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A novel ABCB11 variant in compound heterozygosity: BRIC2 or PFIC2? 一种新型 ABCB11 复合杂合变体:BRIC2还是PFIC2?
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-04-25 eCollection Date: 2024-01-01 DOI: 10.1093/gastro/goae022
Marco Biolato, Rosy Terranova, Nicholas Viceconti, Giuseppe Marrone, Luca Miele, Maria Cristina Giustiniani, Paola Francalanci, Annalisa Gazzellone, Alessia Bauleo, Elena Falcone, Maurizio Genuardi, Antonio Grieco
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引用次数: 0
Texture analysis of apparent diffusion coefficient maps: can it identify nonresponse to neoadjuvant chemotherapy for additional radiation therapy in rectal cancer patients? 表观扩散系数图的纹理分析:它能识别直肠癌患者对新辅助化疗的非响应性,从而进行额外放疗吗?
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-04-22 DOI: 10.1093/gastro/goae035
Qianyu Wu, Yongju Yi, Bingjia Lai, Jiao Li, Yanbang Lian, Junhong Chen, Yue Wu, Xinhua Wang, Wuteng Cao
Background Neoadjuvant chemotherapy (NCT) alone can achieve comparable treatment outcomes to chemoradiotherapy in locally advanced rectal cancer (LARC) patients. This study aimed to investigate the value of texture analysis (TA) in apparent diffusion coefficient (ADC) maps for identifying non-responders to NCT. Methods This retrospective study included patients with LARC after NCT, and they were categorized into nonresponse group (pTRG 3) and response group (pTRG 0–2) based on pathological tumor regression grade (pTRG). Predictive texture features were extracted from pre- and post-treatment ADC maps to construct a TA model using RandomForest. The ADC model was developed by manually measuring pre- and post-treatment ADC values and calculating their changes. Simultaneously, subjective evaluations based on magnetic resonance imaging assessment of TRG were performed by two experienced radiologists. Model performance was compared using the area under the curve (AUC) and DeLong test. Results A total of 299 patients from two centers were divided into three cohorts: the primary cohort (center A; n = 194, with 36 non-responders and 158 responders), the internal validation cohort (center A; n = 49, with 9 non-responders) and external validation cohort (center B; n = 56, with 33 non-responders). The TA model was constructed by post_mean, mean_change, post_skewness, post_entropy, and entropy_change, which outperformed both the ADC model and subjective evaluations with an impressive AUC of 0.997 (95% confidence interval [CI], 0.975–1.000) in the primary cohort. Robust performances were observed in internal and external validation cohorts, with AUCs of 0.919 (95% CI, 0.805–0.978) and 0.938 (95% CI, 0.840–0.985), respectively. Conclusions The TA model has the potential to serve as an imaging biomarker for identifying nonresponse to NCT in LARC patients, providing a valuable reference for these patients considering additional radiation therapy.
背景 在局部晚期直肠癌(LARC)患者中,单用新辅助化疗(NCT)可获得与化疗放疗相当的治疗效果。本研究旨在探讨表观扩散系数(ADC)图中的纹理分析(TA)在识别 NCT 无应答者方面的价值。方法 该回顾性研究纳入了经 NCT 治疗的 LARC 患者,根据病理肿瘤回归分级(pTRG)将其分为无反应组(pTRG 3)和反应组(pTRG 0-2)。从治疗前和治疗后的 ADC 图中提取预测纹理特征,使用 RandomForest 构建 TA 模型。ADC 模型是通过手动测量治疗前和治疗后的 ADC 值并计算其变化而建立的。同时,由两名经验丰富的放射科医生根据磁共振成像对 TRG 进行主观评估。使用曲线下面积(AUC)和 DeLong 检验比较模型性能。结果 两个中心共 299 名患者被分为三个队列:主要队列(中心 A;n = 194,其中有 36 名无应答者和 158 名应答者)、内部验证队列(中心 A;n = 49,其中有 9 名无应答者)和外部验证队列(中心 B;n = 56,其中有 33 名无应答者)。TA模型由post_mean、mean_change、post_skewness、post_entropy和entropy_change构建而成,在主要队列中的AUC为0.997(95%置信区间[CI],0.975-1.000),优于ADC模型和主观评价。在内部和外部验证队列中也观察到了稳健的表现,AUC 分别为 0.919(95% CI,0.805-0.978)和 0.938(95% CI,0.840-0.985)。结论 TA 模型有可能成为识别 LARC 患者对 NCT 无应答的影像生物标志物,为这些患者考虑额外放疗提供有价值的参考。
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引用次数: 0
Animal models of inflammatory bowel disease: category and evaluation indexes 炎症性肠病动物模型:类别和评价指标
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-04-17 DOI: 10.1093/gastro/goae021
Changlin Wen, Dan Chen, Rao Zhong, Xi Peng
Inflammatory bowel disease (IBD) research often relies on animal models to study the etiology, pathophysiology, and management of IBD. Among these models, rats and mice are frequently employed due to their practicality and genetic manipulability. However, for studies aiming to closely mimic human pathology, non-human primates such as monkeys and dogs offer valuable physiological parallels. Guinea pigs, while less commonly used, present unique advantages for investigating the intricate interplay between neurological and immunological factors in IBD. Additionally, New Zealand rabbits excel in endoscopic biopsy techniques, providing insights into mucosal inflammation and healing processes. Pigs, with their physiological similarities to humans, serve as ideal models for exploring the complex relationships between nutrition, metabolism, and immunity in IBD. Beyond mammals, non-mammalian organisms including zebrafish, Drosophila melanogaster, and nematodes offer specialized insights into specific aspects of IBD pathology, highlighting the diverse array of model systems available for advancing our understanding of this multifaceted disease. In this review, we conduct a thorough analysis of various animal models employed in IBD research, detailing their applications and essential experimental parameters. These include clinical observation, Disease Activity Index score, pathological assessment, intestinal barrier integrity, fibrosis, inflammatory markers, intestinal microbiome, and other critical parameters that are crucial for evaluating modeling success and drug efficacy in experimental mammalian studies. Overall, this review will serve as a valuable resource for researchers in the field of IBD, offering insights into the diverse array of animal models available and their respective applications in studying IBD.
炎症性肠病(IBD)研究通常依赖动物模型来研究 IBD 的病因学、病理生理学和治疗方法。在这些模型中,大鼠和小鼠因其实用性和遗传可操作性而经常被采用。然而,对于旨在近似模拟人类病理的研究,猴子和狗等非人灵长类动物提供了宝贵的生理相似性。豚鼠虽然不常用,但在研究 IBD 神经和免疫因素之间错综复杂的相互作用方面具有独特的优势。此外,新西兰兔擅长内窥镜活检技术,可以深入了解粘膜炎症和愈合过程。猪的生理结构与人类相似,是探索 IBD 中营养、代谢和免疫之间复杂关系的理想模型。除哺乳动物外,斑马鱼、黑腹果蝇和线虫等非哺乳动物也为 IBD 病理学的特定方面提供了专门的见解,凸显了可用于推进我们对这种多发性疾病的认识的模型系统的多样性。在这篇综述中,我们对 IBD 研究中使用的各种动物模型进行了深入分析,详细介绍了它们的应用和基本实验参数。这些参数包括临床观察、疾病活动指数评分、病理评估、肠道屏障完整性、纤维化、炎症标志物、肠道微生物组以及其他对评估哺乳动物实验研究中建模成功率和药物疗效至关重要的参数。总之,这篇综述将为 IBD 领域的研究人员提供宝贵的资源,让他们深入了解现有的各种动物模型及其在 IBD 研究中的应用。
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引用次数: 0
Instant duodenal decompression after endoscopic retrograde cholangiopancreatography can effectively reduce the incidence of post-ERCP pancreatitis and hyperamylasemia. 内镜逆行胰胆管造影术后立即进行十二指肠减压可有效降低逆行胰胆管造影术后胰腺炎和高淀粉酶血症的发病率。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-04-05 eCollection Date: 2024-01-01 DOI: 10.1093/gastro/goae025
Yu-Zhen Bi, Si-Jia Yan, Li-Min Zhou, Yan Sun, Jun Zhang

