首页 > 最新文献

Wiley最新文献

英文 中文
IF:
ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor. ZNT1和Zn2+控制巨噬细胞中TLR4和PD-L1的内吞作用,以提高对肝肿瘤的化疗效果。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2023-10-09 DOI: 10.1097/HEP.0000000000000629
Dan Yang, Taikun Tian, Xiaojing Li, Baokai Zhang, Linlin Qi, Fang Zhang, Mingshun Han, Shuang Wang, Jun Xiao, Yingying Gou, Raorao Zhang, Qiaojie Liu, Sheng Su, Jiahui Liu, Xiaowu Huang, Qiang Gao, Lijian Hui, Huiru Tang, Yuncong Chen, Hongyan Wang, Bin Wei

Background and aims: HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy.

Approach and results: Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib.

Conclusions: Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells.

背景目的:肝细胞癌(HCC)与炎症和免疫调节密切相关,目前正在广泛研究将化疗与其他策略相结合以获得更好的疗效。HCC伴有锌缺乏。本研究旨在了解锌如何影响巨噬细胞功能及其在HCC治疗中的应用。方法结果:肝癌患者和小鼠肝肿瘤的肝内巨噬细胞中Zn2+和锌转运蛋白1(ZNT1,SLC30A1)显著减少。在HCC患者中,较低的ZNT1表达与较高的IL-6产生和较短的生存时间有关。至关重要的是,ZNT1调节TLR4和PD-L1内吞的内体Zn2+水平,从而减少巨噬细胞诱导的炎症和免疫抑制,以保护肝脏免受肿瘤的侵袭。小鼠中ZNT1的骨髓特异性缺失增加了慢性炎症、肝纤维化、肿瘤数量和大小。值得注意的是,补锌可以减少巨噬细胞中的炎症和表面PD-L1表达,同时增加CD8+T细胞的细胞毒性,这协同了索拉非尼/乐伐替尼的抗肿瘤功效。结论:我们的研究提出了一个新的概念,即ZNT1和锌调节内吞体以维持表面受体,锌补充剂可能与化疗协同治疗炎症相关肿瘤,特别是那些含有PD-L1+髓系细胞的肿瘤。
{"title":"ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor.","authors":"Dan Yang, Taikun Tian, Xiaojing Li, Baokai Zhang, Linlin Qi, Fang Zhang, Mingshun Han, Shuang Wang, Jun Xiao, Yingying Gou, Raorao Zhang, Qiaojie Liu, Sheng Su, Jiahui Liu, Xiaowu Huang, Qiang Gao, Lijian Hui, Huiru Tang, Yuncong Chen, Hongyan Wang, Bin Wei","doi":"10.1097/HEP.0000000000000629","DOIUrl":"10.1097/HEP.0000000000000629","url":null,"abstract":"<p><strong>Background and aims: </strong>HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy.</p><p><strong>Approach and results: </strong>Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib.</p><p><strong>Conclusions: </strong>Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Letter to the Editor: Scavenger receptor a is a major homeostatic regulator that restrains drug-induced liver injury. 致编辑的信清道夫受体a是抑制药物性肝损伤的主要平衡调节因子
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2023-12-18 DOI: 10.1097/HEP.0000000000000725
Qi Wang, Qingfa Bu, Bozhou Pan, Yin Yin, Lei Liu
{"title":"Letter to the Editor: Scavenger receptor a is a major homeostatic regulator that restrains drug-induced liver injury.","authors":"Qi Wang, Qingfa Bu, Bozhou Pan, Yin Yin, Lei Liu","doi":"10.1097/HEP.0000000000000725","DOIUrl":"10.1097/HEP.0000000000000725","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Gut microbiome-brain-cirrhosis axis. 肠道微生物群-脑-肝硬化轴。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2023-03-06 DOI: 10.1097/HEP.0000000000000344
Maren L Smith, James B Wade, Jennifer Wolstenholme, Jasmohan S Bajaj

Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.

