Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions. Part 2: Solving substrate interactions of CYP1A2 with non-PAH substrates on the template system

In our previous paper (Drug Metabolism Parmacokinet 31: 363, 2016), a simulation system for ligand interactions of human CYP1A2 was developed using “Template” composed of hexagonal grids focusing on polyaromatic hydrocarbons (PAHs). The system has been expanded for the application of non-PAH chemicals including medical drugs, industrial chemicals and natural products in the present study. Additions of two Templates C and D around Ring C/E and Ring B, respectively, perpendicular each to Template A, offered the accommodation of non-PAH substrates. The size and shape of Templates C and D were defined from the reciprocal comparison of experimental data of ligands with simulation on Templates. The requirements of occupancies at Trigger region (Ring B) and at region of Facial-side Movement (Ring C) as well as Site of Oxidation were found to be mutual throughout CYP1A2 good substrates tested for over the 450 reactions, irrespective of their shapes and flexibilities. The CYP1A2 Template system was also verified with distinct types of poor substrates (47 chemicals) and inhibitors (37 inhibitors) and found to offer the information on probable structural causes. Present CYP1A2 Template system offers a unified evaluation of human CYP1A2 ligands, which aids for toxicological assessments as well as drug metabolism studies.     

Genetic findings in patients with primary fibrotic atrial cardiomyopathy

Primary fibrotic atrial cardiomyopathy (PF-ACM) is a novel type of cardiomyopathy characterized by primary atrial fibrosis with arrhythmogenicity and increased stroke risk without ventricular myocardium involvement. However, genetic analysis regarding PF-ACM and genotype–phenotype correlations is lacking. A cohort of PF-ACM patients was recruited and followed up. Whole-exome sequencing (WES) was applied, and genes were screened using a cardiovascular disease (CVD)-related gene panel. Echocardiography and cardiac magnetic resonance (CMR) were performed. The pathogenicity of the identified mutations was evaluated using in silico analysis. Thirty-three unrelated patients were referred for WES. Thirty-three rare variants of 19 CVD-related genes were identified in 21 patients, with 10 patients harboring more than one variation. TTN was the most frequent gene observed. Further analysis demonstrated that variations in sarcomeric (SV) or non-sarcomeric (NSV) genes were found in 16 and 10 patients, respectively. Patients carrying variants regardless of SV or NSV had larger left atrial dimensions determined by echo and larger left atrium areas determined by CMR. There was no discrepancy in disease severity between SV carriers and NSV carriers. Our genetic investigation into PF-ACM has identified several genetic culprits, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing for this condition.     

Effect of linalool as a component of Humulus lupulus on doxorubicin-induced antitumor activity

As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na⁺. This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na⁺-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator.     

抗反流手术治疗老年食管裂孔疝合并胃食管反流病对阻塞性睡眠呼吸暂停的影响

目的 分析老年食管裂孔疝（HH）合并胃食管反流病（GERD）患者中阻塞性睡眠呼吸暂停（OSA）的患病情况,并探索抗反流手术（腹腔镜下食管裂孔疝修补术联合胃底折叠术）治疗老年GERD合并HH对OSA的影响。 方法 根据多导睡眠监测（PSG）结果,将77例HH合并GERD患者分为OSA组,和非OSA组。对所研究指标进行差异性及相关性分析。结果 OSA组患者AHI、ODI、LAT、ESS评分、血清IL-8、TNF-α水平高于非OSA组,LSaO2低于非OSA组,差异有统计学意义（P＜0.05）;血清TNF-α水平与AHI、ODI、LAT正相关,与LSaO2负相关（r = 0.647、0.579、0.477、- 0.312,P均＜0.05）;血清IL-8水平与AHI、ODI正相关,与LSaO2负相关（r = 0.422、0.501、- 0.330,P均＜0.05）;与术前相比,术后AHI、ODI、LSaO2、LAT、ESS评分、GERD-Q评分、血清IL-8、TNF-α水平有改善,差异均有统计学意义（P＜0.05）;手术前后血清TNF-α差值与AHI、ODI、LAT差值正相关,与LSaO2差值负相关（r =0.329、0.408、0.529,- 0.312,P均＜0.05）;手术前后IL-8差值与AHI、ODI、LAT差值正相关,与LSaO2差值负相关（r =0.343、0.371、0.350,- 0.330,P均＜0.05）。结论 老年GERD合并HH患者OSA的患病率较高,男女患病比例接近,以轻中度OSA为主。通过抗反流手术治疗不仅能够改善患者反流症状,也能改善OSA的病情及相关炎症反应,术后需针对OSA进行随访和治疗。     

Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs

Breast cancer (BCa) remains chemo-unresponsive by inevitable progression of resistance to first-line treatment with docetaxel (doc). Emerging studies indicate that exosomes act as mediators of intercellular communication between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development. Such modulatory effects have been related to the constant shuttle of biologically active molecules including microRNAs (miRNAs). Here, we aimed to investigate the relevance of exosome-mediated miRNA delivery in resistance transmission of BCa subpopulations. Using microarray and polymerase chain reaction, we found that exosomes from doc-resistant BCa cells (D/exo) loaded cellular miRNAs. Following D/exo transfer to the fluorescent sensitive cells (GFP-S), some miRNAs were significantly increased in recipient GFP-S. Target gene prediction and pathway analysis revealed the involvement of the top 20 most abundant miRNAs of D/exo in pathways implicated in therapy failure. Coculture assays showed that miRNA-containing D/exo increased the overall resistance of GFP-S to doc exposure. Moreover, D/exo was able to alter gene expression in GFP-S. Our results open up an intriguing possibility that drug-resistant BCa cells may spread chemoresistance to sensitive ones by releasing exosomes and that the effects could be partly attributed to the intercellular transfer of specific miRNAs.     

