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Serum Iron Overload Activates the SMAD Pathway and Hepcidin Expression of Hepatocytes via SMURF1. 血清铁超载通过 SMURF1 激活 SMAD 通路和肝细胞的 Hepcidin 表达
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-28 Epub Date: 2024-02-04 DOI: 10.14218/JCTH.2023.00440
Ning Zhang, Pengyao Yang, Yanmeng Li, Qin Ouyang, Fei Hou, Guixin Zhu, Bei Zhang, Jian Huang, Jidong Jia, Anjian Xu

Background and aims: Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.

Methods: A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.

Results: Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.

Conclusions: SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.

背景和目的:肝脏铁超载可诱导肝脏表达骨形态发生蛋白(BMP)6,并激活 BMP/SMAD 通路。然而,血清铁超载也能激活 SMAD,但不会诱导 BMP6 的表达。因此,血清铁超载激活 BMP/SMAD 通路的机制仍不清楚。本研究旨在阐明SMURF1在血清铁超载和BMP/SMAD通路中的作用:方法:用 2 毫克/毫升全转铁蛋白(Holo-Tf)处理肝细胞,建立血清铁超载细胞模型。通过向 C57BL/6 小鼠腹腔注射 10 毫克 Holo-Tf,并给予高铁饮食 1 周后再给予低铁饮食 2 天,建立了血清铁超载小鼠模型和肝脏铁超载小鼠模型。用 Western 印迹和实时 PCR 评估 BMP/SMAD 通路的激活情况和肝素的表达情况:结果:Holo-Tf增强了肝细胞对BMP6的敏感性和反应性。E3泛素蛋白连接酶SMURF1介导了Holo-Tf诱导的SMAD1/5活化和肝素的表达;特别是,当血清铁浓度增加时,SMURF1的表达急剧下降。此外,参与 BMP/SMAD 信号转导的重要分子 SMURF1 底物的表达也显著上调。此外,体内分析证实,在血清铁超载期间,SMURF1能特异性调控BMP/SMAD通路:结论:在血清铁超载期间,SMURF1可通过增强肝细胞对BMPs的反应性来特异性调节BMP/SMAD通路。
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引用次数: 0
Impact of Onset Time, Number, Type, and Sequence of Extrahepatic Organ Failure on Prognosis of Acute-on-chronic Liver Failure. 肝外器官衰竭的发病时间、数量、类型和顺序对急性慢性肝衰竭预后的影响
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-28 Epub Date: 2024-01-31 DOI: 10.14218/JCTH.2023.00379
Shaotian Qiu, Qian Zhang, Jiaxuan Hu, Lewei Wang, Rui Chen, Yingying Cao, Fang Liu, Zhenjun Yu, Caiyan Zhao, Liaoyun Zhang, Wanhua Ren, Shaojie Xin, Yu Chen, Zhongping Duan, Tao Han

Background and aims: The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients.

Methods: ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan-Meier analysis and log-rank tests.

Results: A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan-Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts.

Conclusions: The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

背景和目的:肝外器官功能衰竭(EHOF)的发病时间、数量、类型和顺序等特征对急性-慢性肝衰竭(ACLF)患者预后的影响尚不清楚。本研究旨在确定 EHOF 的特征与 ACLF 患者预后之间的关联:方法:将中国六家医院的 ACLF 受试者纳入分析。根据 EHOF 的特征评估死亡风险。通过卡普兰-梅耶尔分析和对数秩检验比较研究组的生存率:结果:共纳入 736 例 ACLF 患者。402名患者(54.6%)出现了EHOF,其中295名患者(73.4%)出现了单发EHOF(SEHOF),107名患者(26.6%)出现了多发EHOF(MEHOF)。最常见的 EHOF 是凝血功能衰竭(47.0%),其次是肾功能衰竭(13.0%)、脑功能衰竭(4.9%)、呼吸功能衰竭(4.3%)和循环功能衰竭(2.3%)。生存分析发现,MEHOF 或 SEHOF 脑衰竭患者的预后较差。然而,在分析发病时间和器官衰竭顺序对预后的影响时,没有发现明显的结果。根据EHOF特征,患者被进一步分为三个风险亚组。Kaplan-Meier分析显示,风险分层的结果是,在训练组和验证组中,患者的死亡风险不同:结论:ACLF患者的死亡率取决于EHOF的数量和类型,而不是发病时间和顺序。适用于临床实践的风险分层已经确立。
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引用次数: 0
Prognostic Biomarkers for Hepatocellular Carcinoma Based on Serine and Glycine Metabolism-related Genes. 基于丝氨酸和甘氨酸代谢相关基因的肝细胞癌预后生物标志物
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-28 Epub Date: 2024-02-09 DOI: 10.14218/JCTH.2023.00457
Xufan Cai, Fang Xu, Zhaohong Wang, Hui Chen, Shengzhang Lin

