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Ursodeoxycholic acid inhibits glioblastoma progression via endoplasmic reticulum stress related apoptosis and synergizes with the proteasome inhibitor bortezomib.

熊去氧胆酸通过内质网应激相关凋亡抑制胶质母细胞瘤进展,并与蛋白酶体抑制剂硼替佐米协同作用。

  • 影响因子:3.8610
  • DOI:10.1021/acschemneuro.0c00095
  • 作者列表:"Yao Z","Zhang X","Zhao F","Wang S","Chen A","Huang B","Wang J","Li X
  • 发表时间:2020-04-02
Abstract

:Ursodeoxycholic acid (UDCA) has demonstrated cancer suppressive potential in several tumors. Here, we investigated the antitumor potential and biochemical mechanism of UDCA on glioblastoma multiforme (GBM), the deadliest form of brain cancer with a median survival of 15 months. Cell viability was assessed using the CCK-8 and colony forming assays. Expression profiles were obtained using RNA sequencing, PCR and western blot were used to validate changes in related markers at the RNA and protein levels. Flow cytometry was used to examine cell cycle, apoptosis, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). UDCA inhibited GBM cell viability in a dose- and time-dependent manner. Flow cytometry demonstrated that cells were arrested in the G1 phase and underwent apoptosis. The RNA sequencing results showed UDCA treatment in part targeted gene expression related to mitochondria and endoplasmic reticulum (ER). UDCA indeed led to decreased MMP, overproduction of ROS and ER stress. Three critical ER stress sensors ATF6, IRE1 and PERK were increased in the acute phase. Additionally, combining UDCA with the proteasome inhibitor bortezomib (BTZ) achieved a synergistic effect through enhancing the PERK/ATF4/CHOP pathway and protracting ER stress. UDCA inhibited GBM progression and the combination with BTZ achieved a synergistic effect via protracted ER stress. Thus, UDCA, alone or with combination of BTZ, shows promise as a possible therapeutic agent for the treatment of GBM.

摘要

: 熊去氧胆酸 (UDCA) 已证明在几种肿瘤中具有抑制癌症的潜力。在此,我们研究了 UDCA 对多形性胶质母细胞瘤 (GBM) 的抗肿瘤潜力和生化机制,GBM 是脑癌的最致命形式,中位生存期为 15 个月。使用 CCK-8 和集落形成试验评估细胞活力。使用 RNA 测序获得表达谱,使用 PCR 和 western blot 在 RNA 和蛋白水平验证相关标记物的变化。流式细胞仪检测细胞周期、细胞凋亡、线粒体膜电位 (MMP) 和活性氧 (ROS)。UDCA 以剂量和时间依赖性方式抑制 GBM 细胞活力。流式细胞术显示细胞阻滞于 G1 期并发生凋亡。RNA 测序结果显示 UDCA 处理部分靶向基因表达与线粒体和内质网 (ER) 相关。UDCA 确实导致了 MMP 的降低、 ROS 的过度产生和 ER 应激。三个临界 ER 应力传感器 ATF6 、 IRE1 和 PERK 在急性期均升高。此外,UDCA 与蛋白酶体抑制剂硼替佐米 (BTZ) 联合应用通过增强 PERK/ATF4/CHOP 通路和延长 ER 胁迫达到协同作用。UDCA 抑制 GBM 进展,与 BTZ 联合通过延长 ER 应激达到协同作用。因此,UDCA 单独或联合 BTZ 显示出作为治疗 GBM 的可能治疗剂的前景。

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影响因子:3.72
发表时间:2020-01-16
DOI:10.1093/ibd/izz325
作者列表:["Peverelle M","Paleri S","Hughes J","De Cruz P","Gow PJ"]

METHODS:BACKGROUND:The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. METHODS:One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. RESULTS:Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). CONCLUSIONS:Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.

翻译标题与摘要 下载文献
影响因子:6.87
发表时间:2020-01-23
DOI:10.1002/hep.31140
作者列表:["Kunzmann LK","Schoknecht T","Poch T","Henze L","Stein S","Kriz M","Grewe I","Preti M","Hartl J","Pannicke N","Peiseler M","Sebode M","Zenouzi R","Horvatits T","Böttcher M","Petersen BS","Weiler-Normann C","Hess LU","Elise Ahrenstorf A","Lunemann S","Martrus G","Fischer L","Li J","Carambia A","Kluwe J","Huber S","Lohse AW","Franke A","Herkel J","Schramm C","Schwinge D"]

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