Background: Post-ERCP pancreatitis (PEP) is significantly influenced by the reflux of duodenal fluid. While gastrointestinal decompression represents a fundamental approach in acute pancreatitis management, the effectiveness of immediate duodenal decompression following ERCP to prevent PEP remains uncertain. This study aimed to investigate the impact of immediate duodenal decompression after ERCP on reducing the incidence of hyperamylasemia and PEP.

Methods: This retrospective study encompassed patients with native papilla who underwent therapeutic ERCP for choledocholithiasis at the Department of Gastroenterology, Chun'an Branch of Zhejiang Provincial People's Hospital (Zhejiang, China) between January 2020 and June 2023. Based on the immediate placement of a duodenal decompression tube post-ERCP, patients were categorized into two groups: the duodenal decompression group and the conventional procedure group. Primary outcomes included the incidence of PEP and hyperamylasemia.

Results: A total of 195 patients were enrolled (94 in the duodenal decompression group and 101 in the conventional procedure group). Baseline clinical and procedural characteristics exhibited no significant differences between the two groups. PEP occurred in 2 patients (2.1%) in the duodenal decompression group, in contrast to 11 patients (10.9%) in the conventional procedure group (Risk difference [RD] 8.8%; 95% confidence interval [CI] 1.7%-16.5%, P =0.014). Hyperamylasemia was observed in 8 patients (8.5%) in the duodenal decompression group, compared to 20 patients (19.8%) in the conventional procedure group (RD 11.3%; 95% CI 1.4%-21.0%; P =0.025). Patients with PEP in both groups showed improvement after receiving active treatment. No severe cases of PEP occurred in either group, and no serious adverse events related to duodenal catheter decompression were reported.

Conclusion: Immediate duodenal decompression following ERCP demonstrates an effective reduction in the incidence of hyperamylasemia and PEP.

