3-dihydro-7,7' '-dimethoxyamentoflavone (1), were isolated from Amentotaxus yunnanensis, and 12 isolates were obtained from Torreya yunnanensis. From the latter plant, a new abietane diterpene, torreyayunnin (7), is reported for the first time. The known isolates from A. yunnanensis have been identified as sequoiaflavone (3), sotetsuflavone (4), 7,7' '-dimethoxyamentoflavone (5), lutein, beta-sitosterol, and sequoyitol. Amentoflavone (2), sotetsuflavone (4), sciadopitysin (6), 12-hydroxydehydroabietinol, meridinol, balanophonin, (+)-pinoresinol monomethyl ether, (+)-pinoresinol monomethyl ether glucoside, erythro-1-(4-hydroxy-3-methoxyphenyl)-2-[4-[2-formyl-(E)-vinyl]-2- methoxyphenoxy]propane-1,3-diol, threo-1-(4-hydroxy-3-methoxyphenyl)-2- [4-[2-formyl-(E)-vinyl]-2-methoxyphenoxy] propane-1,3-diol, and (E)-2-butenedioic acid were identified as known isolates from T. yunnanensis. The presence of the amentoflavone biflavonoids (1, 3-5) in A. yunnanensis supports its placement in the Taxaceae. The occurrence of the biflavonoid sotetsuflavone (4) in both A. yunnanensis and T. yunnanensis suggests that these two genera are closely related. The identification and structural elucidation of these isolates were based on spectral data analysis including 1D and 2D NMR.     

一次性胃管包的研制与临床应用

目的:探讨一次性胃管包用于胃肠破裂患者治疗中的效果.方法:将60例胃肠破裂患/者随机分为观察组与对照组各30例,观察组采用自制一次性胃管包,对照组采用传统的置胃管前准备方法,观察对比两种方法的效果.结果:两组置胃管前准备时间、患者信任度、患者紧张情况、急救时间以及急救成功率的比较均有极显著性差异(P＜0.01);两组患者满意度比较有显著性差异(P＜0.05).结论:使用一次性胃管包为患者置胃管时方便、快捷、安全,可消除患者紧张情绪,提高患者的满意度及信任度,缓解护患矛盾,降低医疗纠纷,同时减少并发症的发生,提高急救成功率.     

Comparative study on the gastrointestinal- and immune- regulation functions of Hedysari Radix Paeparata Cum Melle and Astragali Radix Praeparata cum Melle in rats with spleen-qi deficiency,based on fuzzy matter-element analysis

ContextHedysari Radix Praeparata Cum Melle (HRPCM) and Astragali Radix Praeparata Cum Melle (ARPCM) are used interchangeably in clinics to treat spleen-qi deficiency (SQD) symptom mainly including gastrointestinal dysfunction and decreased immunity, which has unknown differences in efficacy.ObjectiveTo investigate the differences between HRPCM and ARPCM on intervening gastrointestinal- and immune-function with SQD syndrome.Materials and methodsAfter the SQD model was established, the Sprague–Dawley (SD) rats were randomly divided into nine groups (n = 10): normal; model; Bu-Zhong-Yi-Qi Pills; 18.9, 12.6 and 6.3 g/kg dose groups of HRPCM and ARPCM. Gastrointestinal function including d-xylose, gastrin, amylase vasoactive intestinal peptide, motilin, pepsin, H⁺/K⁺-ATPase, Na⁺/K⁺-ATPase, sodium-glucose cotransporter 1 (SGLT1), glucose transporter 2 (GLUT2) and immune function including spleen and thymus index, blood routine, interleukin (IL)-2, IL-6, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), immunoglobulin (Ig) M, IgA, IgG and delayed-type hypersensitivity (DTH) were detected. Finally, the efficacy differences were analysed comprehensively by the fuzzy matter-element method.ResultsIn regulating immune, the doses differences in efficacy between HRPCM and ARPCM showed in the high-dose (18.9 g/kg), but there were no differences in the middle- and low- dose (12.6 and 6.3 g/kg); the efficacy differences were primarily reflected in levels of IL-6, IFN-γ, TNF-α and IgM in serum, and the mRNA expression of IL-6 and IFN-γ in the spleen. In regulating gastrointestinal, the efficacy differences were primarily reflected in the levels of D-xylose, MTL, and GAS in serum, and the mRNA and protein expression of SGLT1 and GLUT2 in jejunum and ileum.Discussion and conclusionsHRPCM is more effective than ARPCM on regulating gastrointestinal function and immune function with SQD syndrome. Therefore, we propose that HRPCM should be mainly used to treat SQD syndrome in the future.     

优秀游泳运动员大运动量训练期间的超声心动图测定

<正> 自1967年Feignbaum首先应用超声心动图测算心搏量以来,发展迅速,目前已广泛用于心脏功能和结构的测定。Morganroth等1975年发表题为“有训练运动员运动性左室肥大”。我国白洁心等于1979年报道了运动员超声心动图的测量分析。近几年来,国内关于运动员的超声心动图已先后发表了二十多篇文章,都是属于一次性的测定,在作横向比较时,由于仪     

Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway

Glioblastoma(GBM)patients have extremely poor prognoses,and currently no effective treatment available including surgery,radiation,and chemotherapy.MAPK-interacting kinases(MNK1/2)as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells.Research has shown that targeting MNKs may be an effective strategy to treat GBM.In this study we investigated the antitumor activity of osimertinib,an FDA-approved epidermal growth factor receptor(EGFR)inhibitor,against patient-derived primary GBM cells.Using high-throughput screening approach,we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients,found that osimertinib(3μM)suppressed the proliferation of a subset(10/22)of EGFR-negative GBM cells(>50%growth inhibition).We detected the gene expression difference between osimertinib-sensitive and-resistant cells,found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway.We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM,respectively,against MNK1 and MNK2 kinases;osimertinib(0.3–3μM)dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E(eIF4E).In GBM patient-derived xenografts mice,oral administration of osimertinib(40 mg·kg^?1·d^?1,for 18 days)significantly suppressed the tumor growth(TGI=74.5%)and inhibited eIF4E phosphorylation in tumor cells.Given the fact that osimertinib could cross the blood–brain barrier and its toxicity was well tolerated in patients,our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.     

Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

Background and AimsHepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body’s defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.MethodsThe expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.ResultsHBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model.ConclusionsOur finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.