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A Comprehensive Review on the Risk of Metabolic Syndrome and Cardiovascular Disease after Liver Transplantation 肝移植术后代谢综合征和心血管疾病风险的综述

Livers

Pub Date : 2022-04-29 DOI: 10.3390/livers2020006

Kashyap Chauhan, Adnan Khan, Salil Chowdhury, H. M. Ross, N. Parra, D. Halegoua-DeMarzio

Survival rates after liver transplantation have increased dramatically over the past 20 years. Cardiovascular disease is the most common extra-hepatic cause of mortality in the long-term post liver transplant. This is intimately linked with both the higher pre-existing rates of metabolic syndrome in these patients as well as increased propensity to develop de novo metabolic syndrome post-transplant. This unfavorable metabolic profile that contributes to cardiovascular disease is multifactorial and largely preventable. This review explores metabolic syndrome and cardiovascular disease and their contributory factors post liver transplantation to highlight areas for potential intervention and thus reduce the significant morbidity and mortality of patients due to metabolic syndrome and cardiovascular disease.

在过去的20年里，肝移植术后的存活率显著提高。心血管疾病是肝移植术后长期死亡最常见的肝外原因。这与这些患者较高的代谢综合征发生率以及移植后发生新发代谢综合征的倾向密切相关。这种导致心血管疾病的不利代谢特征是多因素的，在很大程度上是可以预防的。本文综述了肝移植后代谢综合征和心血管疾病及其影响因素，以突出潜在干预领域，从而降低代谢综合征和心血管疾病患者的显著发病率和死亡率。

引用次数: 4

Anti-Inflammatory Dietary Approach to Prevent the Development and Progression of Non-Alcoholic Fatty Liver Diseases 抗炎饮食预防非酒精性脂肪肝的发展和进展

Livers

Pub Date : 2022-03-02 DOI: 10.3390/livers2010005

Dorothea Portius

Non-alcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide and is associated with insulin resistance, increased visceral fat mass, and cardiovascular problems. Lifestyle factors such as sedentary lifestyle, chronic stress, obesogenic environment as well as a Western pattern diet are main contributors to the development and progression of this disease. In particular, the diet plays a pivotal role. An unhealthy diet including high consumption of red and processed meats, refined carbohydrates, simple sugars, highly processed foods with food additives and conservatives are lighting the fire for a low-grade inflammation. If other risk factors come into play, metabolic and hormonal derangement may occur, leading to the increase in visceral fat, gut dysbiosis and leaky gut, which stoke the inflammatory fire. Thus, lifestyle interventions are the most effective approach to quell the inflammatory processes. An anti-inflammatory and low-glycemic diet named the GLykLich diet, which includes whole and unprocessed foods, may reduce the risk of increased morbidity and mortality. The GLykLich diet suggests a meal consisting of complex carbohydrates (fiber), good quality of protein and healthy fats (DHA/EPA), and is rich in secondary plant products. There is no single nutrient to prevent the progression of NAFLD, rather, it is the complexity of substances in whole unprocessed foods that reduce the inflammatory process, improve metabolic state, and thus reverse NAFLD.

非酒精性脂肪肝（NAFLD）是世界范围内日益严重的健康问题，与胰岛素抵抗、内脏脂肪量增加和心血管问题有关。久坐的生活方式、慢性压力、肥胖环境以及西方饮食等生活方式因素是导致这种疾病发展和进展的主要因素。特别是，饮食起着关键作用。一种不健康的饮食，包括大量食用红肉和加工肉、精制碳水化合物、单糖、含有食品添加剂的高度加工食品和保守派，正在为轻度炎症点燃火种。如果其他风险因素起作用，可能会发生代谢和激素紊乱，导致内脏脂肪增加、肠道生态失调和肠道渗漏，从而引发炎症。因此，生活方式干预是平息炎症过程的最有效方法。一种名为GLykLich饮食的抗炎低血糖饮食，包括完整和未加工的食物，可以降低发病率和死亡率增加的风险。GLykLich饮食建议膳食由复合碳水化合物（纤维）、优质蛋白质和健康脂肪（DHA/EPA）组成，并富含次生植物产品。没有单一的营养素可以阻止NAFLD的发展，相反，是整个未加工食品中物质的复杂性减少了炎症过程，改善了代谢状态，从而逆转了NAFLD。

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引用次数: 1

Acknowledgment to Reviewers of Livers in 2021 向2021年的肝脏评论家致谢

Livers

Pub Date : 2022-02-07 DOI: 10.3390/livers2010004

Rigorous peer-reviews are the basis of high-quality academic publishing [...]