肝硬化的特点是肝组织炎症、变性和纤维化。肝硬化是导致肝功能衰竭和肝移植的最常见原因,同时也是多种神经精神疾病的重要危险因素。其中最常见的是肝性脑病,其特征是认知和共济失调症状,这是由于肝功能衰竭导致代谢毒素积累所致。然而,肝硬化患者罹患神经退行性疾病(如阿尔茨海默病和帕金森病)以及情绪障碍(如焦虑症和抑郁症)的风险也明显增加。近年来,人们越来越关注肠道和肝脏之间以及它们与中枢神经系统之间的交流,以及这些器官对彼此功能的影响。这种双向交流被称为肠道-肝脏-大脑轴。肠道微生物群已成为影响肠道-肝脏、肠道-大脑和大脑-肝脏交流的关键机制。临床研究和动物模型已经证明,当肝硬化时,无论是否同时伴有酒精使用障碍,肠道菌群失调的模式都很显著,并提供了令人信服的证据,证明这种菌群失调也会影响认知和情绪相关行为。在这篇综述中,我们总结了与肝硬化相关的病理生理学和认知效应、与肝硬化相关的肠道微生物组破坏的联系,以及目前临床和临床前研究中关于调节肠道微生物组作为肝硬化和相关神经精神疾病治疗方法的证据。
{"title":"Gut microbiome-brain-cirrhosis axis.","authors":"Maren L Smith, James B Wade, Jennifer Wolstenholme, Jasmohan S Bajaj","doi":"10.1097/HEP.0000000000000344","DOIUrl":"10.1097/HEP.0000000000000344","url":null,"abstract":"<p><p>Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10165554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis. 基于核磁共振的代谢组特征:诊断和研究自身免疫性肝炎发病机制的重要工具。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-05 DOI: 10.1097/HEP.0000000000000767
Aikaterini Dimou, Kalliopi Zachou, Christina Kostara, Kalliopi Azariadis, George Giannoulis, Aggeliki Lyberopoulou, Eleni Bairaktari, George N Dalekos

Background and aims: Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in autoimmune hepatitis (AIH) has not been investigated in depth. Therefore, we investigated the metabolomic signature of AIH and its significance as a diagnostic and pathogenetic tool.

Approach and results: Metabolites in plasma samples from 50 patients with AIH at diagnosis, 43 healthy controls, 72 patients with primary biliary cholangitis (PBC), 26 patients with metabolic dysfunction-associated liver disease, and 101 patients with chronic viral hepatitis were determined by 1 H NMR (nuclear magnetic resonance) spectroscopy. Fifty-two metabolites were quantified, and metabolic pathway analysis was performed. Multivariate analysis revealed that AIH could be differentiated from healthy controls and each of the disease controls ( p <0.001). Fifteen metabolites differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction-associated liver disease) (95% sensitivity and 92% specificity). Ten distinct metabolic pathways were altered in AIH compared to disease controls. The metabolic pathway of branched-chain amino acids (lower valine, leucine, and isoleucine levels and their catabolic intermediates in PBC), methionine (lower methionine, 2-aminobutyrate, and 2-hydroxybutyrate levels in PBC), alanine-aspartate-glutamate (lower metabolites in PBC), and that of metabolites associated with gut microbiota (lower choline, betaine, and dimethylamine levels in PBC) were significantly different between AIH and PBC ( p <0.01).

Conclusions: 1 H NMR spectroscopy could be a promising novel tool to diagnose and study AIH pathogenesis as there is no need for much sample handling, is highly reproducible with high sensitivity and specificity, and low cost.