背景:ERCP术后胰腺炎(PEP)在很大程度上受十二指肠液反流的影响。虽然胃肠减压是急性胰腺炎治疗的基本方法,但ERCP术后立即进行十二指肠减压以预防PEP的效果仍不确定。本研究旨在探讨ERCP术后立即进行十二指肠减压对降低高淀粉血症和PEP发病率的影响:这项回顾性研究涵盖了2020年1月至2023年6月期间在浙江省人民医院淳安分院消化内科接受ERCP治疗胆总管结石的原发性乳头患者。根据ERCP术后是否立即置入十二指肠减压管,将患者分为两组:十二指肠减压组和传统手术组。主要结果包括 PEP 和高淀粉血症的发生率:共有 195 名患者入选(94 名十二指肠减压术组患者和 101 名传统手术组患者)。两组患者的基线临床和手术特征无明显差异。十二指肠减压组有 2 名患者(2.1%)发生 PEP,而传统手术组有 11 名患者(10.9%)发生 PEP(风险差异 [RD] 8.8%;95% 置信区间 [CI] 1.7%-16.5%,P = 0.014)。十二指肠减压组有 8 名患者(8.5%)出现高淀粉酶血症,而传统手术组有 20 名患者(19.8%)出现高淀粉酶血症(风险差异 11.3%;95% 置信区间 [CI]1.4%-21.0%;P = 0.025)。两组 PEP 患者在接受积极治疗后均有好转。两组患者均未出现严重的PEP病例,也未报告与十二指肠导管减压相关的严重不良事件:结论:ERCP术后立即进行十二指肠减压可有效降低高淀粉血症和PEP的发生率。
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引用次数: 0
Isolated gastrointestinal histoplasmosis with a negative urine antigen test mimicking ulcerative colitis flare: a case report. 模仿溃疡性结肠炎复发的尿抗原检测阴性的孤立胃肠道组织胞浆菌病:病例报告。
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-04-02 eCollection Date: 2024-01-01 DOI: 10.1093/gastro/goae013
Jianyi Yin, Neeraja Balachandar, Dipti Karamchandani, Roopa Vemulapalli, David I Fudman
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引用次数: 0
Testing region selection and prognostic analysis of MLH1 promoter methylation in colorectal cancer in China 中国结直肠癌 MLH1 启动子甲基化的检测区域选择和预后分析
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-04-02 DOI: 10.1093/gastro/goae011
Xiaoli Tan, Yongzhen Fang, Xinjuan Fan, Weihao Deng, Jinglin Huang, Yacheng Cai, Jiaxin Zou, Zhiting Chen, Hanjie Lin, Liang Xu, Guannan Wang, Huanmiao Zhan, Shuhui Huang, Xinhui Fu
Background MLH1 promoter methylation analysis is recommended in screening for Lynch syndrome (LS) in patients with MLH1-deficient colorectal cancer (CRC). The study aims to identify specific methylation regions in the MLH1 promoter and to evaluate the clinicopathologic characteristics of and prognosis for patients with MLH1 methylation. Methods A total of 580 CRC cases were included. The DNA mismatch repair (MMR) protein expression was assessed by using immunohistochemistry (IHC). The methylation status of the Regions A, B, C, D, and E in the MLH1 promoter was tested by using bisulfite sequencing PCR. The specificities of the five regions were calculated. Associations between MLH1 methylation and clinicopathologic characteristics were evaluated. Kaplan–Meier analyses for overall survival (OS) were carried out. Results In 580 CRC cases, the specificities of the methylation test in Regions D and E were both 97.8%. In the MLH1-deficient CRCs, the frequencies of MLH1 methylation and BRAFV600E mutation were 52.6% and 14.6%, respectively; BRAFV600E mutation occurred in 27.7% of patients with MLH1-methylated CRC. In the MMR-deficient patients, compared with MLH1 unmethylation, MLH1 methylation was more common in patients who were aged ≥50 years, female, had no family history of LS-related tumors, and had tumors located at the right colon. In the MMR-deficient patients, the MLH1-methylated cases had lower OS rates than the unmethylated cases with a family history of LS-related tumors (P = 0.047). Conclusions Regions D and E in the MLH1 promoter are recommended for determining the MLH1 methylation status in screening for LS in MLH1-deficient CRC. In MMR-deficient patients, the MLH1-methylated cases had a worse OS than the unmethylated cases with a family history of LS-related cancer.
背景 MLH1启动子甲基化分析被推荐用于筛查MLH1缺陷性结直肠癌(CRC)患者的林奇综合征(LS)。本研究旨在确定 MLH1 启动子中的特定甲基化区域,并评估 MLH1 甲基化患者的临床病理特征和预后。方法 共纳入 580 例 CRC 病例。采用免疫组化(IHC)方法评估DNA错配修复(MMR)蛋白的表达。使用亚硫酸氢盐测序 PCR 检测 MLH1 启动子中 A、B、C、D 和 E 区的甲基化状态。计算了五个区域的特异性。评估了 MLH1 甲基化与临床病理特征之间的关联。对总生存期(OS)进行卡普兰-梅耶分析。结果 在580例CRC病例中,D区和E区甲基化检测的特异性均为97.8%。在MLH1缺陷型CRC中,MLH1甲基化和BRAFV600E突变的频率分别为52.6%和14.6%;在MLH1甲基化型CRC患者中,27.7%发生了BRAFV600E突变。在MMR缺陷患者中,与MLH1未甲基化相比,MLH1甲基化在年龄≥50岁、女性、无LS相关肿瘤家族史、肿瘤位于右侧结肠的患者中更为常见。在MMR缺陷患者中,MLH1甲基化病例的OS率低于有LS相关肿瘤家族史的未甲基化病例(P = 0.047)。结论 在筛查MLH1缺陷型CRC的LS时,推荐使用MLH1启动子中的D区和E区来确定MLH1甲基化状态。在MMR缺陷患者中,MLH1甲基化病例的OS比有LS相关癌症家族史的未甲基化病例更差。