严格的同行评议是高质量学术出版的基础[…]

引用次数: 0

Oxidative Stress in Non-Alcoholic Fatty Liver Disease 非酒精性脂肪肝的氧化应激

Livers

Pub Date : 2022-02-01 DOI: 10.3390/livers2010003

C. Smirne, E. Croce, D. Di Benedetto, V. Cantaluppi, C. Comi, P. Sainaghi, R. Minisini, E. Grossini, M. Pirisi

Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.

非酒精性脂肪性肝病(NAFLD)是一种由多种因素引起的具有挑战性的疾病，这可能部分解释了为什么它仍然是一个缺乏适当治疗的孤儿。本文综述了氧化应激(OS)与脂质代谢紊乱之间的相互作用。几种活性氧发生器，包括胃肠道中产生的活性氧发生器，在“多重平行撞击模型”中导致脂肪酸及其多种生物活性代谢物对肝脏(和肝外)造成脂毒性损伤。这会导致炎症和纤维化，并促进NAFLD的进展。氧化/抗氧化平衡的改变也会影响代谢相关的细胞器，导致脂质过氧化、线粒体功能障碍和内质网应激。这种os引起的损伤至少部分被生理抗氧化反应所抵消。因此，调节这一防御系统成为预防NAFLD发展和进展的一个有趣的靶点。例如，益生菌、益生元、饮食和粪便微生物群移植是针对肠道微生物群失调的新治疗方法。OS及其反调控也受到个体遗传和表观遗传因素的影响。在不久的将来，考虑到遗传或环境表观遗传风险因素的精准医学，加上新的OS生物标志物，可能有助于非侵入性诊断和监测NAFLD的进展以及进一步的个性化治疗。

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引用次数: 59

Cellular and Molecular Mechanisms Underlying Scope and Limitation of Ongoing and Innovative Therapies for Treating Chronic Hepatitis B 慢性乙型肝炎持续治疗和创新治疗的范围和局限性的细胞和分子机制

Livers

Pub Date : 2022-01-06 DOI: 10.3390/livers2010001

S. M. Akbar, Mamun Al Mahtab, O. Yoshida, Y. Hiasa

Millions of people of the world suffer from chronic hepatitis B (CHB), a pathological entity in which the patients are chronically infected with hepatitis B virus (HBV) and express hepatitis B surface antigen (HBsAg) and HBV DNA, as well as evidence of liver damages. Considerable numbers of CHB patients develop cirrhosis of the liver and hepatocellular carcinoma if untreated. Two groups of drugs (interferons and nucleoside analogs) are used to treat CHB patients, but both are endowed with considerable adverse effects, increased costs, extended duration of therapy, and limited efficacy. Thus, there is a pressing need to develop new and innovative therapeutics for CHB patients, and many such drugs have been developed during the last four decades. Some of these drugs have inspired considerable optimism to be a game-changer for the treatment of CHB. Here, we first discuss why ongoing therapeutics such as interferon and nucleoside analogs could not stand the test of time. Next, we dissect the scope and limitation of evolving therapies for CHB by dissecting the cellular and molecular mechanisms of some of these innovative therapeutics.

世界上有数百万人患有慢性乙型肝炎(CHB)，这是一种病理实体，患者慢性感染乙型肝炎病毒(HBV)并表达乙型肝炎表面抗原(HBsAg)和HBV DNA，以及肝脏损伤的证据。如果不治疗，相当数量的慢性乙型肝炎患者会发展为肝硬化和肝细胞癌。两组药物(干扰素和核苷类似物)用于治疗慢性乙型肝炎患者，但两者都具有相当大的不良反应，费用增加，治疗时间延长，疗效有限。因此，迫切需要为慢性乙型肝炎患者开发新的和创新的治疗方法，在过去的四十年中已经开发了许多这样的药物。其中一些药物已经激发了相当大的乐观情绪，有望成为慢性乙型肝炎治疗的游戏规则改变者。在这里，我们首先讨论为什么正在进行的治疗，如干扰素和核苷类似物不能经受时间的考验。接下来，我们通过剖析一些创新疗法的细胞和分子机制来剖析CHB治疗方法的范围和局限性。