背景目的:代谢组学可用于预测、诊断和监测代谢紊乱,但也有报道称包括自身免疫性疾病在内的多种疾病的代谢组特征发生了改变。然而,自身免疫性肝炎(AIH)的代谢组学特征尚未得到深入研究。因此,我们研究了自身免疫性肝炎的代谢组特征及其作为诊断和致病工具的意义:采用 1H-NMR 光谱法测定了 50 例 AIH 患者诊断时的血浆样本、43 例健康对照(HC)、72 例原发性胆汁性胆管炎(PBC)患者、26 例代谢功能障碍相关性肝病(MASLD)患者和 101 例慢性病毒性肝炎(CVH)患者血浆样本中的代谢物。对 52 种代谢物进行了定量,并进行了代谢途径分析。多变量分析表明,AIH 可与 HC 和各疾病对照组区分开来(p 结论:1H-NMR 光谱法是诊断和研究 AIH 发病机制的一种很有前途的新工具,因为它不需要处理大量样本,重复性好,灵敏度和特异性高,而且成本低廉。
{"title":"NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis.","authors":"Aikaterini Dimou, Kalliopi Zachou, Christina Kostara, Kalliopi Azariadis, George Giannoulis, Aggeliki Lyberopoulou, Eleni Bairaktari, George N Dalekos","doi":"10.1097/HEP.0000000000000767","DOIUrl":"10.1097/HEP.0000000000000767","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in autoimmune hepatitis (AIH) has not been investigated in depth. Therefore, we investigated the metabolomic signature of AIH and its significance as a diagnostic and pathogenetic tool.</p><p><strong>Approach and results: </strong>Metabolites in plasma samples from 50 patients with AIH at diagnosis, 43 healthy controls, 72 patients with primary biliary cholangitis (PBC), 26 patients with metabolic dysfunction-associated liver disease, and 101 patients with chronic viral hepatitis were determined by 1 H NMR (nuclear magnetic resonance) spectroscopy. Fifty-two metabolites were quantified, and metabolic pathway analysis was performed. Multivariate analysis revealed that AIH could be differentiated from healthy controls and each of the disease controls ( p <0.001). Fifteen metabolites differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction-associated liver disease) (95% sensitivity and 92% specificity). Ten distinct metabolic pathways were altered in AIH compared to disease controls. The metabolic pathway of branched-chain amino acids (lower valine, leucine, and isoleucine levels and their catabolic intermediates in PBC), methionine (lower methionine, 2-aminobutyrate, and 2-hydroxybutyrate levels in PBC), alanine-aspartate-glutamate (lower metabolites in PBC), and that of metabolites associated with gut microbiota (lower choline, betaine, and dimethylamine levels in PBC) were significantly different between AIH and PBC ( p <0.01).</p><p><strong>Conclusions: </strong>1 H NMR spectroscopy could be a promising novel tool to diagnose and study AIH pathogenesis as there is no need for much sample handling, is highly reproducible with high sensitivity and specificity, and low cost.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139670926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
HCC risk in patients who are HBeAg-positive and have chronic hepatitis B under long-term nucleos(t)ide analogue therapy: New insights from Asia. 长期接受核苷(t)ide 类似物治疗的 HBeAg 阳性慢性乙型肝炎患者发生肝细胞癌的风险:来自亚洲的新见解。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-16 DOI: 10.1097/HEP.0000000000000796
George Papatherodoridis, Pietro Lampertico
{"title":"HCC risk in patients who are HBeAg-positive and have chronic hepatitis B under long-term nucleos(t)ide analogue therapy: New insights from Asia.","authors":"George Papatherodoridis, Pietro Lampertico","doi":"10.1097/HEP.0000000000000796","DOIUrl":"10.1097/HEP.0000000000000796","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139904629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Epigenetic memory of environmental exposures as a mediator of liver disease. 环境暴露的表观遗传记忆是肝病的介质。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2023-04-21 DOI: 10.1097/HEP.0000000000000414
Ryan A Hlady, Keith D Robertson

Epigenetic changes are a common feature of human disease, including liver disease and its progression to liver cancer. The most frequent form of liver cancer, HCC, is unusual because most of its causes, or etiologic drivers, are known and are dominated by environmental exposures, including viral infection, alcohol abuse, and overnutrition/metabolic syndrome. The epigenome is a regulatory system overlayed on the genetic material that regulates when, where, and to what extent genes are expressed in developmental, cell type, and disease-associated contexts. Deregulation of the epigenome has emerged as a major player in the pathologic effects of liver disease driving exposures, particularly during their early phases when genetic changes are uncommon. Although it is inherent in the definition of an epigenetic process to be reversible, emerging evidence indicates that epigenetic changes persist after the removal of the exposure and contribute to long-term risk of disease progression. In other systems, environmental exposures lead to beneficial adaptive changes in expression that facilitate processes such as wound healing, and these too are driven by epigenetic changes. What remains unclear, however, is what drives the transition from a beneficial epigenetic memory to a maladaptive scar, the epigenetic processes involved in forming these memories, and whether this process can be modulated for therapeutic purposes. In this review, we discuss these concepts in relation to liver disease and more broadly using examples from other tissue types and diseases, and finally consider how epigenetic therapies could be used to reprogram maladaptive epigenetic memories to delay and/or prevent hepatocarcinogenesis.