Background and aims: Targeted therapy and immunotherapy have emerged as treatment options for hepatocellular carcinoma (HCC) in recent years. The significance of serine and glycine metabolism in various cancers is widely acknowledged. This study aims to investigate their correlation with the prognosis and tumor immune microenvironment (TIME) of HCC.

Methods: Based on the public database, different subtypes were identified by cluster analysis, and the prognostic model was constructed through regression analysis. The gene expression omnibus (GEO) data set was used as the validation set to verify the performance of the model. The survival curve evaluated prognostic ability. CIBERSORT was used to evaluate the level of immune cell infiltration, and maftools analyzed the mutations. DsigDB screened small molecule compounds related to prognostic genes.

Results: HCC was found to have two distinct subtypes. Subsequently, we constructed a risk score prognostic model through regression analysis based on serine and glycine metabolism-related genes (SGMGs). A nomogram was constructed based on risk scores and other clinical factors. HCC patients with a higher risk score showed a poor prognosis, and there were significant differences in immune cell infiltration between the high- and low-risk groups. In addition, three potential drugs associated with prognostic genes, streptozocin, norfloxacin, and hydrocotarnine, were identified.

Conclusions: This study investigated the expression patterns of SGMGs and their relationship with tumor characteristics, resulting in the development of a novel model for predicting the prognosis of HCC patients. The study provides a reference for clinical prognosis prediction and treatment of HCC patients.

背景和目的:近年来,靶向治疗和免疫治疗已成为肝细胞癌(HCC)的治疗选择。丝氨酸和甘氨酸代谢在各种癌症中的重要性已得到广泛认可。本研究旨在探讨它们与 HCC 预后和肿瘤免疫微环境(TIME)的相关性:方法:基于公共数据库,通过聚类分析确定不同亚型,并通过回归分析构建预后模型。采用基因表达总库(GEO)数据集作为验证集,以验证模型的性能。生存曲线评估了预后能力。CIBERSORT 用于评估免疫细胞浸润水平,maftools 分析了突变。DsigDB 筛选了与预后基因相关的小分子化合物:结果:发现 HCC 有两种不同的亚型。随后,我们通过基于丝氨酸和甘氨酸代谢相关基因(SGMGs)的回归分析构建了风险评分预后模型。根据风险评分和其他临床因素构建了一个提名图。风险评分较高的 HCC 患者预后较差,而高风险组和低风险组之间的免疫细胞浸润存在显著差异。此外,研究还发现了三种与预后基因相关的潜在药物:链脲霉素、诺氟沙星和氢化可他宁:本研究调查了 SGMGs 的表达模式及其与肿瘤特征的关系,从而建立了预测 HCC 患者预后的新模型。该研究为 HCC 患者的临床预后预测和治疗提供了参考。
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引用次数: 0
Late-onset Cholestasis with Paucity of Portal Area Secondary to HNF1β Deficiency in Adulthood: A Case Report. 继发于成人 HNF1β 缺乏症的晚发性胆汁淤积症伴门静脉区缺失:病例报告。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-28 Epub Date: 2024-02-19 DOI: 10.14218/JCTH.2023.00464
Xuemei Zhang, Kun Liu, Xiaona Lu, Wenlan Zheng, Jia Shi, Shihan Yu, Hai Feng, Zhuo Yu

Hepatocyte nuclear factor 1β (HNF1β) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1β mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1β defect could induce late-onset cholestasis with paucity of the portal area in adulthood.