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引用次数: 0

Biliary hCGβ Is a Potential Novel Marker for Prediction of Biliary Neoplasia in Primary Sclerosing Cholangitis Patients 胆道hCGβ是预测原发性硬化性胆管炎患者胆道肿瘤的潜在新标志物

Livers

Pub Date : 2021-12-15 DOI: 10.3390/livers1040025

H. Koistinen, S. Boyd, J. Arola, K. Jokelainen, R. Koistinen, Anna Lempiäinen, K. Hotakainen, U. Stenman, M. Färkkilä

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease, which is associated with an increased risk of cholangiocarcinoma (CCA). Novel markers, to complement or replace CA19-9, are urgently needed for the screening of PSC-associated biliary neoplasia. Previous studies have suggested that serum trypsinogen-2 and human chorionic gonadotropin β-subunit (hCGβ) may serve as such markers. Using highly specific in-house immunoassays, we studied trypsin(ogen)-2 and -3, SPINK1 and hCGβ in bile samples of 214 patients, referred for endoscopic retrograde cholangiography. We found that biliary trypsinogen-2 was decreased (p = 0.027) and hCGβ was elevated (p < 0.001) in PSC patients who were diagnosed 1.6 years (median, range 0.1–8.8 years) later with CCA or in whom biliary dysplasia was observed at least twice in brush cytology (n = 11) as compared to PSC patients without CCA or repeated dysplasia (n = 171). The other studied markers did not show significant differences between these groups. Our results warrant further evaluation of hCGβ as a predictive marker for PSC-associated biliary neoplasia.

原发性硬化性胆管炎（PSC）是一种慢性炎症性疾病，与胆管癌（CCA）风险增加有关。新的标志物，补充或取代CA19-9，迫切需要用于PSC相关胆道肿瘤的筛查。先前的研究表明，血清胰蛋白酶原-2和人绒毛膜促性腺激素β亚基（hCGβ）可能是此类标志物。使用高度特异性的内部免疫测定，我们研究了214名患者胆汁样本中的胰蛋白酶（原）-2和-3、SPINK1和hCGβ，这些患者被转用于内镜逆行胆管造影。我们发现，与没有CCA或重复性发育不良的PSC患者（n=171）相比，1.6年后（中位数为0.1-8.8年）被诊断为CCA的PSC患者，或在刷状细胞学中至少两次观察到胆汁发育不良的患者（n=11），胆汁胰蛋白酶原-2降低（p=0.027），hCGβ升高（p<0.001）。其他研究的标记物在这些组之间没有显示出显著差异。我们的结果值得进一步评估hCGβ作为PSC相关胆道肿瘤的预测标志物。

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引用次数: 1

Statistical Machine Learning Approaches to Liver Disease Prediction 肝脏疾病预测的统计机器学习方法

Livers

Pub Date : 2021-12-01 DOI: 10.3390/livers1040023

Fahad B. Mostafa, E. Hasan, Morgan R. Williamson, Hafiz T A Khan

Medical diagnoses have important implications for improving patient care, research, and policy. For a medical diagnosis, health professionals use different kinds of pathological methods to make decisions on medical reports in terms of the patients’ medical conditions. Recently, clinicians have been actively engaged in improving medical diagnoses. The use of artificial intelligence and machine learning in combination with clinical findings has further improved disease detection. In the modern era, with the advantage of computers and technologies, one can collect data and visualize many hidden outcomes such as dealing with missing data in medical research. Statistical machine learning algorithms based on specific problems can assist one to make decisions. Machine learning (ML), data-driven algorithms can be utilized to validate existing methods and help researchers to make potential new decisions. The purpose of this study was to extract significant predictors for liver disease from the medical analysis of 615 humans using ML algorithms. Data visualizations were implemented to reveal significant findings such as missing values. Multiple imputations by chained equations (MICEs) were applied to generate missing data points, and principal component analysis (PCA) was used to reduce the dimensionality. Variable importance ranking using the Gini index was implemented to verify significant predictors obtained from the PCA. Training data (ntrain=399) for learning and testing data (ntest=216) in the ML methods were used for predicting classifications. The study compared binary classifier machine learning algorithms (i.e., artificial neural network, random forest (RF), and support vector machine), which were utilized on a published liver disease data set to classify individuals with liver diseases, which will allow health professionals to make a better diagnosis. The synthetic minority oversampling technique was applied to oversample the minority class to regulate overfitting problems. The RF significantly contributed (p<0.001) to a higher accuracy score of 98.14% compared to the other methods. Thus, this suggests that ML methods predict liver disease by incorporating the risk factors, which may improve the inference-based diagnosis of patients.