表观遗传变化是人类疾病的常见特征,包括肝病及其向肝癌的发展。最常见的肝癌形式--HCC--不同寻常,因为其大多数病因或病因驱动因素都是已知的,而且主要是环境暴露,包括病毒感染、酗酒和营养过剩/代谢综合征。表观基因组是覆盖在遗传物质上的一个调节系统,它调节基因在发育、细胞类型和疾病相关环境中表达的时间、地点和程度。表观基因组的失调已成为肝病病理效应的主要驱动因素,尤其是在基因变化不常见的早期阶段。虽然表观遗传过程的固有定义是可逆的,但新出现的证据表明,表观遗传变化在暴露消除后仍会持续,并导致疾病进展的长期风险。在其他系统中,环境暴露会导致有益的适应性表达变化,从而促进伤口愈合等过程,而这些变化也是由表观遗传变化驱动的。然而,目前仍不清楚的是,是什么驱动了有益的表观遗传记忆向不适应性疤痕的转变,形成这些记忆所涉及的表观遗传过程,以及是否可以通过调节这一过程来达到治疗目的。在这篇综述中,我们将结合肝病讨论这些概念,并以其他组织类型和疾病为例进行更广泛的讨论,最后考虑如何利用表观遗传疗法来重塑不良表观遗传记忆,从而延缓和/或预防肝癌的发生。
{"title":"Epigenetic memory of environmental exposures as a mediator of liver disease.","authors":"Ryan A Hlady, Keith D Robertson","doi":"10.1097/HEP.0000000000000414","DOIUrl":"10.1097/HEP.0000000000000414","url":null,"abstract":"<p><p>Epigenetic changes are a common feature of human disease, including liver disease and its progression to liver cancer. The most frequent form of liver cancer, HCC, is unusual because most of its causes, or etiologic drivers, are known and are dominated by environmental exposures, including viral infection, alcohol abuse, and overnutrition/metabolic syndrome. The epigenome is a regulatory system overlayed on the genetic material that regulates when, where, and to what extent genes are expressed in developmental, cell type, and disease-associated contexts. Deregulation of the epigenome has emerged as a major player in the pathologic effects of liver disease driving exposures, particularly during their early phases when genetic changes are uncommon. Although it is inherent in the definition of an epigenetic process to be reversible, emerging evidence indicates that epigenetic changes persist after the removal of the exposure and contribute to long-term risk of disease progression. In other systems, environmental exposures lead to beneficial adaptive changes in expression that facilitate processes such as wound healing, and these too are driven by epigenetic changes. What remains unclear, however, is what drives the transition from a beneficial epigenetic memory to a maladaptive scar, the epigenetic processes involved in forming these memories, and whether this process can be modulated for therapeutic purposes. In this review, we discuss these concepts in relation to liver disease and more broadly using examples from other tissue types and diseases, and finally consider how epigenetic therapies could be used to reprogram maladaptive epigenetic memories to delay and/or prevent hepatocarcinogenesis.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC. HOIL-1对癌症干性和索拉非尼耐药性的非规范调节确定了pixarrone是一种新的肝细胞癌治疗剂。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2023-10-11 DOI: 10.1097/HEP.0000000000000623
Peng Chen, Zheyu Dong, Wei Zhu, Junling Chen, Yuxin Zhou, Qiuyue Ye, Xinxin Liao, Yongfa Tan, Chuanjiang Li, Yuhao Wang, Huajin Pang, Chunhua Wen, Yuchuan Jiang, Xiaoqing Li, Bo Li, Aihetaimu Aimaier, Li Lin, Jian Sun, Jiajie Hou, Libo Tang, Jinlin Hou, Yongyin Li

Background and aims: Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs.

