Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

CDC42 controls intestinal epithelial(IEC)stem cell(IESC)division.How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear.We utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia.Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer.Cdc42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient mice.Irradiation,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC repair.Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD colon.Colonic Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt dysplasia.Colonic Cdc42 depletion markedly enhanced irra-diation-or chemical-induced colitis.Depletion or inhibition of Cdc42 reduced colonic Lgr5+IESC regeneration.In conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal inflammation.Constitutive monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.

动机性访谈在肠造口患儿照顾者中的应用

目的探讨基于自我效能理论的动机性访谈在肠造口患儿照顾者中的应用效果。方法在文献研究和前期研究基础上制订动机性访谈方案,拟订访谈策略,筛选和培训访谈护士;采用随机数字表法将72对肠造口患儿及其照顾者随机分为2组,每组各36对患儿及其照顾者,试验组在对照组干预措施的基础上于住院期间和出院后1、2、3个月分别实施5次动机性访谈,对照组实施常规健康宣教和随访。比较两组患儿照顾者出院后1、2、3个月自我效能得分、焦虑水平及患儿出院后3个月肠造口相关并发症的发生情况。结果干预3个月后试验组患儿照顾者自我效能水平高于对照组,焦虑水平低于对照组,差异有统计学意义(P<0.05);试验组患儿造口周围皮炎的发生率明显低于对照组,差异有统计学意义(P<0.05)。结论动机性访谈能够提高肠造口患儿照顾者的自我效能水平,降低其焦虑水平,有助于降低肠造口患儿造口周围皮炎的发生率。

脑卒中患者发生深静脉血栓危险因素的Meta分析

目的明确脑卒中患者发生深静脉血栓的危险因素,为预防脑卒中患者发生深静脉血栓提供依据。方法计算机检索Cochrane Library、PubMed、Embase、中国期刊全文数据库、万方数据库、维普数据库和中国生物医学文献数据库,搜集建库至2018年8月关于脑卒中患者发生深静脉血栓危险因素的文献,利用RevMan 5.3软件进行Meta分析。结果共纳入14篇文献,包括22项相关危险因素,有统计学意义的危险因素为年龄≥65岁(OR=1.93)、糖尿病(OR=1.63)、冠心病(OR=2.31)、心房颤动(OR=1.55)、瘫痪(OR=7.14)、深静脉穿刺(OR=3.08)、卧床(OR=7.36)、心力衰竭(OR=1.96)、感染(OR=2.48)、入院时美国国立卫生研究院脑卒中评分(OR=5.78)、下肢美国国立卫生研究院脑卒中评分≥2分(OR=2.28)。结论年龄≥65岁、糖尿病、冠心病、心房颤动、瘫痪、有深静脉穿刺史、卧床、心力衰竭、感染等是脑卒中患者深静脉血栓的危险因素。