医学诊断对改善患者护理、研究和政策具有重要意义。对于医疗诊断，卫生专业人员使用不同类型的病理学方法，根据患者的医疗状况对医疗报告做出决定。最近，临床医生积极参与改进医学诊断。人工智能和机器学习的使用与临床发现相结合，进一步改进了疾病检测。在现代，借助计算机和技术的优势，人们可以收集数据并可视化许多隐藏的结果，例如处理医学研究中缺失的数据。基于特定问题的统计机器学习算法可以帮助人们做出决策。机器学习（ML），数据驱动的算法可以用来验证现有的方法，并帮助研究人员做出潜在的新决策。本研究的目的是使用ML算法从615人的医学分析中提取肝病的重要预测因素。实施了数据可视化，以揭示重大发现，如缺失值。采用链式方程（MICE）的多重输入生成缺失数据点，并采用主成分分析（PCA）降维。使用基尼指数进行变量重要性排序，以验证从主成分分析中获得的显著预测因素。ML方法中用于学习的训练数据（ntrain=399）和测试数据（ntest=216）用于预测分类。该研究比较了二元分类器机器学习算法（即人工神经网络、随机森林（RF）和支持向量机），这些算法被用于已发表的肝病数据集，对肝病患者进行分类，这将使卫生专业人员能够做出更好的诊断。将合成少数过采样技术应用于少数类的过采样，以调节过拟合问题。与其他方法相比，射频显著提高了98.14%的准确率（p＜0.001）。因此，这表明ML方法通过结合风险因素来预测肝病，这可能会提高对患者的推断诊断。

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引用次数: 14

Redrawing the map to novel DILI biomarkers in circulation: Where are we, where should we go, and how can we get there? 重新绘制新的DILI生物标志物的地图:我们在哪里，我们应该去哪里，我们如何到达那里?

Livers

Pub Date : 2021-12-01 DOI: 10.3390/livers1040022

Joel H Vazquez, Mitchell R McGill

Circulating biomarkers of drug-induced liver injury (DILI) have been a focus of research in hepatology over the last decade, and several novel DILI biomarkers that hold promise for certain applications have been identified. For example, glutamate dehydrogenase holds promise as a specific biomarker of liver injury in patients with concomitant muscle damage. It may also be a specific indicator of mitochondrial damage. In addition, microRNA-122 is sensitive for early detection of liver injury in acetaminophen overdose patients. However, recent events in the field of DILI biomarker research have provided us with an opportunity to step back, consider how biomarker discovery has been done thus far, and determine how to move forward in a way that will optimize the discovery process. This is important because major challenges remain in the DILI field and related areas that could be overcome in part by new biomarkers. In this short review, we briefly describe recent progress in DILI biomarker discovery and development, identify current needs, and suggest a general approach to move forward.

在过去的十年中，药物性肝损伤(DILI)的循环生物标志物一直是肝病学研究的焦点，并且已经确定了一些具有某些应用前景的新型DILI生物标志物。例如，谷氨酸脱氢酶有望作为伴随肌肉损伤患者肝损伤的特定生物标志物。它也可能是线粒体损伤的一个特定指标。此外，microRNA-122在对乙酰氨基酚过量患者肝损伤的早期检测中具有敏感性。然而，DILI生物标志物研究领域最近发生的事件为我们提供了一个机会，让我们退后一步，考虑到目前为止生物标志物的发现是如何完成的，并确定如何以一种优化发现过程的方式前进。这一点很重要，因为DILI领域和相关领域仍然存在重大挑战，新的生物标志物可以部分克服这些挑战。在这篇简短的综述中，我们简要地描述了DILI生物标志物的发现和开发的最新进展，确定了当前的需求，并提出了前进的一般方法。

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引用次数: 11

Perfluoroalkyl Carboxylic Acids Interact with the Human Bile Acid Transporter NTCP. 全氟烷基羧酸与人胆汁酸转运体NTCP相互作用。

Livers

Pub Date : 2021-12-01 DOI: 10.3390/livers1040017

Melissa J Ruggiero, Haley Miller, Jessica Y Idowu, Jeremiah D Zitzow, Shu-Ching Chang, Bruno Hagenbuch