Approach and results: We found that HOIL-1, but not the other components of LUBAC, played a contributing role in LUBAC-mediated HCC sorafenib resistance, independent of its ubiquitin ligase activity. Both in vitro and in vivo assays revealed that the upregulated HOIL-1 expression enhanced the CSC properties of HCC. Mechanistically, HOIL-1 promoted sorafenib resistance and the CSC properties of HCC through Notch1 signaling. Mass spectrometry, co-immunoprecipitation, western blot, and immunofluorescence were used to determine that the A64/Q65 residues of HOIL-1 bound with the K78 residue of Numb, resulting in impaired Numb-mediated Notch1 lysosomal degradation. Notably, pixantrone was screened out by Autodock Vina, which was validated to disrupt HOIL-1/Numb interaction to inhibit Notch1 signaling and CSC properties by targeting the Q65 residue of HOIL-1. Moreover, pixantrone exerted synergistic effects with sorafenib for the treatment of HCC in different HCC mouse models.

Conclusions: HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC.

背景目的:癌症干细胞(CSCs)参与了肝细胞癌(HCC)的治疗耐药性。线性泛素链组装复合体(LUBAC)已被报道可加速癌症的进展,但其在HCC的索拉非尼反应中的作用尚不明确。在此,我们研究了LUBAC对索拉非尼耐药性和HCC CSC特性的影响,并探索了潜在的靶向药物。方法:评价LUBAC对索拉非尼反应的影响。在体外和体内研究了HOIL-1在促进索拉非尼耐药性中的作用以及HCC的CSCs特性。采用质谱、免疫共沉淀和蛋白质印迹等方法探讨了HOIL-1调节Numb/Notch1轴的机制。使用Autodock Vina筛选HOIL-1抑制剂,并评估pixantrone的抗肿瘤作用。结果:HOIL-1对LUBAC介导的HCC索拉非尼耐药性的作用与其泛素连接酶活性无关。上调的HOIL-1表达增强了HCC的CSC特性。从机制上讲,HOIL-1通过Notch1信号传导促进索拉非尼耐药性和HCC的CSC特性。HOIL-1的A64/Q65残基与Numb的K78残基结合以损害Numb介导的Notch1溶酶体降解。值得注意的是,pixantrone通过靶向HOIL-1的Q65残基,中断了HOIL-1/Numb的相互作用,以抑制Notch1信号传导和CSC特性。此外,吡喃酮与索拉非尼在HCC治疗中发挥协同作用。结论:HOIL-1通过Notch1信号传导在促进索拉非尼耐药性和HCC CSC特性中起关键作用。靶向HOIL-1的Pixantrone抑制索拉非尼耐药性,并为HCC提供潜在的治疗干预。
{"title":"Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC.","authors":"Peng Chen, Zheyu Dong, Wei Zhu, Junling Chen, Yuxin Zhou, Qiuyue Ye, Xinxin Liao, Yongfa Tan, Chuanjiang Li, Yuhao Wang, Huajin Pang, Chunhua Wen, Yuchuan Jiang, Xiaoqing Li, Bo Li, Aihetaimu Aimaier, Li Lin, Jian Sun, Jiajie Hou, Libo Tang, Jinlin Hou, Yongyin Li","doi":"10.1097/HEP.0000000000000623","DOIUrl":"10.1097/HEP.0000000000000623","url":null,"abstract":"<p><strong>Background and aims: </strong>Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs.</p><p><strong>Approach and results: </strong>We found that HOIL-1, but not the other components of LUBAC, played a contributing role in LUBAC-mediated HCC sorafenib resistance, independent of its ubiquitin ligase activity. Both in vitro and in vivo assays revealed that the upregulated HOIL-1 expression enhanced the CSC properties of HCC. Mechanistically, HOIL-1 promoted sorafenib resistance and the CSC properties of HCC through Notch1 signaling. Mass spectrometry, co-immunoprecipitation, western blot, and immunofluorescence were used to determine that the A64/Q65 residues of HOIL-1 bound with the K78 residue of Numb, resulting in impaired Numb-mediated Notch1 lysosomal degradation. Notably, pixantrone was screened out by Autodock Vina, which was validated to disrupt HOIL-1/Numb interaction to inhibit Notch1 signaling and CSC properties by targeting the Q65 residue of HOIL-1. Moreover, pixantrone exerted synergistic effects with sorafenib for the treatment of HCC in different HCC mouse models.</p><p><strong>Conclusions: </strong>HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC. LTβ-LTβR-RELB轴的病因无关性激活驱动肝细胞癌的侵袭性并预测预后不良。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2023-11-02 DOI: 10.1097/HEP.0000000000000657
Anna-Lena Scherr, Luisa Nader, Kaiyu Xu, Christin Elssner, Dirk A Ridder, Federico Nichetti, Manuel Mastel, Sarah Fritzsche, Eblina Kelmendi, Nathalie Schmitt, Paula Hoffmeister-Wittmann, Sofia M E Weiler, Felix Korell, Thomas Albrecht, Maximilian Schwab, Hanna Isele, Annika Kessler, Jennifer Hüllein, Agnieszka Seretny, Liangtao Ye, Toni Urbanik, Stefan Welte, Anne-Laure Leblond, Christoph E Heilig, Mohammad Rahbari, Adnan Ali, Suchira Gallage, Bénédicte Lenoir, Nina Wilhelm, Ulrike Gärtner, Simon J Ogrodnik, Christoph Springfeld, Darjus Tschaharganeh, Stefan Fröhling, Thomas Longerich, Henning Schulze-Bergkamen, Dirk Jäger, Lydia Brandl, Peter Schirmacher, Beate K Straub, Achim Weber, Enrico N De Toni, Benjamin Goeppert, Mathias Heikenwalder, Rene Jackstadt, Stephanie Roessler, Kai Breuhahn, Bruno C Köhler