肝细胞核因子 1β(HNF1β)对胆道发育至关重要,而其遗传缺陷会引发小叶间胆管发育不良,导致危及生命的肝炎和胆汁淤积症。迄今为止,这种疾病主要见于新生儿。在此,我们报告了一例因新生 HNF1β 基因突变而导致胆汁淤积的成年患者。肝脏活检显示门静脉区明显缩小,同时门静脉区的小叶间胆管、静脉和动脉减少或缺失。我们的病例表明,HNF1β缺陷可诱发晚发型胆汁淤积症,并在成年后出现门静脉区缺失。
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引用次数: 0
A Novel Algorithm for Streamlining Diagnosis of Advanced Liver Fibrosis in CHB Patients with Concurrent Hepatic Steatosis. 简化合并肝脏脂肪变性的慢性阻塞性肺病患者晚期肝纤维化诊断的新算法。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-02-28 Epub Date: 2024-01-29 DOI: 10.14218/JCTH.2023.00362
Xiaoming Xu, Fajuan Rui, Wenjing Ni, Chao Wu, Junping Shi, Jie Li

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引用次数: 0
Corrigendum: Osteopontin Promotes Macrophage M1 Polarization by Activation of the JAK1/STAT1/HMGB1 Signaling Pathway in Nonalcoholic Fatty Liver Disease. 更正:骨蛋白通过激活非酒精性脂肪肝中的 JAK1/STAT1/HMGB1 信号通路促进巨噬细胞 M1 极化。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-28 Epub Date: 2023-11-13 DOI: 10.14218/JCTH.2021.00474C

[This corrects the article DOI: 10.14218/JCTH.2021.00474.].

[此处更正了文章 DOI:10.14218/JCTH.2021.00474]。
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引用次数: 0
Unique Genetic Features of Lean NAFLD: A Review of Mechanisms and Clinical Implications. 瘦型非酒精性脂肪肝的独特遗传特征:机制与临床意义综述。
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-28 Epub Date: 2023-08-25 DOI: 10.14218/JCTH.2023.00252
Jasmine Tidwell, George Y Wu

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population. About 20% have a normal body mass index (BMI) and a variant known as lean NAFLD. Unlike typical NAFLD cases associated with obesity and diabetes, lean NAFLD causes liver disease by mechanisms not related to excess weight or insulin resistance. Genetic disorders are among the major factors in developing lean NAFLD, and genome-wide association studies have identified several genes associated with the condition. This review aims to increase awareness by describing the genetic markers linked to NAFLD and the defects involved in developing lean NAFLD.

非酒精性脂肪肝(NAFLD)影响着全球 25% 的人口。约20%的人体重指数(BMI)正常,但有一种变异型非酒精性脂肪肝,被称为 "瘦型非酒精性脂肪肝"。与肥胖和糖尿病相关的典型非酒精性脂肪肝不同,瘦型非酒精性脂肪肝导致肝病的机制与体重超标或胰岛素抵抗无关。遗传性疾病是导致非酒精性脂肪肝的主要因素之一,全基因组关联研究已经发现了几个与该病相关的基因。本综述旨在通过描述与非酒精性脂肪肝相关的遗传标记以及导致非酒精性脂肪肝的缺陷来提高人们的认识。
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引用次数: 0
Improving the Conversion Success Rate of Hepatocellular Carcinoma: Focus on the Use of Combination Therapy with a High Objective Response Rate 提高肝细胞癌的转阴成功率:关注客观反应率高的联合疗法的应用
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-10 DOI: 10.14218/jcth.2023.00403
Qi-Feng Chen, Song Chen, Minshan Chen, N. Lyu, Ming Zhao
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引用次数: 0
Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements 肝癌中的γδT 细胞免疫调节网络与治疗:最新趋势和进展
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-08 DOI: 10.14218/jcth.2023.00355
Kunli Yin, Kai-Jian Chu, Ming Li, Yu-Xin Duan, Yanxi Yu, Meiqing Kang, Da Fu, Rui Liao
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引用次数: 0
Hepatocellular Carcinoma Incidence and Mortality in the USA by Sex, Age, and Race: A Nationwide Analysis of Two Decades 美国按性别、年龄和种族分列的肝细胞癌发病率和死亡率:二十年来的全国性分析
IF 3.6 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-01-02 DOI: 10.14218/jcth.2023.00356
Yazan Abboud, Mohamed Ismail, Hamza Khan, Esli Medina-Morales, S. Alsakarneh, F. Jaber, Nikolaos T. Pyrsopoulos
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引用次数: 0
期刊
Journal of Clinical and Translational Hepatology
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