Drug D,a Diosgenin Derive,Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD^-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.     

Effect of Calcium Carbide Residue on Strength Development along with Mechanisms of Cement-Stabilized Dredged Sludge

The purpose of this research is to explore the feasibility of using calcium carbide residue (CCR), a by-product from acetylene gas production, as a solid alkaline activator on the strength development in CCR–Portland cement-stabilized dredged sludge (CPDS). The effects of cement content, CCR content and curing time on the strength development of CPDS were investigated using a series of unconfined compressive strength (UCS), pH and electric conductivity (EC) tests. Scanning electron microscopy and X-ray diffraction analyses were performed to gain additional insight into the mechanism of strength development. Meanwhile, the carbon footprints of CPDS were calculated. Following the results, it was found that CCR can significantly improve the strength of cemented dredged sludge. On the basis of the strength difference (ΔUCS) and strength growth rate (UCS_gr), it was recommended that utilizing 20% cement with the addition of 20% CCR is the most effective way to develop the long-term strength of CPDS. In addition, the microstructural analysis verified that the optimum proportion of CCR benefits the formation of hydration products in CPDS, particularly needle-like gel ettringite, resulting in a less-porous and dense inter-locked structure. Furthermore, the solidification mechanism of CPDS was discussed and revealed. Finally, it was confirmed that CCR can be a sustainable alternative and effective green alkaline activator for the aim of improving cemented dredged sludge.     

集成便携式辅助诊疗系统是脉诊、舌诊研究走向临床的切入点

基于成熟的脉诊、舌诊信息提取与识别的关键技术,集成便携式辅助诊疗系统突出脉诊、舌诊在中医诊疗中的重要作用,并融合其他四诊信息,实现自动辨证处方的临床辅助诊疗功能。便携式辅助诊疗系统体现了"四诊合参"的中医辨证诊断理念,其便携化、智能化、人性化的特点贴合临床实际,为脉诊、舌诊研究成果的推广应用奠定了完备的条件。     

“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.     

不同剂量舒芬太尼在全麻诱导中对异丙酚TCI效应室浓度的影响

目的：研究不同剂量舒芬太尼在全麻诱导中对异丙酚TCI效应室浓度的影响。结果：45例年龄27岁-68岁,ASA（Ⅰ-Ⅱ）级择期行腹部手术的病人,随机分为三组：Ⅰ组（n=15）麻醉诱导时加用为芬太尼,Ⅱ组（n=15）则加用小剂量舒芬太尼（O．31μ／kg）;Ⅲ组（n=15）加用大剂量舒芬太尼（0．45μ／kg）。记录麻醉前（T0）、插管前即刻（T1）、插管后1min（T2）、3minB）、5min（T4）、10min（T5）各时点的平均动脉压（MAP）、心率（HR）及异丙酚效应室浓度（Ce）。同时记录脑电双频指数（BIS值）。结果：MAP在T2、T3、T4时点Ⅲ组较其它二组低（P〈0．05）;心率在T2、T3时点Ⅱ组明显高于Ⅰ组和Ⅲ组（P〈0．05）;异丙酚Ce在T2、T3、T4、T5时点Ⅲ组低于Ⅰ组和Ⅱ组（P〈0．05或0．01）,而Ⅰ组和Ⅱ组间差别无统计学意义。结论：诱导用量为0.45μ／kg的舒芬太尼在腹部手术全麻诱导过程中不仅能保持稳定的血流动力学（MAP和HR）,而且能降低异丙酚效应室浓度。     

辛伐他汀对急性冠脉综合征早期C反应蛋白和血脂的影响

目的　观察急性冠脉综合征的早期应用辛伐他汀后C反应蛋白和血脂的变化。方法　70例急性冠脉综合征患者随机分为对照组(无服用任何调脂药物,34例)和治疗组(辛伐他汀10mg/d ,36例) ,测定治疗前后C反应蛋白和血脂的变化。结果　治疗组治疗5d后C反应蛋白水平下降35 % ,与治疗前比较差异有显著意义(P <0 . 0 5 ) ;治疗4周后TC、LDL C分别下降30 %、4 0 % ,与治疗前比较差异有显著意义;而且随访期间治疗组的心肌梗死发生率、再住院率均明显低于对照组。结论　在急性冠脉综合征早期予以辛伐他汀治疗是可行及有效的,可明显降低血脂和血浆炎症因子的水平,可能有利于动脉粥样斑块的稳定。     

灸药并用治疗小儿久咳127例

目的:观察灸药并用治疗脾虚痰湿型小儿咳嗽的疗效。方法:127例久咳患儿辨证属脾虚痰湿型,采用内服二陈汤加减、温和灸膏肓等穴、捏脊疗法综合治疗,7次为1个疗程,连治3个疗程,并随访1年。结果:127例患儿中,治愈21例,好转88例,未愈18例,总有效率为87%。结论:灸、药、捏脊疗法三者并用,能有效治疗脾虚痰湿型小儿久咳,本法可作为临床的首选疗法之一。     

计算化学方法在基于受体结构的药物分子设计中的基础理论及应用

近年来生物学领域的研究进展极大地加深了对疾病密切相关的靶标分子的结构和功能的认识。然而,如何有效地利用生物大分子的结构信息,进而合理地设计出具有特异性结合活性的小分子药物,还需要进一步开发精确计算受体配体结合自由能的方法。近年来计算能力迅猛增长及研究大分子体系的理论和算法日趋成熟,基于物理学原理的计算化学方法在药物分子设计中的重要作用日益凸显。本文就计算化学在基于受体结构的药物分子设计中的方法及典型应用实例进行了系统的综述,包括小分子结合位点的成药性评估、化合物数据库的虚拟筛选、先导化合物的结构优化等,同时对目前的应用方法存在的主要问题进行了探讨,提出了切实可行的处理策略。     

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。