Background and aims: HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of noncanonical NF-κB and its downstream effectors is not established.

Approach and results: Four human HCC cohorts (total n = 1462) and 4 mouse HCC models were assessed for expression and localization of NF-κB signaling components and activating ligands. In vitro , NF-κB signaling, proliferation, and cell death were measured, proving a pro-proliferative role of v-rel avian reticuloendotheliosis viral oncogene homolog B (RELB) activated by means of NF-κB-inducing kinase. In vivo , lymphotoxin beta was identified as the predominant inducer of RELB activation. Importantly, hepatocyte-specific RELB knockout in a murine HCC model led to a lower incidence compared to controls and lower maximal tumor diameters. In silico , RELB activity and RELB-directed transcriptomics were validated on the The Cancer Genome Atlas HCC cohort using inferred protein activity and Gene Set Enrichment Analysis. In RELB-active HCC, pathways mediating proliferation were significantly activated. In contrast to v-rel avian reticuloendotheliosis viral oncogene homolog A, nuclear enrichment of noncanonical RELB expression identified patients with a poor prognosis in an etiology-independent manner. Moreover, RELB activation was associated with malignant features metastasis and recurrence.

Conclusions: This study demonstrates a prognostically relevant, etiology-independent, and cross-species consistent activation of a lymphotoxin beta/LTβR/RELB axis in hepatocarcinogenesis. These observations may harbor broad implications for HCC, including possible clinical exploitation.