Na⁺/taurocholate cotransporting polypeptide (NTCP) is important for the enterohepatic circulation of bile acids, which has been suggested to contribute to the long serum elimination half-lives of perfluoroalkyl substances in humans. We demonstrated that some perfluoroalkyl sulfonates are transported by NTCP; however, little was known about carboxylates. The purpose of this study was to determine if perfluoroalkyl carboxylates would interact with NTCP and potentially act as substrates. Sodium-dependent transport of [³H]-taurocholate was measured in human embryonic kidney cells (HEK293) stably expressing NTCP in the absence or presence of perfluoroalkyl carboxylates with varying chain lengths. PFCAs with 8 (PFOA), 9 (PFNA), and 10 (PFDA) carbons were the strongest inhibitors. Inhibition kinetics demonstrated competitive inhibition and indicated that PFNA was the strongest inhibitor followed by PFDA and PFOA. All three compounds are transported by NTCP, and kinetics experiments revealed that PFOA had the highest affinity for NTCP with a K_m value of 1.8 ± 0.4 mM. The K_m value PFNA was estimated to be 5.3 ± 3.5 mM and the value for PFDA could not be determined due to limited solubility. In conclusion, our results suggest that, in addition to sulfonates, perfluorinated carboxylates are substrates of NTCP and have the potential to interact with NTCP-mediated transport.

Na+/牛磺酸胆酸共转运多肽(NTCP)对胆汁酸的肠肝循环很重要，这被认为是人类全氟烷基物质的长血清消除半衰期的原因之一。我们证明了一些全氟烷基磺酸盐是通过NTCP转运的;然而，人们对羧酸盐知之甚少。本研究的目的是确定全氟烷基羧酸盐是否会与NTCP相互作用并可能作为底物。在没有或存在不同链长的全氟烷基羧酸盐的情况下，在稳定表达NTCP的人胚胎肾细胞(HEK293)中测量了[3H]-牛磺胆酸盐的钠依赖性转运。含有8个碳(PFOA)、9个碳(PFNA)和10个碳(PFDA)的PFCAs是最强的抑制剂。抑制动力学表现为竞争性抑制，表明PFNA是最强的抑制剂，其次是PFDA和PFOA。动力学实验表明，PFOA对NTCP的亲和力最高，Km值为1.8±0.4 mM, PFNA的Km值估计为5.3±3.5 mM, PFDA的Km值由于溶解度有限而无法确定。总之，我们的研究结果表明，除了磺酸盐外，全氟羧酸盐也是NTCP的底物，并且有可能与NTCP介导的转运相互作用。

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引用次数: 11

Noncoding RNAs Interactions in Hepatic Stellate Cells during Hepatic Fibrosis 肝纤维化过程中肝星状细胞中非编码RNA的相互作用

Livers

Pub Date : 2021-11-29 DOI: 10.3390/livers1040021

S. A. Sulaiman, Vicneswarry Dorairaj, Khairun Nur Abdul Ghafar, N. A. Abdul Murad

Hepatic fibrosis is a reversible wound healing process following liver injury. Although this process is necessary for maintaining liver integrity, severe excessive extracellular matrix accumulation (ECM) could lead to permanent scar formation and destroy the liver structure. The activation of hepatic stellate cells (HSCs) is a key event in hepatic fibrosis. Previous studies show that most antifibrotic therapies focus on the apoptosis of HSCs and the prevention of HSC activation. Noncoding RNAs (ncRNAs) play a substantial role in HSC activation and are likely to be biomarkers or therapeutic targets for the treatment of hepatic fibrosis. This review summarizes and discusses the previously reported ncRNAs, including the microRNAs, long noncoding RNAs, and circular RNAs, highlighting their regulatory roles and interactions in the signaling pathways that regulate HSC activation in hepatic fibrosis.

肝纤维化是肝损伤后可逆的伤口愈合过程。尽管这一过程对于维持肝脏完整性是必要的，但严重过量的细胞外基质积累（ECM）可能导致永久性瘢痕形成并破坏肝脏结构。肝星状细胞（HSCs）的活化是肝纤维化的一个关键事件。先前的研究表明，大多数抗纤维化治疗侧重于HSC的凋亡和预防HSC活化。非编码RNA（ncRNA）在HSC激活中起着重要作用，可能是治疗肝纤维化的生物标志物或治疗靶点。这篇综述总结并讨论了先前报道的ncRNA，包括微小RNA、长非编码RNA和环状RNA，强调了它们在肝纤维化中调节HSC激活的信号通路中的调节作用和相互作用。

引用次数: 2

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