{"title":"Testing region selection and prognostic analysis of MLH1 promoter methylation in colorectal cancer in China","authors":"Xiaoli Tan, Yongzhen Fang, Xinjuan Fan, Weihao Deng, Jinglin Huang, Yacheng Cai, Jiaxin Zou, Zhiting Chen, Hanjie Lin, Liang Xu, Guannan Wang, Huanmiao Zhan, Shuhui Huang, Xinhui Fu","doi":"10.1093/gastro/goae011","DOIUrl":"https://doi.org/10.1093/gastro/goae011","url":null,"abstract":"Background MLH1 promoter methylation analysis is recommended in screening for Lynch syndrome (LS) in patients with MLH1-deficient colorectal cancer (CRC). The study aims to identify specific methylation regions in the MLH1 promoter and to evaluate the clinicopathologic characteristics of and prognosis for patients with MLH1 methylation. Methods A total of 580 CRC cases were included. The DNA mismatch repair (MMR) protein expression was assessed by using immunohistochemistry (IHC). The methylation status of the Regions A, B, C, D, and E in the MLH1 promoter was tested by using bisulfite sequencing PCR. The specificities of the five regions were calculated. Associations between MLH1 methylation and clinicopathologic characteristics were evaluated. Kaplan–Meier analyses for overall survival (OS) were carried out. Results In 580 CRC cases, the specificities of the methylation test in Regions D and E were both 97.8%. In the MLH1-deficient CRCs, the frequencies of MLH1 methylation and BRAFV600E mutation were 52.6% and 14.6%, respectively; BRAFV600E mutation occurred in 27.7% of patients with MLH1-methylated CRC. In the MMR-deficient patients, compared with MLH1 unmethylation, MLH1 methylation was more common in patients who were aged ≥50 years, female, had no family history of LS-related tumors, and had tumors located at the right colon. In the MMR-deficient patients, the MLH1-methylated cases had lower OS rates than the unmethylated cases with a family history of LS-related tumors (P = 0.047). Conclusions Regions D and E in the MLH1 promoter are recommended for determining the MLH1 methylation status in screening for LS in MLH1-deficient CRC. In MMR-deficient patients, the MLH1-methylated cases had a worse OS than the unmethylated cases with a family history of LS-related cancer.","PeriodicalId":54275,"journal":{"name":"Gastroenterology Report","volume":"68 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Choledocholithotripsy using peroral direct cholangioscopy through a standard gastroscope for a giant common bile duct stone: a case report. 利用经口直接胆道镜通过标准胃镜治疗巨大胆总管结石的胆总管切开取石术:病例报告。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-29 eCollection Date: 2024-04-01 DOI: 10.1093/gastro/goae014
Qiu-Yue Tu, De-Liang Li, Dan Liu, Qing-Fen Zheng, Bing-Rong Liu
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引用次数: 0
Medical food therapy for the long-term management of non-alcoholic fatty liver disease. 长期治疗非酒精性脂肪肝的药膳疗法。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-29 eCollection Date: 2024-01-01 DOI: 10.1093/gastro/goae020
Chester Yan Jie Ng, Keyi Pan, Enkang Wang, Jianye Yuan, Linda L D Zhong
{"title":"Medical food therapy for the long-term management of non-alcoholic fatty liver disease.","authors":"Chester Yan Jie Ng, Keyi Pan, Enkang Wang, Jianye Yuan, Linda L D Zhong","doi":"10.1093/gastro/goae020","DOIUrl":"10.1093/gastro/goae020","url":null,"abstract":"","PeriodicalId":54275,"journal":{"name":"Gastroenterology Report","volume":"12 ","pages":"goae020"},"PeriodicalIF":3.6,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140337683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HBV infection may sensitize patients to alcoholic steatohepatitis and non-alcoholic steatohepatitis. HBV 感染可能使患者对酒精性脂肪性肝炎和非酒精性脂肪性肝炎过敏。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-28 eCollection Date: 2024-01-01 DOI: 10.1093/gastro/goae018
Hua Wang
{"title":"HBV infection may sensitize patients to alcoholic steatohepatitis and non-alcoholic steatohepatitis.","authors":"Hua Wang","doi":"10.1093/gastro/goae018","DOIUrl":"10.1093/gastro/goae018","url":null,"abstract":"","PeriodicalId":54275,"journal":{"name":"Gastroenterology Report","volume":"12 ","pages":"goae018"},"PeriodicalIF":3.6,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140337682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model. 在急性-慢性肝衰竭小鼠模型中通过 Nrf2/DKK1 协同刺激激活人间叶干细胞用于移植治疗
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-25 eCollection Date: 2024-01-01 DOI: 10.1093/gastro/goae016
Feng Chen, Zhaodi Che, Yingxia Liu, Pingping Luo, Lu Xiao, Yali Song, Cunchuan Wang, Zhiyong Dong, Mianhuan Li, George L Tipoe, Min Yang, Yi Lv, Hong Zhang, Fei Wang, Jia Xiao