背景目的:肝细胞癌(HCC)是最常见的原发性肝肿瘤,在世界范围内发病率不断上升。HCC是一种异质性恶性肿瘤,通常发生在慢性损伤的肝脏中。核因子κB(NF-κB)信号网络由经典分支和非经典分支组成。HCC中典型NF-κB的激活被记录在案。然而,非经典NF-κB及其下游效应物的功能和临床相关作用尚未确定。方法结果:评估了四个人类HCC队列(总n=1462)和四个小鼠HCC模型的NF-κB信号成分和活化配体的表达和定位。在体外,测量了NF-κB信号传导、增殖和细胞死亡,证明了RELB通过NIK激活的促增殖作用。在体内,淋巴毒素β(LTβ)被鉴定为RELB激活的主要诱导物。重要的是,与对照组相比,小鼠HCC模型中肝细胞特异性RELB敲除导致较低的发病率和较低的最大肿瘤直径。在计算机上,使用推断的蛋白质活性和基因集富集分析(GSEA)在TCGA HCC队列中验证了RELB活性和RELB定向转录组学。在RELB活性HCC中,介导增殖的途径被显著激活。与RELA相反,非典型RELB表达的核富集以病因独立的方式确定预后不良的患者。此外,RELB的激活与恶性肿瘤的转移和复发有关。结论:本研究表明,在肝癌发生中,LTβ/LTβR/RELB轴的激活具有预后相关性、病因独立性和跨物种一致性。这些观察结果可能对HCC具有广泛的意义,包括可能的临床利用。
{"title":"Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC.","authors":"Anna-Lena Scherr, Luisa Nader, Kaiyu Xu, Christin Elssner, Dirk A Ridder, Federico Nichetti, Manuel Mastel, Sarah Fritzsche, Eblina Kelmendi, Nathalie Schmitt, Paula Hoffmeister-Wittmann, Sofia M E Weiler, Felix Korell, Thomas Albrecht, Maximilian Schwab, Hanna Isele, Annika Kessler, Jennifer Hüllein, Agnieszka Seretny, Liangtao Ye, Toni Urbanik, Stefan Welte, Anne-Laure Leblond, Christoph E Heilig, Mohammad Rahbari, Adnan Ali, Suchira Gallage, Bénédicte Lenoir, Nina Wilhelm, Ulrike Gärtner, Simon J Ogrodnik, Christoph Springfeld, Darjus Tschaharganeh, Stefan Fröhling, Thomas Longerich, Henning Schulze-Bergkamen, Dirk Jäger, Lydia Brandl, Peter Schirmacher, Beate K Straub, Achim Weber, Enrico N De Toni, Benjamin Goeppert, Mathias Heikenwalder, Rene Jackstadt, Stephanie Roessler, Kai Breuhahn, Bruno C Köhler","doi":"10.1097/HEP.0000000000000657","DOIUrl":"10.1097/HEP.0000000000000657","url":null,"abstract":"<p><strong>Background and aims: </strong>HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of noncanonical NF-κB and its downstream effectors is not established.</p><p><strong>Approach and results: </strong>Four human HCC cohorts (total n = 1462) and 4 mouse HCC models were assessed for expression and localization of NF-κB signaling components and activating ligands. In vitro , NF-κB signaling, proliferation, and cell death were measured, proving a pro-proliferative role of v-rel avian reticuloendotheliosis viral oncogene homolog B (RELB) activated by means of NF-κB-inducing kinase. In vivo , lymphotoxin beta was identified as the predominant inducer of RELB activation. Importantly, hepatocyte-specific RELB knockout in a murine HCC model led to a lower incidence compared to controls and lower maximal tumor diameters. In silico , RELB activity and RELB-directed transcriptomics were validated on the The Cancer Genome Atlas HCC cohort using inferred protein activity and Gene Set Enrichment Analysis. In RELB-active HCC, pathways mediating proliferation were significantly activated. In contrast to v-rel avian reticuloendotheliosis viral oncogene homolog A, nuclear enrichment of noncanonical RELB expression identified patients with a poor prognosis in an etiology-independent manner. Moreover, RELB activation was associated with malignant features metastasis and recurrence.</p><p><strong>Conclusions: </strong>This study demonstrates a prognostically relevant, etiology-independent, and cross-species consistent activation of a lymphotoxin beta/LTβR/RELB axis in hepatocarcinogenesis. These observations may harbor broad implications for HCC, including possible clinical exploitation.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71418932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Letter to the Editor: On the use of nonselective beta-blockers in cirrhosis. 致编辑的信:关于肝硬化患者使用非选择性β受体阻滞剂。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-04-16 DOI: 10.1097/HEP.0000000000000888
Eric M Przybyszewski, Irun Bhan, Joseph C Yarze
{"title":"Letter to the Editor: On the use of nonselective beta-blockers in cirrhosis.","authors":"Eric M Przybyszewski, Irun Bhan, Joseph C Yarze","doi":"10.1097/HEP.0000000000000888","DOIUrl":"10.1097/HEP.0000000000000888","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Letter to the Editor: Chronic hepatitis B baseline viral load and on-treatment liver cancer risk-A multinational cohort study of HBeAg-positive patients. 致编辑的信:慢性乙型肝炎基线病毒载量与治疗后患肝癌的风险:一项针对 HBeAg 阳性患者的跨国队列研究。
IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-04-12 DOI: 10.1097/HEP.0000000000000882
Taiyu He, Dazhi Zhang
{"title":"Letter to the Editor: Chronic hepatitis B baseline viral load and on-treatment liver cancer risk-A multinational cohort study of HBeAg-positive patients.","authors":"Taiyu He, Dazhi Zhang","doi":"10.1097/HEP.0000000000000882","DOIUrl":"10.1097/HEP.0000000000000882","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
期刊
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1