Mechanisms involved in antineuralgic effects of Paeonia Lactiflora: prediction based on network pharmacology

目的:白芍的镇痛作用已被广泛应用于中医临床,但对其潜在机制知之甚少.本研究旨在从网络药理学的角度阐明其有效成分和镇痛机制.方法:通过中药系统药理学分析平台(TCMSP)筛选出其可能的活性成分及CAS.从Pubchem 中获得其SMILES,并通过在Swiss Target Prediction 数据库中反向对接获得潜在的靶点.从GeenCards 数据库中提取疼痛相关分子,采用韦恩图筛选出芍药治疗疼痛的预测靶点.机制分析采用String 构建蛋白-蛋白相互作用,运用DAVID 平台进行靶点GO 功能富集和KEGG 信号通路富集.结果:通过GO 和KEGG 分析我们发现疼痛相关的信号通路主要涉及血清素能突触、钙信号通路、调控TRP 通道的炎症介质.利用基于网络的系统生物学和分子对接分析,我们预测了白芍中的11 种活性成分和97 个潜在的治疗靶标.PRKCA、CASP3、ALOX15、SLC6A4、PRKCG、ALOX5、PRKCB、ALOX12、 EGFR、ADRB2、RYR3、RYR1、NOS2、PTAFR、PRKCQ、PRKCD 等基因参与了白芍的镇痛作用.结论:白芍可通过调节TRP 通道炎症介质、钙信号通路和5-羟色胺受体减轻疼痛.PRKCA、PRKCB、PRKCD、 PRKCQ 和PRKCG 可能是疼痛治疗的新靶标.

Primary duct closure versus T-tube drainage after laparoscopic common bile duct exploration:a meta-analysis

Background and aims:Laparoscopic common bile duct exploration(LCBDE)is considered a safe and effective method for the removal of bile duct stones.However,the choice of primary duct closure(PDC)or T-tube drainage(TTD)technique after LCBDE is still controversial.This study aimed to compare the safety and effectiveness of PDC and TTD after LCBDE.Methods:Studies published before May 1,2021 in Pub Med,Web of Science,and Cochrane Library databases were searched to screen out randomized controlled trials(RCTs)and cohort studies to compare PDC with TTD.Meta-analyses of fixed effect and random effect models were performed using Rev Man 5.3.Results:A total of 1865 patients were enrolled in six RCTs and ten cohort studies.Regarding RCTs,the PDC group was significantly better than the TTD group in terms of operation time,total postoperative complications,postoperative hospital stay,and hospitalization expenses(all P<0.05).Based on cohort studies of the subgroup,the PDC group had shorter operation time,shorter postoperative hospital stay,less intraoperative blood loss,and limited total postoperative complications.Statistically,there were no significant differences in bile leakage,retained stones,stone recurrence,bile duct stricture,postoperative pancreatitis,other complications,or postoperative exhaust time between the TTD and PDC groups.Conclusions:Based on the available evidence,compared with TTD,PDC is safe and effective,and can be used as the first choice after transductal LCBDE in patients with choledocholithiasis.

PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

5-Fluorouracil(5-FU)is known as a first-line chemotherapeutic agent against colorectal cancer(CRC),but drug resistance occurs frequently and significantly limits its clinical success.Our previous study showed that the protocadherin 17(PCDH17)gene was frequently methylated and functioned as a tumor suppressor in CRC.However,the relationship between PCDH17 and 5-FU resistance in CRC remains unclear.Here,we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues,and high expression of PCDH17 was correlated with high BECN1 expression.Moreover,this expression profile contributed to superior prognosis and increased survival in CRC patients.Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death.Furthermore,autophagy played a dominant role in PCDH17-induced cell death,as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK.PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity.Mechanistically,we showed that c-Jun NH2-terminal kinase(JNK)activation was a key determinant in PCDH17-induced autophagy.The compound SP600125,an inhibitor of JNK,suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells.Taken together,our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death.PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.