Anti-tumor activities of matrine and oxymatrine: literature review

Matrine (MT) and oxymatrine (OMT), two kinds of alkaloid components found in the roots of Sophora species, have various pharmacological activities and are demonstrated to have anti-inflammatory, anti-allergic, anti-virus, anti-fibrotic, and cardiovascular protective effects. They are recently proved to have anti-cancer potentials, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- or radiotherapy-induced toxicity when combined with other chemotherapeutic drugs. In this review, we summarize the recent investigations regarding the anti-cancer activities and possible molecular targets of MT and OMT for cancer prevention and treatment in order to provide clues and references for further study.     

肥胖相关性高血压患者中心动脉压与靶器官损害相关性分析

【摘要】目的 探讨肥胖相关性高血压患者靶器管损害程度及中心动脉压（CBP）对靶器管损害的影响。方法 纳入徐州市中心医院2014年6月至2019年6月收住入院的高血压患者150例。根据高血压患者体质量指数，将样本分为正常体重高血压组（BMI<24Kg/m2）、超重高血压组(24 Kg/m2≤BMI<28 Kg/m2)、肥胖高血压组（BMI≥28 Kg/m2）。比较三组患者靶器管损害的差异及其与中心动脉压、24小时动态血压的相关性。结果 (1)与正常体重高血压组、超重高血压组比较，肥胖高血压组BMI、腰围、空腹血糖、同型半胱氨酸（HCY）、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-c）、颈-股脉搏波传导速度(c-fPWV)、左心室质量（LVM）、左心室质量指数（LVMI）、尿微量白蛋白（mALB）较高（P<0.05）。(2)高血压患者c-fPWV与中心动脉脉压差（CPP）呈正相关（r=0.580，P=0.001）；LVMI与中心动脉收缩压（CSBP）呈正相关（r=0.279，P=0.004）；mALB与CSBP呈正相关（r=0.333，P=0.001）。结论 体重增加可进一步加重高血压患者靶器管损害，中心动脉压较24小时动态血压对高血压患者靶器管损害更为密切。     

基于Oncomine数据库分析SNRPB基因在乳腺癌中的表达及临床意义

目的:研究小核糖体核蛋白B（small nuclear ribonucleoprotein polypeptides B and B1，SNRPB)在乳腺癌中的表达及临床意义。方法:运用Oncomine数据库搜索乳腺癌与SNRPB基因相关的数据，通过Kaplan-Meier Plotter数据库分析SNRPB基因与乳腺癌患者预后的关系。结果:Oncomine数据库中SNRPB基因癌组织／正常组织表达量分析结果共有414个，在癌组织中显著高表达109个，低表达3个。其中13个分析结果显示SNRPB在乳腺癌组织(包括6个侵袭性乳腺癌分析结果)中显著高表达，低表达的分析结果为1个。运用Kaplan-Meier Plotter数据库分析结果显示，高表达SNRPB的乳腺癌患者其总体生存率（OS）、无复发生存率（PFS）、无远处转移生存率（DMFS）显著低于低表达SNRPB的乳腺癌患者(P＜0.05)。结论:SNRPB基因在乳腺癌中高表达，可以作为有效的生物标志物预测乳腺癌患者转移的发生及判断预后，可为乳腺癌的靶向治疗提供依据。     

阿帕替尼联合调强放疗治疗老年中晚期宫颈癌的疗效及安全性分析

目的:探讨阿帕替尼联合调强放疗治疗老年中晚期宫颈癌的疗效及安全性。方法:选取2015年1月至2019年7月徐州医科大学附属医院放疗科收治的60例经病理组织学确诊的年龄≥65岁的中晚期宫颈癌患者（IIb-IVa期），患者随机分为阿帕替尼联合调强放疗组（实验组）和单纯调强放疗组（对照组）,实验组30例，对照组30例。比较两组的近期疗效及不良反应发生率。结果:实验组和对照组患者的总有效率分别为70.0%和43.3%，差异有统计学意义(P＜0.05)。实验组高血压及蛋白尿的发生率明显高于对照组（P＜0.05），但予以内科对症支持治疗后症状均得到明显改善，骨髓抑制、手足综合征及出血等差异并无统计学意义。结论:阿帕替尼联合调强放疗是治疗老年中晚期宫颈癌的有效方案，不良反应可以耐受。