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes.

Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4).

Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs.

Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.

背景:由于提高干细胞在应激环境中的恢复能力对基于干细胞的肝病移植的疗效至关重要,本研究旨在确定基于瞬时质粒的预处理策略对提高间充质基质细胞(MSCs)在受体肝细胞中的抗炎/抗氧化防御能力和旁分泌作用的功效。方法:对人脂肪间充质干细胞(hADMSCs)进行转移,无论是否含有核因子红细胞2相关因子2(Nrf2)/Dickkopf1(DKK1)基因,然后暴露于TNF-α/H2O2。急性慢性肝衰竭(ACLF)小鼠模型随后注射了转染或未转染的间充质干细胞。这些 hADMSCs 和 ACLF 小鼠模型被用来研究 Nrf2/DKK1 与肝细胞受体细胞骨架相关蛋白 4(CKAP4)之间的相互作用:结果:Nrf2和DKK1的激活增强了间充质干细胞的体外抗应激能力。在ACLF小鼠模型中,通过质粒转染瞬时共重表达Nrf2和DKK1可提高间充质干细胞抗炎和抗氧化能力,提高间充质干细胞移植疗效,并促进受体肝脏再生。重要的是,当受体肝细胞中与DKK1相互作用的受体CKAP4被特异性移除时,间充质干细胞移植的治疗效果就会失效。然而,移除另一种受体低密度脂蛋白受体相关蛋白6(LRP6)对间充质干细胞移植的有效性没有影响。此外,在长期观察中,小鼠移植瞬时预处理间充质干细胞后未发现肿瘤发生:结论:通过CKAP4依赖性旁分泌机制,与Nrf2/DKK1共同刺激可安全地提高基于人类间充质干细胞的疗法在小鼠ACLF模型中的疗效。
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引用次数: 0
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Gastroenterology Report
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